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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. and Statistical Manual (DSM) 5th edition stratifies dementia into nine subtypes of neurocognitive disorders (NCDs). These include: Alzheimer’s disease (AD), frontotemporal lobar degeneration, Lewy body disease, vascular disease (previously vascular dementia, VaD), traumatic brain injury, substance/medication-induced, HIV infection, prion disease, and Parkinson’s disease. AD and VaD (also known as vascular cognitive impairment) comprise 60-80% and 15-20% of the total NCD cases, respectively. As the overwhelming majority of the cases, AD afflicts one in nine individuals above the age of 65. Presently about 5.3 million Americans are suffering from AD. Compared to the most prevalent fatal diseases, only in the case of AD is the number of deaths steadily increasing. The seven-fold increase in fear of dementia over cancer in the elderly population can perhaps be attributed to the lack of effective treatment coupled with inevitability of the outcome. This absence of adequate medical intervention is largely due to a poor understanding of the pathogenesis and etiology of most types of NCDs, AD included. Here we present selected studies that have demonstrated an abnormal cerebrovasculature as the inciting factor in two of the most prevalent dementias, AD and VaD. We also attempt to address some of the controversies that have contributed to holding back adequate recognition of the key role of the abnormal cerebrovasculature in the pathoetiology of these diseases. Abnormalities of the Cerebrovasculature may Contribute to Impaired Brain Homeostasis, Neurodegeneration, and Ultimately Dementia The phrase “abnormal cerebrovasculature” is terminology intended to blanket all kinds of perturbations to blood vessels in the cerebral cortex of the brain. Other terminologies implying damage Eric L Goldwaser1-3#, Nimish K Acharya1,3# and Robert G Nagele1,3* 1Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine,

journal of parkinson's disease and alzheimer's disease

Cerebrovascular and Blood-Brain Barrier Compromise: A Mechanistic Link between Vascular Disease and Alzheimer’s Disease Subtypes of Neurocognitive Disorders