Treatment of vascular dementia — evidence from clinical trials with cholinesterase inhibitors Timo Erkinjuntti a, * , Gustavo Roma ´n b , Serge Gauthier c a Helsinki University Central Hospital, Helsinki, Finland b University of Texas Health Science Center at San Antonio and the A. Murphy Veterans Administration Hospital, San Antonio, TX 78229, USA c MCSA Alzheimer’s Disease Research Unit, McGill Centre for Studies on Aging, Montreal, PQ, Canada Available online 8 October 2004 Abstract Cerebrovascular disease (CVD), as well as secondary ischemic brain injury from cardiovascular disease, are common causes of dementia and cognitive decline in the elderly. In addition, CVD frequently contributes to cognitive loss in patients with Alzheimer’s disease (AD). Progress in understanding the pathogenetic mechanism involved in vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising treatments of these conditions. Cholinergic deficits in VaD are due to ischemia of basal forebrain nuclei and of cholinergic pathways and can be treated with the use of the cholinesterase inhibitor agents used in AD. Controlled clinical trials with donepezil, galantamine and rivastigmine in VaD, as well as in patients with AD plus CVD, have demonstrated improvements in cognition, behavior and activities of daily living. D 2004 Elsevier B.V. All rights reserved. Keywords: Vascular dementia; Alzheimer’s disease; Cholinesterase inhibitors 1. Cholinergic dysfunction in vascular dementia Cholinergic deficit in VaD, independently of any con- comitant AD pathology, has been well documented. Chol- inergic structures are vulnerable to ischemic damage. Indeed, hippocampal CA1 neurons are particularly susceptible to experimental ischemia, and hippocampal atrophy is common in patients with VaD in the absence of AD [1]. Selden et al. [2] described two highly organized and discrete bundles of cholinergic fibres in human brains that extend from the nucleus basalis to the cerebral cortex, hippocampus and amygdala. Both pathways travel in the white matter, and together carry widespread cholinergic input to the neocortex. Localized strokes may interrupt these cholinergic bundles. Mesulam et al. [3] demonstrated cholinergic denervation from pathway lesions, in the absence of AD, in a young patient with CADASIL, a pure genetic form of VaD. In experimental rodent models, such as the spontane- ously hypertensive stroke prone rat, there is a significant reduction in cholinergic markers including acetylcholine (ACh) in the neocortex, hippocampus and CSF [4]. White matter infarction in rodent models results in substantial decreases in cholinergic markers, presumably through an impact on cholinergic projection fibres [5]. In human disease, there is a reported loss of cholinergic neurons in 70% of AD cases and in 40% of VaD patients examined neuropathologically, and reduced ACh activity in the cortex, hippocampus, striatum, and CSF [6]. 2. Cholinesterase inhibitors in vascular dementia Four cholinesterase inhibitors (AChEIs) have been approved for use in AD: tacrine, donepezil, rivastigmine and galantamine. In controlled trials, secondary outcomes have varied, but often included ADL and behavioral scales. 0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2004.09.018 * Corresponding author. Tel.: +358 9 471 7 2352; fax: +358 9 471 7 2353. E-mail address: Timo.Erkinjuntti@HUS.fi (T. Erkinjuntti). Journal of the Neurological Sciences 226 (2004) 63 – 66 www.elsevier.com/locate/jns