Alzheimer's disease and vascular dementia are two major diseases associated with dementia, which is common among the elderly. While the etiology of dementia is multi-factorial and complex, neurodegeneration may be the major cause of these two diseases. Effective drugs for treating dementia are still to be discovered. Current western pharmacological approaches against neurodegeneration in dementia develop symptom-relieving and disease-modifying drugs. Current integrative and holistic approaches of Chinese medicine to discovering drugs for neurodegeneration in dementia include (1) single molecules from the herbs, (2) standardized extracts from a single herb, and (3) herbal formula with definite composition. This article not only reviews the concept of dementia in western medicine and Chinese medicine but also evaluates the advantages and disadvantages of these approaches.
Alzheimer's disease (AD) and vascular dementia (VaD) are the major forms of dementia. In addition, in the postmortem brains of the late stage of Parkinson's disease/Lewy body disease also find pathological hallmarks of AD  . Senile dementia is the progressive decline of memory and some related cognitive functions in the elderly. The global dementia population is predicted to reach 81.1 million by 2040  . In 2010, the estimated prevalence of senile dementia in China is 6.0 to 7.0 million, accounting for about one-sixth of the global prevalence; the prevalence is expected to increase to 22.5 million by 2040, accounting for one-fourth of the global prevalence by that time  . The rapid increase in the number of dementia patients urgently demands effective prevention and treatment. Current approaches to dementia-related neurodegenerative diseases still highly rely on relieving symptoms. As some Chinese medicinal herbs have been used in treating dementia, many researchers are now turning to Chinese medicine for identifying potential neuroprotective agents or disease-modifying agent. This article reviews the strategy in the research of Chinese medicine in dementia related-neurodegenerative diseases.
Dementia and medical sciences
AD is clinically characterized by the progressive loss of memory, cognitive functions and behavioral changes. The pathogenesis of AD has been widely studied [4,5] , in which beta-amyloid (Aβ) peptide and hyperphosphorylated tau protein as components of extracellular senile plaques and intracellular neurofibrillary tangles, respectively, are believed to be the targets for developing disease-modifying drugs. Current AD treatments are all symptom-relieving agents and heavily rely on the use of acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine and galantamine). AChE inhibitors slow down the degradation of the neurotransmitter acetylcholine, thereby increasing its bioavailability. Another approved AD treatment aims to reduce glutamate excitotoxicity. Memantine, the only approved drug in this category, acts as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist to reduce glutamate-mediated neurotoxicity  .
Development and progression of VaD are associated with a number of risk factors, many of which are related to the pathogenesis of atherosclerosis  . Stroke is also a critical factor for VaD; it was reported that 79.5% of VaD patients had a history of stroke  . As there is no cure for VaD, management of VaD emphasizes on the prevention of new stroke and control of vascular risk factors.
Dementia and Chinese medicine
According to Chinese medicine theory, there is no distinction between AD and VaD. Dementia is caused by (1) deficiency of vital energy of the Kidney (Shen), Marrow (Sui), Heart (Xin) and Spleen (Pi) and (2) stagnation of Blood (Xie) and/or Phlegm (Tan). Thus, herbs used for dementia are not specific for the nervous system but tend to be multi-functional  .
Standardization of dementia subtype classification and research guidelines
Guideline for Chinese Medicine Diagnosis, Classification and Clinical Research of Senile Dementiawas published in 1990. The guideline classified dementia into six subtypes according to the CM theory: (1) the Bone Marrow (Gusui) deficiency syndrome, (2) the Liver (Gan) and Kidney (Shen) Yin deficiency syndrome, (3) the Spleen (Pi) and Kidney (Shen) Yang deficiency syndrome, (4) the Qi stagnation and Blood (Xie) stasis syndrome, (5) the Phlegm Turbid (Tan Zhuo) blocking Orifice (Qing Qiao) syndrome, and (6) the Heart (Xin) and Liver Fire (Gan Huo) syndrome  . Since then, clinical studies on dementia in China have been based on this guideline  . More recently, the Guideline Principles for Clinical Research on New Chinese Medicine (trial version)  provides more detailed description on the diagnostic criteria and describes the severity of disease subtypes quantitatively. The Mini-Mental State Examination (MMSE) score has also been introduced as the main reference index  . Criteria for the Diagnosis, Differentiation of Syndrome and Evaluation of Efficacy of Vascular Dementia for Research Studies were published on 2002, emphasizing that the diagnosis of VaD must meet the NINDS-AIREN criteria (developed by the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN)) and that the differentiation of syndromes in Chinese medicine should be based on the scale for the differentiation of syndromes of vascular dementia (SDSVD) published in 2000  . It classifies VaD in 7 syndromes according to CM diagnosis: (1) the Kidney Essence (Shen Jing) deficiency syndrome, (2) the Phlegm Turbid (Tan Zhuo) blocking Orifice (Qing Qiao) syndrome, (3) the vessels obstructed by Blood Stasis (Xie Yu) syndrome, (4) the brain aggressed by Liver's (Gan)Yang syndrome, (5) the Heat (Re) and Toxin (Du) accumulation syndrome, (6) the Qi and Blood (Xie) deficiency syndrome, and (7) the constipation and toxin in intestines syndrome. SDSVD employs a detailed scoring system to assist syndrome differentiation and diagnosis  .
Chinese medicine approaches based on the etiology of dementia
Chinese medicine theory considers dementia to be a more holistic and integrated approach, rather than a problem in just one organ. Dementia is complex and may involve multiple causes. During progression of dementia, the significant of different pathological factors may also change. In Chinese medicine, it is believed that the disease is highly correlated to the abnormal functions of other organs including the Kidney (Shen), Liver (Gan), Heart (Xin) and Spleen (Pi), although the pathological site of dementia is in the brain. For example, dementia patients who initially have Kidney (Shen) deficiency may also develop stagnation of Blood (Xie) and Phlegm (Tan) leading to dementia. All these clinical experiences, stagnation of blood and kidney deficiency, become two important concepts in Chinese medicine to explain the origin of sickness leading to dementia[14-16] .
Chinese medicine studies on the prevalence and distribution of dementia subtypes
In order to integrate Chinese medicine diagnosis, some researchers investigated the prevalence and distribution of dementia subtypes. Wang et al. found that deficiency of Qi, Blood (Xie), Essence (Jing) was present in most dementia cases and that Heart (Xin) and Kidney (Shen) were most commonly afflicted by the condition  . Yang et al. found that stagnation of Blood (Xie) and Phlegm (Tan) were frequently present in moderate and severe AD cases  . While these data are not diagnostic criteria, they provide important information for the prevention of pathological progression in dementia.
Chinese medicine research on treatment of dementia
Nowadays, the development of Chinese herbal medicine mainly adopted three approaches, which include the single molecule approach, standardized extracted approach and fixed herbal formula approach. In the following sections, we will discuss the recent development of each approach. It is beyond the scope of our report to review the pharmacological effects of all medicinal herbs for dementia treatment in detail. In fact, our aim is to use several representative examples to illustrate the advantages and disadvantages of each approach.
Single molecules from a single herb
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