An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Abstract

Background: Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD). It is believed to contribute additively to the cognitive impairment and to lower the threshold for the development of dementia. However, accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Vascular processes even proceed AD neuropathology, implicating a causal role in the etiology of AD. Thus, the review aims to provide an integrated view on vascular dysfunction in AD. Summary: In AD, the cerebral vasculature undergoes pronounced cellular, morphological and structural changes, which alters regulation of blood flow, vascular fluid dynamics and vessel integrity. Stiffening of central blood vessels lead to transmission of excessive pulsatile energy to the brain microvasculature, causing endorgan damage. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its mediators interact synergistically. Changes of the cerebral vasculature are triggered and driven by systemic vascular abnormalities that are part of aging, and which can be accelerated and aggravated by cardiovascular diseas-es. Key Messages: In AD, the cerebral vasculature is the locus where multiple pathogenic processes converge and contribute to cognitive impairment. Understanding the molecular mechanism and pathophysiology of vascular dysfunction in AD and use of vascular blood-based and imaging biomarker in clinical studies may hold promise for future prevention and therapy of the disease.

X-ray Phase Contrast Tomography Serves Preclinical Investigation of Neurodegenerative Diseases

“…We used holo-nano-XPCT to achieve single plaque details, such as the presence of neurites – appearing as black dense spots – inside and around the plaque corona ( Figure 6B ). In AD, the deposition of Aβ inside the vessels determines their lumen reduction or even occlusions, as well as wall breakages, culminating in a reduced cerebral blood flow ( Klohs, 2019 ). Holo-nano-XPCT can reveal fine details from a 3D volume ( Figure 7 , left panel) to capillary and cell levels.…”

Deep clinical phenotyping of Alzheimer’s Disease Patients Leveraging Electronic Medical Records Data Identifies Sex-Specific Clinical Associations

“…A lower clotting time (aPTT, PT), bilirubin, and lactate and greater platelet count, prealbumin, and cholesterol levels in female AD patients may provide a multivariate way to identify potential AD phenotype in females. Prior studies have shown high thrombin 97, 98 , abnormalities of hemostasis 99, 100 , and abnormal platelet activation 101–,103 in AD patients that may contribute to a pro-thrombotic state in AD 104 , leading to microinfarcts and cerebrovascular dysfunction 105, 106 , although sex specific associations have not been studied previously. Furthermore, control sex phenotype may demonstrate protective labs or biomarkers that decrease risk of AD.…”

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimer’s disease mouse model

“…In DR inhibition of the vascular inflammatory receptor ICAM-1 leads to reduced leukostasis and vascular leakage ( 70 ), and VEGF-A leads to increased levels of ICAM-1 in the vasculature ( 71 ). In AD low level chronic vascular inflammation is also present ( 72 ). This is supported by recent single-nucleus transcriptome analysis of endothelial cells, which have shown an increased level of genes involved in vascular inflammation in aged healthy humans ( 50 ), and patients with AD ( 54 ).…”