Pathologic sequelae of vascular cognitive impairment and dementia sheds light on potential targets for intervention

Abstract

Vascular contributions to cognitive impairment and dementia (VCID) is one of the leading causes of dementia along with Alzheimer's disease (AD) and, importantly, VCID often manifests as a comorbidity of AD(Vemuri and Knopman 2016; Schneider and Bennett 2010)(Vemuri and Knopman 2016; Schneider and Bennett 2010). Despite its common clinical manifestation, the mechanisms underlying VCID disease progression remains elusive. In this review, existing knowledge is used to propose a novel hypothesis linking well-established risk factors of VCID with the distinct neurodegenerative cascades of neuroinflammation and chronic hypoperfusion. It is hypothesized that these two synergistic signaling cascades coalesce to initiate aberrant angiogenesis and induce blood brain barrier breakdown trough a mechanism mediated by vascular growth factors and matrix metalloproteinases respectively. Finally, this review concludes by highlighting several potential therapeutic interventions along this neurodegenerative sequalae providing diverse opportunities for future translational study.

Keywords: Angiogenesis; Blood brain barrier; Cerebral hypoperfusion; Matrix metalloproteinases; Neuroinflammation; Vascular contributions to cognitive impairment and dementia.

Fig. 1.

Schematic representing the induction and coalescence of the MMP2 and MMP9 systems. Scissors represent enzymatic cleavage and conversion of a substrate. Abbreviations in the figure are: HIF-1α, hypoxia inducible factor-1α; MMP, matrix metalloproteinase; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; NF-κβ, nuclear factor-κβ; BBB, blood brain barrier.

Fig. 2.

Schematic representing the induction of angiogenic factors VEGF and PlGF. Abbreviations in the figure are: HIF-1α, hypoxia inducible factor-1α; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; NF-κβ, nuclear factor-κβ.

Fig. 3.

Working hypothesis for the mechanism relating known VCID risk factors with the development of VCID pathology. Abbreviations in the figure are: HHCy, hyperhomocysteinemia; CAA, cerebral amyloid angiopathy; HIF-1α, hypoxia inducible factor-1α; BBB, blood brain barrier; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; NF-κβ, nuclear factor-κβ.