Vascular cognitive impairment - Past, present, and future challenges.

Vascular cognitive impairment (VCI) is a lifelong process encompassing a broad spectrum of cognitive disorders, ranging from subtle or mild deficits to prodromal and fully developed dementia, originating from cerebrovascular lesions such as large and small vessel disease. Genetic predisposition and environmental exposure to risk factors such as unhealthy lifestyles, hypertension, cardiovascular disease, and metabolic disorders will synergistically interact, yielding biochemical and structural brain changes, ultimately culminating in VCI. However, little is known about the pathological processes underlying VCI and the temporal dynamics between risk factors and disease mechanisms (biochemical and structural brain changes). This narrative review aims to provide an evidence-based summary of the link between individual vascular risk/disorders and cognitive dysfunction and the potential structural and biochemical pathophysiological processes. We also discuss some key challenges for future research on VCI. There is a need to shift from individual risk factors/disorders to comorbid vascular burden, identifying and integrating imaging and fluid biomarkers, implementing a life-course approach, considering possible neuroprotective influences of positive life exposures, and addressing biological sex at birth and gender differences. Finally, this review highlights the need for future researchers to leverage and integrate multidimensional data to advance our understanding of the mechanisms and pathophysiology of VCI.

Neurovascular Coupling in Hypertension Is Impaired by IL-17A through Oxidative Stress.

Hypertension, a multifactorial chronic inflammatory condition, is an important risk factor for neurovascular and neurodegenerative diseases, including stroke and Alzheimer's disease. These diseases have been associated with higher concentrations of circulating interleukin (IL)-17A. However, the possible role that IL-17A plays in linking hypertension with neurodegenerative diseases remains to be established. Cerebral blood flow regulation may be the crossroads of these conditions because regulating mechanisms may be altered in hypertension, including neurovascular coupling (NVC), known to participate in the pathogenesis of stroke and Alzheimer's disease. In the present study, the role of IL-17A on NVC impairment induced by angiotensin (Ang) II in the context of hypertension was examined. Neutralization of IL-17A or specific inhibition of its receptor prevents the NVC impairment (p < 0.05) and cerebral superoxide anion production (p < 0.05) induced by Ang II. Chronic administration of IL-17A impairs NVC (p < 0.05) and increases superoxide anion production. Both effects were prevented with Tempol and NADPH oxidase 2 gene deletion. These findings suggest that IL-17A, through superoxide anion production, is an important mediator of cerebrovascular dysregulation induced by Ang II. This pathway is thus a putative therapeutic target to restore cerebrovascular regulation in hypertension.

Inflammation: A Mediator Between Hypertension and Neurodegenerative Diseases.

Hypertension is the most prevalent and modifiable risk factor for stroke, vascular cognitive impairment, and Alzheimer's disease. However, the mechanistic link between hypertension and neurodegenerative diseases remains to be understood. Recent evidence indicates that inflammation is a common pathophysiological trait for both hypertension and neurodegenerative diseases. Low-grade chronic inflammation at the systemic and central nervous system levels is now recognized to contribute to the physiopathology of hypertension. This review speculates that inflammation represents a mediator between hypertension and neurodegenerative diseases, either by a decrease in cerebral blood flow or a disruption of the blood-brain barrier which will, in turn, let inflammatory cells and neurotoxic molecules enter the brain parenchyma. This may impact brain functions including cognition and contribute to neurodegenerative diseases. This review will thus discuss the relationship between hypertension, systemic inflammation, cerebrovascular functions, neuroinflammation, and brain dysfunctions. The potential clinical future of immunotherapies against hypertension and associated cerebrovascular risks will also be presented.

Arterial Stiffness Due to Carotid Calcification Disrupts Cerebral Blood Flow Regulation and Leads to Cognitive Deficits.

Background Arterial stiffness is associated with cognitive decline and dementia; however, the precise mechanisms by which it affects the brain remain unclear. Methods and Results Using a mouse model based on carotid calcification this study characterized mechanisms that could contribute to brain degeneration due to arterial stiffness. At 2 weeks postcalcification, carotid stiffness attenuated resting cerebral blood flow in several brain regions including the perirhinal/entorhinal cortex, hippocampus, and thalamus, determined by autoradiography ( P<0.05). Carotid calcification impaired cerebral autoregulation and diminished cerebral blood flow responses to neuronal activity and to acetylcholine, examined by laser Doppler flowmetry ( P<0.05, P<0.01). Carotid stiffness significantly affected spatial memory at 3 weeks ( P<0.05), but not at 2 weeks, suggesting that cerebrovascular impairments precede cognitive dysfunction. In line with the endothelial deficits, carotid stiffness led to increased blood-brain barrier permeability in the hippocampus ( P<0.01). This region also exhibited reductions in vessel number containing collagen IV ( P<0.01), as did the somatosensory cortex ( P<0.05). No evidence of cerebral microhemorrhages was present. Carotid stiffness did not affect the production of mouse amyloid-ß (Aß) or tau phosphorylation, although it led to a modest increase in the Aß40/Aß42 ratio in frontal cortex ( P<0.01). Conclusions These findings suggest that carotid stiffness alters brain microcirculation and increases blood-brain barrier permeability associated with cognitive impairments. Therefore, arterial stiffness should be considered a relevant target to protect the brain and prevent cognitive dysfunctions.

CD4+ Regulatory T Lymphocytes Prevent Impaired Cerebral Blood Flow in Angiotensin II-Induced Hypertension.

Background Immune cells are key regulators of the vascular inflammatory response characteristic of hypertension. In hypertensive rodents, regulatory T lymphocytes (Treg, CD 4+ CD 25+) prevented vascular injury, cardiac damage, and endothelial dysfunction of mesenteric arteries. Whether Treg modulate the cerebrovascular damage induced by hypertension is unknown. Methods and Results C57 BL /6 mice were perfused with angiotensin II (Ang II ; 1000 ng/kg per minute) for 14 days and adoptive transfer of 3×105 CD 4+ CD 25+ T cells was performed via 2 intravenous injections. Control mice received a sham surgery and PBS . Treg prevented Ang II -induced neurovascular uncoupling ( P<0.05) and endothelial impairment ( P<0.05), evaluated by laser Doppler flowmetry in the somatosensory cortex. The neuroprotective effect of Treg was abolished when they were isolated from mice deficient in interleukin-10. Administration of interleukin-10 (60 ng/d) to hypertensive mice prevented Ang II -induced neurovascular uncoupling ( P<0.05). Treg adoptive transfer also diminished systemic inflammation induced by Ang II ( P<0.05), examined with a peripheral blood cytokine array. Mice receiving Ang II + Treg exhibited reduced numbers of Iba-1+ cells in the brain cortex ( P<0.05) and hippocampus ( P<0.001) compared with mice infused only with Ang II. Treg prevented the increase in cerebral superoxide radicals. Overall, these effects did not appear to be directly modulated by Treg accumulating in the brain parenchyma, because only a nonsignificant number of Treg were detected in brain. Instead, Treg penetrated peripheral tissues such as the kidney, inguinal lymph nodes, and the spleen. Conclusions Treg prevent impaired cerebrovascular responses in Ang II -induced hypertension. The neuroprotective effects of Treg involve the modulation of inflammation in the brain and periphery.