Dementia – Orthodox Western And Traditional Chinese Medical Approaches

About the Author

Dr Tony Reid

Master of Acupuncture, Master of Traditional Chinese Medicine (UWS) Sun Herbal co-founder, Director of Education, Research and Development. www.SunHerbal.com

Preamble

The incidence of various types of dementia, including Alzheimer’s disease, is steadily increasing.  The prevalence rates rise with increasing age. In Australia, the prevalence is 2% for people in their 60’s increasing to over 32% for those in their 80’s and beyond. Moreover, these figures are expected to double by the year 2020. With the increasing numbers of people living into old age in both the developed and developing nations, this represents an impending healthcare crisis. The dementias accounts for a huge burden on patients, their care-givers and the community; indeed the disability weight for dementia is higher than for almost any other health condition, apart from spinal-cord injury and terminal cancer. (1) This paper focuses on the three most common presentations of dementia: Alzheimer’s disease, vascular dementia and the condition that precedes dementia, variously known as ‘cognitive decline’ or ‘mild cognitive impairment’ or ‘cognitive impairment no dementia’. This paper supports early detection and intervention as the best approach to this problem. The potential for reducing the incidence of full blown dementia in the latter group through the timely administration of TCM treatments is explored and discussed.

Introduction

Although the criteria for diagnosis of the various types of dementia are still evolving, (2) the current classification of dementia syndrome includes both reversible and irreversible types. The former are potentially curable, once the underlying cause has been addressed. The causes of reversible dementia include: chronic drug intoxication, vitamin deficiencies (B12 and folate), subdural hematoma/s, major depression, normal pressure hydrocephalus, and hypothyroidism. These causes may not always be apparent and therefore should be borne in mind when approaching a patient who is showing signs of cognitive impairment. Other more obvious causes of reversible or temporary dementia include head trauma, and infections (bacterial, viral, fungal). (4, 2, 5)

The true dementias include: Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy Bodies (DLB) and fronto-temporal dementia (FTD). The most common being AD (which accounts for around 50-60% of cases), VaD and mixed dementia (i.e. AD together with VaD). The prevalence rates of the various dementias vary considerably from one country to another, e.g. in Japan VaD accounts for 50% of all dementias in those over 65; in Europe VaD and mixed dementia account for 20% and 40% of cases, respectively; in Australia the rate for VaD is 13% and mixed dementia is 28%. (6)

The precursor to dementia, variously known as ‘cognitive decline’ or ‘mild cognitive impairment’ (MCI) or ‘cognitive impairment no dementia’ (here referred to as MCI) is a much more common condition. Estimates of prevalence range from 11% to 17% of the over 60 years population in North America and Europe.

In middle aged and elderly patients MCI represents changes in cognition that exceed the expected age-related decline, with sparing of functional activities. However, within 4 years of detection around half of these patients will end up with clinical dementia (mostly AD). In contrast to the general average of 1 – 2% per year, these patients develop dementia at a rate of 10 – 12% per year. (10, 11, 35)  Thus, patients with MCI represent a very high risk group for dementia.

Diagnosis

The diagnosis of dementia is still primarily based upon the DSM-IV, TR[1] criteria although recent efforts within the profession are moving towards a substantial revision of these criteria. (2, 3)

  1. Impairment of memory
  2. Impairment in at least one other cognitive domain:
  1. Aphasia,
  2. Agnosia,
  3. Apraxia, and
  4. Disturbance in executive function

The above impairments interference with social, work or daily activities and represent a significant decline from previous functioning. (13)

The standard approach that privileges memory loss is now being questioned, and many clinicians prefer to define dementia as impairment in at least two domains of cognitive function. (2) However, the diagnosis is essentially based on clinical findings from a case history from the patient, a collateral history from an informant and a physical examination. This is supplemented by a cognitive assessment, using one of the brief cognitive tests such as the Mini-Mental State Examination (MMSE). (2, 3) It is important to note that the patient’s history must include interrogation of an independent informant, due to the impaired cognition of the patient.

In making a diagnosis, it is important to exclude other commonly occurring conditions that may mimic the clinical features of the true dementias; the two main ones being delirium and depression. (3) However, it should be noted that, as one would expect, the prospect of progressive cognitive decline, increasing dependency and an early death will inevitably provoke feelings of anxiety, and sadness in most people. (9) In addition, some degree of apathy is also part of the syndrome of AD. Therefore it remains a clinical challenge for the practitioner to ascertain to what degree the patient’s emotional state is a normal human response to loss, part of the clinical syndrome of AD or a separate psychiatric disorder. Delirium in an elderly patient is a medical emergency, and is therefore an important differential diagnostic consideration. The key clinical features are impaired attention and fluctuations in levels of consciousness. (3)

The risk factors for dementia include: elevated as well as low blood pressure; presence of type 2 diabetes; the presence of clinical strokes or silent infarctions (on neuroimaging); elevated total serum cholesterol; high serum homocysteine levels; higher levels of total estradiol in women; depression; smoking; high dietary fat intake and low omega 3 fat intake; history of moderate to severe head injury with loss of consciousness; low education level (less than 12 years of education); occupational exposure to pesticides, fertilizers, fumigants and defoliants. Factors resulting in a lower risk for AD include: adherence to a Mediterranean-style diet; consumption of fish; regular physical activity (particularly high level exercise, i.e. greater intensity than walking, 3 or more times per week); intellectually challenging activity; moderate consumption of wine (250-500 ml/day). (14)

ALZHEIMER’S DISEASE

Introduction

Alzheimer’s disease (AD) is generally defined with reference to its specific neuropathology (i.e. toxic amyloid plaques, neurofibrillary tangles and cerebrocortical atrophy predominantly involving the medial aspect of the temporal lobe). However, the diagnosis rests on the clinical findings, as discussed above. In AD the history generally reveals an insidious onset and progressive cognitive decline with predominant memory loss in a patient with normal (i.e. not clouded) consciousness. The disease typically occurs between the ages of 40 and 90. (7, 2) Although more than 90% of cases are older than 60 years (7) the disease may also be seen in patients under 40 (2). In addition AD may occur with sudden onset (e.g. after a delirium). (2) The underlying pathology of AD is the accumulation of beta-amyloid causing toxic amyloid plaques (also known as senile plaques [SP]), which in turn lead to the development of neurofibrillary tangles (NFT). The resulting widespread neuronal cell death leads to cerebrocortical atrophy, which predominantly involves the association regions and particularly the medial aspect of the temporal lobe. Thus the major functions affected are learning and memory as well as thinking and planning.  As the disease progresses, there is progressive impairment of the ability to speak and understand speech as well as the sense of where the body is in relation to surrounding objects. In advanced AD there is global loss of cerebral function and marked shrinkage of the brain. (7, 8) However, it has been noted that findings on autopsy after death do not always correlate. (2, 7, 8) As noted by Rockwood et al., ‘the comforting notion of the gold standard no longer seems valid. Although neuropathology has an important contribution to make, the recognition that people with apparently identical lesions can differ widely in their cognitive function and that differing sets of neuropathologic criteria yield differing estimates of dementias in the same brains each suggest that its role, like that of other measures, best provides construct (cf. criterion) validity. Similarly, the sharp line between normal aging and pathology is not as clear as it once was.” (2) Thus clinical examination provides the cornerstone of diagnosis with laboratory tests and imaging studies being used to rule out other causes of dementia. (2, 7, 8)

Patients with Alzheimer disease most commonly present with insidiously progressive memory loss, to which other spheres of cognitive impairment are added over several years. After memory loss occurs, patients may also have language disorders (e.g. anomia) and impairment in their visuospatial skills and executive functions. The main focus of current diagnostic guidelines consists in verifying the initial finding of mild, slowly progressive memory loss and that additional spheres of cognition are also compromised, and also that other possible causes for dementia have been excluded. (7, 8, 2) In a small number of patients the cognitive decline may plateau for a time or it may decline rapidly. (2)

As histological confirmation of AD can only be carried out after death, the outcome of a positive diagnosis (based on case history and cognitive tests) is ‘probable AD’. This approach has high sensitivity but low specificity, (8) as would be expected based on the critical issues discussed above.

In addition, diagnosis should be supplemented with a general neurological and physical examination in order to rule out other conditions that may present with dementia as well as to detect any relevant co-morbidities. (7, 8)

Risk factors

The risk factors for AD include: genetic (for early onset type AD); systolic hypertension (> 160mm/Hg); elevated total serum cholesterol (6.5 mmol/L); smoking; high dietary fat intake and low omega 3 fat intake; low education level (less than 12 years of education); occupational exposure to pesticides, fertilizers, fumigants and defoliants. Factors resulting in a lower risk for AD include: adherence to a Mediterranean-style diet; consumption of fish; regular physical activity (particularly high level exercise, i.e. greater intensity than walking, 3 or more times per week); intellectually challenging activity; moderate consumption of wine (250-500 ml/day); non steroidal anti-inflammatory drugs; vitamin supplements; oestrogens (in women). It should be noted that the evidence for these factors is fairly weak, being based mainly on longitudinal cohort studies, population-based studies and epidemiological studies. (14, 15)

Differential Diagnosis

In addition to differentiating AD from the other dementias, treatable conditions that may present with cognitive impairment need to be ruled out. Laboratory tests include: erythrocyte sedimentation rate, complete blood cell count, vitamin B12 levels, electrolytes, calcium, glucose, renal and liver function tests, and thyroid stimulating hormone. Other tests that may be requires according to the particular needs of the patient include: serological tests for syphilis, HIV, and Borrelia.

Lumbar puncture may be required to rule out such condions as normal-pressure hydrocephalus, neurosyphilis, neuroborreliosis and cryptococcosis. Neuroimaging studies are used to detect lesions that may cause cognitive impairment such as stroke, tumor, small vessel disease. These include Computerised Tomography (CT) scan or Magnetic resonance imaging (MRI). The single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans are only used in atypical cases, where there is diagnostic uncertainty. (7, 8)

Management

Baseline and ongoing assessment of behavioural and psychological symptoms as well as assessment of activities of daily living are important components of both diagnosis as well as management. The degree of deterioration of function will determine the most appropriate course of action in regards to therapy as well as decision making concerning the patient’s expected degree of autonomy. It also provides a basis for evaluation of the complex needs of the patient and caregiver during the course of the disorder. Regular follow-up visits by both patient and caregiver to family as well as specialist physicians are an important component of management and allow for: monitoring of the patient’s cognitive, emotional, behavioural and functional status; response to medication; prompt identification of complications or concomitant conditions; assessment of the needs of the caregiver; assessment of support services; provision of ongoing advice and guidance to both patient and caregiver on health and psychological issues, safety, driving, legal and financial matters; administration of appropriate interventions. (7, 8)

Current medical treatment involves use of centrally acting cholinesterase inhibitors (ChEI’s), which increase levels of acetylcholine, a key neurotransmitter.  These drugs can produce modest improvements in the rate of decline of cognitive function and activities of daily living, especially in early stages of the disease. (7, 8, 16) Moderate to severe AD is now treated with memantine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.  This drug prevents excitotoxicity (which may be a factor causing symptoms in AD), allowing physiological activation of the receptor during memory formation. It has been found to be of benefit to some patients. This drug may be taken alone or in combination with a ChEI. (7, 8, 17, 18, 19)

Prognosis

Treatment outcomes of current pharmaceutical interventions are symptomatic only and do not affect the underlying rate of progression of disease. Most patients do not respond to treatment and in those that do the effects are modest and temporary, with small improvements in the rate of decline of cognitive function and activities of daily living. (7) Unfortunately these ‘modest improvements’, only refer to a statistically significant improvement. However, it is very doubtful whether or not these improvements are clinically significant. (20) In other words, while it may be possible to measure a small amount of improvement (which represents a retardation in the expected rate of decline) in the patient’s cognitive abilities, functional ability, behaviour and psychological state, this only occurs in 1 patient out of every 10 to 12 that receive treatment and will generally not make an appreciable difference to the course of the illness and the burdens on the caregivers. (16, 17, 20)

Alzheimer disease is a leading cause of death, ranked third after cardiovascular disease and cancer in the U.S. The primary cause of death is intercurrent illness, such as pneumonia, in a patient who has become severely demented from Alzheimer disease. Patients lose the ability to walk and swallow. Difficulty swallowing may lead to aspiration pneumonia. (7)

TCM Treatments

In light of the extremely poor outcomes associated with the use of pharmaceuticals, it is difficult to interpret the results of clinical trials into the use of acupuncture and/or Chinese herbal medicines in AD. The trials (Chinese, Japanese and Korean) that report positive, statistically significant outcomes appear to follow the model of Western pharmaceutical trials in that the clinical significance of the results is often not clearly stated and the results are mostly described in terms of the ‘efficacy’ of Western pharmaceutical interventions. Moreover, due to small sample sizes, methodological weaknesses and lack of long term follow up, further high quality research is needed in order to verify the generally positive findings. (21, 22, 23) Thus, while the best available evidence for the CHM treatment of AD is not of a very high level, it does point to the possibility that this form of treatment is potentially as good as, if not better than current pharmaceutical interventions.

One formula that has been studied quite extensively is Yi Gan San (yokukansan in Japanese). It has been shown to ameliorate the behavioral and psychological symptoms in AD and that patents who take this formula require less anti-psychotic medication. (23, 24) It appears to act via several mechanisms: direct action on the benzodiazepine receptors (26); a neuroprotective effect against beta amyloid-induced cytotoxicity (27); a neuroprotective effect against glutamate-induced excitotoxicity (28, 29); enhances serotonergic and dopaminergic transmissions in the prefrontal cortex (30).

VASCULAR DEMENTIA

Introduction

Vascular dementia (VaD) refers to the group of preventable dementias that are due to various vascular mechanisms, which result in ischemic changes in the cerebral cortex and or subcortex. The diagnostic categories are based on the underlying lesion/s: mild vascular cognitive impairment; multi-infarct dementia; vascular dementia due to a strategic single infarct; vascular dementia due to lacunar lesions (‘lacunar state’); vascular dementia due to hemorrhagic lesions; Binswanger disease; subcortical vascular dementia; mixed dementia (AD together with vascular dementia). (31)  The diagnosis is usually made on the basis of clinical findings together with neuroimaging, or neuropathological evidence of cerebral ischemia. The underlying causes include systemic disorders, cardiac disease, and occlusion of local large or small blood vessels. Cerebral lesions may be focal or diffuse, depending on the underlying disorder: vascular occlusion due to a thrombus or embolus results in the former; while multiple infarcts and small vessel disease give rise to the latter. (31, 32) Thus, VaD results from brain injury caused by stroke and cerebral ischemia.

As discussed above in Part 1, diagnostic accuracy in the dementias is not always possible, especially in those patients with atypical presentations and the fact that VaD occurs more commonly together with AD, as mixed dementia. (2)

Typically, progressive cognitive decline and dementia result from multiple small cerebral infarcts over time. The frontal subcortical regions appear to be especially prone to degenerative changes in patients with poorly controlled hypertension and/or diabetes mellitus. (32) On the other hand, a single ischemic or thrombo-embolic infarct occurring in a critical area of the dominant hemisphere (e.g. the angular gyri, mediodorsal thalamus or anterior thalamus) may cause dementia with only minimal loss of cerebral tissue. Other causes of cerebral atrophic changes include: global hypoxic-ischemic injury (e.g. due to cardiac arrest); coronary bypass surgery; Binswanger encephalopathy; temporal arteritis; polyarteritis nodosa; primary cerebral angiopathy; lupus erythematosus; moyamoya disease; and a rare specific genetic disorder. (31, 32)

Patients with VaD ‘typically’ present with signs of cognitive impairment that are patchy (i.e. not global as in AD), which began acutely or subacutely after an acute neurological event (e.g. stroke), with a stepwise progression. (31, 32) However, a recent review of diagnostic criteria notes that the majority of patients will present with a slowly progressive cognitive deterioration (rather than stepwise), most likely due to silent infarctions. (2) Patients often also have focal neurological signs and symptoms. Moreover, the major deficit in the majority of patients is frontal/executive dysfunction and not memory loss. (2, 33)

In addition to fulfilling the clinical criteria of dementia (discussed above), the following are also present:

  • Vascular risk factors such as hypertension, coronary disease, and diabetes mellitus
  • Specific evidence of cerebrovascular disease, e.g. strokes and transient ischemic attacks: The cerebrovascular insult should precede by no more than 3 months, or coincide with the onset or worsening of cognitive impairment.
  • Neuroimaging evidence of strokes
  • Lateralizing neurologic signs
  • Mood and behavioral disturbances, such as emotional lability, depression, apathy.

(31)

Frequency and Risk factors

In Western counties the prevalence rate for VaD is 1.5%. In patients who have had a stroke, the prevalence is 9 times higher than in controls. (32) The main risk factors for VaD are the same as for cerebrovascular disease: increasing age, male sex, diabetes mellitus, hypertension, cardiomyopathy, smoking and possibly also: elevated homocysteine levels, elevated total serum cholesterol and a high fat diet. Factors resulting in a lower risk for VaD include: consumption of fish and seafood; regular physical activity (particularly high level exercise, i.e. greater intensity than walking, 3 or more times per week); intellectually challenging activity; moderate consumption of wine (250-500 ml/day); non steroidal anti-inflammatory drugs; vitamin supplements; oestrogens (in women). It should be noted that the evidence for these factors is fairly weak, being based mainly on longitudinal cohort studies, population-based studies and epidemiological studies. (14, 15, 32)

Diagnosis

The same protocol is applied as per AD above, in order to detect or rule out reversible causes of dementia. Neuroimaging studies, such as CT scan or MRI of the head may reveal multiple cortical, and more commonly subcortical, infarcts or single strokes affecting the thalamus, angular gyrus, and the territory supplied by the anterior cerebral arteries.

Findings on physical examination may include:

  • Decreased pulsatility, local tenderness, and thickening of the temporal arteries (giant cell arteritis)
  • Fundoscopic findings consistent with hypertension and/or diabetes mellitus.
  • Cardiac arrhytmias or valvular abnormalities.
  • Spasticity, hemiparesis, visual field defects, pseudobulbar palsy, and extrapyramidal signs (i.e. signs of localized cerebral lesions)

(32)

Cognitive testing reveals patchy cognitive defects. The patient should also be assessed for depression according to DSM-IV-TR criteria. In addition, an informant should be questioned in order to provide relevant details of the case history that may not be forthcoming from the patient (e.g. duration of the disorder, severity of the disorder, associated behavioral and psychological symptoms). (31, 32)

Management

Patient and caregiver education is the same as for AD, discussed above. As the life expectancy for patients with VaD is poorer than for those with AD, it is important that critical issues relating to long term care planning, the patient’s autonomy and estate management be addressed promptly. (31, 32)

Currently there are no approved drugs for the treatment of VaD, and treatment is directed at prevention of new strokes, managing cerebrovascular disease and alleviation of psychiatric disturbances such as depression, agitation or psychosis. The main medications for the cerebrovascular component are antiplatelet (e.g. aspirin, ticlopidine, clopidogrel) and hemorheological (e.g. pentoxifylline) drugs. (31, 32) There is some evidence that cholinesterase inhibitors, as used in AD, may also have a place in the treatment of VaD, especially in cases with mixed pathology. (32, 33)

Prognosis

Patients with VaD have a higher mortality rate than those with AD; 50% die within 4 years of the diagnosis. As dementia progresses patients may exhibit increasingly poor judgment, agitation, aggression, wandering, sleep disorders, inappropriate sexual behavior and psychosis. They are prone to falls (and this limits the usefulness of anti-coagulant medication), aspiration pneumonia, decubitus ulcers. Causes of death are generally due to complications of dementia, cardiovascular disease, or miscellaneous factors such as malignancy. (31)

Caregivers are placed under increasing stress and are thus subject to increased psychiatric and medical disorders. Therefore ongoing monitoring of the caregiver/s is essential and the decision for placement of the patient into an institution should be made when the problem behaviors have become unmanageable or caring duties exceed the capacity of the caregiver/s. (31, 32)

TCM Treatments

There is some evidence for both acupuncture and Chinese herbal medicine in the treatment of VaD. However, the improvements are modest or minimal, and appear to be about the same as those obtained with pharmaceutical interventions. (34, 21)

Comments

In the light of the paucity of effective treatments for VaD, one may question the necessity for a specific diagnosis of the subcategory of VaD (e.g. multi-infarct dementia; VaD due to a strategic single infarct; lacunar state, etc.). Indeed, the question needs to be asked: ‘Is the administration of diagnostic tests a cost-effective endeavor?’ At present the only justification for the use of resources to this end is in the pursuit of specific treatments for each subcategory. Thus such efforts are presently only justified in research, not in the day to day assessment and management of patients. Moreover, recent findings suggest that perhaps the most significant differential diagnosis within the dementias is between MCI and dementia. (2) This is partly because of the sad fact that there is at least some hope of effective treatment in the former group and virtually none in the latter.

PART 3: MILD COGNITIVE IMPAIRMENT

Mild cognitive impairment (MCI) is a precursor to dementia and may be detected in patients of all ages, although most commonly in the middle aged to elderly population. (2, 10, 11) This condition was first described by Kral in 1962, who used the term ‘benign senescent forgetfulness’. (35) It represents a worse decline in cognitive function than would be expected for the patient’s age, and does not meet the criteria for dementia. It is now regarded as a ‘transitional state between the cognitive changes of normal ageing and very early dementia’. (10, 35, 37) In the hope of averting the impending healthcare crisis that the rapidly escalating incidence of the dementias represents, considerable research into MCI has been undertaken in recent years. It has been found that the annual conversion rate of those with MCI who progress to full blown dementia is around 10 – 12% (but may be up to 15%). (35) This is in contrast to the expected rate of healthy elderly persons who develop dementia, with is below 4% (generally 1 – 2%). (36) However, it is important to note that about 5% per year of those diagnosed with MCI improve to normal. (35) A major area of interest in research is in trying to predict which of those with MCI will progress to dementia. However no precise indicators that are clinically useful have as yet been found. (10, 35)

MCI patients are categorized as amnestic (exhibiting memory impairment) and nonamnestic (impairment of non-memory cognitive functions such as language, attention span, executive function or visouspatial skills). Those with memory impairment are strongly disposed towards AD, the more severe the memory impairment the more likely the progression. (10, 35) Petersen et al. further subdivide amnestic and non amnestic MCI into single domain and multiple domain subtypes. As one would expect, patients with amnestic MCI-multiple domain subtype are likely to progress (i.e. deteriorate) more rapidly than those with amnestic MCI-single domain. (35) 

Differential Diagnosis

Any disorder that causes cerebral dysfunction will exhibit some degree of cognitive impairment. On the other hand, patients with MCI tend to have lack of insight and denial in regard to their cognitive state. This makes the identification of MCI patients a difficult task for the first contact medical practitioner, whether general practitioner or hospital internist, where limited time is allocated for patient assessment. Common causes of non MCI cognitive impairment include: cerebrovascular disease, Parkinson’s disease, frontotemporal degenerations, thyroid disease, HIV infection, metabolic and endocrine diseases, cerebral infection, traumatic brain injury, adverse effects of drugs and intoxicants on the CNS, vitamin B12 deficiency, chronic psychological stress, sleep disorders and depression. (10)

Presentation and Diagnostic tests

Patients may present at the insistence of a close relative or of their own volition. The patient or relative reports a decline in one or more of the following:

Memory, executive function (e.g. driving, handling finances, meal planning), behaviour and mood (e.g. agitation, anxiety, apathy, disinhibition), language, orientation, performance of familiar tasks.

The Mini-Mental State Examination (score 18-23), and, if necessary, the Montreal Cognitive Assessment or DemTect may be administered to demonstrate objective cognitive loss. (37) Generally specialist neuropsychological testing should also be conducted. (10, 36, 37)

Management

At present there are no medications approved for MCI. Healthy lifestyle changes are recommended (e.g. participation in physical and mental activity, improved diet). Vascular risk factors should be assessed and treated (e.g. hypertension, coronary artery disease). (10, 36, 37) As noted above, the general consensus is that if an effective treatment for MCI can be found and if this treatment is begun as early as possible, then this would represent the best option for prevention of progression to dementia

TCM Treatments

A recent review by May et al. has found evidence that Chinese herbal therapy is effective for MCI and age related memory impairment. The best available evidence is for two Chinese herbal formulas: Jia Wei Wu Zi Yan Zong Ke Li and Nao Li Bao Wan. However due to methodological and reporting issues, this evidence is inconclusive. (47)

COGNITIVE IMPAIRMENT AND DEMENTIA IN TCM

Dementia

TCM literature mainly deals with the topics ‘senile dementia’ and ‘Alzheimer’s disease, and these terms are often poorly defined and are sometimes used interchangeably. (38, 39, 40, 41, 42) Therefore, the expositions on AD by Western authors who have compiled the information from Chinese sources most likely pertain to dementia with predominant amnestic features, rather than AD per se. Having said that, a brief summary of AD as it is described by three eminent contemporary authors (two Western and one Chinese) is included below.

Dharmananda provides a succinct summary of the various underlying pathodynamics of AD, which have been proposed in the Chinese TCM literature (both classical and modern):

  1. Degeneration of the brain tissue (which represents a decline in the substance of the brain) is due to decline or depletion of the Kidney.
  2. Memory, cognition and other cognitive functions are regulated by the Heart and may become impaired in any pathology of the Heart, particularly when Phlegm obstructs the Heart ‘orifices’.
  3. Collapse of the original or source Qi (yuan qi ) together with obstruction  of the channels and Heart orifices by pathogens.
  4. Liver Qi constraint leading to depletion of the Stomach Qi, which in turn impairs the Stomach’s digestive function resulting in the retention of Phlegm, which eventually obstructs the orifices of the Heart.
  5. Blood stasis, which is a major feature of ageing and may also arise due to Liver constraint. (38)

Dharmamananda goes on to describe six syndrome-patterns that may be seen in AD:

  1. Spleen qi deficiency, with phlegm and stagnating blood obstructing the orifices to the brain.
  2. Liver qi stagnation, with entanglement of qi, accumulation of phlegm, and stagnating blood:
  3. Hot phlegm clogging the orifices.
  4. Spleen and kidney yang deficiency, with phlegm and stagnating blood obstructing the orifices to the brain
  5. Deficiency of liver and kidney yin, with phlegm and stagnating blood obstructing the orifices and with generation of internal wind: Liu Wei Di Huang Wan
  6. Qi and blood stagnation, obstructing the orifices to the brain. (38)

In their discussion on AD Flaws and Sionneau describe several additional disease causes, including: Heart Blood deficiency; Liver Yang hyperactivity (due to Yin deficiency); exuberant Heart Fire (also due to Yin deficiency); stirring of Liver Wind. They describe the following syndrome-patterns (and base formulas):

  1. Liver constraint, Qi stagnation: Wu Shi Gan Yu Fang
  2. Deficiency of the Liver and Kidney Yin, with Phlegm and stagnant Blood: Liu Wei Di Huang Wan
  3. Spleen-Kidney Yang deficiency with Phlegm and stagnant Blood: Fu Zi Nan Xing Yu Jin Tang
  4. Heart-Spleen dual deficiency: Yang Xin Tang
  5. Ascendant Liver Yang hyperactivity: Tian Ma Gou Teng Wan
  6. Heart Fire: Xie Xin Tang and Dao Chi San
  7. Damp and Phlegm misting the orifices: Xi Xin Tang (43)

Yan, under the heading of Senile Dementia, describes a condition characterized by ‘extensive cerebral atrophy, which is marked in the frontal lobe. The weight of the brain is at least 100g lighter than of a normal elderly person.’ Apart from localizing the loss of brain tissue to the frontal lobe (could this be a translation issue?) the description fits with AD. However, one presumes that the exposition on clinical treatments includes all of the various dementias. He lists the disease causes and mechanisms as follows:

  1. Depletion of the Qi and Blood due to ageing
  2. Loss of mutual regulation between the Ying-nutritive Qi and the Wei-defense Qi
  3. Deficiency of all the Zang organs with loss of harmonious interaction between them
  4. Failure of the middle Jiao Qi to send the clear Yang Qi upwards and the turbid Yin Qi downwards
  5. Qi stagnation
  6. Blood stasis
  7. Retention of Phlegm, which obstructs the Heart orifices

In addition he points to the fact that most elderly people take multiple prescription medications, which are poorly broken down and excreted, resulting in chronic drug toxicity. Emotional factors such as loneliness, grief due to loss of friends and relatives, separation from the children and decrease in social activities also play an important role in this condition. He sums up the disease mechanism as ‘lack of connection of the visceral Qi with the brain Qi’. (40) This is due to the above listed factors, summarized as deficiency (Qi, Blood and essence), obstruction by Blood stasis and retained Phlegm. The three treatment protocols discussed reflect this distinction: A. Qi stagnation and Blood stasis; B. Qi deficiency and Blood stasis; C. Phlegm and (Blood) stasis joining and obstructing.

Dharmananda and Liu also concur that the core pathologies that contribute to dementia are deficiency of the Kidney, retention of Phlegm obstructing the orifices of the Heart and Blood stasis obstructing the Channels-Collaterals of the brain. (38, 39)

Senile dementia as described by Flaws and Lake appears to be a compilation of various Chinese sources. As noted above, these sources include all of the various dementias distinguished by Western medicine under this heading. They describe the disease causes and mechanisms as per Yan (above), expanding on items 1, 3 and 7 to emphasize the key role of Kidney and Spleen in the generation of these pathological changes. (44)

Flaws and Lake describe the following for syndrome-patterns (and base formulas) in senile dementia:

  1. Kidney Essence deficiency: Da Zao Wan
  2. Kidney Yin deficiency with deficiency Heat: Zhi Bai Di Huang Wan
  3. Spleen-Kidney Yang deficiency: Shen Qi Wan (Ba Wei Di Huang Wan) plus Shen Qi Da Bu Wan
  4. Qi-Blood dual deficiency: Gui Pi Tang
  5. Phlegm misting the clear orifices: Wen Dan Tang
  6. Blood stasis obstruction in the brain: Tong Qiao Huo Xue Tang
  7. Liver constraint, Qi stagnation: Xiao Yao San (44)

An additional category is included, which refers to delirium due to a febrile illness or poisoning and is not included here. However, this may be relevant in China where, as sometimes happens in remote areas, a severe febrile illness may leave a patient with permanent brain damage due to lack of effective treatment.

In summary, the basic pathology underling dementia consists of the following interwoven pathodynamic factors:

  • Deficiency of the Kidney essence.
  • Phlegm retention, which obstructs the orifices of the Heart.
  • Blood stasis.

Associated pathologies may include:

  • Liver Qi constraint, Qi stagnation
  • Heart deficiency (Qi, Blood and/or Yin)
  • Spleen Qi deficiency
  • Liver Yin deficiency
  • Heat
  • Interior Wind due to Liver Yang hyperactivity (38, 39, 40, 41, 42)

The core pathodynamic factors (Kidney deficiency, Phlegm obstruction and Blood stasis) directly underlie the major symptoms of cognitive decline in dementia. As discussed above, Western medicine clearly distinguishes between reversible temporary causes of cognitive impairment and irreversible ones. However, this is not so in most of the TCM literature that has been reviewed herein. Western medicine is able to make this very necessary distinction, which facilitates the practitioner to differentiate diseases of other systems that may affect brain functioning from a disease process within the brain itself.  While TCM analysis may reveal that the source of the pathological changes in the brain is located in various other organ systems, it is essential that the primary treatment strategy should focus on these core pathologies, described in terms of the Kidney essence, Phlegm and Blood stasis.

As discussed above, although positive outcomes have been reported in Chinese, Japanese and Korean research, it is likely that the potential for herbal treatment of AD is on a par with or a little better than Western pharmaceuticals. As the latter generally provides only statistically significant (but not clinically significant) outcomes in one patient out of 10-12 treated, it appears that herbal therapy may also be of minimal benefit.

 

Early stage dementia

Because the main focus of this paper is on early detection and prevention of progression the lack of clear differentiation between the various dementias is not problematic. Moreover, recent changes in the understanding of the dementias in Western medicine, as discussed above in the introductory section on Dementia, make it more practical to consider AD, VD and MCI as a single disease entity. Thus it is assumed, for the purposes of this paper, that MCI, AD and VD have common underlying causes, common pathodynamics and a common treatment approach. As noted above, under MCI, the best available evidence, although still inconclusive, points to the application of Chinese herbal therapy to early stage dementia. The herbal formulations that have been the subject of the best designed studies generally address Kidney essence deficiency; Phlegm obstruction of the Heart orifices; Blood stasis, Liver Blood and Yin deficiency and deficiency of the source (yuan) Qi (addition of panax ginseng).

I would like to propose a pragmatic approach to the treatment of early stage dementia/MCI. Firstly, the diagnosis should be suspected in any person over the age of 60 who appears to exhibit lower than expected cognitive function for their age. This may manifest in impaired activities of daily living, behavior and/or cognitive function. Although the patient may not be seeking treatment for cognitive decline, in view of the seriousness of the consequences, the patient should be educated about the risks of dementia. The Folstein Mini-Mental State Examination may be used to detect and roughly quantify the degree of cognitive impairment. A score between 18 and 23 indicates a possible early stage dementia. (39, 45, 46) It should be noted that allowance is to be made for the patient’s level of education and other factors such as anxiety over being tested, fatigue and medical conditions. A copy of the Folstein MMSE is included in the appendix.

Treatment should address the basic factors of Kidney essence deficiency, Phlegm obstruction and Blood stasis. In addition, whatever other imbalances are detected in the individual patient should also be treated, paying particular attention to the Heart, Liver and Spleen. As noted above, although the TCM  literature describes various clinical syndrome patterns that may be encountered, it should be noted that the essential pathology of dementia is always present and that, while other syndrome-patterns may be superimposed upon it, the main thrust of treatment should be to tonify the Kidney essence; dispel Phlegm and resolve Blood stasis.

Formulas that may be used to address the core pathological features of early stage dementia include:

1. Kidney deficiency (select one of the following):

  • Liu Wei Di Huang Wan (Rehmannia Six Formula) – nourishes the Kidney Yin-essence. For patients with signs of Kidney Yin deficiency: low back pain; seminal emissions; overactive libido; dizziness; tinnitus; poor memory; dry mouth; night sweating; red tongue with little or no coat.
  • Fu Gui Ba Wei Wan (Rehmannia Eight Formula) – warms and invigorates the Kidney Yang-essence. For patients with signs of Kidney Yang deficiency: low back pain with a cold sensation; intolerance of cold; cold extremities and lower abdomen; sexual hypofunction; urination is copious and clear
  • Qi Bao Mei Ran Dan (Polygonum & Cuscuta Formula) – nourishes the Kidney and Liver. Traditionally developed to prevent hair loss, this formula has a marked action on patients exhibiting the early signs of ageing. Essential clinical features include: pain in the hypochondrium; pain and weakness of the low back and knees; tinnitus; seminal emissions (male); vivid sexual dreams (female); signs of deficiency Heat or Fire (dry mouth and throat, red cheeks, night sweats, red tongue with little or no coat, rapid pulse, etc.)
  • Jiao Niao Yi Zhi Fang (Memor-Aid Formula) – an empirical formula that mainly nourishes the Kidney essence; also nourishes the Heart and calms the Spirit, resolves Phlegm and opens the Heart orifices, activates the Blood and dispels stasis. Clinical features include: sleep disturbance; fatigue; postural dizziness; tinnitus; pain and weakness of the low back and knees; cold hands and feet; tongue is pale; pulse is weak and thready or deep and weak

2. Blood stasis (select one of the following):

  • Bu Yang Huan Wu Wan (Astragalus & Lumbricus Formula) – resolves Blood stasis, tonifies the Qi and nourishes the Blood. Traditionally used for hemiplegia, this formula has broad applications in muscle wasting disorders and various neuropathies. This would be the formula of choice to address Blood stasis in patients with early dementia/MCI. Possible reasons not to use it (and use dan shen instead) would include: very mild condition; inability of the patient to tolerate a treatment composed of many different herbal ingredients.
  • Salvia tablets (Dan Shen Pian) – a gentle on the stomach treatment for Blood stasis. It has a calming action, is cooling and detoxifying and mildly Blood nourishing.

3. Phlegm obstruction of the Heart orifices (select one or more of the following):

  • An Shen Ding Zhi Wan – Clear the Heart orifices, nourishes the Heart and calms the Spirit. Clinical features include: insomnia or disturbed sleep, forgetfulness, anxiety, agitation, timidity, apprehensiveness, palpitations, depressed mood, poor concentration, nervous laughter, pale tongue, thready and weak pulse
  • Wen Dan Tang (Bamboo & Hoelen Formula) – resolves Phlegm, mildly clears Heat and redirects counterflowing Qi. Key clinical features include: thick and greasy tongue coat; slippery pulse; nausea, vomiting or acid reflux; sense of fullness and discomfort in the chest.
  • Xiang Sha Liu Jun Zi Tang (Saussurea & Cardamon Formula) – resolves Phlegm and tonifies the Spleen Qi. This formula is more appropriate for patients with clear signs of Spleen deficiency. Key clinical features include: Fatigue, muscular weakness; sensation of bodily heaviness; poor appetite with a sensation of fullness after eating small amounts; epigastric or abdominal distension with mild pain; nausea, vomiting or belching; loose stools; pale tongue with a white greasy or thick white coat; weak pulse that is also slippery.

Although this basic protocol may also be applied to patients with clinical dementia, the best available evidence suggests that Chinese herbal therapy will achieve optimal results in patients who are showing the very early signs of dementia (i.e. MCI). In this we are following the advice given in the Huang Di Nei Jing Su Wen (‘The Yellow Emperor’s Classic of Medicine’): ‘In the old days the sages treated disease by preventing illness before it began, just as a good government or king was able to take the necessary steps to avert war. Treating an illness after it has begun is like suppressing a revolt after it has broken out.’ (49)

REFERENCES

  1. Ferri, C., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K. Hasegawa, K., Hendrie, H., Huang Y. Jorm, A., Mathers, C., Menezes, P., Rimmer, E., Scazufca, M. (2005). Global prevalence of dementia: a Delphi consensus study. The Lancet, 366 (9503): 2112-7
  2. Rockwood, K., Bouchard, R., Camicioli, R., Léger, G. (2007). Toward a revision of criteria for the dementias. Alzheimers Dement. 3(4):428-40.
  3. Feldman, H., Jacova, C., Robillard, A., Garcia, A., Chow, T., Borrie, M., Schipper, H., Blair, M., Kertesz, A., Chertkow, H. (2008). Diagnosis and treatment of dementia: 2. Diagnosis. CMAJ. 178(7): 825–836.
  4. Sucholeiki, R., Caselli, R., (2007). Dementia: Overview of Pharmacotherapy. From eMedicine Specialties, Neurology, Behavioral Neurology and Dementia. Retrieved Nov.’09 from: http://emedicine.medscape.com/article/1136306-overview
  5. Feldman, H., Jacova, C., Robillard, A., Garcia, A., Chow, T., Borrie, M., Schipper, H., Blair, M., Kertesz, A., Chertkow, H., (2008). Diagnosis and treatment of dementia: 2. Diagnosis. CMAJ. 178(7):825-36
  6. Alagiakrishnan, K.., Masaki, K., (2009). Vascular Dementia. From eMedicine Specialties, Psychiatry, Geriatric. Retrieved Nov. 2009 from: http://emedicine.medscape.com/article/292105-overview
  7. Anderson, H. (2009). Alzheimer Disease. From eMedicine Specialties, Neurology, Behavioral Neurology and Dementia. Retrieved Nov. ’09, from: http://emedicine.medscape.com/article/1134817-overview
  8. Waldemar, G., Dubois, B., Emre, M., Georges, J., McKeith, I., Rossor, M., Scheltens, P., Tariska, P., Winblad, B., (2007). Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol. 14(1):e1-26
  9. Horowitz, A., Wakefield, J. (2007). The Loss of Sadness: How Psychiatry Transformed Normal Sorrow into Depressive Disorder. New York, Oxford University Press
  10. Anderson, H., Kuljis, R. (2008). Mild Cognitive Impairment. From eMedicine Specialties, Neurology, Behavioral Neurology and Dementia. Retrieved Nov. 2009 from: http://emedicine.medscape.com/article/1136393-overview
  11. Mitchell, A., Shiri-Feshki, M., (2009). Rate of progression of mild cognitive impairment to dementia–meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. 119(4):252-65.
  12. Levey, A., Lah, J., Goldstein, F., Steenland, K., Bliwise, D., (2006). Mild cognitive impairment: an opportunity to identify patients at high risk for progression to Alzheimer’s disease. Clin Ther. 28:991–1001.
  13. American Psychiatric Association (2000). Diagnostic and Statistical manual of mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington DC: APA
  14. Patterson, C., Feightner, J., Garcia, A., MacKnight, C., (2007). General risk factors for dementia: a systematic evidence review. Alzheimers Dement. 3:341-7
  15. Patterson, C., Feightner, J., Garcia, A., Hsiung, R., MacKnight, C., Sadovnick, D., (2008).  Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ. 178 (5): 548-56
  16. Lanctôt, K., Herrmann, N., Yau, K., Khan, L., Liu, B., LouLou, M., Einarson, T., (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ .169:557-64.
  17. Tampi, R., van Dyck, C.,  (2007). Memantine: efficacy and safety in mild-to-severe Alzheimer’s disease. Neuropsychiatr Dis Treat. 3(2): 245–258.
  18. van Dyck, C., Schmitt, F., Olin, J., Memantine MEM-MD-02 Study Group, (2006). A responder analysis of memantine treatment in patients with Alzheimer disease maintained on donepezil. Am J Geriatr Psychiatry. 14(5):428-37.
  19. McShane, R., Areosa Sastre, A., Minakaran, N., (2006). Memantine for dementia. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD003154. DOI: 10.1002/14651858.CD003154.pub5.
  20. Lanctôt, K., Rajaram, R., Herrmann, N., (2009). Review: Therapy for Alzheimer’s Disease: How Effective Are Current Treatments? Ther Adv Neurol Disorders. 2(3):163-180
  21. May, B., Lit, M., Xue, C., Yang, A., Zhang, A., Owens, M., Head, R., Cobiac, L., Li, C., Hugel, H., Story, D., (2009). Herbal medicine for dementia: a systematic review. Phytother Res. 23(4):447-59.
  22. Peng, X., Dong, K., (2009). Clinical observation on acupuncture combined with Yizhi Jiannao granules for treatment of Alzheimer’s disease. Zhongguo Zhen Jiu. 29(4):269-71.
  23. Man, S., Durairajan, S., Kum, W., Lu, J., Huang, J., Cheng, C., Chung, V., Xu, M., Li, M., (2008). Systematic review on the efficacy and safety of herbal medicines for Alzheimer’s disease. J Alzheimers Dis. 14(2):209-23.
  24. Shinno, H., Inami, Y., Inagaki, T., Nakamura, Y., Horiguchi, J., (2008). Effect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptoms of dementia. Prog Neuropsychopharnacol Biol Psychiatry. 32(3):881-5
  25. Mizukami, K., Asada, T., Kinoshita, T., Tanaka, K., Sonohara, K., Nakai, R., Yamaguchi, K., Hanyu, H., Kanaya, K., Takao, T., Okada, M., Kudo, S., Kotoku, H., Iwakiri, M., Kurita, H., Miyamura, T., Kawasaki, Y., Omori, K., Shiozaki, K., Odawara, T., Suzuki, T., Yamada, S., Nakamura, Y., Toba, K., (2009). A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia. Prog Neuropsychopharmacol Biol Psychiatry. 33(2):308-11.
  26. Kamei J, Miyata S, Ohsawa M., (2009). Involvement of the benzodiazepine system in the anxiolytic-like effect of Yokukansan (Yi-gan san). Prog Neuropsychopharmacol Biol Psychiatry. 33(8):1431-7.
  27. Tateno M, Ukai W, Ono T, Saito S, Hashimoto E, Saito T., (2008). Neuroprotective effects of Yi-Gan San against beta amyloid-induced cytotoxicity on rat cortical neurons. Prog Neuropsychopharmacol Biol Psychiatry. 32(7):1704-7.
  28. Takeda A, Itoh H, Tamano H, Yuzurihara M, Oku N. (2008). Suppressive effect of Yokukansan on excessive release of glutamate and aspartate in the hippocampus of zinc-deficient rats. Nutr Neurosci. 11(1):41-6.
  29. Kawakami Z, Kanno H, Ueki T, Terawaki K, Tabuchi M, Ikarashi Y, Kase Y. (2009). Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells. Neuroscience. 159(4):1397-407.
  30. Mizoguchi K, Tanaka Y, Tabira T., (2009). Anxiolytic effect of a herbal medicine, yokukansan, in aged rats: Involvement of serotonergic and dopaminergic transmissions in the prefrontal cortex. J Ethnopharmacol. doi:10.1016/j.jep.2009.09.048
  31. Alagiakrishnan, K., Masaki, K., (2009). Vascular Dementia. From eMedicine Specialties, Psychiatry, Geriatric. Retrieved November, 2009 from: http://emedicine.medscape.com/article/292105-overview
  32. Chawla, J., Grutzendler, J., d’Avossa, G., Revilla, F., (2009). Vascular Dementia. From eMedicine Specialties, Neurology, Behavioral Neurology and Dementia. Retrieved December, 2009 from: http://emedicine.medscape.com/article/1135408-overview
  33. Bocti, C., Black, S., Frank, C., (2007). Management of dementia with a cerebrovascular componentAlzheimers Dement. 3(4): 398-403
  34. Huang, H., Xu, Y., Lu, R., Zhou, X., Zhou, C. (2009). Controlled study of auricular point taping and pressing therapy for treatment of vascular dementia. Zhongguo Zhen Jiu. 29(2):95-7.
  35. Petersen, R., Negash, S. (2008). Mild Cognitive Impairment: An Overview. CNS Spectr. 13(1):45-53
  36. Prince, M. (2008). The prevalence of dementia worldwide. Alzheimers Disease International. Retrieved, Jan. 2010 from: http://www.alz.co.uk/adi/pdf/prevalence.pdf
  37. Chertkow H, Massoud F, Nasreddine Z, Belleville S, Joanette Y, Bocti C, Drolet V, Kirk J, Freedman M, Bergman H., (2008). Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia. CMAJ. 178(10):1273-85.
  38. Dharmananda, S., (1996). Alzheimer’s Disease: Treatment with Chinese Herbs. Institute for Traditional Medicine Online, retrieved January, 2010 from: http://www.itmonline.org/arts/alzheimers.htm
  39. Liu, J., (2009). Neurological disorders in Chinese Medicine. Lecture notes University of Western Sydney Master of Acupuncture Program.
  40. Yan, D., (1995). Aging & Blood Stasis A New TCM Approach to Geriatrics. Boulder Co: Blue Poppy Press, pp. 243-250
  41. Hou, J. (chief ed.) (1996). Traditional Chinese Treatment for Psychogenic and Neurogenic Diseases. Beijing: Academy Press, pp.118-120
  42. Hou, J., Geng, X. (chief ed.) (1997). Traditional Chinese Treatment for Senile Diseases. Beijing: Academy Press, pp.282-287
  43. Flaws, B. & Sionneau, P. (2001). The Treatment of Modern Western Diseases With Chinese Medicine: A Textbook & Clinical Manual. Boulder, CO: Blue Poppy Press, pp. 53-58
  44. Flaws, B. & Lake, J. (2001). Chinese Medical Psychiatry: A Textbook & Clinical Manual. Boulder: Blue Poppy Press, pp. 292-297
  45. Folstein, M., Folstein, S., McHugh, P., (1975). ‘Mini-mental state’.  A practical method for grading the cognitive state of patients for the physician. J Psychiatr Res. 12:189–198.
  46. Folstein Mini Mental State Examination. British Columbia Ministry of Health Services Home and Community Care. Retrieved January, 2010 from: https://www.health.gov.bc.ca/exforms/commcare/14.pdf 
  47. May, B., Yang, A., Zhang, A., Owens, M., Bennett, L., Head, R., Cobiac, L., Li, C., Hugel, H., Story, D., Xue, C., (2009). Chinese herbal medicine for Mild Cognitive Impairment and Age Associated Memory Impairment: a review of randomised controlled trials. Biogerontology. 10:109–123
  48. dos Santos-Neto, L., de Vilhena Toledo, M., Medeiros-Souza, P., de Souza, G., (2006). The Use of Herbal Medicine in Alzheimer’s Disease – A Systematic Review. Evid Based Complement Alternat Med. 3(4): 441–445.
  49. Ni, M., (1995). The Yellow Emperor’s Classic of Medicine. A New Translation of the Neijing Suwen with Commentary. Boston: Shambala Publications Inc.
[1] American Psychiatric Association (2000). Diagnostic and Statistical manual of mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington DC: APA