Journal of neuropathology and experimental neurology, 2003-12, Vol.62 (12), p.1287-1301
Sporadic, late-onset Alzheimer disease (AD) constitutes the most frequent cause of dementia in the elderly population. AD-related pathology is often accompanied by vascular changes. The predominant vascular lesions in AD are cerebral amyloid angiopathy (CAA) and arteriosclerosis/lipohyalinosis (AS/LH). The present study was carried out to examine the coincidence of these small vessel pathologies during the development of cognitive deficits, amyloid β-protein (Aβ) deposition, and neurofibrillary tangle (NFT) formation in sporadic late-onset AD. We correlated the clinical dementia rating (CDR) score, the sequential extension of AD-related Aβ deposition into different parts of the brain, and the extension of NFTs to involve more brain regions with the distribution of CAA and AS/LH in 52 human autopsy brains. The extension of CAA and AS/LH to involve different areas of the brain was associated with a rise of CDR scores and an increase in the extension of Aβ deposition and NFT generation. AD cases showed a higher number of regions with CAA and AS/LH compared to nondemented patients with AD-related pathology and controls. Moreover, we demonstrated a hierarchical sequence in which the different regions of the brain exhibited CAA and AS/LH-affected vessels, allowing the distinction of 3 stages in the development of CAA and AS/LH. The first stage of CAA involved leptomeningeal and neocortical vessels. The second stage was characterized by additional Aβ deposition in allocortical and midbrain vessels. Finally, in a third stage, CAA was observed in the basal ganglia, the thalamus, and in the lower brainstem. In contrast, AS/LH initially affected the basal ganglia in stage A. In stage B this pathology made inroads into the deep white matter, the leptomeningeal arteries of the cortex, the cerebellum, and into the thalamus. Stage C was characterized by AS/LH in brainstem vessels. Our results demonstrate widespread CAA and AS/LH to be associated with the development of cognitive deficits in AD. A combination of both CAA and AS/LH may, therefore, contribute to neurodegeneration in AD. These data also suggest that small vessel disease due to arteriosclerosis and fibro- lipohyalinosis is a potential target for the treatment of AD.
Neurology ; Biological and medical sciences ; Medical sciences ; Intracranial Arteriosclerosis - pathology ; Alzheimer Disease - physiopathology ; Cognition Disorders - physiopathology ; Cerebral Amyloid Angiopathy - physiopathology ; Humans ; Middle Aged ; Cognition Disorders - pathology ; Male ; Alzheimer Disease - pathology ; Cerebral Amyloid Angiopathy - pathology ; Analysis of Variance ; Aged, 80 and over ; Female ; Aged ; Intracranial Arteriosclerosis - physiopathology ; Index Medicus
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