Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

Abstract

The arteriosclerosis-dependent alteration of brain perfusion is one of the major determinants in small vessel disease, since small vessels have a pivotal role in the brain’s autoregulation. Nevertheless, as far as we know, endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia that is related to small vessel disease (SVD), also being defined as subcortical vascular dementia (sVAD), as well as microglia activation, chronic hypoxia and hypoperfusion, vessel-tone dysregulation, altered astrocytes, and pericytes functioning blood-brain barrier disruption. The molecular basis of this pathology remains controversial. The apparent consequence (or a first event, too) is the macroscopic alteration of the neurovascular coupling. Here, we examined the possible mechanisms that lead a healthy aging process towards subcortical dementia. We remarked that SVD and white matter abnormalities related to age could be accelerated and potentiated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors, which are, to the best of our knowledge, mostly unknown. Metabolic demands, active neurovascular coupling, correct glymphatic process, and adequate oxidative and inflammatory responses could be bulwarks in defense of the correct aging process; their impairments lead to a potentially catastrophic and non-reversible condition.

Impact of the Severities of Glaucoma on the Incidence of Subsequent Dementia: A Population-Based Cohort Study

“…Regarding other risk factors of dementia, several cardiovascular diseases lead to a higher rate of dementia development, which may due to the correlation of vessel damage and brain degeneration proven in previous research [1,7,8,23]. Besides, DM is associated with the occurrence of cardiovascular disease and can also lead to certain types of dementia, which correlated to the finding of the current study [9].…”

“…The advanced age accounts for the majority of involution dementia worldwide [1], while depression may play a role in general dementia development [21]. For specific pathophysiology of dementia, the direct damage to brain tissue via ischemic stroke or intracranial hemorrhage is the mechanism of VD [22], and evensmall vessel disease can cause following VD episodes [23]. The AD, featured with the accumulation of both the protein beta-amyloid and tau tangles, leads to synapse decline and neuron death progressively [5].…”

An Iatrogenic Model of Brain Small-Vessel Disease: Post-Radiation Encephalopathy

“…There is an elevation of caspase 3 RNA, and of matrix-metalloprotease 2 (MMP-2) expression [136,137], with a marked astrocytosis at the first part of the process, and then with their death (the following part has not been described in the post-RT brain, probably due to the long-lasting observation period, typical of SVD and not of post-RT) [138][139][140][141][142]. In SVD, the astrocytic death includes a severe alteration of the precarious neurovascular coupling system, leading to its destruction [143].…”

“…The effects of the inflammation in the SVD act indirectly on the endothelium [143,144]. It is widely demonstrated that, due to an altered response to endothelium-derived nitric oxide-vasodilators [145,146], prostacyclin [147] and endothelium-derived hyperpolarizing factors (EDHF) [148], there is an accelerated mitochondrial senescence of the endothelium walls [144].…”

“…Inflammation for SVD has been evoked as a priming effect, even at a distance, in the so-called microbiome-gut-brain axis [166][167][168][169][170][171]. Age is the main dominant promoting factor that leads to a series of altered responses to inflammation and oxidative process in the brain; SVD is a potentiated aging process [117,143]. Recently, neurodegeneration-inflammation-aging has been defined as "inflammaging" [172][173][174][175][176].…”