The Complex Vascular Contribution to Age-Related Neurodegeneration

Vascular issues arguable precede the protein aggregates and other noted signs of neurodegenerative conditions. The brain is an energy-hungry organ, and the nutrients and oxygen to fuel it arrive via blood flow through the vasculature. Parts of the brain already operate at the edge of capacity, as illustrated by the ability of exercise to rapidly improve neural function such as memory for a short period of time, due to increased blood flow. The decline of the vasculature with age impairs the brain in a range of different ways, not just a reduced supply of nutrients, but also leakage of the blood brain barrier to provoke inflammation, as well as other issues.

Vascular contributions to cognitive impairment and dementia (VCID) is a complex syndrome that encompass a diverse array of pathologies resulting in disruptions of blood flow in the brain. It is becoming increasingly recognized that VCID is one of the leading causes of dementia along with Alzheimer's disease (AD) and is frequently found co-morbid with AD pathologies. Experts project a significant increase in the number of patients presenting with both cerebrovascular and neurodegenerative co-morbidities as the number of persons living into their 80s and 90s increases. Recent studies have even demonstrated pathologic vascular changes precede the appearance of amyloid (Aβ) plaques and neurofibrillary tangles, characteristic proteinopathies associated with AD, further implicating cerebrovasculature pathologies as an important topic of study in the fields of dementia and neurodegeneration.

The overlap between VCID and AD continues when considering significant risk factors associated with their disease progressions. Hypertension, diabetes, hyperhomocysteinemia (HHCy) and hyperlipidemia are risk factors for both AD and VCID all leading to a state of both chronic neuroinflammation and chronic cerebral hypoperfusion or hypoxia. Neuroinflammation is both an important instigator and consequence of cerebrovascular pathology making this an important potential therapeutic target for impeding disease progression. While there is currently no cure for VCID, several studies have been focused on mitigating the aforementioned risk factors leading to chronic hypoxia and inhibiting the subsequent neuroinflammatory sequalae.

In the following review a brief overview of the current knowledge surrounding VCID will be provided with a focus on the basic mechanisms linking well-established risk factors with the distinct signaling cascades of neuroinflammation and chronic hypoperfusion. Then the coalescence of these two pathologic signaling cascades and their synergistic impact on the downstream activation of further neurodegenerative sequalae will be discussed. Finally, several potential therapeutic interventions to target specific aspects of the degenerative cascade leading to VCID progression will be highlighted.


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