Cerebrovascular and Blood-Brain Barrier Compromise: A Mechanistic Link between Vascular Disease and Alzheimer’s Disease Subtypes of Neurocognitive Disorders
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Journal of Parkinson's disease and Alzheimer’s disease
Alzheimer’s disease (AD) and vascular dementia (VaD) are the most common subtypes of neurocognitive disorders (NCDs), with overlapping clinical presentation and risk factors. Studies on AD brains have demonstrated increased extravasation of plasma components through a functionally compromised blood-brain barrier (BBB). The BBB includes endothelial cells, astrocyte foot processes, basement membrane, and pericytes, and its function is to maintain brain homeostasis by limiting entry of plasma components into the brain. The pathogenesis of VaD is commonly attributed to cerebrovascular lesions, and neuroimaging studies have demonstrated extravasation of plasma components. Although the pathogenesis of AD and VaD is unknown, much evidence suggests that an abnormal cerebrovasculature may be a common mechanistic link. The primary aims of this review are to highlight studies that embrace or oppose this theory, and to examine the potentially causal relationship between cerebrovascular abnormalities and pathological hallmarks of AD. A major challenge to elucidate the role of the BBB in AD pathology has been the inability to demonstrate BBB dysfunction in neuroimaging studies. Computed tomography and magnetic resonance imaging can detect leakage from larger vessels, significant for VaD, but fail to detect smaller chronic vascular leakages common to AD. The latter are, however, detected by routine immunohistological techniques in postmortem tissues. If we consider AD and VaD from the vascular perspective, they have many features in common. By placing these diseases along a continuum of vascular pathology manifesting as dementia, it becomes apparent that the observed clinical differences are mostly attributable to the extent and location of the vascular leak. Lastly, we propose a novel hypothesis that we believe can potentially account for much of the phenomenology surrounding AD and its pathogenesis, including mechanisms of intraneuronal amyloid deposition and amyloid plaque formation, and the role of the BBB and autoantibodies in this process.
Goldwaser, Eric; Acharya, Nimish; and Nagele, Robert, "Cerebrovascular and Blood-Brain Barrier Compromise: A Mechanistic Link between Vascular Disease and Alzheimer’s Disease Subtypes of Neurocognitive Disorders" (2015). School of Osteopathic Medicine Faculty Scholarship. 7.
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Goldwaser EL, Acharya NK, Nagele RG. Cerebrovascular and Blood-Brain Barrier Compromise: A Mechanistic Link between Vascular Disease and Alzheimer’s Disease Subtypes of Neurocognitive Disorders. J Parkinsons Dis Alzheimer Dis. 2015;2(2): 10.