Masafumi Ihara

The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25-30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood-brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

BACKGROUND AND PURPOSE: Cerebrovascular white matter (WM) lesions are closely associated with cognitive impairment and gait disorders in the elderly. We have successfully established a mouse model of chronic cerebral hypoperfusion that may provide new strategies for the molecular analysis of cerebrovascular WM lesions. METHODS: Adult C57Bl/6 male mice were subjected to bilateral common carotid artery stenosis (BCAS) using external microcoils with varying inner diameters from 0.16 to 0.22 mm. Cerebral blood flow (CBF) in the frontal cortices was measured by laser-Doppler flowmetry at 2 hours and at 1, 3, 7, 14, and 30 days after BCAS. The brains were then removed and examined at 30 days with histological stains and immunohistochemistry for markers of microglia and astroglia. RESULTS: At 2 hours, the CBF values (ratio to the preoperative value) did not change in the 0.22 mm group but decreased significantly to 77.3+/-13.4% in the 0.20 mm group, 67.3+/-18.5% in the 0.18 mm group, and 51.4+/-11.5% in the 0.16 mm group. At day 1, the CBF began to recover in all groups but remained significantly lower until 14 days in comparison to the control group. In the 0.20 mm and 0.18 mm groups, WM lesions occurred after 14 days without any gray matter involvement. These lesions were the most intense in the corpus callosum adjacent to the lateral ventricle but were mild in the anterior commissure and optic tract. In contrast, 4 of 5 mice developed some gray matter changes in the 0.16 mm group. The proliferation of activated microglia and astroglia was observed in the WM beyond 3 days after BCAS. CONCLUSIONS: WM lesions were successfully induced after chronic cerebral hypoperfusion with relative preservation of the visual pathway. These features in this mouse model are appropriate for cognitive assessment and genetic analysis, and it may provide a powerful tool to understand the pathophysiology of WM lesions.

INTRODUCTION: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. METHODS: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. RESULTS: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. DISCUSSION: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration.

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.