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.

TLDR: The relevance and advantages of rodent models in elucidating the pathogenesis of VCID are discussed, the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD is explored and the use of such models is proposed for tackling the urgently needed translational gap from preclinical models to clinical treatments.

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.

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Chronic cerebral hypoperfusion
Citation for published version:
Duncombe, J, Kitamura, A, Hase, Y, Ihara, M, Kalaria, RN & Horsburgh, K 2017, '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', Clinical
science, vol. 131, no. 19, pp. 2451-2468. https://doi.org/10.1042/CS20160727
Digital Object Identifier (DOI):
10.1042/CS20160727
Link:
Link to publication record in Edinburgh Research Explorer
Document Version:
Peer reviewed version
Published In:
Clinical science
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Download date: 09. Aug. 2022

1
Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive
impairment and dementia (VCID)
Closing the translational gap between rodent models and human VCID.
Jessica Duncombe
#1
, Akihiro Kitamura
1#
, Yoshiki Hase
#
,
Masafumi Ihara, Raj N. Kalaria, Karen Horsburgh
*
1
University of Edinburgh, UK,
2
National Cerebral and Cardiovascular Center, Osaka, Japan,
3
Institute of Neuroscience, Newcastle University, UK
#
Joint first authors
*Corresponding author: Prof. Karen Horsburgh, Centre for Neuroregeneration, University of
Edinburgh, Chancellor's Building. 49 Little France Crescent. Edinburgh. EH164SB, United
Kingdom. Tel. 44-(0)131-242-6216; Email: karen.horsburgh@ed.ac.uk
Running Title: Rodent Models of Cerebral Hypoperfusion
Abbreviations list:
Alzheimer’s disease (AD)
Amyloid (A
Amyloid precursor protein (APP)
Bilateral carotid artery stenosis (BCAS)
Blood brain barrier (BBB)
Cerebral amyloid angiopathy (CAA)
Cerebral blood flow (CBF)
Extracellular matrix (ECM)
Intercellular adhesion molecule-1 (ICAM-1)

2
Matrix metalloproteinase (MMP)
Mild cognitive impairment (MCI)
Small vessel disease (SVD)
Spontaneously hypertensive stroke prone rat (SHRSP)
Vascular cell adhesion molecule-1 (VCAM-1)
Transgenic mice with amyloid precursor protein mutations (TgAPP)
Vascular cognitive impairment and dementia (VCID)

3
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. White matter changes increase the risk for stroke, dementia and
disability. A major gap has been the lack of mechanistic insights in 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 to elucidating the pathogenesis of VCID and explore the
interplay been hypoperfusion and the deposition of amyloid β protein, as it relates to AD. We
use examples of our recent investigations to illustrate the utility of the model in pre-clinical
testing of candidate drugs and life-style factors. We propose that the use of such models is
necessary for tackling the urgently needed translational gap from preclinical models to
clinical treatments .
Key words: Alzheimer’s disease; animal models; cerebral hypoperfusion; cognitive
impairment; dementia; small vessel disease; stroke; vascular dementia
Summary statement:
Vascular cognitive impairment and dementia (VCID) is an important contributor to the global
burden of disease. While there are no perfect animal models to recapitulate all the features
of VCID, current laboratory rodent models which simulate cerebral hypoperfusion allow
some aspects of VCID to be explored. Despite their limitations, rodent models are still useful
to evaluate specific mechanisms for testing drug targets and close the translational gap
between animal models and VCID.

4
Introduction
Vascular disease has been invariably linked to cognitive impairment. There is increasing
evidence that vascular risk factors contribute to neurodegeneration and dementia. Recent
analysis on a large sample, as part of the Alzheimer’s Disease Neuroimaging Initiative,
surprisingly revealed that early vascular dysfunction plays a role in Alzheimer’s disease (AD)
(1). However, one of the most common causes of vascular cognitive impairment and
dementia (VCID) is cerebral small vessel disease (SVD), which affects small arteries,
arterioles, venules and capillaries in the brain leading to arteriolar occlusion, lacunes and
white matter changes. The main clinical features of VCID may include pure motor,
sensorimotor, pure sensory, ataxic hemiparesis or gait impairment, dysarthria, cognitive
dysexecutive slowing and depression (2). Cerebral amyloid angiopathy (CAA), another form
of SVD, is found in almost all AD patients and more than 50% of the elderly over 90 years
old (2, 3). CAA mostly leads to lobar haemorrhage, white matter damage and cortical
microinfarcts (4). Moderate to severe CAA is also considered an independent risk factor for
dementia (5).
It is now recognised that there is considerable overlap between VCID and AD. Several
previous reports, including recent ones from the AD research centres in the USA, suggest
that some form of brain vascular pathology exists in up to 80% of sporadic late onset AD (6).
Moreover, cerebrovascular lesions increase the clinical expression of AD syndrome.
Traditional risk factors for stroke and cardiovascular disease (e.g. hypertension, diabetes,
hyperlipidaemia) are recognised as risks for both VCID and AD with salt intake, chronic
inflammation and gut infection now emerging as additional risk factors (7,8). Although the
mechanisms by which these different factors may impact on VCID and AD are currently ill
defined, considerable evidence, including that derived from neuroimaging and pathology
studies, indicates that endothelial dysfunction is pivotal to the pathophysiology (see reviews
9, 10, 11). It is proposed that risk factors may alter vascular haemodynamics and impact on
endothelial cell function. Endothelial dysfunction can in turn reduce vasomotor reactivity and
impede cerebral hemodynamic changes. Related to this vascular factors may impair
neurovascular coupling, leading to transient or chronic cerebral hypoperfusion which
exacerbates small vessel pathology including white matter damage. Alternatively, it is
proposed that the blood brain barrier (BBB) is initially compromised in VCID leading to a
chronic hypoxic state and hypoperfusion (see reviews 9, 10, 11).
Cerebral hypoperfusion is emerging as a major contributor to cognitive decline and
degenerative processes leading to dementia. Reduced cerebral perfusion correlates with the

Frequently asked questions

Q1. What have the authors contributed in "Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia (vcid) closing the translational gap between rodent models and human vcid" ?

Duncombe et al. this paper found that chronic cerebral hypoperfusion is a key mechanism leading to vascular cognitive impairment and dementia. 

Q2. What is the role of MMPs in neurodegenerative diseases?

MMPs are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in BBB breakdown in neurodegenerative diseases (52). 

Q3. What is the importance of monitoring blood flow in the preclinical animal studies?

Since the basis of the models are dependent on the extent of reduction of cerebral perfusion, it would be critical to monitor blood flow in each study. 

Q4. What is the role of astrocytes in the repair of white matter damage?

Astrocytes have also been shown to support oligodendrogenesis through secretion of brain derived nerve growth factor (BDNF) in order to promote repair of white matter damage following BCAS in mice (110). 

Q5. How long after BCAS did the brain develop a deficit in spatial working memory?

After long-term i.e. 6 months of hypoperfusion after BCAS, both spatial working memory and spatial reference memory were impaired (48). 

Q6. How is the BBB disrupted in the gradual stenosis model?

In the rat 2 vessel occlusion model, BBB disruption is observed as early as 3 hours postocclusion most likely as a result of the sharp and severe CBF reduction in this model (51). 

Q7. What is the method for assessing regional alterations in blood flow?

MRI with arterial spin labelling or similarly sensitive methods would be ideal to assess regional alterations in blood flow, particularly in subcortical areas. 

Q8. How does BCAS affect blood flow in young adult C57Bl/6J mice?

Bilateral common carotid artery stenosis (BCAS), by application of microcoils, reduces luminal diameter to approximately 50% in young adult C57Bl/6J mice (36). 

Q9. What are the main factors that need to be considered in the preclinical testing of future drug?

Age and additional co-morbidities (such as systemic inflammation) need to be carefully factored in to preclinical testing of future drug targets if the authors are to enable meaningful translation from models to the clinic. 

Q10. How long does it take to recover blood flow in young mice?

With increasing time there is a recovery of blood flow in young mice to 15-20% baseline levels at 1 month when measured by laser Doppler ultrasound or laser speckle imaging (36, 37). 

Q11. What did Weaver et al. (116) demonstrate?

Weaver et al. (116) demonstrated the utility of electron paramagnetic resonance oximetry to study white matter pO2 reductions longitudinally in a mixed SHRSP/Japanese Permissive Diet model with unilateral common carotid artery occlusion. 

Q12. What is the need to provide mechanistic insight of white matter changes through the development of animal?

In addition to correlative pathological and imaging studies in human, there is a need to provide mechanistic insight of white matter changes through the development of relevant animal models and translate these findings to the clinic (24). 

Q13. How did Nishio et al. (58) find the hippocampal?

Nishio et al. (58) reported no apparent change in cortex or corpus callosum at 8 months following BCAS surgery, however the hippocampal volume was found to be significantly reduced in hypoperfused mice. 

Q14. What is the link between impaired neurovascular coupling and white matter lesion development?

a direct causal link between impaired neurovascular coupling and white matter lesion development has yet to be proven, as disrupted neurovascular coupling may reflect reduced tissue metabolic demand as a result of other ongoing pathological processes. 

Q15. How did the occlusion model of chronic cerebral hypoperfusion work?

In order to study early pathological events that may lead to VCID, rodent models of chronic cerebral hypoperfusion were first established using occlusion or ligation of both common carotid arteries in rats (2 vessel occlusion) (see review 28). 

Q16. In what model of CAA did Okamoto et al. (120) show?

In another TgAPP model of CAA, Okamoto et al. (120) showed that blood flow reductions at 12 weeks following BCAS were greater in TgAPP than in wild type mice.