Description of the condition

Vascular dementia (VaD) is a term used to describe a constellation of cognitive and functional impairment that can be viewed as a subset of the larger syndrome of vascular cognitive impairment associated with cerebrovascular brain injury (Aggarwal 2007). It is the second most common form of dementia after Alzheimer's disease among the elderly (O'Brien 2003). Subtypes of VaD can be briefed as follows (O'Brien 2006;Demaerschalk 2007):

• Multi‐infarct dementia (cortical VaD:predominantly resulting from large cortical infarcts)

• Small‐vessel dementia (subcortical VaD, predominantly resulting from subcortical lacunes, white and/or deep grey matter lesions)

• Strategic infarct dementia (resulting from a unilateral or bilateral infarct in strategic area (i.e. thalamus, hippocampus))

• Hypoperfusion dementia (resulting from brain damage from hypoperfusion)

• Hemorrhagic dementia

• Alzheimer's disease with CVD (sometimes known as "mixed dementia")

• Hereditary vascular dementia (CADASIL)

A meta‐analysis of the European studies on the incidence of dementia showed that vascular dementia constituted 17.6% of all incident dementia (Grossman 2006). In Europe and North America, Alzheimer's disease (AD) predominates over VaD in a 2:1 ratio; in contrast, in Japan and China, VaD accounts for almost 50% of all dementias (Roman 2004). The divergent epidemiological trend may be due to different diagnostic criteria and study populations (Karirajan 2007). With increasing aging people in most parts of the world, including China and India where more than two billion people live, it is likely that the interactions between dementia, stroke, and cardiovascular disease will become increasingly important. It is anticipated that with progressive aging of the population and decline in mortality after stroke, vascular dementia will become the most common form of dementia (Gustavo 2005). However, there is no definitive medical or surgical treatment for vascular dementia. Cholinergic deficits are well documented in VaD, independent of any concomitant AD pathology (Erkinjuntti 2004). Cholinergic structures in the brain are vulnerable to ischemic damage. In humans, there is a loss of cholinergic neurons in 40% of VaD patients examined neuropathologically, with reduced acetylcholine activity in the cortex, hippocampus, and striatum (Demaerschalk 2007). It is believed that cholinesterase inhibitors, which are indicated for the treatment of mild to moderate AD, may also provide benefit for patients with VaD (Farlow 2006).The best evidence to date supports the benefit of donepezil in improving cognition function, clinical global impression and activities of daily living in patients with probable or possible mild to moderate vascular cognitive impairment after six months treatment and data confirmed that donepezil was well tolerated, and most of the side effects (nausea, diarrhoea, anorexia and cramp which appeared most frequently) were transient and were resolved by stopping the medication, and there were no significant differences for donepezil compared with placebo for the number who suffered serious adverse events (Malouf 2004). Galantamine was also effective in the areas of cognition and executive functioning in one trial but this was not seen in a second trial which included a smaller numbers of relevant patients. In both considered trials galantamine produced higher rates of gastrointestinal side effects (Craig 2006). Due to insufficient evidence, rivastigmine cannot yet be recommended for the treatment of vascular cognitive impairment (Craig 2004). With memantine, the small beneficial effect on cognition was not clinically detectable in those with vascular dementia and was detectable in those with AD; memantine is well tolerated. There was no significant difference in the number of patients experiencing at least one adverse event (McShane 2006).

Description of the intervention

Some traditional Chinese herbal medicines have been developed for treating VaD. Huperzine A is one such herbal medicine, which is a kind of alkaloid isolated from the Chinese herb Huperzia serrata.

How the intervention might work

It is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE) of the central nervous system. It has been authorized for treating AD and benign memory deficits since 1994 in China (Han 2006). The drug is available as a nutraceutical in the US (Little 2008). However, there have been no published controlled clinical trials outside China assessing its toxicity and efficacy. Few side effects were observed in clinical trials and the side effects (those most frequently observed are mild dizziness, abdominal distention, and nausea) were transient and were resolved by stopping the medication or improved with symptomatic treatment (Li 2001; Wang 2004; Zhong 2004).

Compared with tacrine, donepezil, and rivastigmine, Huperzine A has better penetration through the blood‐brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action (Wang 2006).

Recent data have shown that Huperzine A may have neuroprotective effects that go beyond the inhibition of AChE. These effects include modification of beta‐amyloid peptide processing, reduction of oxidative stress, neuronal protection against apoptosis, and regulation of the expression and secretion of nerve growth factor (NGF) and NGF signalling (Zhang 2006).

Why it is important to do this review

With the extension of clinical application, Huperzine A has even been considered as an alternative treatment in clinical practice and used as a standard control intervention in clinical trials, but its effectiveness and safety in vascular dementia are still uncertain. We therefore sought to undertake a rigorous systematic review of the existing evidence to determine whether Huperzine A can be recommended for routine use in patients with vascular dementia.