The neuropathology and cerebrovascular mechanisms of dementia

Abstract

The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer's Disease prioritized Alzheimer's disease-related dementias to include: Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and bloodbrain barrier permeability responsible for disease etiology and progression will be discussed.

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

“…The profound socioeconomic impact of AD has stimulated extensive research in the last decade, with increased attention on the contribution of cerebrovascular dysfunction in dementia and cognitive decline (Snyder, 2015;Raz et al, 2016). It is clearly critical to elucidate the mechanisms that regulate Ab egress from the human brain, as well as understand how to protect cerebrovascular health during aging, yet there are significant barriers toward mechanistic experimentation in a human context.…”

O2‐09‐03: Orthostatic Hypotension and the Long‐Term Risk of Dementia: A Population‐Based Study

“…Autonomic nervous system function is responsible for maintaining continuous cerebral perfusion, together with local vasoreactivity, which has previously been associated with the risk of dementia in the general population [6]. Brief episodes of hypoperfusion elicited by sudden blood pressure drops may lead to hypoxia, with detrimental effects on brain tissue via, for instance, neuroinflammation and oxidative stress [26]. These mechanisms have been suggested to be of particular relevance in the pathogenesis of small vessel disease [27], and orthostatic blood pressure drops in patients with dementia have been associated with deep white matter and basal ganglia hyperintensities [28], albeit not with overall white matter lesion volume [29].…”

Current Pathogenetic Concepts of Vascular Cognitive Impairment

“…The molecular mechanisms active in VaD and shared among almost all the dementia types include neuronal damage, BBB alterations, hypoxia, oxidative and nitrosative stress, mitochondrial dysfunction, autophagy, neuroinfl ammation, neurodegeneration, etc., due to reduced brain perfusion, which contribute to and exacerbate the etiology and course of the disease [51,53]. These molecular links between VaD and AD have been discussed recently [54].…”