Vascular cognitive impairment and dementia: Mechanisms, treatment, and future directions

Abstract

Worldwide, around 50 million people live with dementia, and this number is projected to triple by 2050. It has been estimated that 20% of all dementia cases have a predominant cerebrovascular pathology, while perhaps another 20% of vascular diseases contribute to a mixed dementia picture. Therefore, the vascular contribution to dementia affects 20 million people currently and will increase markedly in the next few decades, particularly in lower- and middle-income countries.In this review, we discuss the mechanisms of vascular cognitive impairment (VCI) and review management. VCI refers to the spectrum of cerebrovascular pathologies that contribute to any degree of cognitive impairment, ranging from subjective cognitive decline, to mild cognitive impairment, to dementia. While acute cognitive decline occurring soon after a stroke is the most recognized form of VCI, chronic cerebrovascular disease, in particular cerebral small-vessel disease, can cause insidious cognitive decline in the absence of stroke. Moreover, cerebrovascular disease not only commonly co-occurs with Alzheimer's disease (AD) and increases the probability that AD pathology will result in clinical dementia, but may also contribute etiologically to the development of AD pathologies.Despite its enormous health and economic impact, VCI has been a neglected research area, with few adequately powered trials of therapies, resulting in few proven treatments. Current management of VCI emphasizes prevention and treatment of stroke and vascular risk factors, with most evidence for intensive hypertension control. Reperfusion therapies in acute stroke may attenuate the risk of VCI. Associated behavioral symptoms such as apathy and poststroke emotionalism are common. We also highlight novel treatment strategies that will hopefully lead to new disease course-modifying therapies. Finally, we highlight the importance of including cognitive endpoints in large cardiovascular prevention trials and the need for an increased research focus and funding for this important area.

Keywords: Alzheimer’s disease; Vascular cognitive impairment; dementia; small-vessel disease; stroke; vascular risk factors.

Figure 1.

Trajectories of different types of vascular dementia. In all figures, the dotted blue line represents cognitive decline with age in the absence of cerebrovascular disease: (A) Following a stroke cognition declines, and then recovers to a variable extent. The extent of the poststroke cognitive decline will depend both on the site and extent of the stroke, as well as brain resilience. Brain resilience depends on pre-existing brain diseases (e.g. AD and SVD), cognitive reserve (e.g. educational level and cognitive activity), and other demographic or medical conditions (e.g. age, diabetes, and frailty); (B) following stroke cognition can continue to decline in the longer term at a rate faster than that prestroke as illustrated by the red line; (C) cerebrovascular disease can result in gradual decline in cognition in the absence of stroke. This pattern is particularly seen with SVD; (D) other insults such as delirium and intercurrent infection (arrowed) can result in a decline in cognition which does not return to the pre-insult level. Source: © Hugh Markus.

Figure 2.

MRI appearances of SVD: Note the right side of the brain is represented on the left-hand side of the images: (A) An right hemisphere acute lacunar infarct visible as high signal on diffusion-weighted imaging; (B) a chronic lacunar infarct on the left visible as an area of low signal on FLAIR MRI; (C) white matter hyperintensities particularly in the posterior periventricular white matter; (D) a close-up of a T2-weighted MRI showing enlarged PVSs; (E) gradient echo MRI from a patient with sporadic hypertensive SVD showing multiple CMB visible as small dots of low intensity. These as predominantly subcortical, in contrast to mainly cortical CMB seen in CAA. There is also a larger area of low density in the left hemisphere representing changes from an old subcortical intracerebral hemorrhage; (F) gradient echo MRI from a patient with CAA showing multiple cortical CMB (arrowed), as well as a right frontal lobar intracerebral hemorrhage. © Hugh Markus.

Figure 3.

Interplay of vascular dysfunction and neurodegenerative pathways in Aβ and tau pathology. This figure highlights the complex relationship between vascular dysfunction and pathways leading to the accumulation of Aβ and tau protein formation. Modifiable vascular risk factors probably cause dysfunction of the neurovascular unit (NVU), leakage of the BBB, and neuroinflammation. The disruption of tight junctions facilitates the increased entry of Aβ from the bloodstream into the brain. Features of NVU dysfunction, such as pericyte constriction and loss, along with AQP4 mis-localization and decreased levels of LRP1, lead to inefficient Aβ clearance and promote its accumulation in the brain. In addition, activated microglia and reactive astrocytes intensify neuroinflammation, which further exacerbates BBB leakage and NVU dysfunction. All these changes contribute to the formation of Aβ plaques and the hyperphosphorylation of tau proteins, resulting in neurofibrillary tangles. The figure also connects vascular risk factors with changes in vascular smooth muscle cells that lead to arteriosclerotic luminal narrowing. Furthermore, conditions like LAD and heart–brain axis dysfunction, exemplified by atrial fibrillation, also aggravate cerebral hypoperfusion. The cerebral hypoperfusion may exacerbate NVU dysfunction, BBB leakage, and neuroinflammation, further promoting Aβ deposition and tau pathology. Aβ deposition in turn reverberates with neuroimmune and vascular dysfunction, further exacerbating the progression of this process. Aβ: amyloid-beta; BBB: blood–brain barrier; NVU: neurovascular unit; AQP4: aquaporin 4; LRP1: low-density lipoprotein receptor-related protein 1; HT: hypertension; DM: diabetes mellitus.