Cholinesterase inhibitors in vascular cognitive impairment.

Vascular Cognitive Impairment (VCI) includes vascular dementia, mixed dementia (Alzheimer’s disease [AD] with cerebrovascular disease), and vascular mild cognitive impairment, and it is a common cause of cognitive dysfunction1. Some may even contend that it is the most common cause of cognitive impairment. This is based principally on clinicopathological data showing that most aged individuals with significant cognitive impairment have mixed vascular and neurodegenerative neuropathology2. Vascular risk factor prevention and treatment are a mainstay of VCI management. Based on data showing disruption of cholinergic pathways in vascular dementia, cholinesterase inhibitors (ChEI) have also been widely used for symptomatic treatment3. Following a comprehensive review and analysis of the literature, the third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) published in 2007 concluded that there was fair evidence for a modest benefit of donepezil on clinical outcomes in vascular dementia4. The third CCCDTD also concluded that there was fair evidence of modest benefit of galantamine in mixed AD with cerebrovascular disease. Similarly, the American Stroke Association and American Heart Association in their statement on Vascular Contribution to Cognitive Impairment and Dementia recommended donepezil for “cognitive enhancement” in patients with vascular dementia, and galantamine for patients with mixed AD with vascular dementia1. Clinical trials in VCI published since then have shown positive results for other cholinesterase inhibitors in mixed dementia, but inconsistent results in vascular dementia. This led the fourth and most recent CCCDTD, published in 2012, to recommend all ChEIs as symptomatic treatment options in mixed dementia5. However, it concluded that there was insufficient evidence to recommend for or against symptomatic treatment with ChEIs in vascular dementia. Vascular Cognitive Impairment, particularly vascular dementia, usually presents with a fronto-sub-cortical pattern of impairment with prominent executive dysfunction and relative sparing of memory, which is distinct from the typical clinical picture seen in cortical dementias such as AD. This poses a diagnostic challenge in clinical practice as commonly used cognitive screening tools such as Folstein’s Mini-Mental Status Examination (MMSE) are limited by their capacity to capture executive dysfunction. More recently developed screening tests, the Montreal Cognitive Assessment (MOCA) being a salient example6, have refined executive function evaluation and are better suited for screening of VCI7. The clinical pattern of VCI also constitutes a challenge in the selection of appropriate and responsive outcome measures in clinical trials of pharmacological interventions. The study published by Rockwood et al, in this issue of the Canadian Journal of Neurological Sciences deals specifically with this topic of using appropriate outcome measures in clinical trials of VCI and translating the results of Cholinesterase Inhibitors in Vascular Cognitive Impairment