A Big Role for Small Vessels in the Brain : Cerebral Amyloid, Vascular Dysfunction, Inflammation, and Cognitive Impairment
Anand Viswanathan, MD, PhD Department of Neurology Massachusetts General Hospital Harvard Medical School
In recent years, there has been growing evidence to suggest that vascular risk factors contribute to Alzheimer’s disease. Vascular dementia has been traditionally considered to be secondary to stroke and vascular disease, and has been distinguished from Alzheimer disease, considered as a purely neurodegenerative disease. However, it now appears that there is a spectrum: ranging from patients with “pure” vascular dementia to patients with “pure” Alzheimer’s disease and including a large majority of patients with contributions from both Alzheimer’s and vascular pathologies.
One such example is seen in the small vessel disease cerebral amyloid angiopathy (CAA). While β-amyloid protein (Aβ) is a key feature of the senile plaques of Alzheimer disease (AD), advanced cerebrovascular Aβ deposition is also seen in CAA. CAA results from Aβ deposition in small vessels of the brain, causing vascular dysfunction, vessel fragility and brain hemorrhage. Neuroimaging and neuropathological studies suggest that the two types of Aβ deposits can occur either relatively independently of one another, or can overlap.
Furthermore, CAA may be the basis of the inflammatory response that halted a recent phase IIa therapeutic trial of active Aβ immunization in AD. The features of both cases who died from this experimental treatment were consistent with advanced CAA and perivascular inflammation, similar to that in spontaneous CAA-related vascular inflammation.
More broadly, CAA is one example of small vessel brain disease that may interact with AD to generate a dementia caused by both vascular and Alzheimer-related pathologies. Defining both the precise contribution and underlying mechanisms of vascular disease in cognitive impairment represent the key next steps in ongoing research in the field.
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