Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

Abstract

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

Brain‐derived and circulating vesicle profiles indicate neurovascular unit dysfunction in early Alzheimer’s disease

“…Our preliminary ASL data also showed that prolonged reduction of CBF in BCAS model was sustained over longer period of 16 weeks. Furthermore, oxygen deficit and debt using oximetry in the BCAS model has already been robustly established as we recently detailed . Therefore, we suggest that long‐term BCAS mouse model in the current study induces prolonged reproducible chronic cerebral hypoperfusion similarly to that seen in AD patients, and this support our findings that key molecules in brain EVs of both BCAS mouse model and early AD subjects are induced by chronic cerebral hypoperfusion.…”

White matter degeneration in vascular and other ageing‐related dementias

“…Several animal models have been developed to gain mechanistic insights into the pathophysiology of the WM matter and enable translation to the clinic (Duncombe et al . ). While efficient models to examine the sequelae of global and focal ischaemic injury have been useful, they have been limited to explore fully the various features of WM changes in the context of cerebral hypoperfusion and cerebral SVD.…”

Transient receptor potential vanilloid 4 channels are important regulators of parenchymal arteriole dilation and cognitive function

“…6 Vascular and cognitive dysfunction could be associated with reduced cerebral perfusion. 28 Therefore, we examined cerebral perfusion in the WKY-Trpv4 em4Mcwi rats using MRI with continuous arterial spin labeling. Our data show that the TRPV4-deficient rats have reduced cerebral perfusion.…”