Super Affiliates

Permanent Unwanted Tattoo Removal by Tattoo Expert

Permanent Unwanted Tattoo Removal by Tattoo Expert
Safely, Painlessly, Laserlessly and Naturally in Removing any Unwanted Tattoos in 2 to 8 Weeks, Guaranteed

Friday, 10 July 2015

The holistic Prevention, Management and Treatment of Dementia under The Microscope of Conventional Medicine

Kyle J. Norton (Scholar)


Health article writer and researcher; Over 10.000 articles and research papers have been written and published on line, including world wide health, ezine articles, article base, healthblogs, selfgrowth, best before it's news, the karate GB daily, etc.,.
Named TOP 50 MEDICAL ESSAYS FOR ARTISTS & AUTHORS TO READ by Disilgold.com Named 50 of the best health Tweeters Canada - Huffington Post
Nominated for shorty award over last 4 years
Some articles have been used as references in medical research, such as international journal Pharma and Bio science, ISSN 0975-6299.

  Abstract 
Dementia is defined as neuro degeneration syndrome among elder, affecting memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement over 47 millions
of worldwide population, mostly in the West. The evaluation of the syndrome by holistic medicine has been lacking, especially through conventional medicine research and studies. The aim of this essay is to provide accurate information of how effective of holistic medicine in prevention, management and treatment of dementia through searching data base of PubMed.
This is the third time, a research paper has been written this way to general public that you will not find any where in the net. We would like to provide more of this kind of research, but unfortunately, it is time consuming and burdened financially, we have run out of time and the site will be shut down Monday(July 6, 2015). If you like what you read, please donate generously to our site.
at http://kylejnorton.blogspot.ca/
Kyle J. Norton

                                               Contents


 Most common diseases of elders  - Nutrients Requirements for elder
I. The Types  (1 - 2)
II. Causes  (2 - 19)
1. The Deficient Causes of Dementia
2.  Free radical causes of dementia (Alzheimer’s disease)
3.  Free radical causes of Parkinson's disease
4.  Free radical causes of dementia (Parkinson's disease, PD)
5.  Free radical causes of dementia (Multiple Sclerosis, MS)
6.  Free radical causes of dementia (Lou Gehrig's disease(Amyotrophic lateral sclerosis))
7.  Diseases causes of dementia
8.  Hormonal Causes of Dementia
9.  Substance Abused Causes of Dementia
10. Diet Causes of Dementia
11. Medication Causes of Dementia
12.  Life Style Causes of Dementia
13. Genetic mutation Causes of Dementia

III. The Diseases's symptoms and Complications (19 - 24)
14. Symptoms of Dementia
15. Complications of Dementia

III. The preventions and managements (24 - 38)
16. The Preventive Do's and Do Not's list
17. The Preventive Antioxidant enzymes
18. The Preventive Metals Binding Proteins
19. The Preventive Common Free Radical Scavengers
20. The Preventive Phytochemical Rosemarinol
21. The Preventive Phytochemicals Gingerole and Naringenin
22. The Preventive Phytochemicals Tangeritin and Curcumin
23. The Preventive Phytochemicals Gallic acid and Cinnamic acid
24. The Preventive Phytochemicals Tyrosol and Silymarin

IV. Treatments (38 - 105)
A. In conventional Medicine
25. Treatments of Alzheimer's disease and Diminished quality of acetylcholine
26. Treatments of Wernicke-Korsakoff Syndrome due to long-term alcohol abuse
27. Treatments of Dementia associated with Parkinson's disease
28. Treatments of Dementia associated with Creutzfeldt-Jakob disease (CJD)
29. Treatments of Dementia associated with Multi-infarct dementia
30. Treatments of Dementia associated with Subdural hematoma

B. In Herbal Medicine
31. Herbal Treatments: Ginkgo Biloba(bai Guo)
32. Herbal Treatments: Lemon Balm
33. Herbal Treatments: Lavender
34. Herbal Treatments: Huperzine A.
35. Herbal Treatments: Bacopa
36. Herbal Treatments: Other Potential Herbs


C. In Traditional Chinese Medicine
The herbs
38. Treatments in Traditional Chinese Herbal Medicine Poria cocos(Fu Ling)
39. Treatments in Traditional Chinese Herbal Medicine Radix polygalae(Yuan Zhi)
40. Treatments in Traditional Chinese Herbal Medicine: Radix glycyrrhizae(Gan Cao)
41.Treatments in Traditional Chinese Herbal Medicine: Radix Angelica Sinensis(Dang Qui)
42. Treatments in Traditional Chinese Herbal Medicine: Radix rehmanniae(Di Huang)

Dementia caused by Kidney Qi deficiency
43. TCM Herbal treatments of Dementia Caused by Kidney Qi Deficiency
Dementia caused by Heart Qi deficiency
44. TCM Dan shen treatments of Dementia Caused by Heart Qi Deficiency
45. TCM Ren shen (Ginseng) treatments of Dementia Caused by Heart Qi Deficiency
46. TCM XI Yang Shen (American Ginseng) treatments of Dementia Caused by Heart Qi Deficiency
47. TCM Sang Shen (Mulberry Fruit) treatments of Dementia Caused by Heart Qi Deficiency


Dementia Caused by Spleen Qi Deficiency
48. TCM Herbal Peony (Chi Shao) treatments of Dementia Caused by Spleen Qi Deficienc
49. TCM Herbal Chai Hu (Bupleurum) in treatments of Dementia Caused by Spleen Qi Deficiency
50. TCM Herbal Safflower (Hong Hua) treatments of Dementia Caused by Spleen Qi Deficiency
51. TCM Herbal Cinnamonin treatments of Dementia Caused by Spleen Qi Deficiency

Dementia caused by Blood Stasis
52. TCM Herbal Gou Qi treatments of Dementia Caused by Blood Stasis
53. TCM Herbal Polygonum multiflorum (He shou wu) treatments of Dementia Caused by Blood Stasis


Dementia Caused by Toxins accumulation
54. TCM herbal Shui Fei Zi (Milk thistle) treatments of Dementia Caused by Toxin Accumulation
55. TCM herbal Xiu Hui Xiang (Fennel) treatments of Dementia Caused by Toxin Accumulation
56. TCM herbal Da Suan (Garlic) treatments of Dementia Caused by Toxin Accumulation

Dementia due to aging Kidney essence gradual depletion 
57. TCM herbal Dong Chong Cao(Cordyceps) treatments of Dementia Caused by Kidney Jing Depletion
58. TCM herbal Shi Hu(Dendrobium) treatments of Dementia Caused by Kidney Jing Depletion 
59. TCM herbal Du Zhong(Eucommia bark) treatments of Dementia Caused by Kidney Jing Depletion 
60. TCM herbal Huang Qi(Astragalus) treatments of Dementia Caused by Kidney Jing Depletion


Nutrients Requirements for elder

Consuming foods and drinks, containing protein and a specific range of vitamins, minerals and trace elements are necessary to provide sources of energy (calories). Especially plant food phytochemicals with various groups of structure include 3000-4000 individual compounds with possession of a number of different properties(175)

Daily intakes for micro nutrients recommended by the Department of Health DRVs (Dietary Reference Values)(176)
A. Nutrient and                 Recommended daily intake
1. Calcium (mg)                        700
2. Phosphorus (mg)                  550
3. Magnesium (mg)                   270
4. Sodium (mg)                       1600
5. Potassium (mg)                   3500
6. Chloride (mg)                     2500
7. Iron (mg)                               14.8
8. Zinc (mg)                                 9
9. Copper (mg)                            1.2
10. Selenium (μg)                      60
11. Iodine (μg)                         140
12. Vitamin A (μg)                   600
13. Thiamin (mg)                        0.8
14. Riboflavin (mg)                   1.1
15. Niacin (mg)                       12
16. Vitamin B6 (mg)                  1.2
17. Vitamin B12 (μg)                 1.5
18. Folate (μg)                      200
19. Vitamin C (mg)                 40
20. Vitamin D* (μg)                10

B. Estimated Average Requirements (EARs) for energy
Age (years), Estimated energy requirement for males (kcals per day), Estimated energy requirement for females (kcals per day)
51-59                      2550                                                                        1900
                                                             2

60-64                      2380                                                                        1900
65-74                      2330                                                                        1900
75+                        2100                                                                        1810

C. Proteins
Age (years)   Estimated protein requirement for males (kcals per day)   For females
51+                                            53.3                                                    46.5



                                   Types of dementia

1. Alzheimer's disease
 Alzheimer's disease is a brain disorder named for German physician Alois Alzheimer(1). Alzheimer's destroys brain cells, causing problems with memory, thinking and behavior severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal(2). Over 1 million people in US alone are currently afflicted by Alzheimer's disease because of degeneration of hippocampus and cerebral cortex(3) of the brain where memory, language and cognition(4) are located. With this mental disorder, brain cells gradually die and generate fewer and fewer chemical signals day by day resulting in diminished of functions. Overtime memory thinking as well as behavior deteriorates. Today, there is no known cure.

2. Absence of acetylcholine
 If the nerves located in front of the brain perish(5), caused by diminished quality of acetylcholine due long term alcohol abused may result of cognitive dysfunction(6) causes of language difficulty, memory loss, concentration problem, and anxiety- and depression-like behaviors(8),reduced moblile skills because of lacking reaction in muscular activity and refection(7).

3. Dementia due to long-term alcohol abuse
 Dementia is common in patients with alcoholism(9). Most classic is the Korsakoff's dementia resulted in extremely poor short term memory(10) and
                                                       3

often associated with the memory losses of confabulations due to diminished processing resources and/or an encoding or retrieval deficit(11).

4. Multi-infarct dementia
Also known as vascular dementia, is the second most common form of dementia after Alzheimer's disease in older adults caused by different mechanisms all results in vascular lesions(12) of the brain(13).

5. Dementia associated with Parkinson's disease
 Parkinson disease (PD) is a disabling, progressive condition, causes of cognitive deficits due to the interruption of frontal-subcortical loops that facilitate cognition and parallel the motor loop(15)(16) due to loss of substantia nigra pars compacta (SNc) dopamine (DA) neurons(14).

6. Creutzfeldt-Jakob disease (CJD)
People who have eaten contaminated beef(18) for many years may be infected without even knowing it. Creutzfeldt-Jakob disease is a quickly progressing and fatal disease consisted of dementia(19), muscle abnormal functions(17).

7. Subdural hematoma
It is the accumulation of blood beneath the outer cover of the brain resulted from the rupture of blood vessel(20)(21). Subdural hemorrhages may increase intracranial pressure(22), causing compression and damage to delicate brain tissue. Acute subdural hematoma has a high mortality rate(23).

Other types of dementia include metabolic disorders, dementia due to long-term substance abuse, hypothyroidism, and hyperethyroidism.



                               Causes of dementia


A. Deficient cause of dementia due to aging
1. Vitamin D and 1,25-dihydroxyvitamin D(3) deficiency
Vitamin D levels not only plays an  important role in the pathogenesis of many age-associated diseases including cancer, heart disease, type 2 diabetes
                                                       4

mellitus and stroke, but  also associate with increased risk of prevalent cognitive dysfunction. According to number of studies, raising vitamin D plays a role in decreased cognitive dysfunction and dementia(a).  Evidence from epidemiological also insisted the association between 25(OH)D concentrations and systolic blood pressure, risk for CV disease-related deaths, symptoms of depression, cognitive deficits, and mortality(b).

2. Folic acid with vitamin B12 deficiency
Folates are vitamins essential to the development of the central nervous system. Deficiency of folate can increase the risk of dementia. According to Cochrane Dementia and Cognitive Improvement Group, folic acid plus vitamin B12 were effctive in reducing the serum homocysteine concentrations, with no adverse effects(c).

3. Vitamin B12 deficiency
An association between neuropsychiatric disorders and vitamin B12 deficiency has been recognized since 1849. Deficiency of Vitamin B12 are found in many elders and might contribute to age-associated cognitive impairment, according to the Scientist at Cochrane Dementia and Cognitive Improvement Group(d).

4. Vitamin B6 deficiency
 Vitamin B6 supplementation showed to reduce the risk of developing cognitive impairment in older healthy people, and improve cognitive functioning of people with cognitive decline and dementia, according the study conducted by Cochrane Dementia and Cognitive Improvement Group(e).

5. Deficiency of Insulin-like growth factor (IGF)-1and growth hormones
Deficiency of Insulin-like growth factor (IGF)--1 hormone may contribute to the genesis of cognitive impairment and dementia in the elderly patients. Old age, in the absence of circulating IGF-1, a hormone with a complex role in brain function has seen to link to an acceleration of neurological diseases(f). Growth hormone and IGF-1 replacement showed to increase neurogenesis, vascular density, and glucose utilization, and alter NMDA receptor subunit composition in brain areas implicated learning and memory, in animal (g)and children(h) studies.
                                                         5

8. Deficiency of cerebrospinal fluid melatonin
 Melatonin plays an essential role in ventricular system via choroid plexus portals. In Alzheimer's disease, inadequate melatonin increases risk of the neuropathological changes due to hydroxyl radicals cause of damage mitochondria and initiated cascade of oxygen radicals(i).

9. Decreased dehydroepiandrosterone (DHEA)  
Dehydroepiandrosterone sulfate (DHEAS) concentrations
DHEA, a neurosteroid secreted by the adrenal cortex. is also a neurosteroid. The levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) concentrationsare decline in concentration with age(j).

10. Etc.

B. Free radical causes of dementia
B.1. Alzheimer’s disease
1. Free radical and Alzheimer’s disease
Free radicals causes of Alzheimer’s disease is well defined in many researches(25)(26). Oxidative stress-induced injury involved the selective modification of different intracellular proteins may lead to the neurofibrillary degeneration of neurons in the brain(27)(28).

2.  Antioxidants and Alzheimer’s disease
a. Docosahexaenoic acid (DHA)
Change of brain aging in DHA metabolism, was found in patients with Alzheimer's disease(29). DHA, a naturally occurring component found in every cell membrane(29) with ability to increase phosphatidylserine(30)(31) is important in decreased production of proinflammatory omega-6 eicosanoids causes of Alzheimer's disease(31) and in improved the memory of animals with Alzheimer's disease by suppressing oxidative damage in the brain(32).

b. Vitamin E
Vitamin E, and drugs(memantine) reduced generalized inflammation, may slow the decline of mental and physical abilities in people with Alzheimer's disease (AD) over the long term(33). Also vitamin E inhibited cells damage and cells death caused by beta-amyloid(34)(35), which is toxic to brain cells(36).

                                                         6

c. Phosphatidylserine
Patients who had Alzheimer’s disease taken100 milligrams per day (mg/day) of phosphatidylserine scored significantly better on standardized memory tests at the end of the 12-week trial period than patients without(37)(38).

d. Antioxidants
Antioxidant are found at much lower levels for patients with Alzheimer’s disease(39)(40)(41), such as serum of vitamin A, C, E, zinc and transfferin.

e. Muscarinic cholinergic receptors 
 Alzheimer’s disease patients showed to exhibit the significant loss of muscarinic cholinergic receptors neurons(42) causes of reduced volume of neural transmission that can lead to loss of memory(43).

B.2. Parkinson's disease
1. Free radicals and Parkinson's disease

 Patients with Parkinson's disease have low levels of polyunsaturated fat in the substania nigra(44)(45). Also patients with the disease found to contain waste pigments of lipofusion(46) and other polymers in the neurons(47) where dopamine is most active.

2. Aging and Parkinson's disease
According to Julius-Maximilians-University, physiological aging and OS-dependent aggregation of proteins, accompanied with environment toxins(49) are found to associate to the progression of the disease(48).

3. Antioxidants and Parkinson's disease
Antioxidants play an vital role for patients with Parkinson's disease.
a. Superoxide dismutase
Researcher found that the progression of the disease may be associated with the decrease levels of superoxide dismutase, a antioxidant enzyme(50). According to University of Thessaloniki, patients with advanced Parkinson' diseases showed a statistically significant decrease of SOD activity in whole blood and in red blood cells(51).

b. NADH ubiquinone reductase
 Levels of NADH ubiquinone reductase is decreased in the substania
                                                          7

nigra(52) in patients with PD, causing neurons apoptosis, but this can be treated with antioxidants Acetyl-L-carnitine (53) and alpha lipoic acid(54).

c. Uric acid
 People with a high blood level of the natural antioxidant uric acid have a lower risk of developing Parkinson's disease(55) than do people with lower levels(56), but high levels of uric acid increases the risk of kidney diseases(57) and gout(58).

d. Glutathione
 Glutathoine showed to deactivate the harmful product HNE of lipid peroxidation(59).

f. Etc.

B.3. Multiple Sclerosis
1. Free radicals and Multiple Sclerosis
Free radical activity is a contributory factors in MS(60) due to proinflammatory cytokines in free radicals production in the peripheral immune and central nervous system (CNS)(60).

2. Antioxidants and Multiple sclerosis
Antioxidants protect the neural tissues from damage against inflammation caused by oxidative stress.
a. TNFalpha 
TNFalpha, an imflammatory cytokine showed to associate with MS inhibited by antioxidants(61)) of green tea(62), and curcumin(63).

b. Melatonin
Melatonin functions as an antioxidant has the ability to protect neurons(65)(66) from free radicals cause of lipid peroxidation(64).

c Selenium
Some studies found that the level of selenium in the blood of people with MS was lower than in that of people without(67)(68). In patients with MS, all abnormalities may be normalized by daily intake of selenium(69),


                                                           8

d. Niacin
Niacin acting as antioxidant is a key to the successful treatment of multiple sclerosis, profoundly prevents the degeneration(70) of demyelinated axons and improves the behavioral deficits(71).

e. Vitamin D
Serum of 25(OH)D level showed to regulate expression dynamics of a large gene-gene interaction system in immune modulatory processes of MS activity(72). According to the study published by the journal Neurology, group receiving vitamin D supplement demonstrated a remarkable 41 percent reduction in new MS events with no meaningful side effects(73).

f. Etc.




B.4. Lou Gehrig's disease(Amyotrophic lateral sclerosis)
1. Free radicals and Lou Gehrig's disease
Researchers found that glutamate in the synapses enhances the production of free radicals(77) only in motor nerve cells but spares other nerve cells(74) such as cells control senses and other body functions, causing disruption of astrocytes in regulated glutamate levels(76).

2. Antioxidants and Lou Gehrig's disease
a. Vitamin B12 (methylcobalamin)
High doses of vitamin B12 as an antioxidant have shown to improve or slow muscle wasting in the later stages of patients with ALS disease(78)(79).

b. Vitamin E

Vitamin E protected against cell membranes from lipid peroxidation damage(80) in reduced the risk of breakdown of the cell membrane cause of ALS(81).

c. Superoxide dismutase enzyme 
Mutations in the superoxide dismutase enzyme can increase the risk ALS(82) in catalyzing the dismutation of superoxide into oxygen and hydrogen peroxide(83).
                                                              9


d. Cerebral cortex
 Oxidative stress and DNA alternation triggered neurons damage(84) were found in elevating levels in  mice with ALS(85).

e. Amino acids 
 Diet high in amino acids as antioxidants have shown some promising effect in treating ALS(86)(87).


C. Diseases Causes of Dementia
 1. Alzheimer's disease
Alzheimer's disease is a brain disorder named for German physician Alois Alzheimer. Alzheimer's destroys brain cells, effecting memory, thinking and behavior severe enough to affect language communication, memory, lifelong hobbies or social life.

 2. Stroke (Vascular problems) 
Strokes caused by uncontrolled diet with high in saturated and trans fats, can lead to bad cholesterol building up(88) in blocking the circulation of blood to the body, thus increasing volume of infarction, in the brain(89). If oxygen is not delivered to the brain cells, some cells die off and can not reproduce(90), causing stroke(89). Others happen, when a blood vessel in the brain ruptures(91), it causes the cells in your brain deprived of oxygen with symptoms of vascular dementia(92)(93)(94).
According to the prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia  by University Department of Clinical Neurology, 10% of patients had dementia before first stroke, 10% developed new dementia soon after first stroke, and more than a third had dementia after recurrent stroke(95).

3. Dementia with Lewy bodies
Lewy bodies is a condition of spherical masses displaced other cell components with symptoms of fluctuating cognitive ability with pronounced variations in attention and alertness, recurrent visual hallucinations and spontaneous motor features, including akinesia, rigidity and tremor(97). Abnormal aggregates of protein develop inside nerve cells are also found in Parkinson's disease (PD), Lewy Body Dementia and some other
                                                           10

disorders.(96).  According to Mayo Clinic in MRI analysis of the characterizing the tissue abnormalities characteristic of Alzheimer disease and DLB, loss of tissues due to increased amygdalar diffusivity in dementia with Lewy bodies (DLB) may be related to small cavity in the cytoplasm of a cell, a common pathology associated with Lewy body disease(98).

4. Fronto-temporal dementia
Fronto-temporal dementia (FTD) or Pick's disease is clinical syndrome caused by degeneration of the frontal lobe(lobes of the brain lying immediately behind the forehead) of the brain, lead to symptoms of depression and executive dysfunction triggering the loss of autonomy, the risk of fall and of malnutrition in elderly patients(100). Early diagnosis of fronto-temporal dementia (FTD) is often difficult because of the non-specific presentation, a delayed-gross estimation of injury or dysfunction of the frontal lobe(99).

5. Progressive supranuclear palsy
Progressive supranuclear palsy, a condition of a movement disorder occurred as a result of damage to certain nerve cells with relatively specific patterns of atrophy, involving the brainstem, the latter frontoparietal regions, pontine tegmentum and the left frontal eye field(102) in the brain may lead to serious and progressive problems with control of gait and balance, including an inability to aim the eyes properly(101).

6. Korsakoff's syndrome 
Korsakoff's syndrome, named after Sergei Korsakoff, a Russian neuropsychiatris, a neurological disorder caused by deficiency of Vitamin B1 (thiamine) in the brain and associated closely to chronic alcohol abuse and/or severe malnutrition, can lead to spontaneous alternation performance impaired in PTD accompanied by a significant reduction (30%) in phosphorylated synapsin I(103). Korsakoff's syndrome has been linked to neurotoxic effect of chronic alcohol consumption causes of medial thalami, mammillary bodies, and corpus callosum(104)
According to University of Campinas (Unicamp), the main causes of thiamine deficiency and viral infection or toxins in the blood, other adjunct factors, include magnesium depletion and chronic alcohol misuse, in the development of Korsakoff's syndrome(105)
                                                            11

7. Binswanger's disease
Binswanger disease also known as subcortical vascular dementia is a type of small vessel vascular dementia caused by microscopic areas of damage to the deep layers of white matter in the brain, including mostly of glial cells and myelinated axons in transmitting signals from one region of the cerebrum to another and between the cerebrum and lower brain centers.  
Binswanger's disease frequency increased with age, independent of other risk factors, is associated with white matter hyperintensities (WMHs) deficits in selected cognitive functions(106). The disease is considered as
a progressive dementia, depression and "subcortical" dysfunction such as gait abnormalities, rigidity and neurogenic bladder(107). Control of hypertension may help prevent further progression of white matter disease(107).

8. Acquired immunodeficiency syndrome (AIDS)
 Acquired immunodeficiency syndrome (AIDS) is a condition of the progressive failure of the immune system caused by HIV, a lentivirus, originated HIV invasion of CNS by crossing the blood-brain barrier (BBB), through progression of  chronic inflammation induced dysfunction in neurons and astrocytes(star-shaped glial cells in the brain)(108). The presence of tumor necrosis factor-alpha (in systemic inflammation) may also increase the risk of the development of neurological dysfunction(109).

9.  Creutzfeldt-Jakob disease (CJD)
Creutzfeldt-Jakob disease (CJD) is a form of incurable, fatal, degenerative neurological disorder cause of rapid decrease of mental function and movement due to the infectious replicate protein, including symptoms of  Mild Cognitive Impairment resembled the final stages of Alzheimer's disease, inexplicable visual disturbances(110).

10. Parkinson's disease 
Parkinson's disease is a condition of  a degenerative disorder of the central nervous system causes of shaking (tremors) and difficulty with walking, movement, etc. with dementia commonly occurring in the advanced stages of the disease. According to study, in a survey of all stages of disease and 18.38 % demented from patients, caregiver and both, spychotic symptoms, mood/Apathy, and impulse control disorders are accounted for 66.63 % of the variance(111).
                                                             12

11. Huntington's disease
Huntington's disease is a condition of a neurodegenerative genetic disorder affected the muscle coordination causes of cognitive decline and psychiatric problems(17). Impairments of  patients with Huntington's disease include speed of processing, initiation, and attention measuresin linear regression(112).

12. Motor Neurone disease (MND)
Motor neuron disease is a group of neurological disorders affected the motor neurones, located in the central nervous system (CNS), causes of cognitive and behavioural changes(113)

13. Multiple Sclerosis
Multiple Sclerosis is a condition of an inflammatory disease due to the damage of the fatty myelin sheaths around the axons of the brain and spinal cord, responded to vision, speech, walking, writing, and memory(114).

14. Obesity
Midlife and late-life obesity may increase the risk of dementia. In 480 persons with incident dementia, risk of dementia was associated to patients with for obese (BMI >30) and uderweight persons (BMI <20) but not overweight (BMI >25-30)(115).
 

D. Hormonal Causes of  Dementia
1. Growth hormone
According to Universidad de Barcelona, Barcelona, physiological decline of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis due to ageing, may involve in the progression of  cognitive deficits(116), probably due to ability of both hormones in stimulation of beta amyloid release from neurons and IGF-I involved on brain amyloid clearance(117).

2.  Estrogen
According to Scientist at the Kings College London, the decreased production of estrogen due to aging in menopausal women may be association to the risk of dementia(118). Estrogen-replacement therapy has shown to reduce prevalence of Alzheimer's disease in postmenopausal women, but weighing risks and benefits of estrogen-replacement therapy
                                                             13

must be taken into account(119)

3. Testosterone 
Lower androgen levels in aging are associated with increased plasma Abeta 40 in older men with memory loss or dementia, according to the comparison of levels of  serum total testosterone and sex hormone binding globulin (SHBG) and plasma levels of amyloid beta peptide 40(120).

4. DHEA
A decreased concentration of dehydroepiandrosterone sulfate (DHEA-S) and lower DHEA-S/DHEA ratio are associated to risk of Alzheimer's disease (AD)(121)(122).

5. Sex-hormone binding globulin 
 Gonadotropins may be involved in processes and contribution to the etiology/pathogenesis of AD due to its involvement on inflammation, cholesterol homeostasis, and insulin status(123).

6. Etc.

E.  Substance Abused Causes of Dementia
Illicit drug used may cause nervous system impairment due to their direct and indirect effects on the integrity and function of nervous system tissue, probably through immune altered effects(124). Injection drug users has shown to increase risk of dementia, up to 40% of patients with HIV infection(125)

1. Heroin 
Heroin (diacetylmorphine or morphine diacetate (INN)), also known as diamorphine (BAN), an opiate drug extracted from the seed pod of the Asian opium poppy plant, showed to induce dysfunction of different components of cortico-striatal (forebrain) circuitry in response to recognition memory, spatial working memory, planning, sequence generation, visual discrimination learning, and attentional set-shifting of groups of subjects(126).

2. Cocaine and Methamphetamine
Cocaine (benzoylmethylecgonine) (INN), a crystalline tropane alkaloid
                                                      14

obtained from the leaves of the coca plant showed to induce  rapidly accelerating HIV dementia accompanied by seizures and an unusual movement disorder(127).

3. Lysergic acid diethylamide (LSD)
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug used to treat patients with mental disorders may temporarily alter the thinking processes, closed and open eye visuals, synaesthesia, an altered sense of time, etc.(128), but regain the ability to judge, to acquire competence and new learning, to focus attention and concentrate, to recall and retrieve relevant information(129)

4. Ecstasy (3,4-methylenedioxymethamphetamine, or MDMA
Ecstasy, a highly addictive drug, is a powerful CNS stimulant with chemically similar to the stimulant methamphetamine and hallucinogen mescaline induced confusion, depression, sleep problems, drug craving, and severe anxiety(130).


5. Other illicit drugs
According to the study at University of Rostock, Dr. Büttner A., drug abuse represents a significant health issue. The major substances abused substances including cannabis, opiatescocaineamphetaminemethamphetamine and 'ecstasy'. altered intracellular messenger pathways, transcription factors and immediate early genes within the brain reward system may lead to cardiovascular complications, psychiatric and neurologic symptoms due to their widespread disturbances within the complex network of central nervous system in cell-to-cell interaction(131).

F. Diet Causes of dementia
 Midlife characteristics of nonsmoking, body mass index (BMI) less than 25.0 kg/m(2), physically active, and having a healthy diet (based on alcohol, dairy, meat, fish, fruits, vegetables, cereals, and ratio of monounsaturated to saturated fat) are associated to reduce risk of dementia(132)


                                                           15

1. Saturated fat and Trans fat(145)
Saturated fat is important for energy, hormone production, cellular membranes, especially in signalling and stabilization processes in the body, but over consumption can cause cholesterol building up in the arteries leading to heart diseases, stroke, diabetes, etc. A high saturated fat and cholesterol intake has shown to increase the risk of dementia, whereas fish consumption may decrease this risk(135)(145), probably due to involvement in the β-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids of peroxisome(133)(145)  in the breaks down molecules into smaller units to release energy of very long chain fatty acids(134). Intake of trans fat is also found to potentially increase the AD risk or cause an earlier onset of the disease due to its effects in increased production of amyloid beta (Aβ) peptides, main components of senile plaques(136).

2. Artificial sweetener
Artificial sweetener can cause obesity risk of dementia independent of diabetes and cardiovascular comorbidities(137). and induced increasing consumption of fat(138).

3. Fast Foods
Fast foods, unwholesome foods, containing high amounts of artificial ingredients, with an aim to be  cooked fast and handed over to the customer in minutes may induce anxiety, tension, depression, difficulty in concentration, and memory of that can lead to onset of senile dementia(139).

4. Artificial ingredients
A standard American diet containing high amount of MSG  and aspartame may induce the early onset of neurodegenerative disease(140)

5. Alcohol
 Moderate alcohol drinking is associated with a reduced risk of unspecified incident dementia and AD(141)(145), but excessive consumption of alcohol not only causes liver damage but also increases risk of neuro-degeneration, including onset of dementia due to its neurotoxic and neuroprotective effect(142).


                                                        16

6. Low intake of fruits and Vegetables
 Nutrition plays a role in the ageing process of the brain and suboptimal nutrient. According to The Chinese University of Hong Kong, older people with questionable dementia have lower intakes of vegetables, fruits(145) and fluid than those who were cognitively normal(143)

7. Meat
The typical American diet containing high amounts of red meat has shown to increase risk of cholesterol building up in the blood vessels and capillaries in causation of heart diseases and stroke(144) and cognitive impairment(135).

8. Etc.

G. Medication Causes of Dementia
As aging, accumulation of toxins of certain medication used to treat certain diseases, such as antidepressants, sedatives, cardiovascular drugs and anti-anxiety medications may cause increased risk of cognitive dysfunction, including dementia-like symptoms(146).
1. Antidepressants, selective serotonin reuptake inhibitors, antipsychotics and benzodiazepines
An Antidepressant is a psychiatric medication used to treat mood disorders, such as major depression and dysthymia and anxiety disorders. According to Johns Hopkins Bayview Medical Center. all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines overtime of medication exposure, induced more rapid cognitive and functional decline in AD(147).

2. Anti-inflammatory drugs (NSAIDs)
Risks for AD and all-cause dementia were lower significantly with the use of any NSAIDs, but there is a weak link associated between usage of NSAIDs and the risk of cognitive impairment but not dementia(148).

3. Cannabis
Cannabis has been  used for the treatment of a number of conditions, including neuropathic pain, spasticity associated with multiple sclerosis, and chemotherapy-induced nausea, etc,. Chronic use of cannabis may impair
                                                         17

intellectual abilities, probably through some causal pathways(149).

4.  Hallucinogens
Hallucinogens, psychedelic drugs, used primary action in altered cognition and perception, may cause distortion of sensory perception, and other psychic and somatic effects, including sweating, heart palpitations, blurring of vision, memory loss, trembling, and itching(150).

5. Risperidone 
The most prescribed antipsychotic medication has shown to increase risk of dementia(152) and other cognitive dysfunction, depending to overtime chronic exposure(151).

5. Others
a. Corticosteroids
Corticosteroids are synthetic drugs closely resemble cortisol, a steroid hormones produced by the adrenal glands to assist the physiologic processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, behavior, etc., but an excessive usage may induce risk of progressive cognitive decline(153)(154).

b. Antibiotics 
 Antibiotics are medication taken to treat a variety of infections found to be associated with increased risk of psychomotor deceleration, delirium and psychosis in elderly patients(155)(156).

c. H2-receptor antagonists 
H2-receptor antagonists are medicines taken to reduce the amount of acid in  the stomach by blocking one important producer of histamine2,  may cause acute and chronic cognitive impairments(157)(158).

d. Etc.


H. Life Style causes of Dementia
 1. Unhealthy diet 
Unhealthy lifestyle choices lead to an increasing incidence of obesity, diabetes mellitus type II, hypertension and disorder of the metabolic
                                                        18

syndrome(159)(160), are found to associate to risk of AD. Recent research supports the hypothesis that calorie intake, among other non-genetic factors, can influence the risk of clinical dementia(161).

2. Psychological and Neurological effects

Dysfunctional mind may be associated to dementia due to its effects on the cognitive profile of ALS, a subclinical behavioural-variant frontotemporal dementia (bvFTD(162). Stress, anxiety, depression(163), negative thoughts(162), unhealthy life style(159)(160), unwholesome diet(161), can cause memory, intellect, attention, thinking, comprehension and personality, with preservation of normal level of consciousness deficits(164)

3. Excessive alcohol drinking
Moderate alcohol drinking of less than 2 cups for men and 1 cups for women of red wine are said to offer possible health benefits(165), but binge drinking in midlife and excessive alcohol usages are associated with an increased risk of dementia, according to the follow-up, 103 participants had developed dementia(166), including central pontine myelinolysis, Marchiafava-Bignami disease(167).

4. Smoking
Smoking is a risk factor for several life-threatening diseases, but its long-term afflicts of dementia is controversial and understudied. According to University of Eastern Finland, heavy smoking in midlife was found to associate with a greater than 100% increase in risk of dementia, AD, and VaD more than 2 decades later, in a follow up study of a total of 5367 people diagnosed with dementia (including 1136 cases of AD and 416 cases of VaD)(168).

5. Etc.

I. Genetic Mutation causes of dementia
Genetic mutation is a condition of changes of DNA structure and alteration in the inherited nucleic acid sequence of the genotype(169). There are always a concern of some dementia patients with inherited trails for passing them to their children.


                                                    19

1. Linkage of Dementia with Lewy bodies (DLB) to 2q35-q26 
 Genetic mutation of chromosome 2q35-q36 Lewy bodies (DLB) are multiplex, due to its complex mechanism than generally monogenic disorders. Identifying the first familial DLB gene may contribute to an entry point of DLB pathology, according to Belgian family,researchers(170)

2. VCP gene R155H mutation
Some patients in the same family with frontotemporal dementia (FTD) have been diagnosed with high risk of cognitive decline due to the recurrent R155H mutation, according to University of Genova(171).


3. Genetic mutation and Alzheimer's disease
4 genes have been identified to affect development of AD. with the amyloid precursor protein (APP ) gene, presenillin gene (PSEN-1), and presenillin gene (PSEN-1)) affect younger people, and apolipoprotein E (APOE ) iaffects older people(172).

4. Chromosome 3 (FTD-3) caused by a truncating mutation in CHMP2B
Presymptomatic CHMP2B mutation  was found to associate to significantly decreased cerebral blood flow (CBF) affecting brain capillaries(173) and contributing to the early on set of dementia.

5. Mutations in the NOTCH3
Mutations in the NOTCH3 gene are responsible for hereditary stroke disorder, contributed to an adult onset of hereditary ischemic stroke, vascular dementia and psychiatric disorders(174).

6. Etc.


             Symptoms and Complications of Dementia


Dementia is a neuropsychiatric disorder induced of cognitive impairment and behavioral disturbances. The behavioral and psychological symptoms of dementia (BPSD) are common, with a progressive loss of memory and other
                                                          20

mental abilities, affecting a person's ability to perform usual tasks in everyday life.
A. Symptoms
A.1. Symptoms of Alzheimer's disease 
Alzheimer's disease is a brain disorder, affecting over 1 million people in US alone with well known  symptoms of lack of concentration (56%), tremors (56%), depression (44%), lack of cooperation (36%), and delusions (32%), psychotic symptoms (delusions, hallucinations, and delirium) and tremors, and emotional symptoms (tearfulness and apathy, lack of concentration and appetite change), according to Hospital de Cruces, Plaza de Cruces s/n, Barakaldo in a study of total of 1014 patients(177). Other symptoms include 

1. Increasing forgetfulness(178)
2. Communication difficulty(179)
3. Anxiety(180)
4. Mood and personal change(181)
5. Delay recall(183)
6. Repeat question(183)
7. Memory loss(182)
8 Aberrant motor behavior (184)
9. Sleep problems (184)
10. Eating problems (184) and
11. Agitation/aggression (184)
10. Etc.

A.2. Symptoms of Diminished quality of acetylcholine
If the nerves located in front of the brain perish, diminished quality of acetylcholine, it can cause language difficulty, memory loss, concentration problem and reduce mobile skills because of lacking reaction in muscular activity and refection.
Symptoms of deficiency of acetylcholine include(185)
1. Difficulty remembering names and faces after meeting people
2. Difficulty remembering peoples birthdays and numbers
3. Difficulty remembering lists, directions or instructions
4. Forgetting common facts
5. Trouble understanding spoken or written language
6. Forget where I put things 

                                                          21

7. Slowed and/or confused thinking
8. Difficulty finding the right words before speaking
9. Disorientation
10. Prefer to do things alone than in groups / social withdrawal
11. Rarely feel passionate
12. Feel despair and lack joy
13. Lost some of my creativity / lack imagination
14 Dry mouth
15. Etc.

A.3. Dementia due to long-term alcohol abuse
Dementia is common in patients with alcoholism. Most symptoms of alcohol dementia are also presented in other types of dementia, with a few qualitative differences(186) involved both cortical and subcortical pathology. According to the article, "What's alcohol-related dementia?" Alcohol dementia induced deterioration in intellectual function with memory not being specifically affected, such as disinhibition, loss of planning, and executive functions and a blithe disregard for the consequences of their behaviour,  affecting mostly of women in  the ages between 30 - 70  with the better rates better than for Korsakoff's Psychosis(187).
Other symptoms in deficits are most frequently observed on tasks of visuospatial function, memory(188) and higher-order (executive) tasks(189)

A.4. Multi-infarct dementia
Also known as vascular dementia, is the second most common form of dementia after Alzheimer's disease in older adults, caused by different mechanisms, affecting the vascular lesions in the brain.with major neurovegetative symptoms of depression accompanied by depressed mood/anhedonia in patients with clinically-diagnosed Alzheimer's disease (AD) and multi-infarct dementia (MID)(190).
Symptoms include memory deficits(192) such as
1. Confusion
2. Memory problems
3. Wandering Getting lost
and
4. At least one of behavioural or psychological symptom, such as appetite disturbances irritability and anxiety and emotional suppresion(such as

                                                             22

laughing inappropriately, crying inappropriately)
(193), and
5. Difficulty following instructions, and 
6. Bladder incontinence
7. Bowel incontinence(191)

A.5. Dementia associated with Parkinson's disease
Parkinson disease (PD) is a disabling, progressive condition cause of cognitive deficits due to the interruption of frontal-subcortical loops that facilitate cognition and that parallel the motor loop, affecting motor function. These include olfactory deficit, sleep problems such as rapid eye movement behaviour disorder, constipation and male erectile dysfunction.(194).
Other symptoms due to dopamine (DA) deficiency, include, dysexecutive behaviors(196), such as planning, abstract thinking, flexibility and behavioural control and postural disabilities(197) and
1. Constipation
2. Difficulty swallowing
3. Choking, coughing, or drooling
4. Excessive salivation
5. Excessive sweating
6. Loss of bowel and/or bladder control(195)

A.6. Creutzfeldt-Jakob disease (CJD)
People who have eaten contaminated beef in many years, may be infected with Creutzfeldt-Jakob disease (CJD) without even knowing it. Creutzfeldt-Jakob disease is a quickly progressing and fatal disease, characterized by rapidly progressive dementia. Initially, individuals experience problems with muscular coordination, personality changes, including impaired memory, judgment, and thinking and impaired vision. People with the disease also may experience insomnia, depression, or unusual sensations.(198).

A.7. Subdural hematoma
 Subdural hemorrhages, the accumulation of blood beneath the outer cover of the brain resulted from the rupture of blood vessel may cause an increase in tracranial pressure, leading compression and damage to delicate brain tissue. Acute subdural hematoma has a high mortality rate.

                                                          23

Other symptoms include
1. Intermittent numbness and weakness of extremity(199) and
2. Loss of consciousnes(201)
3. Irritability
4. Seizures
5. Pain
6. Headache
7. Dizziness
8. Disorientation
9. Weakness
10. Weakness or lethargy
11. Nausea or vomiting
12. Loss of appetite
13. Personality changes
14. Confused speech
15. Difficulty with balance or walking
16. Altered breathing patterns
17. Hearing loss or hearing ringing (tinnitus)
18. Blurred Vision
19. Deviated gaze, or abnormal movement of the eyes(200)



B. The Complications
 According to physical complications of patients with dementia occurred in the 12 months from April 2007 to March 2008 recorded in Ichinomiya City Hospital, Ichinomiya, the physical complications can be divided into two categories:
** Serious emergencies occurred with a possible high risk of mortality within a few days (e.g. pneumonia and upper airway obstruction); and
**Life-threatening complications arising required diagnosis and treatment by specialists from other medical departments (e.g. bone fracture and cancer)(202).

1. Pneumonia
 Pneumonia is common among patients with advanced dementia, especially toward the end of life, due to microbial  infection, according to Beth Israel Deaconess Medical Center(203).

                                                       24

2. Obstructive Sleep Apnea Syndrome (OSAS) 
The prevalence of OSAS increased with aging, occurring in up to 25% of older adults and up to 48% in patients with Alzheimer's disease, showed to induce symptoms of hypoxia, fragmented sleep, daytime sleepiness, cognitive dysfunction, functional decline, and brain damage, due to reduced cerebral blood flow, ischemic brain lesions, microvascular reactivity, white matter lesions, and grey matter loss(204)

3. Bone fracture
Bone mass and dementia in elderly hip fracture patients may be associated to levels of different aluminium concentrations in water supplies in the areas affecting the negative calcium balance of age-related osteoporosis together predispose to senile dementia.(205)

4. Urinary incontinence
 Urinary incontinence is a common problem in dementia. Almost invariably, the person with dementia will develop incontinence as the disease progresses. However, the primary reasons for incontinence are often not because of any significant pathology in the urinary system. Rather, it is due to factors outside the urinary system, including insertion of tube in assisting urinary flow(206)

5. Venous thromboembolism
 Venous thromboembolism (VTE), caused by a blood clot breaking loose and traveling in the blood, in patients with dementia had a high incidence of fatal pulmonary embolism (PE) and fatal bleeding, according to the study of 37988 patients with 1316 (3.5%) having dementia(207).

6. Etc. 


                           Prevention and Management

A. The Do's and Do Not's list
 1. Mediterranean diet
If you are typical American dieter, you are at increased risk for the development of dementia, in advanced age, as the diet is classified as one of
                                                              25

the most unhealthy diet in the existence, according to studies. Mediterranean diet, high monounsaturated fatty acids energy intake appeared to be associated with a high protection against cognitive decline and reduced the prevalence of AD in older people(208). Also recent research supports the hypothesis of calorie intake, among other non-genetic factors, in influence of the risk of clinical dementia.(209).

2. Yoga  

Senile dementia is the mental deterioration, such as loss of intellectual ability associated with old age. Yoga is believed to have beneficial effects on cognition, probably through attenuation of emotional intensity and stress reduction. Yoga participation showed to improve the memory performance, and all other psychophysiological parameters, in patient with dementia, including intellect, attention, thinking, comprehension and personality, with preservation of normal level of consciousness(210), according to G.J. Patel Ayurved College.

3. Aging of theory of mind
According to Aging of theory of mind, educational level and cognitive processing are two factors, influencing the pattern of the aging. Younger and older group with equally high education showed to outperform the older group with less education in false-belief and faux-pas tasks, with younger group outperformed the other two groups in the cognitive processing tasks(211).

3. Moderate alcohol drinking
Moderate alcohol drinking of less than 2 cups for men and 1 cups of red wine for women are said to offers possible health benefits, but Binge drinking (ie, alcohol exceeding the amount of 5 bottles of beer or a bottle of wine on 1 occasion at least monthly) in midlife is associated with an increased risk of dementia, according to the follow-up, 103 participants had developed dementia(212).

4.  Stop Smoking or never smoke before
Smoking is a risk factor for several life-threatening diseases, but its long-term association with dementia is controversial and somewhat understudied.  According to a total of 5367 people (25.4%), heavy smoking in midlife was associated with a greater than 100% increase in risk of
                                                           26

dementia, AD, and VaD more than 2 decades later(213).

5. Drink your tea and coffee
Caffeine in tea and coffee may enhance cognitive function acutely, but its link to dementia is somewhat inconsistent, but most studies support coffee's favourable and protective effects against cognitive decline, dementia or AD. Coffee drinking of 3-5 cups per day at midlife was associated with a decreased risk of dementia/AD by about 65% at late-life(214).

6. Eat your fruits and veggies 
Fruits and veggies containing high amounts of antioxidant enhance the immune system in fighting against forming of free radicals cause to damage to the brain cells in induced early onset of dementia. Vitamin E and vitamin C supplements in combination were associated with reduced prevalence and incidence of AD, according to The Johns Hopkins University(215).

7. Regular and moderate exercise for elder
 Regular and moderate exercise may attenuate  the cognitive dysfunction, but theirs' induced changes in cognition were not correlated with changes in mood/anxiety, probably through some separate neural systems mediation(216).

8.  Avoid nutritional deficiency with balance diet
a. Beyond our believe, an excess of dietary carbohydrates, particularly fructose, alongside a relative deficiency in dietary fats and cholesterol, may lead to the development of Alzheimer's disease(217).
b. For more of Avoid nutritional deficiency with balance diet, please visit(218)

9. Avoid environment risk of dementia
Certain environment toxins produced as a result of industrialization or naturally have been linked to cognitive degenerative diseases. According to University of British Columbia, novel environmental toxins: steryl glycosides, a potential etiological factor for age-related neurodegenerative diseases, showed signs of mimicked ALS-PDC, including progressive deficits in motor, cognitive, and olfactory functions associated with neuron loss in the spinal cord, nigrostriatal system, cortex, hippocampus, and olfactory bulb in fed mice(219).
                                                             27


10. No illicit drug, please(220)
Illicit drug used may cause nervous system impairment as a result of direct and indirect effects on the integrity and function of nervous system tissue and, potentially, through immune effects, especially, up to 40% risk of nervous system impairment for patients with  HIV-1 infection.

11. Prevent prolonged period of using certain drugs
As aging, accumulation of toxins of certain medication used to treat certain diseases, such as antidepressants, sedatives, cardiovascular drugs and anti-anxiety medications may cause increased risk of cognitive dysfunction causes of dementia-like symptoms(221).

12. Etc.


B. Antioxidants and Dementia
B.1. Antioxidant enzymes
Antioxidant enzymes, chemical substances found in plants, protect the body from damage of free radicals by terminating the chain reactions through removing free radical intermediates and inhibiting  oxidation reactions.
1. Catalase
Catalase is an enzyme, found in most living organisms exposed to oxygen for action of converse hydrogen peroxide (free radicals)(226) to water and oxygen. The antioxidants showed to protect cells against the toxic effects of hydrogen peroxide in pathogenesis of oxidative stress-related diseases(222) inducted early stages of aggregation of the amyloid peptides(225), including neurodegeneration(224) such as Alzheimer's diseas(223).

2. Glutathione peroxidase
The function of glutathione peroxidase is to protect the organism from oxidative damage and induced neurodegenerative diseases, such as Alzheimer's disease(228) by removing lipid hydroperoxides(227), causes of oxidation of lipid cell membranes. probably through its major cellular peroxide scavenging enzyme(228) and maintaining the oxidative phosphorylation system and protecting mitochondria(229) and oxidative injury and amyloid toxicity of cortical neurons(230).
                                                             28

3. Glutathione reductase
Glutathione reductase, an antioxidant enzyme capable to regenerate Gglutathione (GSH) levels at 24h(233),  and reduced pair of sulfur atoms glutathione to a organosulfur compound form of antioxidant (consisting of three amino acids joined by peptide bonds) may play an important role in prevention of damage of important cellular components induced neurodegenerative diseases such as PD(231)(232), caused by free radicals and peroxides. probably through its antioxidant and anti-inflammatory properties(231)

4. Super oxide dismutase (both Cu-Zn and Mn)
Super oxide dismutase is an important antioxidant and immune defence(224) in nearly all cells exposed to oxygen by converting superoxide into oxygen and hydrogen peroxide, depending on the metal cofactor such as both Cu-Zn and Mn(225), probably through the attenuation of superoxide dismutases (SODs) and catalases (CATs)(225) in enhanced protection of biochemical/molecular/neurobiological  function(226).

B.2. Metals binding proteins 
1. Ceruloplasmin
Ceruloplasmin, the major copper-carrying protein in the blood, plays a role in iron metabolism(227). Decreased level of ceruloplasmin impaired ferroportin stability(229)(230)may induce progressive action tremor, and cognitive decline(227), causing the forming of  superoxide anion radicals(231) and iron overload in the brain, liver, pancreas, and other organs(232).

2. Ferritin
Ferritin, the protein produced by almost all living organisms, acts as a component to fight against iron deficiency and iron overload(233)(234). In a soluble and non-toxic form, the protein is transported to the body needs, including organs(236) for enhancement of the immune system in the presence of an infection(237), against proliferation of lymphoid and myeloid cells(235), cancer(238) and prevention of the infectious agent in attempt of binding iron to form free radicals(239) in most cellular oxidation reactions(239).
                                                           29


3. Lactoferrin
Lactoferrin, a multifunctional protein of the transferrin family, is one of the components of the immune system(240) of the body used for fighting against foreign invasion of bacteria and virus(241)(242) and lipid oxidation(243) by inhibiting oxidation in a concentration-dependent manner even at concentrations beyond its capacity(244).

4. Metallothionein
Metallothionein, a family of cysteine-rich(24), low molecular weight proteins binds both physiological heavy metals(245) through detoxified fraction of accumulation(245) by capturing harmful superoxide and hydroxyl radicals(246) through binding the metal ions(247)(248) bounded to cysteine(249).

5. Transferrin
Transferrin, a glycoprotein binded iron very tightly but reversibly, enhances the immune system in fighting against infection, inflammation(250) by creating an environment low in free iron(251) impeded to cell oxidation(253)(254), through rapidly evolving sites reverse to bacterial binding in counteract bacterial iron piracy(250). Transferrin deformation and aggregation are found to associate to neurological disorders such as Parkinson's and Alzheimer's disease(252).

6. Hemoglobin
Hemoglobin, the protein molecule in red blood cells enhances the carrying of oxygen from the lungs to the body's tissues and return CO2 from the tissues to the lungs(255)(256). During oxidate stress, the cell membrane is protected by intraerythrocytic hemoglobin from the forming of free radicals(259), probably through regulating NO(258) and auxin homeostasis(257).

7. Myoglobin
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates. The binding of oxygen by myoglobin(260) through interaction with pathogens establishment of successful infection and survival  is probably through peroxidase activity(261) in reducing the free radicals damage caused by oxidate stress(261)(262).
                                                              30


8. Etc.

B.3. Common Free Radical Scavengers 
1. Bilirubin
Bilirubin is a prosthetic group with a unique function in breaking down molecules into smaller units for releasing energy, excreted in bile and urine(263). As a cellular antioxidant, it protected against diseases associated with oxidative stress, through mildly elevated serum bilirubin levels and activation of heme oxygenase(264) and reverted to biliverdin, a green tetrapyrrolic bile pigment, through antioxidant redox cycle in inhibition of the effects of mutagens when oxidized(265). A significant reduction of levels of bilirubin, has shown to associate to patients with Alzheimer's disease(AD)(266).

2. Carotenoids
Carotenoids are organic pigments, occurred in the chloroplasts and chromoplasts of plants and some other photosynthetic organisms like algae, some bacteria. The antioxidant has been under intense scrutiny studies for finding of their potential in modulated chronic disease risk and prevention of vitamin A deficiency(267). Plasma levels of HDL and carotenoids have shown to lower in patients with dementia related vascular disorders(268) and Alzheimer's disease(AD)(269).

Beta-Carotene, an organic compound is classified as a terpenoid, a strongly-coloured red-orange pigment in plants and fruits.
 Beta-Carotene is not toxic and stored in liver for the production of vitamin A(270) showed to inhibit cancer cell in experiment(271)(272). Its anti oxidative effects has shown to cover the main pathways for formation, transformation, and decay of free radicals(273), through its relation to the antioxidant/pro-oxidant properties(274). According to Yale University, the decreased non-enzymatic antioxidants in blood, including β-carotene showed a significant oxidative damage in the process of neurodegeneration(275).

3. Flavonoids
Flavonoid also known as Vitamin P and citrinare, is a yellow pigments having a structure similar to that of flavones occurred in varies plants. The
                                                           31

antioxidant has been in human history for over thousands of years and discovered by A. S. Szent-Gyorgi in 1930. Vitamin C and flavonoids combination has shown to expressed wound healing in animal model(276).
Flavonoids process a property as antioxidants in inhibition of  cell growth, differentiation and development, and overexpressed in gastric cancer, colorectal cancer, pancreatic cancer, etc., probably through cell cycle arrest and induced apoptosis(277). Intake of antioxidant flavonoids is associated  to the reduced  risk of incident dementia(278) and mild cognitive impairment(279).

Although nitric oxide is considered a free radical produced by immune system to destroy microbial(281) and cancerous cells(282)(283). Over produced NO, showed to  induce inflammation(280). Flavonoids processed an ability in inhibited NO production of peroxynitrite(284) found to induce mitochondrial dysfunction associated with PD progression(285) and cause of inappropriate damage to blood and tissues(284).

4. Vitamin A, C, E
a. Vitamin A
Vitamin A occurred in the form retinol is best known for its function in maintaining a critical role in vertebrate development, cell differentiation, reproduction, vision and immune system(286). The vitamin also acts as an the major peroxyl radical scavenger role in biological lipid phases such as membranes or low-density lipoproteins (LDL)(291)(288), including incidence of bronchopulmonary dysplasia (BPD) with respiratory failure(290), in fighting the increased free radicals activity by radiation(287), and enhancement of the productions of insulin pancreas(289).

b. Vitamin C
Vitamin C, presencted in aqueous compartments (e.g. cytosol, plasma, and other body fluids)(292) plays an important role  in synthesis of collagen, carnitine, catecholamine and the neurotransmitter norepinephrine(293). As an water soluble vitamin, vitamin C can be easily carried in blood, operated in many parts of body. By recycling vitamin E, vitamin C also helps to fight against forming of free radicals(294). By enhancing the immune system(295)(296), it promotes against the microbial and viral(298) and irregular cell growth causes of infection and inflammation(297).
Vitamin C also is a free radical scavenger in inhibiting pollution cause of
                                                             32

oxidation(299).

c. Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds, including  both tocopherols and tocotrienols(300), discovered by researchers Herbert Evans and Katherine Bishop. The vitamin not only is important in protecting muscle weakness(300), repairing damage tissues(302) caused by oxidation(303), and promoting blood clotting in healing wound(302), etc., it also, moved into the fatty medium to prevent lipid
peroxidation(301), inhibited free radicals chain reactions by curtailing them before they can start(304) and prevented or delayed cognitive decline, in both ageing population of and mild cognitive impairment in patients with Alzheimer's disease (AD)(306), according to R & D Human Nutrition and Health(305).

5. Etc.

C. Phytochemicals Against Dementia
C.1. Rosemarinol
Rosemarinol is a phytochemical monophenols, found in essential oil of labiate herbs like rosemary and in variety of other plants.
1. Retard autoxidation
Rosemary extract rich in carnosic acid showed a significantly retarded autoxidation, in the fish oil undergoes microencapsulation process(307).

2. Anti-inflammatory effects
The extract of rosemary leaves from supercritical fluid extraction showed a high inhibitory effect on lipid peroxidation, through suppression of the LPS-induced production of nitric oxide (NO)(308) and maintaining oxidative stability(313)

3. Antioxidant defences

 Rosemary extract enhanced  antioxidant defences and improved antioxidant status in aged rats in attenuation of lipid peroxidation and ROS levels through its antioxidant enzyme activity(309). The extract also showed to exhibit its antioxidant effect against the proliferation of irregular cell growth such as human leukemia and breast carcinoma cells(312).

                                                            33

C.2. Gingerole
Gingerole, is also known as gingerol, a phytochemical of flavonoids (polyphenols) found in fresh ginger. and in variety of other plants. The herb has been used for treatment of nausea and vomiting of pregnancy, motion sickness, rheumatoid arthritis, relieve migraine, etc. in folk medicine.
1. Antioxidant and anti-inflammatory effects
 Chemical constituents of Zingiber officinale Rosc.(Zingiberaceae) showed to attenuate oxidative stress, through its scavenging, and inhibiting superoxide and hydroxyl radicals of ROS species(310), via nephroprotective effect on mediation of oxidative stress, inflammatory processes, and renal dysfunction(311).

2. Dementia

 Ginger(70% aqueous/methanolic extract of dried ginger (Zo.Cr)) besides induced spasmolytic activity in stomach fundus in treating dementia in South Asia, it also inhibited butyrylcholinesterase (BuChE) in improvement of cognitive performance patients with dementia(315) and vascular dementia (VaD)(315), probably through cholinergic anti-inflammatory pathway in reduced production of amyloid-β(316).

C.3.  Naringenin

Naringenin, a flavanone, belonging to the red, blue, purple pigments of Flavonoids (polyphenols) found predominantly in citrus fruits is considered as one of powerful antioxidant with many health benefits.
1. Antioxidant, free radical scavenging 
 Naringin showed to reduce DNA damage through its antioxidant capacities in scavenging free radicals hydroxyl and superoxide(317). Cognitively, naringenin ameliorated Alzheimer's disease (AD)-type neurodegeneration(318) by improving learning and memory ability of patient with early onset of the diseases(319). Pharmacologically, the phytochemical was found to be a potential anticancer, antimutagenic, anti-inflammatory, antiproliferative and antiatherogenic agent(320).

2. Anti-inflammatory effects(320)
Neuroinflammation is considered as a constant event in Alzheimer's disease (AD), with no evidences for its direct involvement in development(322). In diabetic mice model, naringenin exhibited its anti inflammatory activity in  lowering blood glucose and urea nitrogen, increasing insulin level and
                                                             34

creatinine clearance(321), probably through inhibition of iNOS protein and anti inflammatory pathways(323).

3. Immunity

Adaptive and innate immune deficit were shown to associate with cognitive dysfunction in patients with AD and mild cognitive impairment (MCI)(325). Naringenin, stimulated the production T cells in regulation of the immune system, and in suppression of  allergies and autoimmune diseases(324) which are considered as Alzheimer's and Parkinson's disease variants(326).

C.4.  Tangeritin
Tangeritin, one of the flavones, is found in tangerine and many citrus peels.
1. Neuroprotective effects
Natural antioxidant tangeretin, may be used as neuroprotective agent, for its significant effects on protection of striato-nigral integrity and functionality in patients with Parkinson's disease(327), probably through its anti-neuroinflammatory activity(328) via mitochondrial depolarization(329) in attenuated reactive oxygen species generation.

2. Antioxidants

Mature and immature calamondin (Citrus mitis Blanco) peel, containing tangeretin showed to exhibit its antioxidant(331) effects in enhancing the highest oxygen radical absorbance capacity (ORAC)  and superoxide scavenging effect(330), as well as ameliorating oxidative stress causes of DNA damage(332), mammary carcinoma(333)(334) and diabetes(335).


C.5. Curcumin

Turmeric, principal curcuminoid of the popular Indian spice, is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae, native to tropical South Asia, used in traditional herbal medicine as an anti-inflammatory agent and to treat gastrointestinal symptoms associated with irritable bowel syndrome and other digestive disorders(336). Curcumin, a phytochemical found abundant in the plant, in acidic solutions (pH <7.4) turns yellow, whereas in basic (pH > 8.6) solutions turns bright red.
1. Alzheimer's disease and Anti-inflammatory agent
a. Alzheimer's disease
Increased antioxidant and anti-inflammatory consumption such as curcumin
                                                             35

may reduce risk of Alzheimer's disease (AD) caused by amyloid beta (Abeta) accumulation(338) through reversal of Abeta-induced cognitive deficits and neuropathology(339). The phytochemical is also found to disaggregate Abeta in preventing fibril and oligomer formation(338). According to Yamagata University, its synthesized curcumin analogues used pharmateutically in treatment of amyloid β aggregation also experience notable result(337). In vitro and animal models, curcumin was effective, in lowering oxidative damage, cognitive deficits, synaptic marker loss, and amyloid depositio in prevented onset of Alzheimer's disease(340).

b. Anti-inflammatory agent

  Curcumin, an anti-inflammatory agent(341), in the pathogenesis of psoriasis and neurodegenerative diseases,, decreased the expression of pro-inflammatory cells signalling in response to inflammation(342)(343), in patients of ear infection and Parkinson's disease and Alzheimer's disease(344)(345), respectively.

2. Antioxidants

Curcumin also consisting anti-proliferative, anti-inflammatory and immunosuppressive activitie(346), in arthritis, strongly inhibited collagenase and stromely in expression at micromolar concentrations(346); in diabetes, scavenged free radicals and reduced LDL oxidation and cellular oxidative stress(347); in cancers, reduced accumulation of ROS causes of abnormal cells(348), through apoptosis(349); in neurodegenerative diseases, exerted autophagy-lysosomal activities, through removing damaged or dysfunctional proteins and cells with specific function(350) and regulating reactive oxygen species (ROS)(351)(352).

G.6.  Gallic acid
Gallic acid is a phytochemical in the class of Phenolic acids, found abundantly in tea, mango, strawberries, rhubarb, soy, etc.
1. Cytotoxic and antioxidative activities(367)
Gallic acid showed to exert its antioxidant in inhibition of free radical effects against 2,2-diphenyl-1-picrylhydrazyl(DPPH), a stable free-radical molecules(354), nitric oxide (NO) and superoxide (SO) radicals(353)(355), probably through its chelation of ferrous ions(355). In bacteria, the phytochemical extract containing gallic acid also exhibited a strong anti microbial effect(357)(358) from species of Hypogymnia physodes and
                                                              36

Cladonia foliacea(356); In cancers, gallic acid induced tumor cytotoxic effects(357), through antiproliferative induced apoptosis(359), cell cycle arrest(362) and suppression of cancer cell-mediated angiogenesis(360), such as mitochondrial dysfunction(361). Neurologically. gallic acid reduced oxidative stress and mitochondrial dysfunction causes of the pathology of secondary neuronal damage in induction of dementia(363); its anti-aggregating effect also inhibited α-synuclein (α-syn) causes of  many neurological disorders including Parkinson's disease (PD), dementia with Lewy bodies(364).


2.  Anti inflammatory activity(367)
Gallic acid showed to inhibit inflammation(366) through its scavenging of superoxide anions, inhibition of myeloperoxidase release and activity via mediation of inflammatory process(365).

C.7. Cinnamic acid

Cinnamic acid is a phytochemical in the class of Hydroxycinnamic acids, found abundantly in cinnamon, aloe. etc.
1. Antioxidant effects
Mitochondrial oxidative damage is associated with a number of clinical disorders. Mitochondria-targeted antioxidant (TPP-OH), including cinnamic acid exhibited its antioxidant activity in protection of cells against H(2)O(2) and linoleic acid hydroperoxide-induced oxidative stress(371)(368). The phytochemical also showed a promising free radical scavenging(369) and anti-inflammatory(375), antidiabetic(374), antimicrobial(371), anticancer(377)(378), lipid-lowering(379)(380), and cardiovascular-disease-lowering activity(369)(370)(380). Neurologically, cinnamon has also been reported to have activities against neurological disorders(372)(375)(376), such as Parkinson's and Alzheimer's diseases(373)(370)

2,  Anti-platelet aggregation
 Novel ligustrazinyloxy-cinnamic acid derivatives showed to inhibit  platelet aggregation in vitro(380), and its p-amidinophenyl esters also exerted antithrombotic effects as irreversible inhibitors of the vitamin-K dependent enzymes(382) which plays an important role in the pathogenesis of chronic obstructive pulmonary disease(381).
                                                               37


C.8. Tyrosol
Tyrosol is a phytochemical compound, a derivative of phenethyl alcohol, belongings to the group of tyrosol esters, found mostly in olive oil. The phytochemical is best known for its antioxidants in protecting the forming of free radicals and lipid oxidation causes of heart disease(383).
 1. Antioxidant effects
 Tyrosol attenuated the elevated cellular concentrations of reactive oxygen species, NO scavenging(386) and lipid peroxidation, against bacterial invasion(386), DNA damage induced by dioxin toxicity(384) and hydrogen peroxide (H2O2)(385) probably through vary antioxidant-dependent mechanisms. Neurologically, tyrosol showed to exhibit its protective effect against dopaminergic neuronal induced degradation(387) and neurotoxicity(388).

2.  Alzheimer Disease

In Alzheimer Disease, tyrosol has shown to protect neuro-cells damage against amyloid-β-Induced toxicity, probably through anti inflammatory pathways(389). In women, the phytochemical also exerted its antioxidative activity(391), in removing harmful compounds from the body, reducing risk of bacterial respiratory tract, intestinal, and genital tract infections(392), suppressing LDL(392) causes of  the development of cardiovascular disease; and preventing oxidation induced diseases and conditions, such as cardiovascular disorders(392), cancer(392), osteoporosis(393)(394), Alzheimer disease(390)(395)(396)(397).


C.9.  Silymarin
Silymarin is a phytochemical in the class of Lignans (phytoestrogens), found abundantly in artichokes, milk thistle, etc.
1. Antioxidants
Silymarin showed to exert the powerful antioxidant activity into protection of cells against arsenical cytotoxicity(399), via reduced lipid hydroperoxide (LHP) formation with no RNS induction and hepoprotective(400)(401) in ntitubercular and alcohol-induced hepatotoxicity assays in rats(400)

2. Neuroprotective effect

In impaired cognitive and neurochemical function of diabetic patients and
                                                            38

streptozotocin induced diabetic rodents, silibinin promoted DNA protection and reduced oxidative stress in a brain specific area, in part via the activation of the HO system(402); In mouse mode with Parkinson's disease(404), treatment of the phytochemical attenuated dopamine levels induced neuro cells damage causes of  apoptosis(403) via reduced brain myeloperoxidase activity associated with AD risk(405) and inflammatory signalling cells(404).

                  Treatments  In conventional Medicine


Depending to the causes of disease, most medication are to control the symptoms
A. Alzheimer's disease and Diminished quality of acetylcholine
A.1. Treatments of mild and moderate Alzheimer's disease and Diminished quality of acetylcholine
1. Cholinesterase inhibitors 
a. Cholinesterase inhibitors are the primary treatment, including tacrine(409)(410)(Cognex), donepezil(411)(412)(Aricept), rivastigmine(407)(408)(Exelon), and galantamine (Reminyl) for reductions in acetylcholine and acetyltransferase activity(406) induced cognitive symptoms of Alzheimer disease (AD).
According to Dr. Trinh NH and the research team at the Massachusetts General Hospital, there was no difference in efficacy among various cholinesterase inhibitors(413). Persistent drug treatment had a positive impact on AD progression in advanced disease(414). 
In the article, Cholinesterase Inhibitors, posted in the Minister of health, the inhibitors, improved the effectiveness of acetylcholine either by increasing the levels in the brain or strengthening the way nerve cells response in communication between nerve cells, may temporarily promote or stabilize the symptoms of Alzheimer's disease(415).

b. Side effects are not limit to(416)(417)
b.1. Nausea    
b.2. Diarrhea    
b.3. Vomiting    
b.4. Indigestion.     
b.5. Abdominal pain    

                                                                 39

b.6. Loss of appetite
b.7. Fatigue
b.8. Weight loss
b.9. Etc.

A.2. Treatment of moderate and Severe Alzheimer's disease and Diminished quality of acetylcholine
1. Namenda®(418)(419)(memantine), an N-methyl D-aspartate (NMDA) antagonist(420) are the most common medication used to treat moderate and severe Alzheimer's disease, through it's therapeutic action in uncompetitive binding to the NMDAR for preservance of the physiological function of the receptor(421). But, according to other in 2 out of 3 six month studies, memantine showed only a small beneficial effect but not in patients with vascular dementia(422).

2. Side effects are not limit to(423)(424)
b.1. Confusion
b.2. Dizziness
b.3. Drowsiness
b.4. Headache
b.5. Insomnia,
b.6. Agitation
b.7. Vomiting
b.8. Anxiety
b.9. Etc.


3. Other medications
3.1. Anticonvulsants
a. Anticonvulsants are a diverse group of pharmaceuticals used in the treatment of seizures(425), chronic neuropathic pain(426), and the clinical syndrome of Alzheimer's disease(427) by suppressing the rapid and excessive firing of neurons(428). Some researchers suggested that seizure pathophysiology may relate to increased amyloid beta-peptide production(429), causing cytoskeletal dysfunction, cerebrovascular changes, neurotransmitter dysfunction or combinations(430). By modification of these pathophysiological pathways, anti-epileptic drugs such as sodium valproate and lacosamide may be useful in the treatment of Alzheimer's
                                                              40

disease(431)

b. Side effects are not limit to(432)(433)
b.1. Dizziness
b.2. Drowsiness
b.3. Unsteadiness
b.4. Nausea
b.5. Vomiting
b.6. Skin rashes
b.7. Etc.

3.2. Sedatives
a. A sedative or tranquilizer is a drug that calms patients(434), reduced irritability and excitement by modulating signals within the central nervous system for neuroprotection(436). The medication are highly addictive. Benzodiazepine, one of the sedative has shown to reduce Aβ plaques through its activation on Aβ-related synaptic and behavioral impairment in AD(437).

 
b. Side effects are not limit to(438)
b.1. Stomach upset
b.2. Blurred vision
b.3. Headache
b.4. Impaired coordination
b.5. Depression
b.6. Memory loss
b.7. Drowsiness
b.8. Risk of fractures and falls(435)
b.9 Etc.

3.3. Antidepressants
a. Antidepressant is a type of psychiatric medication used to treat depression(443), including mood disorder(439), dysthymia(440)(441) and anxiety disorders(442)(443). According to Purpan-Casselardit Hospital, 34.8% of patients with AD are prescribed antidepressant foe daily use in AD(444).
                                                                41


b. Side effects are not limit to(445)
b.1. Dry mouth, 
b.2. Blurred vision
b.5. Drowsiness, 
b.4. Dizziness
b.5. Tremors
b.6. Sexual problems
b.7. Etc. 

B. Treatment of  Wernicke-Korsakoff Syndrome due to long-term alcohol abuse
Wernicke-Korsakoff Syndrome is a type of dementia resulted of long term alcohol abuse causes of irreversible damage of the brain(447) due to thiamine deficiency with high morbidity and mortality(446).
Wernicke-Korsakoff Syndrome (WKS) is not a rare disorder, particularly in individuals who abuse alcohol, but there are insufficient evidence from randomized controlled clinical trials to guide clinicians in the dose, frequency, route or duration of thiamine treatment(450)
1. Initial treatment consists of reversing the thiamine deficiency by giving supplemental thiamine(448) and intravenous (IV) thiamine has little risk(449), Usually, the treatments begin with an initial intravenous or intramuscular dose, then followed by supplemental oral doses(447).

Patients with diabetes are found to associate with 15% high risk of  Wernicke-Korsakoff syndrome(451). Treatments of such patients should be taken accounted of glucose intake(453) as the combined diseases may cause disturbances of consciousness, or intoxication(452) with spiking acute serum glucose level(452).
According to State University of New York at Binghamton, treatment of Wernicke-Korsakoff Syndrome has shown to cause long-term alterations in neurogenesis(reduction of newly neuron generation) and gliogenesis(generation of non-neuronal Glial cells populations)(454).


Thiamine treatment usually can not reverse the loss of memory and intellect of Korsakoff psychosism but stopping alcohol use can prevent

                                                           42

 

additional loss of brain function and damage to the  nerves(456).
         

2. Side effects are not limit to(455)
a. Alcohol withdrawal symptoms
b. Experience hallucinations,
c. Confusion, and/or
d. Agitation.
e. Etc.



 C. Dementia associated with Parkinson's disease
Parkinson disease (PD) is a disabling, progressive condition induced symptoms of olfactory deficit, sleep problems such as rapid eye movement behaviour disorder, constipation and the more recently described male erectile dysfunction(456), due to the interruption of frontal-subcortical loops facilitated cognition and parallel the motor loop(457).
Contrary to common perception, many non-motor symptoms (NMS) also link to early onset of PD(459) and some may even predate the diagnosis of PD based on motor signs(458).

C.1. Treatments of Dementia Associated with Parkinson's Disease
Treatments are depending to the degree of functional and cognitive impairment, according to the suggestion of  the Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM)(480) and Report of the Quality Standards Subcommittee of the American Academy of Neurology(488)
1. Treatments for the non-motor symptoms of Parkinson's disease 
a. Tricyclic antidepressants nortriptyline(459) and desipramine(460) for the treatment of depression or depressive symptoms
b. Macrogol for the treatment of constipation(461)
c.  Methylphenidate(462) and modafinil(463) for the treatment of fatigue
d. Amantadine for the treatment of pathological gambling(464)(465)
e. Donepezil(466)(467), galantamine(468), and memantine(470) for the treatment of dementia

                                                          43

 

f.  Quetiapine(471)(472) for the treatment of psychosis
g. Fludrocortisone(473)(474) and domperidone(475)(476) for the treatment of orthostatic hypotension
h. Sildenafil(477)(478) for the treatment of erectile dysfunction
i. Ipratropium bromide spray(479)for the treatment of sialorrhea
j. Levodopa/carbidopa controlled release (CR)(481), pergolide(482), eszopiclone(483)(484), melatonin(485) 3 to 5 mg and melatonin 50 mg for the treatment of insomnia
k.  Modafinil(486)(487) for the treatment of excessive daytime sleepiness

C.2. Treatments for the motor symptoms of Parkinson's disease
According to the Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM) Review of Treatments for Parkinson's Disease (PD) was first published in 2002 and updated in 2005 to cover clinical trial data up to January 2004 with the treatments on motor symptoms of PD(489), including

a. Piribedil(490)(491), pramipexole(491), pramipexole extended release(492)(493), ropinirole(491), rotigotine(494), cabergoline(491), and pergolide(491) were all efficacious as symptomatic monotherapy
b. Ropinirole prolonged release(495) was likely efficacious as a symptomatic adjunct therapy
c. Prevention/delay of motor fluctuations, pramipexole(496) and cabergoline(497) were efficacious
d. Prevention/delay of dyskinesia, pramipexole(498), ropinirole(499), ropinirole prolonged release(500), and cabergoline(501) were all efficacious, whereas pergolide(502) was likely efficacious.
 e. Duodenal infusion of levodopa(502)(503) was likely efficacious in the treatment of motor complications, but the practice implication is investigational.
 f. Rasagiline conclusions were revised to efficacious as a symptomatic adjunct(504), and as treatment for motor fluctuations(505).
g. Bilateral subthalamic nucleus deep brain stimulation(506), bilateral globus pallidus stimulation(507), and unilateral pallidotomy(508) were updated to efficacious for motor complications.
h. Physical therapy(509)was revised to likely efficacious as symptomatic

                                                            44

 

adjunct therapy.

C.3. Side effects
Most conventional medicine induced certain side effects. If you are taken any of these medicine, please consult your doctor. You also can search them from respectable sources. Here are some examples.
a, Macrogol(Allergic reaction (rash, itching, shortness of breath) changes in your body's fluid or electrolyte levels (swollenankles, other swelling, fatigue, dehydration, increased thirst with headache), Abdominal pain. Mild diarrhoea. Nausea. Vomiting. Swollen abdomen)(510).
b. Methylphenidate (stomach pain, nausea, vomiting, loss of appetite; vision problems, dizziness, mild headache; sweating, mild skin rash; numbness, tingling, or cold feeling in your hands or feet; nervous feeling, sleep problems (insomnia); or. weight loss)(511).
c. Modafinil (Black, tarry stools, blurred vision or other vision changes, chest pain, chills or fever,    clumsiness or unsteadiness, confusion, dizziness or fainting, increased thirst and urination, mental depression, problems with memory, rapidly changing moods, shortness of breath, sore throat,     trembling or shaking, trouble in urinating, uncontrolled movements of the face, mouth, or tongue     unusual bleeding or bruising and unusual tiredness or weakness)(512). 
d. Etc. 


D. Dementia associated to Creutzfeldt-Jakob disease
People who have eaten contaminated beef in a prolonged period of times may be infected by infectious agent prion(514) without even knowing it. Creutzfeldt-Jakob disease is a quickly progressing and fatal disease(513) inducing dementia(515), especially in elder(516), causing degeneration of skeletal muscle, peripheral nerves(517) linked to mutations in the PrP gene(518). CJD is characterized by rapidly progressive dementia(513)(519). Initially, individuals experience  of epilepsy seizure(519), problems with muscular coordination(522); cognitive change (loss of motor planning, loss of motor functioning's, inability to speak)(519), such as  impaired memory(521), loss of functional independence(523) and impaired vision(520). People with the disease also

                                                            45

 

may experience insomnia(524)(525), depression(526)(527), or unusual sensations(522).

 Treatments of Creutzfeldt-Jakob disease (CJD)
There is no treatment that can cure or control CJD. The available treatments are to relieve the symptoms and may help slow the disease.
1. Interleukins
a. Interleukins is defined as any group of naturally occurring proteins that mediate communication between cells(528), produced by while blood cells. The set of interleukins stimulated by a specific infectious agent in determined cells in responding to the infection and influences(528) through its modulated inflammation and immune response.(529).
According to University Hospital Göttingen, interleukin 10 levels, inflammatory cytokines(530) were significantly elevated in the cerebrospinal fluid of CJD, dementia, motoneuron disease patients through it inflammatory cytokines(529). Cyclooxygenase-2 (COX-2)(532) and prostaglandins (PGs)(533) are the most conventional medicine used to treat neurotoxiticy in acute conditions, including in inflammatory chronic diseases, such as Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD)(531).

b. Common side effects are not limit to
b.1. Cyclooxygenase-2 (COX-2)
b.1.1 Insomnia,
b.1.2 Abdominal pain,
b.1.3. Flatulence (gas),
b.1.4. Headache ,
b.1.5.  Nausea and diarrhea.

b.2. Prostaglandins (PGs)
b.2. Dizziness
b.2.2. Fainting
b.2.3. Irregular heartbeat or pulse•
b.2.4. Slow heartbeat

2. Other medication

                                                         46

2.1.  Quinacrine
a. Quinacrine used for treatment of giardiasis caused by Giardia lamblia(535) may be a potential medicine for treatment of Creutzfeldt-Jakob disease(CJD)(536)(537), according to a report in The Mail on Sunday 12 August 2001, entitled "Briton 'cured' in CJD drug trial"(534).
Although Quinacrine at a dose of 300 mg per day was reasonably tolerated, it did not induce significantly affect in course of prion diseases(537), including Creutzfeldt-Jakob disease (CJD(538)(539).
b. Most common side effects are not limit to
b.1. Abdominal and  cramps
b.2. Diarrhea
b.3. Fever
b.4. Headache
b.5. loss of appetite
b.6. Changes in menstrual flow
b.7. Nausea and vomiting

2.2. Gamma-aminobutyric acid, dopamine and serotonin
 a. Other medication used to control aggressive and uncontrolled behavior, such as gamma-aminobutyric acid(541)(542)(543) with functions of inhibitory neurotransmitter in the mammalian central nervous system(540), (541)(543). Dopamine and serotonin(542)(543) also functioning as a neurotransmitter may be helpful.
b. Common side effects are not limit to
b.1. Gamma-aminobutyric acid
b.1.1. Anxiety
b..2.2. Dizziness
b.1.3.Drowsiness
b.1.4 dry mouth
b.1.5. Blurred vision
b.1.6. Constipation
b.1.7. Irritation
b.1.8. Joint or muscle pain
b.1.9. Increased appetite

b.2. Dopamine
b.2.1. Fast heartbeat

                                                               47

 

b.2.2. Headache
b.2.3. Nausea
b.2.4. Vomiting

b.3.. Serotonin
b.3.1. Feeling agitated, shaky or anxious
b.3.2. Indigestion
b.3.3. Diarrhea or constipation
b.3.4. Loss of appetite
b.3.5. Weight loss
b.3.6. Dizziness
b.3.7. Blurred vision
b.3.8. Excessive sweating
b.3.9. Insomnia
b.3.10. Dry mouth

 

E. Multi-infarct dementia
Also known as vascular dementia, is the second most common form of dementia after Alzheimer's disease in older adults between ages of 60 and 75(571), caused by different mechanisms all resulting in vascular lesions in the brain(572)(573) with prevalence of major depression, depressed mood/anhedonia, and subjective and neurovegetative symptoms of depression(574).

Treatments of Multi-infarct dementia
There are no treatments which can reverse the damage to the brain caused by small strokes(575), but the goal of the treatment is to control the symptoms and reduce the risk factors to prevent future strokes(576) by prescribed medicine to make the blood thinner to reduce the risk blood clot causes of future stroke.
E.1. Medication  
1. Plavix
Plavix tablets is pescription-only medicine with function of keeping blood platelets from sticking together and forming clots(577) to prevent blood clotted causes of future stroke(579). In some cases, it is used conjunction

                                                         48

 

with aspirin(578).

b. Side effects are not limit to
 The most common side effects of Plavix (occurring in more than 2 percent of people and more often in the group taking Plavix) include:
b.1. Constipation
b.2. Diarrhea
b.3. Dizziness
b.4. Headache
b.5. Heartburn
b.6.  Joint or muscle pain
b.7. Nausea and vomiting
b.8. Etc.
A sudden choking feeling, sore throat, difficulty swallowing and itchy mouth had been reported in patient taking clopidogrel 75 mg combined with 100 mg acetylsalicylic acid once daily, and metoprolol tartrate 50 mg twice daily(580)

2. Antipsychotics (olanzapine, quetiapine)
a. Antipsychotic drugs effectively treat psychosis caused by a variety of conditions including dementia(581). Psychotic symptoms are classified as either positive or negative. Positive symptoms include hallucinations, delusions, thought disorders, bizarre or disorganized behavior(582). Negative symptoms include anhedonia, flattened affect, apathy, and social withdrawal(583).

b. Side effects are not limit to
In most cases, adverse effects are usually dose dependent and influenced by patient characteristics, including age and gender(584).
 b.1. Constipation,
b.2. Dry mouth and
b.3. Blurred vision
b.4. Sleepiness and slowness
b.5. Weight gain
b.6. Stiffness and shakines

                                                              49

 

b.7. Hormone change
b.8. Diabetes
b.9. Etc.

3. Serotonin-affecting drugs (trazodone, buspirone, or fluoxetine)
a. Precursor amino acids (PAA)of  the neurotransmitters serotonin and dopamine showed clinical and psychologic improvement with conflict results(585)


b. Side effects are not limit to
b.1. Diarrhea
b.2. Drowsiness
b.3. Nausea,
b.4. Vomiting and agitation(585)

4. Anti anticonvulsant
Anti anticonvulsant, clonazepam has shown to control logorrhea, hyperactivity, agitation, intrusiveness, and impulsive violence and to promote cooperation in patient with multi-infarct dementia, according to  East Carolina University School of Medicine(586).

b. Side effects are not limit to
b.1. Dizziness
b.2. Drowsiness
b.3. Unsteadiness
b.4. Nausea
b.5. Vomiting
b.6. Skin rashes
b.7. Etc.

5. Rivastigmine, is a cholinergic agent used for the treatment of mild to moderate dementia(587)
a. On  cognitive function, rivastigmine, at dosages approved for therapeutic use showed to improve all behavioral symptoms in 2 forms of VaD, MID and sVaD(590), except delusions, according to University of Trieste(588).

                                                         50

 

The medicine, unfortunately, has been reported to induce side effects that lead to withdrawal in a significant proportion of patients(589).

b. Side effects are not limit to
b.1. Nausea and vomiting
b.2. Loss of appetite
b.3. Weight loss
b.4. Diarrhea
b.4. Dizziness
b.5. Drowsiness
b.6. Trembling
b.7. Etc.

E.2. Surgery
In case of sensory problems, surgery can be helpful.

F. Subdural hematoma is the accumulation of blood beneath the outer coveri of the brain resulted from the rupture of blood vessel(545)(546). Subdural hemorrhages may cause an increase intracranial pressure(545), induecd compression and damage to delicate brain tissue(547). Acute subdural hematoma has a high mortality rate(546). The diseases are most prevalent among elderly individuals(544).

 Treatments of Subdural hematoma
1. Emergency treatment
An acute subdural hematoma (SDH) is a rapidly clotting blood collection(548) below the inner layer of the dura but external to the brain and arachnoid membrane(549). Two further stages, subacute and chronic, may develop with untreated acute subdural hematoma (SDH)(549). There is always important to maintain survival of the patient with acute subdural hematomas(550)(551) because of its unfavourable outcome in the majority of cases(551). Emergency treatment is necessary to reduce pressure and allow blood to drain by drilling a small hole in the skull and  inserting a temporary small catheter through a hole drilled through the skull and sucking out the hematoma(552)(564).  Although hematoma resolution has been reported, it cannot be reliably predicted, and no medical therapy has

                                                             51

 

been shown to be effective in expediting the resolution of acute or chronic subdural hematomas(552)(553).

2. Medication
In case of chronic subdural hematomas, Mannitol may be used to reduce intracranial pressure (ICP)(554)(555) as it produced a significant reduction in ICP and improved cerebral perfusion pressure(556).
a. Corticosteroids for brain oedema
Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug(557). Researchers found that Methylprednisolone can effectively reduce myelin changes(559) accompanying brain oedema(558) induced by blood-brain barrier opening with an osmotic insult(559).

b. Anticonvulsants for patient with seizures
In some cases, patients with chronic subdural haematoma may be treated with anticonvulsants for seizures prevention(560). The medicine has shown to reduce risk of seizures(562) to none and 1.8%  in 73 patients given prophylactic antiepileptic drug treatment in Tokyo Medical and
Dental University study(561) and Beilinson Medical Center(562) studies, respectively.

c.  Rifampicin for bacterial infection
Rifampicin is a naturally made, non-peptide antibiotic(563). It is bactericidal, killing agent  by disabling the protein expression system universally conserved by all bacterial infection(567), but it can induce thrombocytopenia(565)(566) in acute subdural hematoma treatment.

3. Surgery
Large or symptomatic hematomas require a craniotomy, as a bone flap is temporarily removed from the skull to access the brain for removal of blood clot with suction or irrigation(568). According
University of Cambridge, Cambridge, the use of a drain after burr-hole drainage of chronic subdural haematoma and minimized the incidence of significant recollection(570) is safe and associated with reduced recurrence and mortality at 6 months(569).

 
 

                                                52


  Treatments In Herbal Medicine

A. Ginkgo Biloba(bai Guo)
Ginkgo biloba is the oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America(592). The herb been used in traditional herbal medicine in treating impotence, memory loss, respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting(591).
a. The memory enhancing effects
Capsules containing 60 mg of a standardised extract of Ginkgo biloba (GK501) and 100 mg of a standardised extract of Panax ginseng (G115) significantly improved an Index of Memory Quality(593), including learning and memory  but not working and long-term memory(596). Its extract, in the logical memory test and nonsense picture recognition also exhibited improvement of 58.62% logical memory in compared to baseline(594). Commercial extract Ginkgo biloba EGb 761 is also found to enhance certain neuropsychological/memory processes of cognitively in older adults, 60 years of age and over(595).

b. Cognitive performance 
Administration of single doses (120, 240, 360 mg) of standardised Ginkgo biloba extract (GBE), according to Northumbria University, showed to improve cognitive performance, including speed of attention, accuracy of attention, secondary memory, working memory, speed of memory, quality of memory(597). Combination of standardised extracts of Ginkgo biloba (GK501, Pharmaton SA) and Ginseng (G115, Pharmaton SA) administration showed a  consistent effect on mood and aspects of cognitive performance ("quality of memory", "secondary memory", "working memory", "speed of memory", "quality of attention" and "speed of attention") in doses depend-manner(598). On acute cognitive effects, Ginkgo biloba extract (GBE) with soy-derived phospholipids, improved secondary memory performance and significantly increased speed of memory task performance in comparision to post-dose testing sessions(599).

c. Cognitive impairment
Extracts of the leaves of Ginkgo biloba showed to improve a range of
                                                         53

conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache, recognition, regeneration, understanding, and recitation(603), probably thought its action in increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and the density of oxygen free radicals(600). 
EGb761, a commercial product of Ginkgo biloba at 240 mg/day, stabilized or slow declined in cognition, function, behavior, at 22-26 weeks (602).
According to University of Oxford, the use of Ginkgo biloba treatment of cognitive impairment appeared to be safe with no excess side effects, but with inconsistent results(601).

d. Etc.

B. Lemon Palm

Lemon Balm is a perennial plant in the genus Melissa, belonging to the family Lamiaceae, native to southern Europe and the Mediterranean region. The herb has been used in traditional medicine to treat nervous complaints(604), lower abdominal disorders(605) and as anti-inflammatory(608), antivirus(606), antibacterial agent(607).
a. Behavioral and psychological symptoms
According to
Newcastle University, lemon balm showed to alleviate behavioral and psychological symptoms in patient with dementia (BPSD)(609), including anxiety(614). Lozenge, containing lavender oil, extracts from hops, lemon balm and oat showed to induce a state of relaxation and regeneration for  better cope with psychological and emotional stress(610)(611) and attenuation of mood and anxiety(612). In behavior symttoms, administraion of combined valerian root and lemon balm extracts, improved symptoms of poor ability to focus decreased from 75% to 14%, hyperactivity from 61% to 13%, and impulsiveness from 59% to 22%  as well as general social behavior, sleep symptoms in children(613). On laboratory-induced psychological stress, the standardized M. officinalis extract, a significant increase in the speed of mathematical processing, with no reduction in accuracy(617).


                                                            54

b. Cognitive performance and mood 
A standardised M. officinalis preparation administered showed significantly in eradicated mood change and cognitive impairment(614), according to joint study lead by
Swinburne University. Acute administration of Melissa officinalis (lemon balm) in high dose, enhanced cognition and mood  in both Secondary Memory and Working Memory factors(615)(616), probably through its function in modulation of mood and cognitive performance through lowering both nicotinic and muscarinic binding in healthy humans(616). Due to different preparations derived from the same plant species, some researchers suggested that the effectiveness may exhibit different properties depending on the process used for the sample preparation(616).

c. Etc. 

C. Lavender

Lavender is a flower plant of the genus Lavandula, belonging to the family Lamiaceae, native to Asia. The herb has been used in traditional medicine as antimicrobial, anti-inflammatory and mood alleviating(618), and burns and insect bites effects(623) agents, as well as treatment for depression, stress and mild anxiety(621)  probably through its phytochemicals(constituents (-)-linalool, (+)-α-pinene and (+)-limonene ) in modulation of the immune and neuroendocrine system by interfering with metabolism of tryptophan(618).

a. Spatial performance
Lavender extract (LE, in AD animal model, showed effectively in improvement of spatial performance, through attenuation of Aβ production in histopathology of hippocampus(619) involved in memory forming, organizing, and storing. Its aqueous extract also significantly improved the performance of control and reverse spatial learning and memory deficits(621) in AD rats(620). Inhaled lavender oil, in oxidative stress induced rat, exhibited neuroprotective effects through its potent antioxidant and antiapoptotic activities(622).




                                                          55
b. Behavioural symptoms
Lavender aromatherapy, according to Kongju National University, was effective on emotions and aggressive behavior of elderly with dementia of the Alzheimer's type(624)and reduced disruptive behaviour in people with dementia(625). In agitated behaviour in severe dementia, 2% lavender oil aromatherapy stream administered on the ward for a two hour period, showed a modest effects in compared with placebo(626). The effectiveness of the herb in reduced behaviours in individuals with dementia potentially provide a safer intervention rather than reliance on pharmacology alone. The study's findings will translate easily to other countries and cultures(627).

c. Cognitive performance and Mood disorders
Aromatherapy applied to 28 elderly people with dementia, 17 of whom had Alzheimer's disease (AD), showed significant improvement in personal orientation related to cognitive function on both the Gottfries, Brane, Steen scale (GBSS-J)and Touch Panel-type Dementia Assessment Scale (TDAS), according to Tottori University(628) and emotions and aggressive behavior of elderly with dementia, according to Kongju National University(629). In emotional parameters,  lavender essential oil also significantly enhanced mood responses, including anxiety(631)(633) and
depression(632)(634) probably through its relaxing effect(630).

d. Etc.

D. Huperzine A, a chemical made from the plant Huperzia serrata has been studied for its effect on patient of dementia with conflict results.
a. Cognitive effects
In induced Alzheimer's disease animal study, Huperzine A showed a significant effect in  inhibited acetylcholinesterase, derived from forebrain, hippocampus, cortex and cerebellum(635), through neuron protective effects and enhanced glutamatergic functions(635). In mild to moderate vascular dementia (VaD) patients, the medicine also improved the cognitive function with serious adverse events(636). According to Beijing University of Chinese Medicinealthough Huperzine A showed a beneficial effects on improvement of cognitive function, daily living activity in global clinical assessment in participants with Alzheimer's disease, the findings should be interpreted with caution due to the poor methodological quality of the

                                                             56

 

included trials(638). But according to University of California,, in a phase II trial of huperzine A, regardless to doses, huperzine A did not demonstrate cognitive effect in patients with mild to moderate AD(637).

b. Inhibition of amyloid plaque burden and oligomeric β-amyloid (Aβ)
Huperzine A, showed to reduce in Aβ levels and Aβ burden in AD brain, through activation of  Wnt signaling(regulate cell-to-cell interactions) and targeting of the Wnt/β-catenin signaling pathway in various components in contribution to disease(639) through modulation of amyloidogenic and nonamyloidogenic pathways(640), and reduction of iron in the brain(641) via a multi-target mechanism(642).

c. Mild to moderate vascular dementia (VaD) and Alzheimer's disease
In patients with mild to moderate vascular dementia (VaD), Huperzine A significantly improved the cognitive function in mini-mental state examination (MMSE), clinical dementia rating (CDR), and activities of daily living (ADL) scores(643)(644).
In patients with Alzheimer's disease (AD), Huperzine A also showed improvement in memory function and cognitive enhancement at a dose of 0.4 mg using MMSE, MQ, ADAS-COG, and ADL tests(645); against organophosphate (OP) intoxication and  reduction of glutamate-induced cell death(646). According to
Georgetown University Hospital, the antioxidant and neuroprotective properties of Huperzine A may be useful as a disease-modifying treatment for Alzheimer's disease (AD)(647).
Due to data supporting its use are limited by weak study design, the Massachusetts College of Pharmacy and Health Sciences-Worcester/Manchester suggested that randomized, placebo-controlled trials are necessary to establish the role of huperzine A in the treatment of AD(648).

d. Etc.

E. Bacopa
Commonly known as Waterhyssop or Water Hyssop, the herb is a semi-woody plants, genus of Hyssopus, belonging to the family Lamiaceae, native
                                                     57

to the east Mediterranean to central Asia, used in traditional medicine as an antibiotic(660)(659), carminative, antispasmodic, antifungal(661), and antiseptic(661)(662) agents and to treat bronchitis(663), asthma(664), digestive ailments(665)(668), insomnia(666), diabetes(667), edema(669)(670), etc.
a. Increases Cerebral Blood Flow 
In cerebral blood flow (CBF), Bacopa monnieri's promoted blood flow through its procognitive effect in comparison via dose-dependent hypotensive actions (671). |Together with Ginkgo biloba and donepezil(671)may be a potential attenuation of dementia, Parkinson's disease, and epilepsy(672).

b. Ethnobotanical treatment
Bacopa, ethnobotanically, may be used as brain tonification(676) and to treat various diseases(673), including Alzheimer's disease
through its phytochemicals in alleviation of AD pathology and associated symptoms(674). According to university System HSC College of Medicine, Bacopa monniera extract (BME), administered starting at 2 months of age for either 2 or 8 months on test mice, significant lowered Abeta 1-40 and 1-42 levels in cortex by as much as 60%, and reverses Y-maze performance and open field hyperlocomotion behavioral changes(675). Its natural products (galantamine and rivastigmine), also has been used pharmaceutically for cognitive and behavioural and psychological symptoms of dementia (BPSD)(673).

c. Cognitive performance, anxiety, and depression 
In olfactory bulbectomized mice, alcoholic extract of Bacopa monnieri (L.) showed to ameliorate memory and emotional deficits(678) and enhanced cognitive performance(679) through its protection of cholinergic systems from OBX-induced neuronal damage(677). In normal healthy participants, the herb also attenuated stress reactivity and mood, through its adaptogenic and nootropic effects, probably via reduction in cortisol levels(680). According to National College of Natural Medicine, standardized dry extract of Bacopa monnieri, promoted the improvement depression scores, combined state plus trait anxiety scores,with few adverse events, primarily stomach(681)

    

                                                           58

 

6. Other potential herbs
Herbs used in the treatment and prevention of dementia(682)(683) in traditional medicine, may be due to their effectiveness of phytochemicals in attenuation of oxidative stress and neuro inflammation via neuroglial activation(683).
According to University of Wollongong, herbs and spices, containing high amount of phytochemicals in traditional history of use, with strong roles in cultural heritage, may have a distinguished effect in cognitive decline associated with ageing and the acute effects of psychological and cognitive function(684), probably through active ingredients of spices in modulation of neural response in the peripheral nervous system, via interaction with TRP channel/receptors(685).

Phytochemicals have been studied intensively including
1. Cannabinoids (e.g. cannabidiol) from Cannabis sativa, may be emerging as potential therapeutic agents for treatment of symptoms of dementia(686)(687). In Alzheimer's disease. the phytochemicals have found effectively against multifactorial illnesses as Alzheimer's disease, through inhibition of  BuChE(689) and AChE(690) enzymes by a non-competitive or mixed mechanism(688).

2. Resveratrol (occurs in various plants) showed to improve cognition and reduces oxidative stress, by promoting learning and memory ability in vascular dementia(692) and decrease malonyldialdehyde levels(691). In Alzheimer's Disease, the phytochemical exerted its neuroprotective effect(694)(695), in decreased Aβ accumulation, tau protein phosphorylation, oxidative stress(693), and may be used for aging population in the prevention of various age-related neurological disorders(694).

3. Curcumin (from turmeric [Curcuma longa]), in pharmacological activities, besides promoted cognition and mood in a healthy older population(695), it also exhibited beneficial role in several neurodegenerative disorders(696) against administered streptozotocin (STZ)induced dementia model(696)(698), probably through its antioxidant effect(697). In Alzheimer's Disease, the herb also showed in reversed cognitive deficits, through its function in decreased GSK-3β levels(Glycogen synthase kinase 3,

                                                          59

 

a protein) related to onset of Alzheimer's Disease(699)), and increased promoter activity of the TCF/LEF in binding DNA(600) and cyclin-D1(a protein) in regulating cell cycle progression(701).

4. Crocetin, a phytochemical found in Saffron (Crocus sativus), protected cerebrocortical and hippocampus neurons against ischemia, by improving spatial learning memory after chronic cerebral hypoperfusion in animal study(703) through its antioxidant effects(704) in decreased oxidative stress(704). According to The University of Tokyo, the effectiveness of the herbal phytochemicals  crocetin and crocin, also enhanced learning behaviour and promoted memory recall(705). In severe Alzheimer's Disease and mild-to-moderate Alzheimer's disease patients, saffron extract showed to be comparable with memantine in reducing cognitive decline in 1 year(706) and  reduce cognitive decline in 22 weeks administration(707), respectively.

5. Ginseng (Panax species), showed to be beneficiary on age-related cognitive impairments through the activities of  its members of ginsenosides(708) and Non-ginsenoside nicotinic agents(709).

6. Sage (Salvia species), may also be used as a potential novel natural treatments for the relief of some diseases including dementia, according to Shahid Beheshti University of Medical Sciences(710).

 But according to Jodrell Laboratory, the use of such remedies in complex mixtures of different plants in traditional folk medicine may induce complication in interpretation of pharmacological activity and challenges for quality control(702).


 

Treatments in Traditional Chinese Herbal Medicine

A. In General herbal Chinese medicine

                                                           60

 

According to the Unilever R&D Shanghai, and Unilever R&D Vlaardingen, Dr. and the team of researchers, traditional Chinese medicine (TCM), in 3000 years' literary history, the top 5 TCM herb ingredients including Poria cocos(720), Radix polygalae, Radix glycyrrhizae, Radix angelica sinensis, and Radix rehmanniae have been used extensively for treatment of dementia(*).

A.1. Poria cocos(Fu Ling)
Fu Ling, fu shen or fu ling pi also known as Poria, the bland, sweet and neutral herb has been used in TCM as diuretics(711) and to treat urinary difficulty(711), edema(711), diarrhea(715), emesis(717), vomiting(716), dizziness(716), heart diseases(717)(718), etc., as it eliminates water, strengthens the Spleen, calms the Mind, etc., by enhancing the functions of heart, spleen, lung and kidney channels. The herb has shown to exhibit various biological activities including anti-tumor(713), anti-inflammation(712), immunodepression(712) and antioxidant(711)(713)(714).

Phytochemicals
1. Pachymose
2. Albuninoid
3. Pachymaran
4. B-pachyman
5. B-pachymanase,
6. Pachymic acid,
7. Tumulosic acid,
8. Eburioic acid,
9. Pinicolic acid,
10. Etc.

Fu Ling(720) used for treatment and prevention of dementia(719) in traditional Chinese medicine, may be due to their effectiveness of phytochemicals in attenuation of oxidative stress in initiation of neurodegeneration and enhanced neuroprotection(719).

1. Learning and memory impairments
Kyung-Ok-Ko (KOK), the traditional Chine medicine formula, containing
                                                          61


Poria cocos, showed effectively in exhibition of its anti-inflammatory effects in protection of brain neuron through attenuating memory(721)(722) and learning impairment(723). In senile dementia, herbal Poria cocos also elicited memory-improving effects in vivo and in vitro through its sinapic acid, tenuifolin, isoliquiritigenin, liquiritigenin, glabridin, ferulic acid antioxidants via cholinergic, antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aβ activities(722).Yokukansan (TJ-54), another Chinese medicine formula, containing Poria cocos, also inhibited neurological disorders, including dementia and Alzheimer's disease(723) symptoms of memory and behaviors disturbance(724), probably through its anti-cholinesterase activity(725).

2.  Cognitive dysfunction
In patients of dementia with  cognitive dysfunction, Liuwei Dihuang decoction, containing Poria cocos, showed significantly in attenuated the neural apoptosis, inflammation and Aβ deposition in the hippocampus and cerebral corte(726) causes of cognitive impairment(727) in streptozotocin-induced diabetic rat. In spatial cognition, herbal formula Toki-Shakuyaku-San and fractions of Angelica acutiloba, improved memory and working memory impaired by scopolamine in animal study(728).

3. Alzheimer disease
In mouse model of Alzheimer disease, herbal formula Jangwonhwan, not only showed effectively in ameliorated AD-like pathology, but also exhibited its neuroprotective effects against Abeta-induced cell death, and Abeta accumulation and plaque deposition in the brain(730), probably through attenuation of reactive oxidative stress(729), by suppressed Aβ-induced apoptosis and ROS production(731).

A.2. Radix polygalae(Yuan Zhi)
Yuan Zhi, sweet and slightly cool herb is also known as Thinleaf Milkwort Root, used in TCM as antibiotic property, anti-viral property(732), anti cancer(734) and anti depression(733) agents in treating hepatitis B, tumors in the digestive, respiratory systems and in the uterus, etc., as it calms the heart, transforms phlegm,  resolves furuncle and oedema, expel toxin, etc. by enhancing the functions of spleen, lung and liver channels.
  
                                                        62


Phytochemicals
1. Protein-bound polysaccharide (PSK)
2. Polysaccharopeptides (PSP)
3. Tenuifolin
4. Onjisaponin B
5. Etc.

  Yuan Zhi used in the treatment and prevention of dementia(719) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals in ameliorated amyloid pathology and related cognitive deficits(735). In aging related dementia, based on the history of use, and pharmacological investigation, Yuan Zhi showed a strong evidence in memory improving, including cholinergic, antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aβ activities(736). Palmul-chongmyeong-tang, a traditional Chinese medicine formula containing Yuan zhi, exhibited improvement of learning and memory deficits, through reduction of loss of cholinergic immunoreactivity induced by cerebral ischemia(737).

 1. In Alzheimer's disease (AD)
In free radical involved neuro-degeneration in Alzheimer's disease (AD), pretreament with Paeng-Jo-Yeon-Nyeon-Baek-Ja-In-Hwan (PJBH) prescription significantly exhibited cytoprotective effects, through elevating cell survival, antioxidant enzyme activities and resulted ecreased production  of malondialdehyde (MDA) associated to Alzheimer's disease (AD)(738). Smart Soup (SS), composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), in oral administration of SS ameliorated the cognitive impairment of AD in animal model, effectively reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss(739).

2. In Parkinson's disease
Mutant Huntingtin gene caused by a poly-glutamine expansion in huntingtin( 740)and A53T α-synuclein, a protein found abundantly in the human brain, at the tips of nerve cells (neurons)(741) have shown to be associated with the development of Huntington disease and Parkinson disease. Yuan Zhi phytochemical, onjisaponin B  and ethanol extracts
                                                           63


showed to induce autophagy(743) through signalling pathway in participation of regulation of vascular function(742) in protection  of cells against pro-neuro apoptosis  via the mitochondrial pathway(744). According to college of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, in mouse models of Parkinson's disease, Yuan Zhi  also exhibited it protective effects on dopaminergic neurons induced by toxicity(745).

3. In Huntington diseases
 Mutant Hungtintin caused of  degradation of long-lived cytoplasmic proteins, protein complexes (the gel-like substance enclosed within the cell membrane)(747), or damaged organelles(tiny structures that perform very specific functions within cells)(748) attenuated autophagy in association of  the development of Huntington diseases(746), Onjisaponin B, found in Yuan Zhi,  effectively induced autophagy through its acceleration of both the removal of mutant huntingtin and and α-synuclein in PC-12 cells(749), which contain mixture of neuroblastic cells and eosinophilic cells(750).

 A.3. Radix glycyrrhizae(Gan Cao)
Gan Cao, a sweet and neutral herb, also known as Licorice root, has been used in TCM as anti allergy(752), anti inflammation(751), anti ulcer(753), anti convulsion(754) agents and to treat stomach weakness(755), tired and lack of strength(756), enhance cardiac performance(757) and short of breath(758), cough with abundance of phlegm(751), etc., as it tonifies the Spleen, benefits the Qi, moistens the Lungs, calms cough, deaf or acute pain, by enhancing the function of all 12 channels.

Phytochemicals
1. Glycyrrhizic acid
2. 24-hydroxyglycyrrhetic acid
3. Licorice saponins A3
4. Licochalcone A
5. Licochalcone B
6. Licoflavone
7. Liquiritin
8. Liquiritigenin
9. Isoliquiritigenin
10. Ononins

                                                             64

 

11. 4′,7-dihydroxyflavone
12. Etc.

  Gan Cao used in the treatment and prevention of dementia(719) in traditional Chinese medicine, may be due to their effectiveness of phytochemicals in ameliorated amyloid pathology and related cognitive deficits(759). In senile dementia, Gan Cao exhibited its elicit memory-improving effects, through its antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aβ activities(760).

1. In Alzheimer's disease (AD)
Vascular risk factors (VRF) has shown strong evidence in contribution to cognitive decline and the development of Alzheimer's disease (AD)(763) and dementia(761). Sini Decoction, a TCM formula containing Gan Cao enhanced cardiac function through significant suppression of  lipid peroxidation(765) of myocardial homogenate(764), via scavenge oxygen free radicals activity(764). According to Korea Food Research Institute, Gan Cao attenuated the Amyloid beta protein (Abeta)  involved in the progression of Alzheimer's disease (AD), through inhibition of Acetylcholinesterase activity(762), probably via mediation antioxidant actions against oxidative stress(762).


2. In Parkinson's diseases(PD)
Kampo kami-shoyo-san (TJ-24), a Korean traditional herbal medicine, containing Gan Cao,  significantly reduce  tremor, disturbances in muscular movement in antipsychotic-induced parkinsonism(766). The formula also showed effectively in relieved symptoms of panic attacks, anticipatory anxiety(767). Liquiritin, a flavonoid extracted from Glycyrrhizae radix, significantly promoted the neurite outgrowth in dose dependant manners, through overexpression of neural related genes, such as neurogenin 3, neurofibromatosis 1, associated to Alzheimer's disease or Parkinson's disease(768).

3. In learning and memory
Oral administration of Glycyrrhizae radix (GR) in rat study, showed to

                                                          65

 

reduce anxiety and promote learning and memory in rats, by attenuating the behavioral and neurochemical impairments caused by repeated stress-induced alterations(770). Palmul-chongmyeong-tang, containing Gan Cao used in used as herbal medicine against ischemia, may be a potential agent for treatment of vascular dementia as it significantly improved learning and memory and attenuated cognitive impairment through reduction of the loss of cholinergic immunoreactivity in the hippocampus induced by cerebral ischemia in rat model(769).

A.4. Radix angelica sinensis(Dang Qui)
Dang Qui (Angelica sinensis), a sweet, acrid, bitter, warm herb is a Genus Angelica from the family Apiaceae, indigenous to China, used as a Queen herb in traditional Chinese medicine as antispasmodic(771), analgesic(772) and vasodilatory(772) agents, and to balance the hormones(773) in women for a normal menstrual cycle and menstruation with condition of blood stasis(774)(775) and clots(775) by strengthening heart, spleen, and liver channels. The herb is also used to treat constipation(775), reduced  swelling(776), expels pus(775), etc.

Phytochemicals
1. Beta-sitosterol
2. Coumarins
3. Butylidine
4. Phthalide
5. Ligustilide
6. Sesquiterpenes
7. Carvacrol
8. B-pinene
9. Camphene,
10. P-cymene,
11. B-phellandrene
12. Myrcene
13. 6-n-butyl-cycloheptadiene-1,4, 2-methyl-dodecane-5-one,
14. Acetophenone,
15. B-bisabolene,

                                                           66

16. Isoacroraene,
17. Acoradiene
18. Etc.

Dang qui used in the treatment and prevention of dementia(777) in traditional Chinese medicine, may be due to their effectiveness of phytochemicals in ameliorated amyloid pathology and related cognitive deficits(778). In aging related dementia, based on the history of use, and pharmacological investigation, dang Qui showed a strong evidence in memory improving, through iestrogen-like, cholinergic, antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aβ activities(736). Palmul-chongmyeong-tang, a traditional Chinese medicine formula containing dang qui, exhibited improvement of learning and memory deficits, through reduction of loss of cholinergic immunoreactivity induced by cerebral ischemia(780).

Phthalide, a phytochemical found abundantly in dang qui, also an important bio-active constituent in Si-Wu-Tang and Fo-Shou-San, showed effectively in protect neurons against ROS-induced apoptosis by modulating apoptosis-related genes(781). Z-Ligustilide (LIG), a characterized phthalide, in rat study, exhibited anti vascular dementia and cerebrovascular insufficient activities through its antioxidant effect and improved cholinergic activity(782).

1. In cognitive impairments
In patients with cognitive impairment associated with chronic cerebral hypoperfusion, dang qui prevented neurotoxic effects of β-amyloid (Aβ), through its anti oxidative stress, inflammation and apoptosis functions(783). Its phytochemical Ligustilide (LIG), a main lipophilic component of Danggui also exhibited neuroprotective effect through anti-apoptosis of neuron and anti-proliferation of astrocyte both in cortex and in hippocampus in rat study(784).

2. Oxidative stress
Oxidative stress has been known to induced neurotoxicity and the underlying mechanisms causes of
Alzheimer's disease (AD). Decursin (D) and decursinol angelate (DA) found in dang qui, significantly suppressed Aβ aggregation and increased cellular

                                                         67

resistance to Aβ-induced oxidative injury in the rat study(785). Coumarins, another chemical found in from Angelica, also effectively induced neuroprotective activity against glutamate-induced oxidative stress causes of cognitive deficits and brain damage(786), According to Seoul National University, 4 other new dihydropyranocoumarins were isolated from Angelica gigas roots through neuroprotective activity-guided isolation and were characterized as decursinol derivatives 4"-hydroxytigloyldecursinol, 4"-hydroxydecursin, (2"S,3"S)-epoxyangeloyldecursinol, and (2"R,3"R)-epoxyangeloyldecursinol, also exhibited significant protective activity against glutamate-induced neurotoxicity(787). In transgenic mice model, traditional Chinese herbal formula Jangwonhwan (LMK03-Jangwonhwan), containing dang qui, improved cognitive impairment through detection and inhibition of AD-like pathology, such as cytotoxicity and Abeta(1-42)and Abeta(1-40) levels and beta-amyloid plaque deposition(788)

3. Behavioral and psychological symptoms
In behavioral and psychological symptoms of dementia patients, combination of ferulic acid and Angelica archangelica extract oral administration, significantly attenuated neuropsychiatric symptoms in 19 of 20 patients, including delusions, hallucinations, agitation/aggression, anxiety, apathy/indifference, irritability/lability and aberrant behavior, according to
National Hospital Organization Kikuchi Hospital(789). Yokukansan, also known as TJ-54, composed of seven herbs, including dang qui, showed to inhibit a variety of effects on various neurological symptoms, such as memory disturbance and behavioral and psychological symptoms of dementia(791) without adverse effects(790), probably through its neuroprotective effect against glutamate-induced excitotoxicity(792). In ischemic brain tissue, Z-Ligustilide (LIG), a phytochemical found in dang qui, oral administration of 10 or 40 mg/kg/day, significantly reduced malondialdehyde levels and increased superoxide dismutase activity, probably through its antioxidant effect in improved cholinergic activity(793), anti-apoptosis of neuron and anti-proliferation of astrocyte both in cortex,  hippocampus(794) and ameliorated cognitive dysfunction(795) in 2VO rats study.
 

 

                                                             68

 

A.5. Radix rehmanniae(Di Huang)
Radix rehmanniae, a sweet and bitter herb, is also known as Di huang(sheng di huang is Cold in nature and shu di huang is Warm in nature), used in tradition Chinese medicine over thousand of years for treatment of the weakness caused by tuberculosis, vomiting blood, nose bleeding,  coughing blood, bleeding in the uterus  as its function of blood tonification, by enhancing function of heart, kidney, and liver channels(796).

Phytochemicals(797)
1. Sterol
2. Catalpol
3.  Rehmanniosides A-D
4. Leonuride
5. Aucubin
6. Melittoside
7. Jioglutoside A-B, 6-O-E-feruloyl ajugol
8.  Rehmaglutins A-D
9. Glutinoside, purpureaside C
10. Etc.

 Di huang used in the treatment and prevention of dementia(798) in traditional Chinese medicine, may be due to their effectiveness of phytochemicals in ameliorated amyloid pathology and related cognitive deficits(799). In senile dementia, Di huang  exhibited its elicit memory-improving effects, through its antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aβ activities(760).

1. Neuroprotective effects
Paeng-Jo-Yeon-Nyeon-Baek-Ja-In-Hwan (PJBH), congaing Di huang and 17 other herbs, exhibited anti lipid peroxidation and antioxidant enzyme activities in decreased production of malondialdehyde (MDA) involved in neurodegeneration in Alzheimer's disease (AD)(801), through cholinesterase inhibited effects(802). Other prescriptive formula, palmul-chongmyeong-tang, in ischemia-induced rats, exhibited a protective effect against ischemia-induced neuronal and cognitive impairments of learning and

                                                           69

 

memory(803).
 

2. Psychological symptoms
Polysaccharides extracted from shudihuang (radix rehmanniae preparata) in infant male rats study, significantly inhibited MSG-induced anxiety, through its phytochemicals in down regulation of  beta-synuclein, protein DJ-1, linking to neurodegeneration in patient with dementia. etc.(804).

3. Improved earning and memory
In rats damaged thalamic arcuate nucleus, shu di-huang showed to up regulate the expression of hippocampal NGF, c-fos in improving the function of learning and memory(805). In dementia model, the herb decreased the times of mistakes and prolong the incubation period in step down task, through increased expression of hippocampal receptors, involved brain memory forming, organizing, and storing(806). Other formula, such as Ba-Wei-Di-Huang decoction, also enhanced capacity for learning and memory, through expression  of autocrine motility factor receptor (AMFR), a multifunctional protein involved in cellular adhesion, proliferation, motility and apoptosis on animal model of Alzheimer's disease (AD)(807)(808)(809).


 B. In traditional Chinese Medicine Perspective(*)
Based on Chinese ancient medical records, causes of dementia are the results of (*)
B.1. Deficiency of Qi, mainly due to
B.1.1. Kidney Qi deficiency
Kidney Qi  deficiency is a condition of the inability of kidney in expelling extra fluid in the body through urinary secretion via bladder. If the fluid accumulation(a) or hydration(b) occurs in the brain(a) for a prolong period of time, can induce abnormal function of neurons in information transmitting or gradual death of brain's neurons(c), leading cognitive impairment, including dementia. In elders, kidney Qi deficiency may also be related to gradual depletion of kidney essences(Jing) due to aging, according to

                                                                70

traditional Chinese medicine.

Chinese herbs used to treat kidney Qi  deficiency include
1. Lu rong(810)
Lu rong is also known as deer antler, deer antler velvet,  used in traditional Chinese medicine to reduce the blockage of the meridian liver and kidney for treatment of rheumatoid arthritis(811), osteoarthritis(812), sexual function(813)(814), and sporting performance enhancement(810)(815) by enhancing the yang energy(815). Since qi deficiency is also related to  blood deficiency(816), improving the body yang by strengthening the liver's function in blood formation(816) and kidney's function in fluid distribution(817), reduce the yang deficiency in the body. In neuroprotective effect, deer antler extract  prevented glutamate-induced oxidative stress of reactive oxygen species and lipid peroxidation causes of neurodegenerative disorders(832).

2. Du Zhong
Du Zhong, also known ecommia bark, is one the most used herb to enhance the function of meridian kidney-liver by promoting the qi and blood formation. The liver is a organ in charge of blood storing and blood formation(818) and kidney is in charge of fluid regulation(817).

Administration of the du zhong promotes kidney yang  through action of harmony by increasing blood flow(819) and reducing fluid accumulated(820) in the body (821).  In learning and memory deficits mice caused by oxidative stress, du zhong significantly improved the impairment of short-term or working memory and reversed learning and memory deficits(833), through inhibited acetylcholinesterase (AChE) activity in a dose-dependent manner (834) and oxidative stress causes of neuronal cell death(835)

3. Ba Ji Tian
Ba ji tian, is also known as Chinese morinda root with sweet and warm in nature, used in TCM to strengthen the liver(823), kidney qi(822) and blood yang(824) for enhancing the liver in blood formation and kidney in urinary secretion, According to Academy of Military Medical Sciences, ba ji tian showed a strong anti antidepressant activities through its phytochemicals

                                                                 71

 

succinic acid, nystose, 1F-fructofuranosylnystose, inulin-type hexasaccharide and heptasaccharide(836)(837).

4. Rou Chong Rong
Rou Chong Rong is also known as Herba Cistanche used in traditional Chinese medicine for reducing the blockage of kidney-large intestine meridian(825), by increasing the kidney function in fluid regulation through improved blood circulation(826), assisted urinary secretion and digestive system in moving waste. In  mouse model with learning and memory deficit, rou chong rong extract increased neuronal cell differentiation, neurite length, and synapse formation in  hippocampus, through nerve growth factor (NGF) biological activities, such as preventing neuronal death(838), memory loss, and increaseing long-term potentiation and learning task(839).

5. Bu Gu Zhi
Bu gu zhi is also known as psoralea fruit used in traditional Chinese medicine in treating blockage of meridian kidney-Spleen(827) by tonifying the yang(828), increasing the kidney function(829) and assisting the functions of lung qi(830) and spleen in qi distribution(831). In stem neoronal study, phytochemicals psoralen, oleanolic acid, and stilbene glucoside found in psoralea fruit exerted its anti cognitive protective effect through promoting self-renewal of neural stem cells NSCs and neuron-like differentiation(840). In rat with Huntington's disease (HD) using 3-NP induced  mitochondrial dysfunction in cultured (PC12) cells, psoralea corylifolia Linn seed extracts, showed a significant protective effect against 3-nitropropionic acid (3-NP) induced cytotoxicity(841).


B.2. Heart (Yang) Qi deficiency
Heart  Qi deficiency is a condition of the inability of the heart in transportation of nutrients to body organs, including the brain through blood circulation. Prolong period of malnutrition of brain cells may induce abnormal function of brain's cells in information transmitting  or death of neurons, causing cognitive impairment(844), including learning and memory

                                                          72


deficits(842), changes in brain tissue and behavior patterns(843)(842).
Herbal medicine for Heart Qi deficiency
1. Dan shen
Dan Shen is also known as Red Sage Root with taste of the bitter and slightly cold in nature, used in TCM as antithrombotic(845), antihypertonic (lowering blood pressure)(846), antimicrobial(847), anti-inflammatory(848)(849), agents and to treat coronary and cerebrovascular disease, dysmenorrhea, amenorrhea, hepatitis, hepatocirrhosis, restlessness, insomnia, irritability,(850) etc., by enhancing the functions of heart and liver channels.

Phytochemicals
1. Cryptotanshinone
2. Hydroxytanshinone,
3. Methyltanshinonate
4. Methylene tanshiquinone
5. Przewatanshinquinone A
6. Przewatanshinquinone B
7. Miltirone
8. Dihydrotanshinone I
9. Tanshinol A
10. Tanshinol B
11. Tanshinol C,
12. Nortanshinone
13. 1, 2, 15, 16-tetrahydrotanshiquinone
14. Danshensuan A, B, C
15. Protocatechuic acid,
16. Protocatechuic aldehyde
17. Etc.


1.1. Dementia 
According to Mashhad University of Medical Sciences, dan shen in the pharmacological effects on the central nervous system, showed to exert its neuroprotective activity through antiparkinsonian, relaxant, analgesic and  memory enhancing(850). In PC12 cells, combination application of salvianolic acid B (Sal B) and Ginkgo biloba extract EGb 761, effectively
                                                           73


inhibited the formation of amyloid fibrils and protected PC12 cells(855) from beta-AP25-35-induced cytotoxicity and ROS accumulation(854).

1.2. Alzheimer's disease (AD)
Simple poly hydroxycinnamic acids and diterpenoid quinone, found in dan shen improved cognitive deficits in mice model, through protection of neuronal cells, prevention of amyloid fibril formation and preformed amyloid fibril disaggregation related to Alzheimer's disease(851). Salvianolic acid B (Sal B)isolated from dan shen, in animal model, not only prevented Abeta-induced cytotoxicity(857) but also improved cognitive deficits and protection of neuronal cells(852), through its effects on suppressing the production of ROS, calcium flux, and apoptosis(853),  promoted amyloid precursor protein (APP) metabolism toward the non-amyloidogenic products pathway in cortical neuronal cell(856) and multifunctional machenisms(857). Compound Danshen Tablets (CDST), in rat model, exhibited spatial cognitive protection through decreased beta-APP expression in the cortex and hippocampus, detected via immunohistochemistry(859).

1.3.  In learning and memory impairment
In diabetic rats model, dan shen injection improved the learning and memory decline, through upregulation of expression of MKP-1 in reduced inflammation(861) and hyperglycemia(860). HX106N, a Chimese herbal formula, containing dan shen, in Aβ25-35 peptide mice, enhanced on memory impairment and oxidative stress through increased levels of heme oxygenase-1 (HO-1)(862). In a joint study of renowned institutions, in mouse model, myelophil, a combination of extracts taken from Astragali Radix and Salviae Miltiorrhizae Radix, significantly exhibited its anti-amnesic properties in  memory impairment, through the modulation of cholinergic activity(863). Tanshinones, a group of diterpenoids found in dan shen, also improved learning and memory impairments, through its inhibitory effect on acetylcholinesterase(864)

1.4. In neuroprotective effects
Tanshinone IIA (Tan IIA), one of the major active constituents of dan shen exerted its neuroprotective effects, by inhibiting transcription and translation of genes involved AD development(858). In neurotoxicity of β-amyloid
                                                              74


protein (Aβ), contributed Alzheimer's disease (AD), dan shen extract suppressed the increased intracellular reactive oxygen species levels, through deduction of decreased the protein expression involved in the development of neurodegenerative disease, including ADs(865). According to Eur J Pharmacol and University of Sydney, salvianolic acid B (SalB) found in dan shen, in mouse model, exhibited neuroprotective effects in an amyloid β (Aβ) peptide-induced Alzheimer's disease, through its anti-inflammatory, anti-oxidative effects(866) and ameliorated cholinergic dysfunction- or Aβ(25-35)-induced memory impairment(867), respectively.

2. Ren shen (Ginseng)
Ren Shen is a smells aromatic, tastes sweet and slightly warm herbs, also known as Gingshen, used in TCM as improved immune system(868)(869), Anti Cancer(870)(871), Anti aging(872)(873), Anti stress(874)(875), anti Erectile dysfunction(876)(877), etc. agents and to generates fluids, reduces thirst,  treats symptoms of diabetes(878)(879), for xinqixu (heart qi deficient) related coronary heart disease (CHD)(880)(881), anxiety(882)(883), insomnia(884)(885), depression(886)(887), neurodegenertive disorders(888)(889)(890), bleeding in the vagina not during period(891), seizures(892)(893), chronic fatigue(894)(895), etc. as it strongly tonifies Original Qi, the Spleen and the Lungs, promotes generation of Body Fluids, calms thirst and the Mind,(896) etc. by enhancing the functions of spleen and lung channels(897).

Ingredients
1. Saponins
2. Panaxynol
3. Ginsenyne
4. Alpha pansinsene
5. Beta pansinsene
6. Beta farnesene
7. Bicyclogermacrene
8. Beta elemene
9. Gama elemene
10. Alpha neodovene
11. Beta neodovene

                                                                   75


12. Alpha humulene
13. Beta humulene
14. Ccaryophyllene
15. Beta gurjunene
16. Alpha gurjunene
17. Alpha selinene
18. Beta selinene
19. Gama selinene
20. Selin-4, alpha guaiene
21. Gama cubebene
22. Beta patchoulene
23. Hepatadecanol-1
24. Etc.

Herbal ren shen used in the treatment and prevention of dementia(898) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals in ameliorated amyloid pathology(899)(900) and related cognitive deficits(901). In aging related dementia, based on the history of use, and pharmacological investigation, ren shen showed a strong evidence in cognitive improvement, through cholinesterase inhibitory activity and cholinergic function(902). According to Beijing University of Chinese Medicine, combination extract of Renshen (Panax Ginseng), Yinyanghuo (Herba Epimedii Brevicornus), Yuanzhi (Radix Palygalae) and Jianghuang (Rhizoma Curcumae Longae) (GEPT) exhibited neuroprotecting mechanism for preventing and treating of AD(903).

2.1. In Alzheimer's disease
Alzheimer's disease is a brain disorder named after German physician Alois Alzheimer. The disease destroys brain cells involved inflammation, mitochondrial dysfunction or oxidative stress(904), causing problems with thinking and behavior severe(904) enough to affect language communication(905), memory(906), lifelong hobbies or social life(907).
Ginseng extracts, in Alzheimer's disease (AD) patients significantly  attenuated amyloid plaque deposition in short- and long-term memory impairment. through its phytochemical gintonin effect via the mediation in promotion of non-amyloidogenic processing(908). In amyloid β peptide induced AD cell model, ginsenoside Rg1, the main chemical constituent of
                                                            76


ginseng, improved the memory impairment associated with Alzheimer's disease (AD), through suppressing the signaling transduction pathways and decreasing the inflammation factors(909)(910); increasing cell viability, reducing oxidative damage (including apoptosis), restoring mitochondrial membrane potential(911). According to the join 17-months old male APP/PS1 mice study by University of Michigan and Yunnan University of Traditional Chinese Medicine, total saponin in leaves of Panax notoginseng (LPNS) attenuated reactive oxygen species (ROS) accumulation and cell death in brain cells through activation of Nrf2 (nuclear translocation) and upregulation of downstream antioxidant systems(912).
 Unfortunately, according to the review over 20 databases from the inception to January 2009 and included all randomized clinical trials (RCTs) from Korea Institute of Oriental Medicine, the use of ginseng for treatments of Alzheimer's disease is scarce and inconclusive(913).

2.2. In Parkinson's and Huntington's diseases
Parkinson's disease is a progressive disorder of the nervous system, affecting movement of muscles(917)(918), speech(919), poster, balance, auto functioning(920), etc., with disease's symptoms worsen over time. According to a multicenter study, phosphorylated forms, pS129 is associated to the severity and progression of  Parkinson diseases(914). NFE2L2 gene, an important regulator of the cellular protection against oxidative stress, if defects can contribute to the pathogenesis of the disease(915)(916). In the pathogenesis of Parkinson's disease (PD), Ginsenoside Rb, effectively inhibited or reversed the aggregation process and may represent a viable therapeutic strategy against PD and related disorders, through anti-amyloidogenic and antineurotoxical effects(921). Its water extract in induced cytotoxicity of SH-SY5Y human neuroblastoma cells, also exhibited significant protective effects possibly through the suppression of ROS generation(922). According to Russian Academy of Medical Sciences, use of ginseng and other herbs, such as eleutherococcus, Rhodiola rosea, etc.,  in a complex therapy for Parkinson's disease, may be due to theirs normalized immune, antioxidant, and hormonal parameters(923).
In Huntington's disease, Ginsenosides, the main chemical constituents of ginseng, showed to exert its neuroprotective effect against neurons from glutamate-induced apoptosis in vitro(924).
     
                                                          77


2.3. In cognitive impairment
Klotho Gene Deficiency has been found to associate with oxidative stress related cognitive impairment(925). In aging mice model, ginseng exhibited anti oxidative stress in ameliorated lipid peroxidation,  restored antioxidant capacity(926), and reduced accumulation of intercellular messenger, nitric oxide (NO)(927) activities, may be used as a potential treatment of herbal medicine for cognitive impairment(927). Ginsenoside Rb1, a major chemical constituent found in ginseng, showed to inhibit cognitive impairment caused by diabetes, through GSK3β, (a negative regulator in the hormonal control of glucose homeostasis)-mediated endoplasmic reticulum(ER) stress due to physiological and pathological insults, in high glucose-treated hippocampal neurons(928).

2.4. In neuroprotective effects
In high glucose-induced neurotoxicity in primary cultured rat hippocampal neurons, Ginsenoside Rb1  exerted a wide variety of neuroprotective effects by inhibiting CHOP signaling pathway involved in apoptosis signal in ER stress- and CHOP-mediated apoptosis(940), oxidative stress(926),  mitochondrial dysfunction(929)(941) and neuroinflammation(941). According to University Complutense of Madrid, Ginseng and its major constituents as potential neuroprotective agents against progression of Parkinson's disease(943), may be due to its effectiveness in inhibition of oxidative stress(926), neuroinflammation(941), toxins-induced apoptosis(944) and regulation of channels and receptors activity(945)(942).



B.3. Xi yang shen(946), Yin in nature, the sweet, slightly bitter, cool herb has been used in TCM to treat fatigue(947)(948), diabetes(949), cardiovascular diseases(950)(951) and atopic diseases(952), promote saliva, quench thirst(949)(950), due to yang deficiency of lungs, by enhancing the lung and spleen qi, through increasing the digestive system in absorbing vital energy and reducing the heat causes of qi stagnation through Heart, Lung, Kidney channels.


                                                            78

Phytochemicals
1. Resin
2. Pinene
3. α Phellandrene
4. β Phellandrene
5. α-amyrone,
6. α-amyrinone
7. α-amyrin
8. β-amyrin
8. Viridiflorol
9. Insensole
10. Insensole oxide
11. Ginseng Saponins: ginsenoside -R0, -Rb1, -Rb2, -Rb3, -Rc, -Rd, -Re, -Rf, -Rg1, -Rg2, -Rg3, -Rh1, -RA0, quinquenoside R1, gypenoside X1, F3, F11.
12. Etc.

Herbal xi yang shen used in the treatment and prevention of dementia(953) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals in ameliorated amyloid pathology(953) causes of neuro cells apoptosis(954) and related cognitive deficits(955).

3.1. In Alzheimer's disease
In Alzheimer's disease cell model, induced by Abeta25-35, water extracts of American Ginseng (WEAG), exerted neuroprotective effects of  SH-SY5, a human derived cell line against cells apoptosi(954). Pseudoginsenoside-F11 (PF11), a main component found in American ginseng, in Alzheimer's disease (AD) mice model, induced by scopolamine, morphine and methamphetamine, significantly mitigated learning and memory impairment in 15 days, through inhibited the expressions of β-amyloid precursor protein (APP) and Aβ1-40 in the cortex and hippocampus, restored the activities of antioxidants in decreased the production of malondialdehyde (MDA), a indicators of lipid peroxidation (953).

3.2.  In Huntington’s disease and Parkinson’s disease
In neurodegeneration-like Huntington's disease and Parkinson's disease rat
                                                          79

model, induced by 3-nitropropionic acid (3-NP). preparation of American ginseng leaves and stems significantly reduced brain degeneration through its active phytochemicals, ginsenosides, Rb1, Rb3 and Rd(958), according to Baylor College of Medicine and Austin State University(957). Ginseng saponins, an active ingredients found in ginseng species, including American ginseng also exerted beneficial effects on aging, central nervous system (CNS) disorders, and neurodegenerative diseases through mediated protective mechanisms, including attenuated free radicals(959)(960).

3.3. In Neuroprotective effects
Pseudoginsenoside-F11 (PF11), a phytochemical of Panax quinquefolism (American ginseng) showed to exhibit its neuroprotective effect against impraired locomotor(962)  on methamphetamine (MA)-induced behavioral and neurochemical toxicities in mice(964) and in Parkinson's disease (PD) of rat model, by evoked neuronal excitability and mediated the increased release of glutamate(962), motor balance, coordination, and apomorphine-induced rotation, through inhibiting free radical formation and stimulating endogenous antioxidant release(961). According to the State Key Laboratory of Chinese Medicine and Molecular Pharmacology, water extracts of American Ginseng (WEAG) also exerted its neuroprotective effect on SH-SY5Y cells apoptosis induced by Abeta25-35, in Alzheimer's Disease cellular model(963).

3.4. In  Cognitive impairment 
Amyloid β (Aβ) accumulation, elevated oxidative stress, and apoptosis of the neurons have shown to induce the progression of Alzheimer's disease (AD), Pseudoginsenoside-F11 (PF11) found abundantly in American ginseng, exhibited recognitive improvement effect in mouse model, through its antioxidant status in inhibition of amyloidogenesis and oxidative stress and enhancement of neuronal functions(965) as well as ameliorated cognitive impairment, neuroinflammation, and biochemical alterations caused by accumulation of intercellular messenger, nitric oxide (NO)(966).


B.4. Sang shen also known as Mulberry or Morus Fruit, the sweet, sour and cold herb has been used in TCM as antioxidant(968)(969),
                                                         80

antiinflammatory(969), anti ageing(991) and neuroprotective(968)(970) agents and to treat vertigo, tinnitus, insomnia, atherosclerosis(971)(973), vascular smooth muscle cells(972), lipid accumulation(974), weak digestion, premature white hair, thirst(967), diabetes(967), diarrhea, etc., as it nourishes Yin, and Blood, promotes generation of Body Fluid, moistens the Intestines, etc. by enhancing the functions of heart, liver and kidney channels(975).

Phytochemicals
1. Resveratrol
2. Anthocyanosides
3. Carotene
4. Thiamine
5. Ribflavin
6. Vtamin C
7. Vannin
8. Linoleic acid
9. Stearic acid
10. Etc.

Herbal sang shen used in the treatment and prevention of dementia(977) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals in exertion of its neuroprotective effects(968)(970) through anti oxidative stress(968)(969), anti inflammatory(969) and anti excitotoxic (involved Alzheimer's disease) mechanisms(978) against cell membrane damage and mitochondrial function induced by oxygen-glucose deprivation (OGD) and glutamate-induced cell death(977).

1. In aging Alzheimer's disease(ADs)

Decreased the levels of serum aspartate aminotransferase caused by oxidative stress(979), alanine aminotransferase(980), triglyceride(981) and total cholesterol(982) due to ageing have shown to involve in the development of Alzheimer's disease. In ageing animals, mulberry extracts (ME), rich in phenolics and anthocyanins, significantly demonstrated  less amyloid beta protein and improved learning and memory ability through its

                                                         81

antioxidant enzymes and reduction of oxidative damage(983).

Cyanidin-3-glucoside (C3G) fraction extracted from sang shen effectively protected primary cortical neurons in 7 days, against glutamate-induced cell death cause of dementia, including Alzheimer's disease(ADs(978) in rat model(984).

2. In Parkinson's disease
Parkinson's disease (PD), is one of the most common neurodegenerative disorders as results of dopaminergic deafferentation of the basal ganglia)(985) and oxidative stress(986)(987).
According to Kyung Hee University, 70 % ethanol extract of mulberry fruit (ME), in dose-dependent manner, in vitro and in vivo PD models showed to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal damage(999), through its antioxidant and anti-apoptotic effects, in regulating reactive oxygen species and NO generation(988).
 
3. Neuroprotective effects
Cyanidin-3-O-beta-d-glucopyranoside (C3G) found abundantly in the mulberry fruits exerted significantly  exhibited its cytoprotective effect on PC12 cells(derived from a pheochromocytoma of the rat adrenal medulla) under oxidative stress induced neuro-degenerative diseases(983)(989). In neurological disorders, including Alzheimer's and Parkinson's diseases, caused by cerebral ischemia, mulberry leaves (ML) exhibited neuroprotective actions in reduced the cytotoxicity in the PC12 cells against oxygen glucose deprivation with enhanced accumulation of gamma-aminobutyric acid (GABA)(990).

4. In memory improvement
In mice model, mulberry fruits extract, significantly increased pre- and post-synapse formation(992), acetylcholine synthesisation(993), neuronal cell differentiation(994), neurite outgrowth(995) and neuronal cell proliferation(996) in the hippocampus, against loss of memory through its antioxidant in protecting or enhanced neuronal functions mediated by neurotrophic factors, such as nerve growth factor (NGF)(991). According to
                                                       82

National Chung Hsing University, in memory deterioration in ageing animals, phenolics and anthocyanins, from mulberry fruits, inhibited amyloid beta protein(998) and improved learning and memory ability through induced  higher antioxidant enzyme activity and less lipid oxidation in both the brain and liver(997).


B.3.3. Spleen Qi deficiency
Spleen is a vital organ, according to traditional Chinese medicine, with function in absoring nutrients and transporting them to body's organs and cells. Spleen Qi deficiency is a condition of the inability of the spleen in  maximized transportation of nutrients to body organs, including the brain. Prolong period of malnutrition of brain cells may induce abnormal functions in information transmitting  or death of neurons, causing cognitive impairment(844), including learning and memory deficits(842) and changes in brain tissues and behavior patterns(843)(842).

Herbal medicine for Spleen Qi deficiency
1. Peony (Chi Shao)
Chi Shao or Chi Shao Yao with bitter, sour taste and cool in nature is also known as Peony Root, used in TCM as antispasmodic(1000)(1001), anti-inflammatory(1002)(1003), anti allergic(1004)  antibiotic(1005), anticonvulsant(1006), analgesic(1007), anxiolytic(1008) agents and to lower blood pressure(1009), dilate peripheral blood vessels, coronary arteries against heart attack(1010), treat viral hepatitis(1011), chronic constipation(1012), asthma(1013), whooping cough(1014), diabetes(1015)(1016), etc., as it clears heat, cools blood, eliminates blood accumulation, calms paindilates, etc., by enhancing the functions of liver and spleen channels(1017).
Phytochemicals
1. Essential oil
2. Resin
3. Paeoniflorin
4. Paeonol
5. Paeonin
                                                                 83


6. Albiflorin
7. Triterpenoids
8. Sistosterol
9. Oxypaeoniflorin
10. Benzoylpaeoniflorin
11. Benzoic acid
12. β sitosterol
13. Gallotannin
14. Pedunculagin
15. 1-O-Galloylpedunculagin
16. Eugeniin
17. Tannin acid
18. Etc.

Herbal shao yao used in traditional Chinese medicine for treatment and prevention of dementia(1018)(1019), may be due to its effectiveness of phytochemicals, including major constituent paeoniflorin, in exertion of its neuroprotective effects(1020)(1021) through anti oxidative stress(1022), anti inflammatory(1023), improved neural synapse plasticity(1024) mechanisms, against β-amyloid (Aβ) accumulation(1025) induced  senile dementia and aging-induced cognitive dysfunction(1026).

1.1. Parkinson's disease PD
Strong evidences suggested that peony, possesses wide pharmacological effects in nervous system(1027)(1028). Paeoniflorin, a phytochemical isolated from peony, in PC12 cells induced by 6-OHDA found in patient with Parkinson's disease(1030), showed to suppress mitochondria apoptosis, through its antioxidant capability in increasing glutathione (GSH)(1032), by inhibiting reactive oxygen species (ROS)(1031). In Parkinson's disease (PD) progressive loss of dopaminergic neurons involved movement and in mouse model with mitochondrial dysfunction, peony significantly inhibited mitochondria-mediated apoptosis, via the regulation of expression of immunity, inhibition of cytochrome C associated with the inner membrane of the mitochondrion. release and caspase-3, a protein encoded by in CASP3 gene, activation(1031). According to University of Miami, polyphenols of bai shao, included baicalin, baicalein, wogonin (in scutellaria) paeonol, paeonoside, and paeoniflori, exerted neuroprotective efficacy, probably
                                                               84


through improving cerebral blood circulation, involved alleviation of the symptoms of degenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD)(1033).

1.2. In Alzheimer's disease AD
Abeta42 deposition in hippocampus has shown to induce brain inflammation causes of early onset of Alzheimer's disease AD(1034)(1035). Paeonol(2'-hydroxy-4'-methoxyacetophenone;1-(2-hydroxy-4-methoxyphenyl)ethan-1-one), found in peony, not only protected the nervous system against accumulation of amyloid peptide, Aβ1-42, through its anti-inflammatory and free radical scavenging properties, but also slowed down and regulated  the pathogenic processes associated with AD, through morphological, biochemical and behavioral activities(1036). Aqueous extract of the dry root of Peony in Abeta((1-42))-induced rats, also inhibited Abeta-induced neurotoxicity, through ameliorated cognitive deficit,  cell apoptosis in dose-dependent manner(1037).

1.3. In cognitive impairment
Cognitive impairment is common in patients with the neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD, Paeoniflorin, isolated from the aqueous extract of peony, in rat model, not only showed to promote the cognitive ability, exhibited anti-depressant-like effect and reduced toxicity, but also attenuated the oxidative stress induced Aβ(1-42) by regulating choline acetyltrasferase and the activity of acetylcholine esterase in the hippocampus of Aβ(1-42)(1038)(1039). In Chronic cerebral hypoperfusion, associated with the cognitive deficits of AD, the phytochemical also attenuated cognitive deficit and brain damage through ameliorated astrocytes(star-shaped glial cells in CNS) and microglias(glial cell in CNS) in hippocampus(1040). According to Shanghai Institute of Materia Medica, on cerebral infarction induced neurological symptoms, paeoniflorin (PF) significantly reduced the infarct volume causes of cognitive impairment(1041).

1.4. In learning and memory
Supplementation of paeonol extracted from peony, in d-galactose (D-gal)-induced aging mice, significantly improved the learning and memory ability through reduction of oxidative stress, cognitive impairment and
                                                            85


neurotoxicity, according to China Pharmaceutical University(1042). Danggui-Shaoyao-San (DSS), the herbal formula containing peony and 5 other herbs, used to treat gynecological disorders and neural dysfunctions, in the same model study, showed effectively in improved cognitive ability, through ameliorating oxidative stress induced neuronal apoptosis in the brain(1043). Paeoniflorin, a major constituent of peony, also exhibited its beneficial effect on learning and memory impairment in rodents, by reversed the suppressible effects of adenosine as shown on passive avoidance test and inhibition of long-term potentiation (LTP)(1044).

2. Bupleurum
Chai Hu, the bitter, slightly cold herb is also known as bupleurum root, used in TCM as antitrypanosomal, antimicrobial and antiviral, such as cold and influenza, alternated chill and fever, malaria(1047), cytotoxic(1045)  and anti-cancer agents(1046) and to treat irregular menses, prolapse of uterus and rectum(1048), etc., as it regulates and clears heat, improves liver function, raises Yang(1048) and resolves depression and stagnation, etc. by enhancing the functions of liver, gall bladder, pericardium, triple burner channels.

Phytochemicals
 1. β-terpinene
2. imonene
3. β-fenchene
4. ulegone
5. Isoborneol
6. β-terpineol
7. α-copaene
8. Humulene
9. A-farnesene10. Aromadendrene
11. Cis-caryophyllene
12. β-elemene,13. Gamma-muurolene
14. Patchoulane
15. Pootkatone
16. Ledol
17. Etc.
    
                                                               86


Herbal chai hu used in the treatment and prevention of dementia(1049)(1050) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals in exertion of its neuroprotective effects(1051) through its cytoprotection of neuron, and neuroprotective mechanisms(1052), against apoptosis of neurons(1051) due to Aβ oligomer-induced neuronal damage(1060)  in concentration of corticosterone on hippocampal neurons(1059) in a dose-dependent manner.

Yokukansan, a popular herbal combination in Japan and China, containing chai hu,  may be the next potential herbal formula used for treatment of Alzheimer's disease, Lewy body disease, Parkinson's disease, especially for the behavioral and psychiatric symptoms of dementia BPSD)(1064)(1065)(1066).

2.1. In dementia symptoms
In dementia, Yokukansan, also known as TJ-54, composed of sev Angelica acutiloba, Atractylodes lancea, Bupleurum falcatum, Poria cocos, Glycyrrhiza uralensis, Cnidium officinale and Uncaria rhynchophylla,(1052)showed to ameliorate the memory disturbance, anxiety-like behavior, aggressive behaviors, decrease in social behaviors, learning deficits and non-cognitive defects(1055) through improvement of neuronal and astroglial cells, via inhibit glutamate-mediated excitotoxicity(1053)(1054). According to 1Keimei Memorial Hospital in Japan, the formula also showed to improve behavioral and psychological symptoms of dementia (BPSD) together with donepezil in patients with Alzheimer's disease (AD)(1056).

2.2. In Alzheimer's disease and dementia with Lewy bodies
In Alzheimer's disease, Yokukansan improved psychological symptoms of dementia (BPSD)(1058), such as  hallucinations, agitation, anxiety, irritability or abnormal behavior(1057)  in elderly patients1056). In patients with dementia with Lewy bodies, Kampo medicine, yokukansan (YKS), including chai hu, also improved behavioural and psychological symptoms of dementia (BPSD), through neuropsychiatric Inventory scores(1061).

2.3. In Parkinson's disease
In neuropsychiatric symptoms in patients with Parkinson's disease,
                                                            87


yokukansan, containing Chai hu, using the Unified PD Rating Scale part III (UPDRS-III) and Hoehn and Yahr scale, showed effectively in ameliorated symptoms of delusions, agitation, depression, euphoria, disinhibition with aberrant motor activity but irritability(1062). In behavioral and psychological symptoms, the herbal formula, also exhibited improvements of these symptoms, without worsening cognitive function, ability to perform activities of daily living, or parkinsonism, after 4 weeks(1063). Yokukansankachimpihange, another formula containing chai hu, showed to exhibit anti hallucinate effects, through its major phytochemical atractylenolide III and β-eudesmol, via its antagonistic activity against serotonin receptors induced non-motor symptom of Parkinson's disease and various forms of dementias(1067).

According to traditional Chinese medicine, the effectiveness of a herbal formula, is not results of single ingredient or single herb itself, but the combination of all ingredients of all herbs in the formula, even some herbs in  the formula may show significant efficacies in Western studies and clinical trials.


3. Safflower (Hong Hua)
Safflower, is an acrid, warm herb in nature, used in tradition Chinese medicine as anti-bacterial(1070), anti viral(1068)(1069), analgesic(1071), diabetic(1072)(1073), immune stimulant(1074), anti-inflammatory(1071), anti-spasmodic(1075) agents. As a blood tonic in Chinese medicine, the herb is effective in treating dysmenorrhea(1075), amenorrhea(1075), by breaking up blood stagnation|(1077)(11078), improving blood flow(15) through warm-pungent-liver efficiency network(1079) and regulation of female reproductive hormone(1080) via liver, heart channels(1076).

Phytochemicals
1. Neocarthamin
2. Carthamin
3. Carthamone
4. Carthamidin
5. Saffloryellow

                                                           88

6. Saffloryellow-A
7. Apalmitic acid
8. Myristic acid
9. Lauric acid
10. Etc.

Herbal Safflower (Hong Hua) used in the treatment of symptoms of degenerative diseases(1091) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals, including major constituent hydroxy-safflor yellow A(1081)baicalin, baicalein, wogonin(1088), in exertion of its neuroprotective effects(1082)(1083), through anti oxidative stress(1086), anti inflammatory(1084))(1085) activities, against β-amyloid (Aβ) accumulation(1081) induced neurotoxicity causes of  Alzheimer's disease.(1087)(1089) and neurodegeneration(1090).

3.1. In Alzheimer's disease
Neuroinflammation has shown to be a major contribution to the development of Alzheimer's disease (AD)(1092). Hydroxy-safflor yellow A (HSYA), isolated from safflower, inhibited Aβ 1-43 induced inflammation(1096) through anti microglia-mediated neurotoxicity activity(1094). In PC12 cells induced by β-amyloid neurotoxicity, the phytochemical also inhibited cell viability, glutathione level, through ameliorated enzymes found extensively in body tissues, formation of DNA fragmentation, levels of reactive oxygen species(1095) and reduced pro-inflammatory mediators(1097).


3.2. In Neuroprotective effects(1098)
 Hydroxy-safflor yellow A (HSYA) at the molecular level, showed to inhibite energy metabolism disruption, excitatory amino acid toxicity, oxidative stress caused by impaired metabolism in rats with ischemia, through suppressing proinflammatory and upregulating anti-inflammatory mechanism(1099). According to Tianjin Medical University General Hospita, the herb also exerted its neuroprotective effects by inhibiting the accumulation of amyloid-β peptide (Aβ), a major protein component of senile plaques induced neurotoxicity via decreased production of reactive oxygen and nitrogen species(1101), ROS marker, malondialdehyde, and increased the level of glutathione, stabilized mitochondrial
                                                             89


membrane(1100) and protected against excitotoxic neuronal death(1102).

3.3. In memory dysfunction
Intake of safflower oil has shown to improve learning and memory ability in n-3 fatty acid deficient male mice(1103) and in an age-related neuro deteriorative mouse model(1106), probably through modulated physiological properties of entorhinal cortex neurons(1104) and the balance of ratio of brain phospholipid(1107), respectively. Nicotiflorin, a natural flavonoid extracted from safflower, in cerebral multi-infarct dementia in rats model, showed to enhance spatial memory through reducd ROS production(1105).


4. Cinnamon bark (Rou gui)
Rou gui, an acrid, sweet, very hot herb, is also known as Cinnamon bark, used in TCM  as anti-spasmodic(1110), antibiotic(1111), antigastric ulcers(1112), anti impotent and anti diabetic(1113)(1114) agents and to treat hepatitis(1115), flatulence(1116), weak digestion(1116), pain in solar plexus(1110), breast cancer(1117)(1118), tuberculosis(1119)(1120), etc., as it drains the liver heat, eliminates Qi accumulation, disperses nodules, reduces stagnation, etc.by enhancing the functions of heart, lung, bladder channels(1121).

Ingredients
1. Cinnamic aldehyde
2. Cinnamyl acetate
3. Eugenol
4. Aldehyde
5. Pinene
6. Coumarin
7. Cinnamyl alcohol
8. Cinnamic acid
9. Cinnzeylanol
10. Cinnzeylanine
11. Etc.

Cinnamon bark (Rou gui) used in the treatment of symptoms of neurological impairment(1108)(1109) in traditional Chinese medicine, may
                                                        89


be due to its effectiveness of phytochemicals, including major constituent cinnamaldehyde (CA) and epicatechin (EC)(1122)  in exertion of its neuroprotective effects(1123)(1123), through anti oxidative stress(1125), anti inflammatory(1124)) activities, against β-amyloid (Aβ) accumulation(1126) induced neurotoxicity causes of  Alzheimer's disease.(1126)(1127) and neurodegeneration(1128).

4.1. In Alzheimer's disease 
Cinnamon, a multifaceted medicinal plant have shown to consist activities against neurological disorders, including Alzheimer's diseases(1129) by blocking and reversing tau modification and aggregation(1131)(1130) and ischemic stroke induced cell swelling(1130). In β-amyloid polypeptide (Aβ), associated to the development of Alzheimer's disease(AD) mouses model, oral administration of cinnamon extract exhibited neuroroprotective effects in enhancing the fully recover of  locomotion defects and totally abolished tetrameric species of Aβ in their brain(1132). In a high fat/high fructose diet induced Alzheimer's disease(AD) symptoms, cinnamon (CN) ameliorated enzyme phosphatase and proteins tensin homolog (PTEN),  tau and amyloid precursor, associated to Alzheimer's disease(AD), through improved insulin sensitivity and related changes in the brain(1133).
According to The Business and Technology Center, West Lafayette, Chinese cinnamon, is one of the tested herb with potential  for prevention and treatment of early onset of Alzheimer's disease(AD)(1134).

4.2. In Parkinson's disease
In a mice model, oral administration of cinnamon (Cinnamonum verum) powder upregulaed and/or maintained the level of Parkin/DJ-1, a beneficial proteins associated to degeneration progression of Parkinson's disease(1135). through protection of dopaminergic neurons(1136). In oligomeriztion of α-synuclein (α-syn) formation associated with the symptoms of Parkinson's Disease, cinnamon extract precipitation (CEppt), inhibited oligomeric and fibrillar forms of α-syn through ameliorated aggregation of β-amyloid polypeptide(1137).

4.3. In neuroprotective effects
Oxidative stress has shown to associate to brain damage due to its high

                                                       90


consumption of oxygen.

Cinnamon polyphenols, during oxidative stress, exhibited neuroprotective effects in glial cells by reduced overexpression of the proinflammatory factors(1138) and enhanced prosurvival proteins protein levels (sirtuin 1, 2, and 3, deacetylases) associated to glioma cells survival(1139). Cinnamaldehyde, a major chemical found in cinnamon, inhibited uncontrolled activation of microglia contributing to neuroinflammation involved in the development of neurodegenerative diseases(1140). The herbal water extract, also exerted neuro protective effect against glutamate-induced neuronal death through the inhibition of Ca(2+) influx(1141).

 B.4. Dementia due to Blood Stasis
According to Chinese medical literaure over 3000 years of history, blood stasis may be caused by spleen qi deficiency, but in most cases, it is due to heart qi deficiency cause of inability in transport nutrients to the body organs and cells, including the brain. Prolong period of malnutrition of brain cells may induce abnormal function of brain's cells in information transmitting  or death of neurons, cognitive impairments(844), including learning and memory deficits(842) and changes in brain tissues and behavior patterns(843)(842). Blood statsis induced by cold(1142), emotional disorder(1143), aging(1144), chronic illnesses and consumptive disease(1145), can overload the heart capacity, contributing to long-term hypertension(1146) due to decreased or impeded blood flow(1147) causes of hypo-perfusion in cerebral blood flow or acute focal stroke in memory-related cerebral parenchyma induced progression of cognitive decline(*).

Herbal medicine for treatment of Blood stasis
1. Wolfberry (Gou qi)
Gou Qi, the sweet and neutral herb is also known as wolfberry, used in TCM as anti cancers(1148)(1149), antioxidative(1150)(1151) and anti aging(1156)(1157) agent and to treat back, leg, and stomach pain(1152), hypopigmentation(1154), improve vision(1153)(1154), diabetes(1155), premature aging(1156), enhance immune system(1157), lower blood lipids(1158), elevate level of testosterone(1159), simulate estrogen and anti estrogen effect through different estrogen receptor mechanisms(1160) etc.,
                                                             91

as it nourishes and tonifies Liver and Kidneys, moistens the Lungs, etc., by enhancing the functions of liver, lung and kidney channels(1161). 

Phytochemicals
1. Betaine
2. β-sitosterol
3. Linoleic acid
4. Physalien
5. Cryptoxanthin
6. Atropine
7. Hyoscyamine
8. Scopoletin
9. Amino acids
10. Physalein
11. Zeaxanthin
12. Dipalmitate
13. Carotene
14. Etc.

1.1.  In Alzheimer's disease(AD)
 Elevated plasma homocysteine (Hcy) levels have shown to associate to increased the risk of Alzheime's disease (AD), epidemiologically and clinically. Polysaccharides, phytochemicals derived from wolfberry (LBA) not only inhibited Abeta accumulation but also reduced risk of other factors induced AD(1162). According to the University of Hong Kong, the chemical olysaccharides, also ameliorated glutamate excitotoxicity involved in many neurodegenerative diseases including Alzheimer's disease (AD)(1163). The herbal alkaline extract was found to exhibit neuroprotection, through inhibiting Abeta-peptides induced apoptosis and neuronal cell death(1164).

1.2. In neuroprotective effects
Lycium barbarum polysaccharide (LBP), on focal cerebral ischemic injury in mice model, inhibited neuronal morphological damage and attenuated the neuronal apoptosis through mitochondrial apoptosis pathway(1165). In ischemia-reperfusion-induced damage, chemical Lycium barbarum polysaccharides (LBP), reduced apoptosis and decreasednumber of viable cells in the ganglion cell layer (GCL) and inner nuclear layer (INL), through
                                                           92


its  antioxidant activity(1166), In PC12 cell, Lycium arbarum extracts inhibited neurotoxin  induced Parkinson's disease-like syndrome, through increased intracellular Ca (2+) level and significantly cell viability and cellular ATP levels(1167).

1.3. In cognitive impairment
In prenatal stress-induced cognitive impairment of offspring rats, Lycium barbarum showed to inhibit brain oxidative mitochondrial damage and cognitive dysfunction, through its scavenged hydroxyl and superoxide radicals(1168). Kyung-Ok-Ko (KOK), a traditional herbal prescription, containing Lycium, showed to enhance neuroprotective effects in attenuation of memory impairment, probably through its anti-inflammatory activities(1169).

1.4. In learning and memory
Lycium barbarum polysaccharides, scopolamine (SCO-induced cognitive and memory deficits in rats model, ameliorated and suppressed oxidative stress in hippocampus, and neurons apoptosis(1170). On transgenic mouse model of Alzheimer's disease, Gou qi extracts at 10 mg/kg improved the performance of  the learning and the memory in rieval phases of tested models, through reduced levels of Aβ(1-42) in hippocampal tissue(1171). According to Kyung Hee University, Lycium chinense fruit, in trimethyltin (TMT)-induced neuronal and cognitive impairment rats model, improved learning and memory deficit in impaired learning and memory scores(1172).

 
2. Polygonum multiflorum (he shou wu)
He Shu Wu or Ye Jiao Teng or Shu Wu is also known as Fleece flower root or  Fo-ti.
a. The prepared herb is astringent with some sweetness, mildly warm
b. The raw herb is bitter, sweet and neutral
used in TCM to treatment of hyperlipemia(1173), neurasthenia(1174), split personality(1174), promoted hair grown(1175) and prevent hair loss(1176) due to aging, skin rash due to inflammation(1177), etc., as it tonifies and benefits  the essence and blood, expels toxins, moistens the intestines, etc. by enhancing the (The prepared herb) liver and kidney channels and (The

                                                         93


raw herb) liver, heart and large intestine channels(1178).


Phytochemicals
1. Polygoacetophenoside
2. Chrysophanol
3. Emodin
4. Rhein
5. Emodin-6
6. Physcion
7. Chrysophanic acid
8. Anthrone
9. beta-sitosterol
10. 2,3,5,4′-tetrahydroxystibene-2O-b-D-glucoside
11. Quercetin-3-O-galactoside
12. Querctin-3-O-arabinoside
13. Lecithin
14. Etc.

2.1. In  Alzheimer's disease
Polygonum multiflorum extract, significantly improved AD patients with total effective rate of 93.33% in clinical trial, according to Third Xiangya Hospital(1179). In rat model, induced Alzheimer's disease by injecting Abeta 1-40, the herb exhibited improvement of learning and memory ability, through expression of the fluidity of mitochondria membrane and the activity of mitochondrial COX(1180) and ameliorated hippocampal synapses count and synaptophysin expression(1181). In cognitive deficits induced by Abeta25-35, Polygonum multiflorum water extract, also significantly ameliorated the cognitive deficits, probably due to its antioxidant properties(1182).

2.2. In Parkinson disease
Strong evidences suggested that agricultural chemicals and environment toxins, such as dithiocarbamate fungicides, impacted dopamine systems has shown to associate to the development of Parkinson's disease,(1184)(1185). In nigrostriatal dopaminergic degeneration induced by paraquat and maneb in mice model, ethanol-soluble PME (PME-I) water extracts from
                                                             94


Polygonum multiflorum, improved locomotor activity, motor incoordination, and declines of dopamine level, probably through phytochemicals, in the ethanol-soluble fraction(1183).

2.3. In neuroprotective effects
In focal cerebral ischemia mice, hexane extracts of Polygonum multiflorum, exhibited its neuroprotective effects though significantly decreased infarct size and improved neurological and motor function, (1186) and attenuated glutamate-induced neurotoxicity in a concentration-dependent manner and prevented apoptosis of cortical neurons(1187), in HT22 hippocampal cells(1188), probably through it antioxidant activity. According to Xuanwu Hospital of Capital Medical University, 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) extract from Polygonum multiflorum, also improved mitochondrial function, decreased oxidative stress and inhibited apoptosis against induced cytotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells(1188).

2.4. In learning and memory
 Dietary supplementation with either ethanol or water extracts of Polygonum multiflorum have shown to reduce brain pathological changes and promote learning and memory ability(1191)(1192). In male Sprague-Dawley rats, injected with beta amyloid (Aβ), tetrahydroxystilbene glucoside, an active chemical constituent of extract from  Polygonum multiflorum, significantly improved the learning and memory, through protecting synaptic structure and function(1189) and learning and/or memory ability of aged rats by increased Beta-secretase 1 (BACE1), a beta-site amyloid precursor protein cleaving enzyme 1 and  decreased ADAM10 (metallopeptidase domain 10), a protein associated to the development of Alzheimer's disease(1190).

B.5.  According to TCM philosophy, dementia is also to be induced by the combination/or of Kidney essence vacuity and toxin (turbid phlegm).
 C.5.1. Dementia due to toxins accumulation
Toxins accumulation in internal organs disturbed the balance of immunity(1213)(1214) may cause  impairment of food intake regulation(1215), exhibition of phlegm(1208)(1208)(1210), retention of fluid(1211)(1212) and blood statsis(1209) induced early the onset of dementia, in aging population with depletion of kidney-essence(1208)(1209),
                                                              95


according to traditional Chinese medicine.

Herbal Medicine for toxins elimination
Chinese Herbal medicine for toxins elimination 
1.  Shui Fei Zi or Milk thistle (Silybum marianum)
Shui fei zi, the bitter and cold herb, is also known as milk thistle, native to Western Europe and northern Africa, used in traditional Chinese medicine to improve liver function(1193)(1194)(1210), promote the flow of breast milk(1207), bile secretion(1200), anti depression(1201) and anti tumors(1196)(1197)(1198), inhibit allergic effects(1195)(1199), treat hepatitis C(1202)(1203), cirrhosis(1205) and liver fibrosis(1206), by enhancing function of liver and gallbladder channels(1204)

Phytochemicals
 1. Flavonoid 
2. Fumaric acid
3. Silymarin
4. Isosilybin, 
5. Dehydrosilybin, 
6. Silydianin
7. Silychristin
8. Cinnamic acid
9. Myristic acid
10. Palmitelaidic acid
10. Arachidic acid
11. Etc.  

Shui Fei Zi or Milk thistle used in the treatment and prevention of dementia(1218) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals Silymarin and Silibinin in ameliorated amyloid pathology(1216) and oxidative stress(1216)(1217) through attenuated levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus(1217).

1.1. In Alzheimer's disease

Alzheimer disease (AD). a neurodegenerative disorders is the most prevalent diseases  in the United States, in aging population(1219). Silymarin, a
                                                        96


phytochemical found abundantly in milk thistle, in age related disorders like neurodegenerative diseases improved  locomotion rate, higher response to stimuli and tolerance to stress, in C.elegans Alzheimer's Model, through delayed paralysis via enhanced resistance to oxidative stress(1220). In rat induced Alzheimer's disease model, the phytochemical also inhibited amyloid formation(1222) and suppressed amyloid protein precursor (APP) expression(1222)and reduced neurotoxicity in PC12 cells(1222) in improvement memory(1223) and learning function(1221).

1.2. In Parkinson disease
In a mouse model of Parkinson's disease, causes of mitochondrial dysfunction and selective cells death of dopaminergic neurons, silibinin, derivative of silymarin, protected mitochondria through attenuated motor deficit and dopaminergic neuronal loss(1224) and anti oxidative and anti inflammatory pathways(1225).


1.3. In neuroprotective effects  
In focal cerebral ischemia, silymarin (SM), a mixture of flavonolignans extracted from the milk thistle exerted it neuroprotective effects, in upregulating the antioxidant status and lowering the apoptotic response in slowing down the progression of neurodegeneration(1226) and preventing inflammation-related neurodegenerative disease(1227)  and ROS causs of oxidative damage to macromolecules in the brain(1230).


1.4. In cognitive impairment
In cognitive deficit mice model, silibinin exhibited its anti cognitive impairment effects through amelioration of decreases in dopamine and serotonin levels in the prefrontal cortex and hippocampus, (1228). In amyloid beta peptide-induced memory impairment, the chemicals also improved cognitive memory deficits through attenuated the Abeta(25-35)- accumulation of malondialdehyde and depletion of glutathione in the hippocampus(1229).

2. Xiu Hui Xiang (Fennel)
Xiu Hui Xiang, the acrid and warm herb, is also known as fennel, native
                                                            97


to Mediterranean, used in traditional Chinese medicine as anti microbal(1232)(1233), antioxidant(1234)(1235), emmenagogue(1236), estrogenic(1244) and androgenic(1245) agents and to prevent bone loss in postmenopausal osteoporosis(1237)(1238), treat hepatic fibrosis(1239), gastro intestine disorder(1240)(1241), decrease hair thickness(1243) and increase flow of breast milk(1242) by enhancing function of liver, kidney, spleen, stomach channels(1231).



Phytoshemicals
1. Linoleic acid         
2. Palmitic acid  
3. Arachidic acid  
4. Behenic acid      
5. Quercetin  
6. Phytosteryl b-fructofuranoside  
7. 7-hydroxycoumarin 
8. 6,7-dihydroxycoumarin  
9. Oleanolic acid     
10. Sitosterol  
11. Fenchone 
12. α-pinene  
13. Limonene  
14. β-Pinene  
15. β-Myrcene  
16. α-Phellandrene  
17. P-Cymol  
18. Etc.


Xiu Hui Xiang (Fennel) used in the treatment of symptoms of neurodegenerative disorder, including age-related mental problems of Alzheimer's disease(1246)) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals in acetylcholinesterase inhibition(1246) and anti inflammation(1247) through suppression of the nuclear factor-kappaB activation pathway(1247) involved stress, cell signaling, free
                                                         98


radicals, oxidized LDL activities(1248)(1249)(1250)(1251).

1. In anxiolytic activity
Anxiety is a condition of neurodisorder of unpleasant state of inner turmoil with fear of the presence and future, according to Diagnostic and Statistical Manual of Mental Disorders American Psychiatric Association, effecting patients with dementia, included familial Alzheimer's disease(1252) and other neuropsychiatric disorders(1254). Fennel, a medical herb used in many cultures, has shown effectively in treating anxiety, epidemiologically. In adult Swiss albino male mice, oral administration 100 and 200 mg/kg doses of fennel essential oil significantly increased percent number of entries and time spent in open arms in elevated plus maze (EPM) test(1255).


2. In learning and memory
Fennels, the most widely used herbal plant in the world(1256) used in traditional Iranian medicine and modern phytotherapy for memory enhancing(1257).  In Alzheimer's disease, induced a decline of cognitive abilities in mice model, fennel extract successfully ameliorated the amnesic effect of scopolamine (0.4 mg/kg) and aging- induced memory deficits in 8 days in dose-depend manner, through increased step-down latency and acetylcholinesterase inhibition(1258).


3. Da Suan(Garlic)
3. Da Suan(Garlic) used in the treatment of symptoms of dementia(1283)(1284)(1285), including Alzheimer's pathophysiology(1288)(1289) in traditional Chinese medicine, may be due to its effectiveness of phytochemicals aged garlic extract and S-allyl-L-cysteine and extracts(1284) in oxidative stress inhibition(1284) and anti progression involved association of degeneration and neuro inflammatory activity(1286) through neuro protection against amyloid-beta peptide-induced apoptosis(1285) and toxicity(1287).

3.1. In Alzheimer's disease
Strong evidences suggested that deposited amyloid-beta(Abeta) has shown
                                                    99


to associate to the progression in Alzheimer's disease (AD)(1290)(1291)(1292). In mouse model induced by neurotoxic amyloid beta protein (Aβ), ethyl acetate fractions of garlic extract exhibited high levels of radical scavenging activity involved cognitive impairment against Aβ-induced neuronal deficit and  Aβ-induced learning and memory deficits in vivo(1293). According to Indiana University School of Medicine, the extracts also attenuated synaptic degeneration and neuroinflammatory pathways associated with AD, through major phytochemical S-allyl-L-cysteine (SAC) (1294), including oxidative insults to neurons(1295). In Alzheimer's transgenic model Tg2576, dietary aged garlic extract (AGE) (2%) exhibited anti-amyloidogenic, anti-inflammatory and anti-tangle effects also through its phytochemicals S-allyl-cysteine (SAC) (20 mg/kg) and di-allyl-disulfide (DADS)(1296) without interfering with its antibiotic activity in ameliorate gentamicin (GM)(1297).

3.2. In Parkinson disease
 Olfactory dysfunction(1298)(1299) in non-motor functioning and hyposmia(1300)(1301)/anosmia(1302)(1303) are common manifestation in some neurodegenerative disorders caused by oxidative stress (OS) and inflammatory insults(1305), including Parkinson disease. Dietary supplement S-methyl-L-cysteine, a substrate in the catalytic antioxidant system mediated by MSRA showed to protect cells from oxidative damage through its antioxidative effect(1304) when used conjunction with methionine sulfoxide reductase A in Parkinson's-like symptoms(1304).

3.3. In Cognitive impairment
In early cognitive deficits caused by gradual accumulation of beta-amyloid peptide (Abeta) oligomers of Abeta42 species, aged garlic extract, in mice model, prevented progressive behavioral impairment, slowed plaque development, through protection against deterioration of hippocampal based memory(1306), In Alzheimer's disease induced mice model, S-allyl cysteine, a component of aged garlic extract, ameliorated cognitive deficits and oxidative damage in the hippocampus of intracerebroventricular streptozotocin (ICV-STZ)(1308). According to Gyeongsang National University, the effectiveness of aged garlic extracts, in neurodegenerative disorders, notably Alzheimer's disease(AD), may be due to its antioxidant activities in improvement of cognitive impairment against Aβ-induced
                                                         100


neuronal deficit(1307).

3.4. In learning and memory
Acute and chronic oral administration of aged garlic extract, in mice using step down latency (SDL) by passive avoidance response and transfer latency (TL) using elevated plus maze, improved learning and memory probably due to cortical acetylcholinesterase (AchE) and reduced glutathione (GSH) levels activities and anti-oxidant property(1309). In oxidative damage and spatial learning and memory deficits induced mice model, S-allylcysteine exerted its protective effect against reactive oxygen species. Abeta(25-35)-induced hippocampal toxicity and learning deficits, through its free radical  scavenging and ameliorated lipid peroxidation activities(1310).

 C.5.2. Dementia due to aging depletion of Kidney Essence
Aging related to gradual lost of kidney essence effects the bone and bone marrow in production of red blood cells causes of nutrients and oxygen deficiency in the brain in induction of symptoms of dementia(1311)(1312).
1. Dong Chong Cao(Cordyceps)
Dong Chong Cao, the sweet and warm herb, is also known as cordyceps, used in traditional Chinese medicine as anti-arrhythmia, anti-rejection in cornea transplant, antimicrobal effects and to attenuate contraction of smooth muscles, protect against toxins induced kedney and liver diseases, treat chronic lower back pain, impotence, chronic cough and wheezing, blood in phlegm,... as its tonifies lung yin and kidney yang by enhancing the functions of lung and kidney channels(1313).

Phtochemicals
1. Cordyceps polysaccharide
2. Ergosterol
3. Cordycepic acid
4.  Lysine
5. Aspartic acid
6. Threonine
7. Taurine
8. Etc.
 
                                                           101


In  ivitro and in vivo model of Alzheimer's disease, methanol extracts of dong chon cao, prevented the beta-amyloid((25-35) induced neuro cell death(1314) and in rat model of ADs, its phytochemical ophioglossoides significantly prevented spatial memory loss by intracranial injection of Abeta(1314), probably through its free radical scavenging activity(1314).

2.  Shi Hu(Dendrobium)
The sweet, bland, slightly cold herb, is also known as Dendrobiu, used in traditional Chinese medicine as anti diabetic(1315)(1316), anti-hyperglycemic((1317)(1318))and anti microbial(1319)(1320) agents caused by yin deficiency and to treat thirsty(1315)(1316), thromboangitis obliterans, chronic throat infection, blurry vision(1321)(1322), weak lower back,... by enhancing the lung, stomach channels(1323).

Phytochemicals
1. Ophiopogonin 
2. Ruscogenin 
3. β-sitosterol β
4. Stigmasterol 
5. Dendrobine 
6. Nobilonine 
7. 6-hydroxydendrobine 
8. Etc.

According to Zunyi Medical College,  alkaloids enriched extract from Dendrobium Nobile Lindl. (EDNLA), inhibited paired helical filaments of  hyperphosphorylation of tau protein, in neurofibrillary tangles, a pathological feature of Alzheimer's disease (AD)(1324). In rat model administrated intragastrically with different doses of DNLA (20, 40 mg/kg), attenuated lipopolysaccharide (LPS, 100 μg) injecting into the bilateral ventricle, induced hyperphosphorylation of tau protein in hippocampus and protected against LPS-induced apoptosis in brain(1325).

3. Du Zhong(Eucommia bark)
Du Zhong, the sweet, slightly acrid, and warm, is also known as eucommia bark, used in traditional Chinese medicine as anti stress(1325)(1326), anti
                                                     102


diuretic(1336), anti inflammatory(1327)(1328), anti infectious(1329), sedative and anesthesia and anti-aging(1336) agents and to treat hypertension(1330)(1331), chronic pain in lower back and knees(1332)(1336), lack of strength, dizziness, impotence(1337), irregular menses and frequent urination(1336) and protect against unstable pregnancy(1336),.... by enhancing the functions of liver and kidney channels(1333).


Phytochemicals
1. Eucommiol 
2. Eucommioside 
3. Eucommioside-I
4. Cpmoferom
5. Dehydrodiconife4ryl alcohol-4
6. Gamma'-di-O0betta-D-glucopyranoside
7. Liriodendrin
8. (+) -syringaresinol-di-O-Beta-D-glucopyranoside
9. (+)-syringa resinol  O-Beta-D-glucopyranoside
10. (+)-syringaresinol monoglucoside
11. syringin
12. Etc.

1. In learning and memory
In scopolamine-induced learning and memory impairments by a single intracerebroventricular (i.c.v.) injection of Aβ(25-35) mice models, oral administration of aqueous extract of Eucommia bark or the whole  herb significantly reversed learning and memory deficits, through  inhibition of acetylcholinesterase (AChE)(1335) and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus and frontal cortex in a dose-dependent manner(1334)(1335).

2. In Alzheimer's disease (AD)
In hydrogen peroxide (H(2)O(2))-induced neuronal cell death in human SH-SY5Y neuroblastoma cells, eucommia ulmoides Oliv. Bark. (EUE), increased cell viability and inhibited cytotoxicity and DNA condensation, through attenuated the increase in ROS production and MMP
                                                       103

involved increased risk of dementia reduction(1337).

3. In neuroprotective effects
In PC-12 cells injury mediated by Aβ(25-35) eucommia ulmoides Oliv. (EUO) bark and leaf's phytochemicals, geniposidic acid and chlorogenic acid, significantly protected PC-12 cells against the cytotoxicity(1338). In amyloid beta(25-35) (Aβ(25-35))-induced learning and memory impairments mice
model, the herb laso exhibited neuroprotective effects through inhibition of acetylcholinesterase (AChE) activity in the hippocampus and frontal cortex(1235).

4. Huang qi(Astragalus)
Huang qi, the slightly sweet herb, is also known as astragalus root used in traditional Chinese medicine as immune stimulant(1339)(1342)(1343), tonic(1339)(1344), antioxidant(1339)(1341), hepatoprotectant(1339)(1345)(1346), diuretic(1339), antidiabetic(1339)(1347)(1348), anticancer(1339)(1349)(1350)(1351), expectoran(1339)(1352) and antibiotics(1340) agents and to lessen proteinuria in chronic kidney diseases(1353)(1354), lower blood pressure(1355)(1356) and endothelial dysfunction(1356),  improve endurance and protect liver against diseases(1357)(1358),... by enhancing the functions of lung and spleen channels(1359).

Phytochemicals 
1. Astralagus menbranaceus
2. Astragaloside I
3. Astragaloside II
4. Daucosterol
5. Beta-sitosterol
6. Palmitic acid
7. Astragalus saponin A,B,C
8. Astramenbrangenin
9. Etc.

Huang qi(Astragalus root) used in the treatment of symptoms of dementia(1360)(1261))(1362)(1362), including Alzheimer's
                                                   104

pathophysiology(1363) in traditional Chinese medicine, may be due to its effectiveness of phytochemical astragalosides (AST) and extracts(1365)(1363) in oxidative stress inhibition(1363) and anti progression associated to neuronal cell apoptosis(1363) through inhibiting acetylcholinesterase activity(1364), level glucocorticoids (GCs) and β-amyloid (Aβ) peptide deposition(1367) and decreasing the expression level of amyloid precursor protein (APP) in cerebral cortex and hippocampus(1365)(1366), ROS generation and neurotoxicity(1368)(1369). 

4.1. In learning and memory
Polysaccharides (APS), isolated from Astragalus, in aging female SD rats model, according to  the open-field test and the Morris water maze task, improved  learning and memory functions of aged rats through up-regulation in the hippocampus neural protein expression(1370). In rats induced neurologic damage of hippocampus by electromagnetic field (EMF) acute or chronic irradiation, Chinese medicine diet (CMD) comprised ferulic acid, ginsenoside, astragalus polysaccharide and rhodiola sachalinensis, showed to protect the impaired learning and memory, the neuron apoptosis, through ameliorating superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and reactive oxygen species (ROS)(1371). In intermittent hypoxia-induced hippocampal neurons impairment rats, astragaloside IV, astragaloside II and astragaloside I, the main compounds in Astragalus extract inhibited the apoptosis of hippocampal neurons, decreased the expression of protein level involved imapair learning and memory(1372). According to Anhui Medical University, learning and memory impairments and neurons' apoptosis induced by glucocorticoids in 12-month-old male mice model, extract of Astragalus, improved learning and memory impairments and prevented  neuronal cell apoptosis, through increased immunohistochemistry demonstration in hippocampus and neocortex and decreased activity of mitochondrial death pathway causes of neron cell death(1373).

4.2. In Alzheimer's and Parkinson disease 
Mitochondrial dysfunction caused by amyloid β-peptide (Aβ) and stress-level glucocorticoids correlated with dementia progression have shown to associate to  the pathogenesis of Alzheimer disease(1374)(1375). Astragaloside IV (AS-IV), one of the major active constituents of Astragalus and extract of Astragalus, prevented Aβ1-42-induced neuron cell apoptosis,
                                                        105


and ROS generation(1374) and down regulate the protein level builds up as Alzheimer's disease progresses, involved degeneration of hippocampus (CA1, CA3) and neocortex(1375).
According to Heilongjiang University of Chinese Medicine, Astragalus, one of the herb used in traditional Chinese medicine for treatment neuro degenerative diseases showed to modulate multiple key events or signaling pathways implicated in the pathogenesis of PD(1376), probably through its phytochemical Astragaloside IV in promoted neurite outgrowth and increased  immunoreactive of dopaminergic neurons caused by ROS(1377).

4.3. In neuroprotective effects 
In experimental subarachnoid hemorrhage induced early brain injury rat model, Astragaloside IV, exerted its antioxidative and anti-apoptotic effects(1378)(1379), against increased malondialdehyde (MDA) level, neuronal apoptosis and decreased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)(1378). Myelophil, a combination of extracts isolated from Astragali Radix and Salviae Miltiorrhizae Radix, in brain dysfunctions animal model, also exhibited its anti oxidative stress, ROS activity through attenuated total glutathione (GSH) content, and the activities of GSH-reductase, GSH-S-transferase via ameliorated protein and gene expression(1380) and inflammation and regulating stress hormones(1381).



References
(a)
http://www.ncbi.nlm.nih.gov/pubmed/21790207
(b) http://www.ncbi.nlm.nih.gov/pubmed/20226390
(c) http://www.ncbi.nlm.nih.gov/pubmed/14584018
(d) http://www.ncbi.nlm.nih.gov/pubmed/12918012
(e) http://www.ncbi.nlm.nih.gov/pubmed/14584010
(f) http://www.ncbi.nlm.nih.gov/pubmed/22503992
(g) http://www.ncbi.nlm.nih.gov/pubmed/16024298
(h) http://www.ncbi.nlm.nih.gov/pubmed/15478038
(i) http://www.ncbi.nlm.nih.gov/pubmed/11461164
(j) http://www.ncbi.nlm.nih.gov/pubmed/19665809
25 =43

(59)

(73)
(145)

(201)

(208)

(232) http://www.ncbi.nlm.nih.gov/pubmed/25280422
(233) http://www.ncbi.nlm.nih.gov/pubmed/24814729
(224) http://www.ncbi.nlm.nih.gov/pubmed/25501153
(225) http://www.ncbi.nlm.nih.gov/pubmed/25511255 
(226) http://www.ncbi.nlm.nih.gov/pubmed/25052430
(227) http://www.ncbi.nlm.nih.gov/pubmed/25498860
(228) http://www.ncbi.nlm.nih.gov/pubmed/25464026
(229) http://www.ncbi.nlm.nih.gov/pubmed/20655381
(230) http://www.ncbi.nlm.nih.gov/pubmed/24921009
(231) http://www.ncbi.nlm.nih.gov/pubmed/6284006
(232) http://www.ncbi.nlm.nih.gov/pubmed/25089372
(233) http://www.ncbi.nlm.nih.gov/pubmed/4014070
(234) http://www.ncbi.nlm.nih.gov/pubmed/6830706
(235) http://www.ncbi.nlm.nih.gov/pubmed/18191543
(236) http://www.ncbi.nlm.nih.gov/pubmed/17459943 
(237) http://www.ncbi.nlm.nih.gov/pubmed/19428486
(238) http://www.ncbi.nlm.nih.gov/pubmed/23891969
(239) http://www.ncbi.nlm.nih.gov/pubmed/22155779
(240) http://www.ncbi.nlm.nih.gov/pubmed/21847071
(241) http://www.ncbi.nlm.nih.gov/pubmed/25282173
(242) http://www.ncbi.nlm.nih.gov/pubmed/15222464
(243) http://www.ncbi.nlm.nih.gov/pubmed/22304665
(244) http://www.ncbi.nlm.nih.gov/pubmed/11052766
(245) http://www.ncbi.nlm.nih.gov/pubmed/25528420
(246) http://www.ncbi.nlm.nih.gov/pubmed/18561335
(247) http://www.ncbi.nlm.nih.gov/pubmed/16872588
(248) http://www.ncbi.nlm.nih.gov/pubmed/1342190
(249) http://www.ncbi.nlm.nih.gov/pubmed/24493013
(250) http://www.ncbi.nlm.nih.gov/pubmed/25504720
(251) http://www.ncbi.nlm.nih.gov/pubmed/12476940
(252) http://www.ncbi.nlm.nih.gov/pubmed/22119572
(253) http://www.ncbi.nlm.nih.gov/pubmed/7298642
(254) http://www.ncbi.nlm.nih.gov/pubmed/7925932
(255) http://www.ncbi.nlm.nih.gov/pubmed/23820271
(256) http://www.ncbi.nlm.nih.gov/pubmed/12683610
(257) http://www.ncbi.nlm.nih.gov/pubmed/24905914
(258) http://www.ncbi.nlm.nih.gov/pubmed/24815022
(259) http://www.ncbi.nlm.nih.gov/pubmed/20003712
(260) http://www.ncbi.nlm.nih.gov/pubmed/15756816
(260) http://www.ncbi.nlm.nih.gov/pubmed/1575681
(261) http://www.ncbi.nlm.nih.gov/pubmed/24885788
(262) http://www.ncbi.nlm.nih.gov/pubmed/24885788
(263) http://www.ncbi.nlm.nih.gov/pubmed/24151358
(264) http://www.ncbi.nlm.nih.gov/pubmed/19754364
(265) http://www.ncbi.nlm.nih.gov/pubmed/22438843
(266) http://www.ncbi.nlm.nih.gov/pubmed/16534775
(267) http://www.ncbi.nlm.nih.gov/pubmed/8621054
(268) http://www.ncbi.nlm.nih.gov/pubmed/24448787
(269) http://www.ncbi.nlm.nih.gov/pubmed/24582848
(270) http://www.ncbi.nlm.nih.gov/pubmed/17665093
(271) http://www.ncbi.nlm.nih.gov/pubmed/8127329
(272) http://www.ncbi.nlm.nih.gov/pubmed/7959271
(273) http://www.ncbi.nlm.nih.gov/pubmed/8529916
(274) http://www.ncbi.nlm.nih.gov/pubmed/12630889
(275) http://www.ncbi.nlm.nih.gov/pubmed/23867235
(276) http://www.ncbi.nlm.nih.gov/pubmed/16633732
(277) http://www.ncbi.nlm.nih.gov/pubmed/24707875
(278) http://www.ncbi.nlm.nih.gov/pubmed/10959944
(279) http://www.ncbi.nlm.nih.gov/pubmed/25515512
(280) http://www.ncbi.nlm.nih.gov/pubmed/11515807
(281) http://www.ncbi.nlm.nih.gov/pubmed/15189992
(282) http://www.ncbi.nlm.nih.gov/pubmed/25519577
(283) http://www.ncbi.nlm.nih.gov/pubmed/12528889
(284) http://www.ncbi.nlm.nih.gov/pubmed/10660664
(285) http://www.ncbi.nlm.nih.gov/pubmed/17936517
(286) http://www.ncbi.nlm.nih.gov/pubmed/24662164
(287) http://www.ncbi.nlm.nih.gov/pubmed/24583267
(288) http://www.ncbi.nlm.nih.gov/pubmed/10926898
(289) http://www.ncbi.nlm.nih.gov/pubmed/25451926
(290) http://www.ncbi.nlm.nih.gov/pubmed/24388327
(291) http://www.ncbi.nlm.nih.gov/pubmed/1444060
(292) http://www.ncbi.nlm.nih.gov/pubmed/1444060
(293) http://www.ncbi.nlm.nih.gov/pubmed/23177992
(294) http://www.ncbi.nlm.nih.gov/pubmed/12841645
(295) http://www.ncbi.nlm.nih.gov/pubmed/6604680
(296) http://www.ncbi.nlm.nih.gov/pubmed/20515554
(297) http://www.ncbi.nlm.nih.gov/pubmed/24766384
(298) http://www.ncbi.nlm.nih.gov/pubmed/23988864
(299) http://www.ncbi.nlm.nih.gov/pubmed/13701588
(300) http://www.ncbi.nlm.nih.gov/pubmed/10385606
(301) http://www.ncbi.nlm.nih.gov/pubmed/11579997
(302) http://www.ncbi.nlm.nih.gov/pubmed/24524083
(303) http://www.ncbi.nlm.nih.gov/pubmed/1897277
(304) http://www.ncbi.nlm.nih.gov/pubmed/15593395
(305) http://www.ncbi.nlm.nih.gov/pubmed/25460513
(306)
(353 - 366)

(382)

(406) http://www.ncbi.nlm.nih.gov/pubmed/23862185
(407) http://www.ncbi.nlm.nih.gov/pubmed/23728651
(408) http://www.ncbi.nlm.nih.gov/pubmed/19370562
(409) http://www.ncbi.nlm.nih.gov/pubmed/17636619
(410) http://www.ncbi.nlm.nih.gov/pubmed/10796507
(411) http://www.ncbi.nlm.nih.gov/pubmed/16856114
(412) http://www.ncbi.nlm.nih.gov/pubmed/16437430

(413) http://www.ncbi.nlm.nih.gov/pubmed/12517232
(414) http://www.ncbi.nlm.nih.gov/pubmed/19845950
(415) http://www.health.gov.bc.ca/pharmacare/adti/clinician/cholinesterase.html
(416) http://alzonline.phhp.ufl.edu/en/reading/mmi_cholinesterase.php
(417) http://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor
(418) http://www.ncbi.nlm.nih.gov/pubmed/25523430
(419) http://www.ncbi.nlm.nih.gov/pubmed/25523285
(420) http://www.ncbi.nlm.nih.gov/pubmed/10465680

(421) http://www.ncbi.nlm.nih.gov/pubmed/21875407
(422) http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003154.pub4/abstract;jsessionid=81B82BC5B10FAB9959A92CF39D439C21.d02t02
(423) http://www.medicinenet.com/memantine-oral/page2.htm
(424) http://en.wikipedia.org/wiki/Memantine
(425) http://www.ncbi.nlm.nih.gov/pubmed/23996793
(426) http://www.ncbi.nlm.nih.gov/pubmed/25479151
(427) http://www.ncbi.nlm.nih.gov/pubmed/20096151
(428) http://www.ncbi.nlm.nih.gov/pubmed/24565570
(429) http://www.ncbi.nlm.nih.gov/pubmed/23926248
(430) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385944/
(431) http://www.ncbi.nlm.nih.gov/pubmed/19557550
(432) http://www.webmd.com/bipolar-disorder/anticonvulsant-medication 
(433) http://en.wikipedia.org/wiki/Anticonvulsant 
(434) http://www.ncbi.nlm.nih.gov/pubmed/24552479
(435) http://www.ncbi.nlm.nih.gov/pubmed/18690999
(436) http://www.ncbi.nlm.nih.gov/pubmed/18311185
(437) http://www.ncbi.nlm.nih.gov/pubmed/20980585
(438) http://en.wikipedia.org/wiki/Sedative 
(439) http://www.ncbi.nlm.nih.gov/pubmed/19192442
(440) http://www.ncbi.nlm.nih.gov/pubmed/15738743
(441) http://www.ncbi.nlm.nih.gov/pubmed/25177490
(442) http://www.ncbi.nlm.nih.gov/pubmed/24497254
(443) http://www.ncbi.nlm.nih.gov/pubmed/23737423
(444) http://www.ncbi.nlm.nih.gov/pubmed/19735591
(445) http://www.webmd.com/depression/features/coping-with-side-effects-of-depression-treatment
(446) http://www.ncbi.nlm.nih.gov/pubmed/23582065
(447) http://www.ncbi.nlm.nih.gov/pubmed/20364001
(448) http://www.ncbi.nlm.nih.gov/pubmed/25201422
(449) http://www.ncbi.nlm.nih.gov/pubmed/23157990
(450) http://www.ncbi.nlm.nih.gov/pubmed/14974055
(451) http://www.ncbi.nlm.nih.gov/pubmed/22332852
(452) http://www.ncbi.nlm.nih.gov/pubmed/3596452
(453) http://www.ncbi.nlm.nih.gov/pubmed/3368823
(454) http://www.ncbi.nlm.nih.gov/pubmed/21440532
(455) http://www.healthline.com/health/wernicke-korsakoff-syndrome

(456) http://www.helpguide.org/elder/parkinsons_disease.htm
(457) http://www.ncbi.nlm.nih.gov/pubmed/17726913
(458) http://www.ncbi.nlm.nih.gov/pubmed/20642073
(459) http://www.ncbi.nlm.nih.gov/pubmed/18787880
(460) http://www.ncbi.nlm.nih.gov/pubmed/11481130
(461) http://www.ncbi.nlm.nih.gov/pubmed/25310742
(462) http://www.ncbi.nlm.nih.gov/pubmed/22208450
(463) http://www.ncbi.nlm.nih.gov/pubmed/20687121
(464) http://www.ncbi.nlm.nih.gov/pubmed/23205015
(465) http://www.ncbi.nlm.nih.gov/pubmed/20687121
(466) http://www.ncbi.nlm.nih.gov/pubmed/25514999
(467) http://www.ncbi.nlm.nih.gov/pubmed/16437430
(468) http://www.ncbi.nlm.nih.gov/pubmed/25478019
(469) http://www.ncbi.nlm.nih.gov/pubmed/24035407
(470) http://www.ncbi.nlm.nih.gov/pubmed/24993765
(471) http://www.ncbi.nlm.nih.gov/pubmed/25151200
(472) http://www.ncbi.nlm.nih.gov/pubmed/17606657
(473) http://www.ncbi.nlm.nih.gov/pubmed/17557339
(474) http://www.ncbi.nlm.nih.gov/pubmed/25479834
(475) http://www.ncbi.nlm.nih.gov/pubmed/4005867
(476) http://www.ncbi.nlm.nih.gov/pubmed/2939412
(477) http://www.ncbi.nlm.nih.gov/pubmed/25486996
(478) http://www.ncbi.nlm.nih.gov/pubmed/15509203
(479) http://www.ncbi.nlm.nih.gov/pubmed/17876852
(480) http://www.ncbi.nlm.nih.gov/pubmed/22021174
(481) http://www.ncbi.nlm.nih.gov/pubmed/9617717
(482) http://www.ncbi.nlm.nih.gov/pubmed/15453556
(483) http://www.ncbi.nlm.nih.gov/pubmed/25454802 
(484) http://www.ncbi.nlm.nih.gov/pubmed/20175406
(485) http://www.ncbi.nlm.nih.gov/pubmed/11828891
(486) http://www.ncbi.nlm.nih.gov/pubmed/17708127
(487) http://www.ncbi.nlm.nih.gov/pubmed/16142993
(488) http://www.neurology.org/content/74/11/924.full
(489) http://www.ncbi.nlm.nih.gov/pubmed/22021173
(490) http://www.ncbi.nlm.nih.gov/pubmed/10895396
(491) http://www.ncbi.nlm.nih.gov/pubmed/11978145 
(492) http://www.ncbi.nlm.nih.gov/pubmed/22500116
(493) http://www.ncbi.nlm.nih.gov/pubmed/25385556
(494) http://www.ncbi.nlm.nih.gov/pubmed/20123557
(495) http://www.ncbi.nlm.nih.gov/pubmed/25495896
(496) http://www.ncbi.nlm.nih.gov/pubmed/23861646
(497) http://www.ncbi.nlm.nih.gov/pubmed/17941456
(498) http://www.ncbi.nlm.nih.gov/pubmed/24834511
(499) http://www.ncbi.nlm.nih.gov/pubmed/10816186
(500) http://www.ncbi.nlm.nih.gov/pubmed/24399580
(501) http://www.ncbi.nlm.nih.gov/pubmed/24547918
(502) http://www.ncbi.nlm.nih.gov/pubmed/6932044
(503) http://www.ncbi.nlm.nih.gov/pubmed/17630819
(504) http://www.ncbi.nlm.nih.gov/pubmed/23250679
(505) http://www.ncbi.nlm.nih.gov/pubmed/25322951
(506) http://www.ncbi.nlm.nih.gov/pubmed/25345997
(507) http://www.ncbi.nlm.nih.gov/pubmed/11254768
(508) http://www.ncbi.nlm.nih.gov/pubmed/11606671
(509) http://www.ncbi.nlm.nih.gov/pubmed/14628395
(510) http://drugs.webmd.boots.com/drugs/drug-284-Macrogol+Compound+Npf.aspx 
(511) http://www.rxlist.com/ritalin-side-effects-drug-center.htm
(512) http://www.drugs.com/sfx/modafinil-side-effects.html 
(513) http://www.ncbi.nlm.nih.gov/pubmed/23225013
(514) http://www.ncbi.nlm.nih.gov/pubmed/22196171
(515) http://www.ncbi.nlm.nih.gov/pubmed/22810280
(156) http://www.ncbi.nlm.nih.gov/pubmed/23436051
(517) http://www.ncbi.nlm.nih.gov/pubmed/8287472
(518) http://www.ncbi.nlm.nih.gov/pubmed/7767493
(519) http://www.ncbi.nlm.nih.gov/pubmed/24704099
(520) http://www.ncbi.nlm.nih.gov/pubmed/12506094
(521) http://www.ncbi.nlm.nih.gov/pubmed/21980750
(522) http://www.ninds.nih.gov/disorders/cjd/detail_cjd.htm#186463058
(523) http://www.ncbi.nlm.nih.gov/pubmed/23207489
(524) http://www.ncbi.nlm.nih.gov/pubmed/12733424
(525) http://www.ncbi.nlm.nih.gov/pubmed/20978903
(526) http://www.ncbi.nlm.nih.gov/pubmed/10456721
(527) http://www.ncbi.nlm.nih.gov/pubmed/11781885
(528) http://www.britannica.com/EBchecked/topic/290335/interleukin-IL
(529)  http://www.ncbi.nlm.nih.gov/pubmed/16216944
(530) http://www.ncbi.nlm.nih.gov/pubmed/25579391
(531) http://www.ncbi.nlm.nih.gov/pubmed/17612048
(532) http://www.ncbi.nlm.nih.gov/pubmed/15453089
(533) http://www.ncbi.nlm.nih.gov/pubmed/16101543
(534) http://www.cjd.ed.ac.uk/TREAT.htm
(535) Atabrine package insert (Winthrop—US), Rev 8/85, Rec 9/8/87.
(536) http://www.ncbi.nlm.nih.gov/pubmed/24122181
(537) http://www.ncbi.nlm.nih.gov/pubmed/19278902
(538) http://www.ncbi.nlm.nih.gov/pubmed/24122181
(539) http://www.ncbi.nlm.nih.gov/pubmed/15623716
(540) http://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid
(541) http://www.ncbi.nlm.nih.gov/pubmed/25577325
(542) http://www.ncbi.nlm.nih.gov/pubmed/12373445
(543) http://www.ncbi.nlm.nih.gov/pubmed/16325649
(544) http://www.ncbi.nlm.nih.gov/pubmed/25224156
(545) http://www.ncbi.nlm.nih.gov/pubmed/24313607
(546) http://www.ncbi.nlm.nih.gov/pubmed/19139303
(546) http://www.ncbi.nlm.nih.gov/pubmed/25367584
(547) http://www.ncbi.nlm.nih.gov/pubmed/24049555
(548) http://www.ncbi.nlm.nih.gov/pubmed/24784316
(549) http://emedicine.medscape.com/article/828005-overview
(550) http://www.ncbi.nlm.nih.gov/pubmed/25142860
(551) http://www.ncbi.nlm.nih.gov/pubmed/19570326
(552) http://www.ncbi.nlm.nih.gov/pubmed/23066609
(553) http://emedicine.medscape.com/article/1137207-treatment
(554) http://www.ncbi.nlm.nih.gov/pubmed/4817809
(555) http://www.ncbi.nlm.nih.gov/pubmed/12020522
(556) http://www.ncbi.nlm.nih.gov/pubmed/7936130
(557) http://en.wikipedia.org/wiki/Methylprednisolone
(558) http://www.ncbi.nlm.nih.gov/pubmed/15782554
(559) http://www.ncbi.nlm.nih.gov/pubmed/22286794 
(560) http://www.ncbi.nlm.nih.gov/pubmed/23744552
(561) http://www.ncbi.nlm.nih.gov/pubmed/8229039
(562) http://www.ncbi.nlm.nih.gov/pubmed/8213276
(563) http://en.wikipedia.org/wiki/Rifampicin
(564) http://www.ncbi.nlm.nih.gov/pubmed/19782872
(565) http://www.ncbi.nlm.nih.gov/pubmed/19960218
(566) http://www.ncbi.nlm.nih.gov/pubmed/20827562
(567) http://ijpr.sbmu.ac.ir/?_action=articleInfo&article=1112
(568) http://en.wikipedia.org/wiki/Craniotomy
(569) http://www.ncbi.nlm.nih.gov/pubmed/19960218
(570) http://www.ncbi.nlm.nih.gov/pubmed/14565521 (571)http://www.ninds.nih.gov/disorders/multi_infarct_dementia/multi_infarct_dementia.htm
(572) http://www.ncbi.nlm.nih.gov/pubmed/22705146
(573) http://www.ncbi.nlm.nih.gov/pubmed/22164676
(574) http://jgp.sagepub.com/content/8/2/96.abstract
(575) http://www.ncbi.nlm.nih.gov/pubmed/3046450
(576) http://www.ncbi.nlm.nih.gov/pubmed/21365068
(577)  http://www.aafp.org/afp/2003/0601/p2335.html 
(578) http://www.ncbi.nlm.nih.gov/pubmed/25547900
(579) http://www.ncbi.nlm.nih.gov/pubmed/25507889
(580) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203606/
(581) http://www.ncbi.nlm.nih.gov/pubmed/23896958
(582) http://www.ncbi.nlm.nih.gov/pubmed/21543954
(583) http://www.ncbi.nlm.nih.gov/pubmed/23472837
(584) http://www.ncbi.nlm.nih.gov/pubmed/17927296
(585) http://www.ncbi.nlm.nih.gov/pubmed/301148
(586) http://www.ncbi.nlm.nih.gov/pubmed/3252876
(587) http://www.ncbi.nlm.nih.gov/pubmed/23684446
(588) http://www.ncbi.nlm.nih.gov/pubmed/18184948
(589) http://www.ncbi.nlm.nih.gov/pubmed/23728651
(590) http://www.ncbi.nlm.nih.gov/pubmed/15846730
(682) http://www.ncbi.nlm.nih.gov/pubmed/23055633
(683) http://www.ncbi.nlm.nih.gov/pubmed/20657497
(684) http://www.ncbi.nlm.nih.gov/pubmed/17022438
(685) http://www.ncbi.nlm.nih.gov/pubmed/25359561
(686) http://www.ncbi.nlm.nih.gov/pubmed/24828945
(687) http://www.ncbi.nlm.nih.gov/pubmed/24624670
(688) http://www.ncbi.nlm.nih.gov/pubmed/24378710
(688) http://www.medscape.com/viewarticle/424604_5
(689) http://www.ncbi.nlm.nih.gov/pubmed/24378710
(690) http://www.ncbi.nlm.nih.gov/pubmed/25206513
(691) http://www.ncbi.nlm.nih.gov/pubmed/25206513
(692) http://www.ncbi.nlm.nih.gov/pubmed/24660032
(693) http://www.ncbi.nlm.nih.gov/pubmed/25525597
(694) http://www.ncbi.nlm.nih.gov/pubmed/19090994
(695) http://www.ncbi.nlm.nih.gov/pubmed/25315300
(694) http://www.ncbi.nlm.nih.gov/pubmed/25281824
(695) http://www.ncbi.nlm.nih.gov/pubmed/25277322
(696) http://www.ncbi.nlm.nih.gov/pubmed/20026275
(697) http://www.ncbi.nlm.nih.gov/pubmed/19705549
(698) http://www.ncbi.nlm.nih.gov/pubmed/21195590
(699) http://en.wikipedia.org/wiki/GSK-3
(700) http://en.wikipedia.org/wiki/TCF/LEF_family
(701) http://en.wikipedia.org/wiki/Cyclin_D1
(702) http://www.ncbi.nlm.nih.gov/pubmed/21639405
(703) http://www.ncbi.nlm.nih.gov/pubmed/23988025
(704) http://www.ncbi.nlm.nih.gov/pubmed/21774008
(705) http://www.ncbi.nlm.nih.gov/pubmed/10815004
(706) http://www.ncbi.nlm.nih.gov/pubmed/25163440
(707) http://www.ncbi.nlm.nih.gov/pubmed/19838862
(708) http://www.ncbi.nlm.nih.gov/pubmed/10189953
(709) http://www.ncbi.nlm.nih.gov/pubmed/21639405
(710) http://www.ncbi.nlm.nih.gov/pubmed/24860730
(*) http://www.hindawi.com/journals/ecam/2012/692621/ 
(711) http://www.ncbi.nlm.nih.gov/pubmed/23847967
(712) http://www.ncbi.nlm.nih.gov/pubmed/21347995
(713) http://www.ncbi.nlm.nih.gov/pubmed/24751506
(714) http://www.ncbi.nlm.nih.gov/pubmed/24875321
(715) http://www.ncbi.nlm.nih.gov/pubmed/?term=Poria+cocos+diarrhea
(716) http://www.ncbi.nlm.nih.gov/pubmed/19446542
(717) http://www.ncbi.nlm.nih.gov/pubmed/24933223
(718) http://www.ncbi.nlm.nih.gov/pubmed/15198902
(719) http://www.ncbi.nlm.nih.gov/pubmed/22303969
(720) http://www.ncbi.nlm.nih.gov/pubmed/23433049
(721) http://www.ncbi.nlm.nih.gov/pubmed/22303969
(722) http://www.ncbi.nlm.nih.gov/pubmed/21808655
(722) http://www.ncbi.nlm.nih.gov/pubmed/21305632
(723) http://www.ncbi.nlm.nih.gov/pubmed/20812276
(724) http://www.ncbi.nlm.nih.gov/pubmed/19801831
(725) http://www.ncbi.nlm.nih.gov/pubmed/15500267
(726) http://www.ncbi.nlm.nih.gov/pubmed/24041458 
(727) http://www.ncbi.nlm.nih.gov/pubmed/22310556
(728) http://www.ncbi.nlm.nih.gov/pubmed/15351791
(729) http://www.ncbi.nlm.nih.gov/pubmed/20685330
(730) http://www.ncbi.nlm.nih.gov/pubmed/20669372
(731) http://www.ncbi.nlm.nih.gov/pubmed/21762767
(732) http://www.ncbi.nlm.nih.gov/pubmed/22205352
(733) http://www.ncbi.nlm.nih.gov/pubmed/20541923
(734) http://www.ncbi.nlm.nih.gov/pubmed/?term=Yuan+zhi+tumors
(735) http://www.ncbi.nlm.nih.gov/pubmed/25386946
(736) http://www.ncbi.nlm.nih.gov/pubmed/21808655
(737) http://www.ncbi.nlm.nih.gov/pubmed/17268076
(738) http://www.ncbi.nlm.nih.gov/pubmed/21808655
(739) http://www.ncbi.nlm.nih.gov/pubmed/25386946
(740) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166352/
(741) http://en.wikipedia.org/wiki/Alpha-synuclein
(742) http://www.nature.com/hr/journal/v33/n5/full/hr201011a.html
(743) http://www.ncbi.nlm.nih.gov/pubmed/24248062
(744) http://www.ncbi.nlm.nih.gov/pubmed/17182613
(745) http://www.ncbi.nlm.nih.gov/pubmed/21195155
(746) http://www.ncbi.nlm.nih.gov/pubmed/18637946
(747) http://en.wikipedia.org/wiki/Cytoplasm
(748) http://www.wisegeek.com/what-are-organelles.htm
(749)http://www.ncbi.nlm.nih.gov/pubmed/?term=Radix+polygalae(+and+Huntinton+disease
(750) http://en.wikipedia.org/wiki/PC12_cell_line
(771) http://www.ncbi.nlm.nih.gov/pubmed/24521480
(772) http://www.ncbi.nlm.nih.gov/pubmed/21315572
(773) http://www.ncbi.nlm.nih.gov/pubmed/23746954
(774) http://www.ncbi.nlm.nih.gov/pubmed/16124612
(775) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174116/
(776) http://www.ncbi.nlm.nih.gov/pubmed/22700248
(777) http://www.ncbi.nlm.nih.gov/pubmed/22303969
(778) http://www.ncbi.nlm.nih.gov/pubmed/25386946
(779) http://www.ncbi.nlm.nih.gov/pubmed/21808655
(780) http://www.ncbi.nlm.nih.gov/pubmed/17268076
(781) http://www.ncbi.nlm.nih.gov/pubmed/20110895
(782) http://www.ncbi.nlm.nih.gov/pubmed/17889286
(783) http://www.ncbi.nlm.nih.gov/pubmed/23937197
(784) http://www.ncbi.nlm.nih.gov/pubmed/23022689
(785) http://www.ncbi.nlm.nih.gov/pubmed/21389625
(786) http://www.ncbi.nlm.nih.gov/pubmed/17637179
(787) http://www.ncbi.nlm.nih.gov/pubmed/15679317
(788) http://www.ncbi.nlm.nih.gov/pubmed/20669372
(789) http://www.ncbi.nlm.nih.gov/pubmed/21272180
(790) http://www.ncbi.nlm.nih.gov/pubmed/20812276
(791) http://www.ncbi.nlm.nih.gov/pubmed/19801831
(792) http://www.ncbi.nlm.nih.gov/pubmed/19409210
(793) http://www.ncbi.nlm.nih.gov/pubmed/17889286
(794) http://www.ncbi.nlm.nih.gov/pubmed/23022689
(795) http://www.ncbi.nlm.nih.gov/pubmed/17889286
(796) http://alternativehealing.org/di_huang.htm
(797) http://www.shen-nong.com/eng/herbal/dihuang.html
(798) http://www.ncbi.nlm.nih.gov/pubmed/22303969
(799) http://www.ncbi.nlm.nih.gov/pubmed/25386946
(800) http://www.ncbi.nlm.nih.gov/pubmed/21808655
(801) http://www.ncbi.nlm.nih.gov/pubmed/15287076
(802) http://www.ncbi.nlm.nih.gov/pubmed/10996445
(803) http://www.ncbi.nlm.nih.gov/pubmed/17268076
(804) http://www.ncbi.nlm.nih.gov/pubmed/24187876
(805) http://www.ncbi.nlm.nih.gov/pubmed/15139152
(806) http://www.ncbi.nlm.nih.gov/pubmed/15015384
(807) http://www.ncbi.nlm.nih.gov/pubmed/22313999
(808) http://www.ncbi.nlm.nih.gov/pubmed/22037419
(809) http://www.ncbi.nlm.nih.gov/pubmed/9740363
(810) http://www.ncbi.nlm.nih.gov/pubmed/23321886
(811) http://www.ncbi.nlm.nih.gov/pubmed/12003439
(812) http://www.ncbi.nlm.nih.gov/pubmed/21750784
(813) http://www.ncbi.nlm.nih.gov/pubmed/15949530
(814) http://www.ncbi.nlm.nih.gov/pubmed/23475732
(815) http://www.chineseherbshealing.com/deer-antler-velvet/
(816) http://www.ncbi.nlm.nih.gov/pubmed/24187879
(817) http://tcmbasics.com/zangfu_5zang_kidney.htm
(818) http://www.innerbody.com/image_digeov/card10-new2.html
(819) http://www.ncbi.nlm.nih.gov/pubmed/25244772
(820) http://www.dallasacu.com/articles/chinese-herb-pictures/eucommia-bark/
(821) http://fourflowerswellness.com/EAM/du-zhong/
(822) http://www.tcmwiki.com/wiki/ba-ji-tian
(823) http://www.americandragon.com/Individualherbsupdate/BaJiTian.html(824http://www.yinyanghouse.com/theory/herbalmedicine/ba_ji_tian_tcm_herbal_database
(824) http://cm-cure.com/Rou-Cong-Rong-Chinese-herbs
(825) http://herbprime.com/Cistanche%20Capsules%20(Rou%20Cong%20Rong%20)(NONE%20CITES)
(826) http://menstruationdisorders-51.blogspot.com.au/2009/11/overcome-infertility-how-to-treat.html
(827) http://www.tcmwiki.com/wiki/bu-gu-zhi
(828) http://qiherbs.com/bu-gu-zhi.html
(829) http://plantcures.com/buguzhi.html
(830) http://www.yinyanghouse.com/theory/herbalmedicine/bu_gu_zhi_tcm_herbal_database
(831) http://fourflowerswellness.com/EAM/bu-gu-zhi/
(832) http://www.ncbi.nlm.nih.gov/pubmed/24460377
(833) http://www.ncbi.nlm.nih.gov/pubmed/24404337
(834) http://www.ncbi.nlm.nih.gov/pubmed/20974223
(835) http://www.ncbi.nlm.nih.gov/pubmed/24440915
(836) http://www.ncbi.nlm.nih.gov/pubmed/7626209
(837) http://www.sciencedirect.com/science/article/pii/S0091305701007304
(838) http://www.ncbi.nlm.nih.gov/pubmed/20849880
(839) http://www.ncbi.nlm.nih.gov/pubmed/19788912
(840) http://www.ncbi.nlm.nih.gov/pubmed/25509270
(841) http://www.ncbi.nlm.nih.gov/pubmed/25277760
(842) http://www.ncbi.nlm.nih.gov/pubmed/25313575
(843) http://www.ncbi.nlm.nih.gov/pubmed/24224039
(844) http://www.ncbi.nlm.nih.gov/pubmed/23391905
(868) http://www.ncbi.nlm.nih.gov/pubmed/15035888
(869) http://www.ncbi.nlm.nih.gov/pubmed/18635912
(870) http://www.ncbi.nlm.nih.gov/pubmed/25625815
(871) http://www.ncbi.nlm.nih.gov/pubmed/19277659
(872) http://www.ncbi.nlm.nih.gov/pubmed/24979747
(873) http://www.ncbi.nlm.nih.gov/pubmed/23548988
(874) http://www.ncbi.nlm.nih.gov/pubmed/14737017
(875) http://www.ncbi.nlm.nih.gov/pubmed/15215639
(876) http://www.ncbi.nlm.nih.gov/pubmed/25442300
(877) http://www.ncbi.nlm.nih.gov/pubmed/24824453
(878) http://www.ncbi.nlm.nih.gov/pubmed/23147499
(879) http://www.ncbi.nlm.nih.gov/pubmed/19277974
(880) http://www.ncbi.nlm.nih.gov/pubmed/19960983
(881) http://www.ncbi.nlm.nih.gov/pubmed/18198636
(882) http://www.ncbi.nlm.nih.gov/pubmed/12435210
(883) http://www.ncbi.nlm.nih.gov/pubmed/17089329
(884) http://www.ncbi.nlm.nih.gov/pubmed/25063041
(885) http://www.ncbi.nlm.nih.gov/pubmed/20804838
(886) http://www.ncbi.nlm.nih.gov/pubmed/21273053
(887) http://www.ncbi.nlm.nih.gov/pubmed/19632285
(888) http://www.ncbi.nlm.nih.gov/pubmed/25349145
(889) http://www.ncbi.nlm.nih.gov/pubmed/24316034
(890) http://www.ncbi.nlm.nih.gov/pubmed/23717136
(891) http://www.ncbi.nlm.nih.gov/pubmed/6834589
(892) http://www.ncbi.nlm.nih.gov/pubmed/15660764
(893) http://www.ncbi.nlm.nih.gov/pubmed/16782310
(894) http://www.ncbi.nlm.nih.gov/pubmed/23301896
(895) http://www.ncbi.nlm.nih.gov/pubmed/25032018
(896) http://www.tcmassistant.com/herbs/ren-shen.html
(897) http://alternativehealing.org/ren_shen.htm
(898) http://www.ncbi.nlm.nih.gov/pubmed/18083315
(899) http://www.ncbi.nlm.nih.gov/pubmed/24854439
(900) http://www.ncbi.nlm.nih.gov/pubmed/16511867
(901) http://www.ncbi.nlm.nih.gov/pubmed/24503167
(902) http://www.ncbi.nlm.nih.gov/pubmed/23717087
(903) http://www.ncbi.nlm.nih.gov/pubmed/23789219
(904) http://www.ncbi.nlm.nih.gov/pubmed/19519302
(905) http://www.ncbi.nlm.nih.gov/pubmed/8485510
(906) http://www.ncbi.nlm.nih.gov/pubmed/25632113
(907) http://www.ncbi.nlm.nih.gov/pubmed/25568286
(908) http://www.ncbi.nlm.nih.gov/pubmed/22543851
(909) http://www.ncbi.nlm.nih.gov/pubmed/25340298
(910) http://www.ncbi.nlm.nih.gov/pubmed/22214447
(911) http://www.ncbi.nlm.nih.gov/pubmed/24975829
(912) http://www.ncbi.nlm.nih.gov/pubmed/24916704
(913) http://www.ncbi.nlm.nih.gov/pubmed/19584437 
(914) http://www.ncbi.nlm.nih.gov/pubmed/25637461
(915) http://www.ncbi.nlm.nih.gov/pubmed/25496089
(916) http://www.ncbi.nlm.nih.gov/pubmed/20196834
(917) http://www.ncbi.nlm.nih.gov/pubmed/25467144
(918) http://www.ncbi.nlm.nih.gov/pubmed/24933489
(919) http://www.ncbi.nlm.nih.gov/pubmed/25627959
(920) http://www.ncbi.nlm.nih.gov/pubmed/25573070
(921) http://www.ncbi.nlm.nih.gov/pubmed/25449909 
(922) http://www.ncbi.nlm.nih.gov/pubmed/21349320
(923) http://www.ncbi.nlm.nih.gov/pubmed/21165417
(924) http://www.ncbi.nlm.nih.gov/pubmed/19185022 
(925) http://www.ncbi.nlm.nih.gov/pubmed/23084645
(926) http://www.ncbi.nlm.nih.gov/pubmed/25550330
(927) http://www.ncbi.nlm.nih.gov/pubmed/24132508
(928) http://www.ncbi.nlm.nih.gov/pubmed/24535619
(929) http://www.ncbi.nlm.nih.gov/pubmed/24223941
(940) http://www.ncbi.nlm.nih.gov/pubmed/24535619
(941) http://www.ncbi.nlm.nih.gov/pubmed/24132508
(942) http://www.ncbi.nlm.nih.gov/pubmed/25349145
(943) http://www.ncbi.nlm.nih.gov/pubmed/24316034
(944) http://www.ncbi.nlm.nih.gov/pubmed/14637121
(945) http://www.ncbi.nlm.nih.gov/pubmed/24678300
(967) http://www.ncbi.nlm.nih.gov/pubmed/23936259
(968) http://www.ncbi.nlm.nih.gov/pubmed/25580148
(969) http://www.ncbi.nlm.nih.gov/pubmed/23957352
(970) http://www.ncbi.nlm.nih.gov/pubmed/23424869
(971) http://www.ncbi.nlm.nih.gov/pubmed/24833292
(972) http://www.ncbi.nlm.nih.gov/pubmed/25614977
(973) http://www.ncbi.nlm.nih.gov/pubmed/21619919
(974) http://www.ncbi.nlm.nih.gov/pubmed/24143244
(975) http://alternativehealing.org/sang_shen.htm
(976) http://www.ncbi.nlm.nih.gov/pubmed/22952555
(977) http://www.ncbi.nlm.nih.gov/pubmed/22359473
(978) http://www.ncbi.nlm.nih.gov/pubmed/23481689
(979) http://www.ncbi.nlm.nih.gov/pubmed/18416873
(980) http://www.researchgate.net/publication/13595646_Increased_aspartate_aminotransferase_activity_in_cerebrospinal_fluid_and_Alzheimer%27s
_disease
(981) http://www.ncbi.nlm.nih.gov/pubmed/25076901
(982) http://www.ncbi.nlm.nih.gov/pubmed/12742802
(983) http://www.ncbi.nlm.nih.gov/pubmed/?term=Morus+Fruit+aging+dementia
(984) http://www.ncbi.nlm.nih.gov/pubmed/22359473
(985) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181806/
(986) http://www.ncbi.nlm.nih.gov/pubmed/24252804
(987) http://www.ncbi.nlm.nih.gov/pubmed/12666096
(988) http://www.ncbi.nlm.nih.gov/pubmed/20187987
(989) http://www.ncbi.nlm.nih.gov/pubmed/16181734
(990) http://www.ncbi.nlm.nih.gov/pubmed/16462030
(991) http://www.ncbi.nlm.nih.gov/pubmed/23182412
(992) http://www.google.ca/url?sa=t&rct=j&q=&esrc=s&source=web&cd=9&ved=0CFIQFjAI&url=http%3A%2F%2Fwww.sciencedirect.com%2Fscience%2Farticle%2Fpii%2FS0896627304001825&ei=_zLWVK3lKM6GyASJuoGoDQ&usg=AFQjCNEyc3lFHKLgR23BgeVDvLJlA88EPw&sig2=X0709mxdzLje7Wm8hEa0Cg&bvm=bv.85464276,d.aWw
(993) http://www.google.ca/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CCQQFjAA&url=http%3A%2F%2Fnewsroom.ucla.edu%2Freleases%2Flost-memories-might-be-able-to-be-restored-new-ucla-study-indicates&ei=UTPWVL2RB4r5yATevoCYDg&usg=AFQjCNGgIpa9vkpNArifuMS8d5CLtiNfaA&sig2=Afv4YqTenwLVNXkc0Cr6Cw&bvm=bv.85464276,d.aWw
(994) http://www.ncbi.nlm.nih.gov/pubmed/17978032
(995) http://www.ncbi.nlm.nih.gov/pubmed/15010693
(996) http://www.ncbi.nlm.nih.gov/pubmed/22403568
(997) http://www.ncbi.nlm.nih.gov/pubmed/19443193
(998) http://www.ncbi.nlm.nih.gov/pubmed/23451158
(999) http://www.ncbi.nlm.nih.gov/pubmed/22403568
(1000) http://www.ncbi.nlm.nih.gov/pubmed/19050990
(1001) http://www.ncbi.nlm.nih.gov/pubmed/?term=Peony+spastic
(1002) http://www.ncbi.nlm.nih.gov/pubmed/22921747
(1003) http://www.ncbi.nlm.nih.gov/pubmed/19003727
(1004) http://www.ncbi.nlm.nih.gov/pubmed/18449501
(1005) http://www.ncbi.nlm.nih.gov/pubmed/22891951
(1006) http://www.ncbi.nlm.nih.gov/pubmed/18448067
(1007) http://www.ncbi.nlm.nih.gov/pubmed/24467538
(1008) http://www.ncbi.nlm.nih.gov/pubmed/15970315
(1009) http://www.ncbi.nlm.nih.gov/pubmed/15015358
(1010) http://www.ncbi.nlm.nih.gov/pubmed/21112198
(1011) http://www.ncbi.nlm.nih.gov/pubmed/25479726
(1012) http://www.ncbi.nlm.nih.gov/pubmed/?term=Peony+constipation
(1013) http://www.ncbi.nlm.nih.gov/pubmed/25289045
(1014) http://www.ncbi.nlm.nih.gov/pubmed/?term=Peony+coughs
(1015) http://www.ncbi.nlm.nih.gov/pubmed/9703625
(1016) http://www.ncbi.nlm.nih.gov/pubmed/25045390
(1017) http://alternativehealing.org/bai_shao.htm
(1018) http://www.ncbi.nlm.nih.gov/pubmed/21185921
(1019) http://www.ncbi.nlm.nih.gov/pubmed/19457098
(1020) http://www.ncbi.nlm.nih.gov/pubmed/16086036
(1021) http://www.ncbi.nlm.nih.gov/pubmed/23695964
(1022) http://www.ncbi.nlm.nih.gov/pubmed/25446358
(1023) http://www.ncbi.nlm.nih.gov/pubmed/25165413
(1024) http://www.ncbi.nlm.nih.gov/pubmed/23667997
(1025) http://www.ncbi.nlm.nih.gov/pubmed/21377451
(1026) http://www.ncbi.nlm.nih.gov/pubmed/7816876 
(1027) http://www.ncbi.nlm.nih.gov/pubmed/23980368
(1028) http://www.ncbi.nlm.nih.gov/pubmed/23667997
(1028) http://www.ncbi.nlm.nih.gov/pubmed/16086036
(1029) http://www.ncbi.nlm.nih.gov/pubmed/9120425
(1030) http://www.ncbi.nlm.nih.gov/pubmed/25446358
(1031) http://www.ncbi.nlm.nih.gov/pubmed/24389454
(1032) http://www.ncbi.nlm.nih.gov/pubmed/23023341
(1033) http://www.ncbi.nlm.nih.gov/pubmed/22070681
(1035) http://www.ncbi.nlm.nih.gov/pubmed/9197277
(1036) http://www.ncbi.nlm.nih.gov/pubmed/9798591
(1037) http://www.ncbi.nlm.nih.gov/pubmed/19268972 
(1038) http://www.ncbi.nlm.nih.gov/pubmed/17715794
(1039) http://www.ncbi.nlm.nih.gov/pubmed/19268972
(1040) http://www.ncbi.nlm.nih.gov/pubmed/16678139
(1041) http://www.ncbi.nlm.nih.gov/pubmed/16137717
(1042) http://www.ncbi.nlm.nih.gov/pubmed/19007942
(1043) http://www.ncbi.nlm.nih.gov/pubmed/22414474
(1044) http://www.ncbi.nlm.nih.gov/pubmed/11379768
(1045) http://www.ncbi.nlm.nih.gov/pubmed/24438177
(1046) http://www.ncbi.nlm.nih.gov/pubmed/21143894
(1047) http://www.ncbi.nlm.nih.gov/pubmed/20796273
(1048) http://alternativehealing.org/chai_hu.htm
(1049) http://www.ncbi.nlm.nih.gov/pubmed/20812276
(1050) http://www.ncbi.nlm.nih.gov/pubmed/19801831
(1051) http://www.ncbi.nlm.nih.gov/pubmed/23694845
(1052) http://www.ncbi.nlm.nih.gov/pubmed/?term=Bupleurum+Alzheimer's+disease
(1053) http://www.ncbi.nlm.nih.gov/pubmed/19801831
(1054) http://www.ncbi.nlm.nih.gov/pubmed/19409210
(1055) http://www.ncbi.nlm.nih.gov/pubmed/19146938
(1056) http://www.ncbi.nlm.nih.gov/pubmed/20170698
(1057) http://www.ncbi.nlm.nih.gov/pubmed/20184936
(1058) http://www.ncbi.nlm.nih.gov/pubmed/19538824
(1059) http://www.ncbi.nlm.nih.gov/pubmed/25022209
(1060) http://www.ncbi.nlm.nih.gov/pubmed/23838475
(1061) http://www.ncbi.nlm.nih.gov/pubmed/23279145
(1062) http://www.ncbi.nlm.nih.gov/pubmed/24169925
(1063) http://www.ncbi.nlm.nih.gov/pubmed/19948198
(1064) http://www.ncbi.nlm.nih.gov/pubmed/23055705
(1065) http://www.ncbi.nlm.nih.gov/pubmed/19079814
(1066) http://www.ncbi.nlm.nih.gov/pubmed/25246794
(1067) http://www.ncbi.nlm.nih.gov/pubmed/25237752
(1068) http://www.ncbi.nlm.nih.gov/pubmed/23061633
(1069) http://www.ncbi.nlm.nih.gov/pubmed/23990301
(1070) http://www.ncbi.nlm.nih.gov/pubmed/19712651
(1071) http://www.ncbi.nlm.nih.gov/pubmed/24333963
(1072) http://www.ncbi.nlm.nih.gov/pubmed/22098918
(1073) http://www.ncbi.nlm.nih.gov/pubmed/22180326
(1074) http://www.ncbi.nlm.nih.gov/pubmed/21315002
(1075) http://www.ncbi.nlm.nih.gov/pubmed/24212075
(1077) http://www.ncbi.nlm.nih.gov/pubmed/?term=Red+Sage+Root+and+uterus
(1078) http://www.ncbi.nlm.nih.gov/pubmed/16181539
(11079) http://www.ncbi.nlm.nih.gov/pubmed/25276956
(1080) http://www.ncbi.nlm.nih.gov/pubmed/24960183
(1076) http://alternativehealing.org/carthamus_tinctorius.htm
(1081) http://www.ncbi.nlm.nih.gov/pubmed/24412680
(1082) http://www.ncbi.nlm.nih.gov/pubmed/17448528
(1083) http://www.ncbi.nlm.nih.gov/pubmed/23420419
(1084) http://www.ncbi.nlm.nih.gov/pubmed/24412680
(1085) http://www.ncbi.nlm.nih.gov/pubmed/23333598
(1086) http://www.ncbi.nlm.nih.gov/pubmed/23684718
(1087) http://www.ncbi.nlm.nih.gov/pubmed/16101743
(1088) http://www.ncbi.nlm.nih.gov/pubmed/?term=safflower+Parkinson's+disease+PD
(1089) http://www.ncbi.nlm.nih.gov/pubmed/25672970
(1090) http://www.ncbi.nlm.nih.gov/pubmed/12360580
(1091) http://www.ncbi.nlm.nih.gov/pubmed/22070681
(1092) http://www.ncbi.nlm.nih.gov/pubmed/25674199
(1093) http://www.ncbi.nlm.nih.gov/pubmed/25404051
(1094) http://www.ncbi.nlm.nih.gov/pubmed/24412680
(1095) http://www.ncbi.nlm.nih.gov/pubmed/23420419
(1096) http://www.ncbi.nlm.nih.gov/pubmed/23333598
(1097) http://www.ncbi.nlm.nih.gov/pubmed/24690200
(1098) http://www.ncbi.nlm.nih.gov/pubmed/24373810 
(1099) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654365/
(1100) http://www.ncbi.nlm.nih.gov/pubmed/22042506
(1101) http://www.ncbi.nlm.nih.gov/pubmed/22867942
(1102) http://www.ncbi.nlm.nih.gov/pubmed/20526740
(1103) http://www.ncbi.nlm.nih.gov/pubmed/19763040
(1104) http://www.ncbi.nlm.nih.gov/pubmed/22551210
(1105) http://www.ncbi.nlm.nih.gov/pubmed/?term=Safflower+dementia+symptoms
(1106) http://www.ncbi.nlm.nih.gov/pubmed/7712178
(1107) http://www.ncbi.nlm.nih.gov/pubmed/10024623
(1108) http://www.ncbi.nlm.nih.gov/pubmed/24358170
(1109) http://www.ncbi.nlm.nih.gov/pubmed/23475543
(1110) http://www.ncbi.nlm.nih.gov/pubmed/?term=cinnamon+anti-spasmodic
(1111) http://www.ncbi.nlm.nih.gov/pubmed/24885682
(1112) http://www.ncbi.nlm.nih.gov/pubmed/22760889
(1113) http://www.ncbi.nlm.nih.gov/pubmed/25392573
(1114) http://www.ncbi.nlm.nih.gov/pubmed/25051315
(1115) http://www.ncbi.nlm.nih.gov/pubmed/24337968
(1116) http://www.ncbi.nlm.nih.gov/pubmed/23868387
(1117) http://www.ncbi.nlm.nih.gov/pubmed/25268975
(1118) http://www.ncbi.nlm.nih.gov/pubmed/19969552
(1119) http://www.ncbi.nlm.nih.gov/pubmed/22512578
(1120) http://www.ncbi.nlm.nih.gov/pubmed/23607932
(1121) http://alternativehealing.org/gui_zhi.htm
(1122) http://www.ncbi.nlm.nih.gov/pubmed/23531502
(1123) http://www.ncbi.nlm.nih.gov/pubmed/21360003
(1124) http://www.ncbi.nlm.nih.gov/pubmed/23497886
(1125) http://www.ncbi.nlm.nih.gov/pubmed/25301673
(1126) http://www.ncbi.nlm.nih.gov/pubmed/21305046
(1127) http://www.ncbi.nlm.nih.gov/pubmed/20061605
(1128) http://www.ncbi.nlm.nih.gov/pubmed/15229712
(1129) http://www.ncbi.nlm.nih.gov/pubmed/24817901
(1130) http://www.ncbi.nlm.nih.gov/pubmed/20513336
(1131) http://www.ncbi.nlm.nih.gov/pubmed/19433898
(1132) http://www.ncbi.nlm.nih.gov/pubmed/21305046
(1133) http://www.ncbi.nlm.nih.gov/pubmed/24349472 
(1134) http://www.ncbi.nlm.nih.gov/pubmed/17480132 
(1135) http://www.ncbi.nlm.nih.gov/pubmed/24946862
(1136) http://www.ncbi.nlm.nih.gov/pubmed/25284437
(1137) http://www.ncbi.nlm.nih.gov/pubmed/22575665
(1138) http://www.ncbi.nlm.nih.gov/pubmed/24631135
(1139) http://www.ncbi.nlm.nih.gov/pubmed/24239092
(1140) http://www.ncbi.nlm.nih.gov/pubmed/23497886
(1141) http://www.ncbi.nlm.nih.gov/pubmed/10960905
(1193) http://www.ncbi.nlm.nih.gov/pubmed/9468229
(1194) http://www.ncbi.nlm.nih.gov/pubmed/20564545
(1195) http://www.ncbi.nlm.nih.gov/pubmed/23121838
(1196) http://www.ncbi.nlm.nih.gov/pubmed/23879966
(1197) http://www.ncbi.nlm.nih.gov/pubmed/24574320
(1198) http://www.ncbi.nlm.nih.gov/pubmed/25242120
(1199) http://www.ncbi.nlm.nih.gov/pubmed/23701595
(1200) http://www.ncbi.nlm.nih.gov/pubmed/17692492
(1201) http://www.ncbi.nlm.nih.gov/pubmed/25431050
(1202) http://www.ncbi.nlm.nih.gov/pubmed/25247194
(1203) http://www.ncbi.nlm.nih.gov/pubmed/22797645
(1204)  http://alternativehealing.org/shui_fei_ji.htm
(1205) http://www.ncbi.nlm.nih.gov/pubmed/15277093
(1206) http://www.ncbi.nlm.nih.gov/pubmed/22087179
(1207) http://www.ncbi.nlm.nih.gov/pubmed/23468043 
(1208) http://www.ncbi.nlm.nih.gov/pubmed/24187864 
(1209) http://www.ncbi.nlm.nih.gov/pubmed/22500712
(1210) http://www.ncbi.nlm.nih.gov/pubmed/24155069 
(1211) http://www.ncbi.nlm.nih.gov/pubmed/25155658 
(1212) http://www.ncbi.nlm.nih.gov/pubmed/25162367 
(1213) http://www.ncbi.nlm.nih.gov/pubmed/24719080 
(1214) http://www.ncbi.nlm.nih.gov/pubmed/22866982 
(1215) http://www.ncbi.nlm.nih.gov/pubmed/16769094 
(1216) http://www.ncbi.nlm.nih.gov/pubmed/21185897 
(1217) http://www.ncbi.nlm.nih.gov/pubmed/19552690 
(1218) http://www.ncbi.nlm.nih.gov/pubmed/21071836 
(1219) http://www.ncbi.nlm.nih.gov/pubmed/25696782
(1220) http://www.ncbi.nlm.nih.gov/pubmed/25613505
(1221) http://www.ncbi.nlm.nih.gov/pubmed/24460990
(1222) http://www.ncbi.nlm.nih.gov/pubmed/21071836
(1223) http://www.ncbi.nlm.nih.gov/pubmed/19638571
(1224) http://www.ncbi.nlm.nih.gov/pubmed/25677261
(1225) http://www.ncbi.nlm.nih.gov/pubmed/24660866
(1226) http://www.ncbi.nlm.nih.gov/pubmed/21840019
(1227) http://www.ncbi.nlm.nih.gov/pubmed/20833521
(1228) http://www.ncbi.nlm.nih.gov/pubmed/19857526
(1229) http://www.ncbi.nlm.nih.gov/pubmed/19552690
(1230) http://www.ncbi.nlm.nih.gov/pubmed/19647779
 (1258) http://alternativehealing.org/garlic.htm
(1259) http://www.ncbi.nlm.nih.gov/pubmed/10594976
(1260) http://www.ncbi.nlm.nih.gov/pubmed/11759674
(1261) http://www.ncbi.nlm.nih.gov/pubmed/24066081
(1262) http://www.ncbi.nlm.nih.gov/pubmed/9131291
(1263) http://www.ncbi.nlm.nih.gov/pubmed/25078449
(1264) http://www.ncbi.nlm.nih.gov/pubmed/24859825
(1265) http://www.ncbi.nlm.nih.gov/pubmed/24309133
(1266) http://www.ncbi.nlm.nih.gov/pubmed/23543654
(1267) http://www.ncbi.nlm.nih.gov/pubmed/23923607
(1268) http://www.ncbi.nlm.nih.gov/pubmed/17918162
(1269) http://www.ncbi.nlm.nih.gov/pubmed/10192909
(1270) http://www.ncbi.nlm.nih.gov/pubmed/25141365
(1271) http://www.ncbi.nlm.nih.gov/pubmed/16484559
(1272) http://www.ncbi.nlm.nih.gov/pubmed/24067391
(1273) http://www.ncbi.nlm.nih.gov/pubmed/24172194
(1274) http://www.ncbi.nlm.nih.gov/pubmed/24199984
(1285) http://www.ncbi.nlm.nih.gov/pubmed/25671065
(1276) http://www.ncbi.nlm.nih.gov/pubmed/25575520
(1277) http://www.ncbi.nlm.nih.gov/pubmed/23194526
(1278) http://www.ncbi.nlm.nih.gov/pubmed/24564587
(1279) http://www.ncbi.nlm.nih.gov/pubmed/24122196
(1280) http://www.ncbi.nlm.nih.gov/pubmed/22717023 
(1281) http://www.ncbi.nlm.nih.gov/pubmed/24989289
(1282) http://www.ncbi.nlm.nih.gov/pubmed/16868359
(1283) http://www.ncbi.nlm.nih.gov/pubmed/21376020
(1284) http://www.ncbi.nlm.nih.gov/pubmed/21166677
(1285) http://www.ncbi.nlm.nih.gov/pubmed/12165737
(1286) http://www.ncbi.nlm.nih.gov/pubmed/21728972
(1287) http://www.ncbi.nlm.nih.gov/pubmed/21499478
(1288) http://www.ncbi.nlm.nih.gov/pubmed/18844255
(1289) http://www.ncbi.nlm.nih.gov/pubmed/16842945
(1290) http://www.ncbi.nlm.nih.gov/pubmed/24519982
(1291) http://www.ncbi.nlm.nih.gov/pubmed/20061605
(1292) http://www.ncbi.nlm.nih.gov/pubmed/23713775
(1293) http://www.ncbi.nlm.nih.gov/pubmed/24134394
(1294) http://www.ncbi.nlm.nih.gov/pubmed/21728972
(1295) http://www.ncbi.nlm.nih.gov/pubmed/21166677
(1296) http://www.ncbi.nlm.nih.gov/pubmed/16842945
(1297) http://www.ncbi.nlm.nih.gov/pubmed/15934032
(1298) http://www.ncbi.nlm.nih.gov/pubmed/25640661
(1299) http://www.ncbi.nlm.nih.gov/pubmed/24262869
(1300) http://www.ncbi.nlm.nih.gov/pubmed/25546094
(1301) http://www.ncbi.nlm.nih.gov/pubmed/25506732
(1302) http://www.ncbi.nlm.nih.gov/pubmed/20083801
(1303) http://www.ncbi.nlm.nih.gov/pubmed/20603494
(1304) http://www.ncbi.nlm.nih.gov/pubmed/18032652
(1305) http://www.ncbi.nlm.nih.gov/pubmed/11295356
(1306) http://www.ncbi.nlm.nih.gov/pubmed/17380553
(1307) http://www.ncbi.nlm.nih.gov/pubmed/24134394
(1308) http://www.ncbi.nlm.nih.gov/pubmed/21376020
(1309) http://www.ncbi.nlm.nih.gov/pubmed/24579375
(1310) http://www.ncbi.nlm.nih.gov/pubmed/15087243

(1339) http://www.ncbi.nlm.nih.gov/pubmed/25087616
(1340) http://www.ncbi.nlm.nih.gov/pubmed/24710996
(1341) http://www.ncbi.nlm.nih.gov/pubmed/24456824
(1342) http://www.ncbi.nlm.nih.gov/pubmed/25669325
(1343) http://www.ncbi.nlm.nih.gov/pubmed/21856398
(1344) http://www.ncbi.nlm.nih.gov/pubmed/25690295
(1345) http://www.ncbi.nlm.nih.gov/pubmed/25435153
(1346) http://www.ncbi.nlm.nih.gov/pubmed/25415237
(1347) http://www.ncbi.nlm.nih.gov/pubmed/23049681
(1348) http://www.ncbi.nlm.nih.gov/pubmed/24863354
(1349) http://www.ncbi.nlm.nih.gov/pubmed/25319833
(1350) http://www.ncbi.nlm.nih.gov/pubmed/22992293
(1351) http://www.ncbi.nlm.nih.gov/pubmed/24026428
(1352) http://www.ncbi.nlm.nih.gov/pubmed/25690295
(1353) http://www.ncbi.nlm.nih.gov/pubmed/25137839
(1354) http://www.ncbi.nlm.nih.gov/pubmed/25335553
(1355) http://www.ncbi.nlm.nih.gov/pubmed/22350214
(1356) http://www.ncbi.nlm.nih.gov/pubmed/21555978
(1357) http://www.ncbi.nlm.nih.gov/pubmed/25551689
(1358) http://www.ncbi.nlm.nih.gov/pubmed/24933224
(1359) http://alternativehealing.org/huang_qi.htm
(1360) http://www.ncbi.nlm.nih.gov/pubmed/12971399
(1361) http://www.ncbi.nlm.nih.gov/pubmed/15346617
(1362) http://www.ncbi.nlm.nih.gov/pubmed/7893391
(1363) http://www.ncbi.nlm.nih.gov/pubmed/21538932
(1364) http://www.ncbi.nlm.nih.gov/pubmed/8155947
(1365) http://www.ncbi.nlm.nih.gov/pubmed/20506830
(1366) http://www.ncbi.nlm.nih.gov/pubmed/24956824
(1367) http://www.ncbi.nlm.nih.gov/pubmed/22484447
(1368) http://www.ncbi.nlm.nih.gov/pubmed/24905226
(1369) http://www.medsci.org/v11p1073.htm
(1370) http://www.ncbi.nlm.nih.gov/pubmed/25272845 
(1371) http://www.ncbi.nlm.nih.gov/pubmed/24175560 
(1372) http://www.ncbi.nlm.nih.gov/pubmed/23595393 
(1373) http://www.ncbi.nlm.nih.gov/pubmed/21538932 
(1374) http://www.ncbi.nlm.nih.gov/pubmed/24905226
(1375) http://www.ncbi.nlm.nih.gov/pubmed/21538932
(1376) http://www.ncbi.nlm.nih.gov/pubmed/23266574
(1377) http://www.ncbi.nlm.nih.gov/pubmed/19409437
(1378) http://www.ncbi.nlm.nih.gov/pubmed/25136262
(1379) http://www.ncbi.nlm.nih.gov/pubmed/24724856
(1380) http://www.ncbi.nlm.nih.gov/pubmed/24690775
(1381) http://www.ncbi.nlm.nih.gov/pubmed/23665312