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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.

01 Oct 2017-Clinical Science (Portland Press Ltd.)-Vol. 131, Iss: 19, pp 2451-2468
TL;DR: 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.

Summary (5 min read)

Introduction

  • Vascular disease has been invariably linked to cognitive impairment.
  • 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) .
  • 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) .
  • Thus it is proposed that understanding the earliest events leading to white matter changes could provide vital opportunities to prevent brain damage at the earliest stages and ameliorate its impact on cognitive decline and precipitation of dementia (23) .
  • The authors focus on rodent models which have been developed and refined over the last few years to mimic the chronic hypoperfusive state in VCID and which are used as a basis to probe mechanisms related to reduced perfusion of the brain.

Cerebral blood flow alterations in models

  • 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).
  • A refinement of rat models of cerebral hypoperfusion was introduced to more faithfully represent the subtle reductions in flow in VCI.
  • Bilateral common carotid artery stenosis (BCAS), by application of microcoils, reduces luminal diameter to approximately 50% in young adult C57Bl/6J mice (36) .
  • Thus, the studies emphasise the utility of arterial spin labelling as a quantitative and non-invasive tool for assessing global and regional blood flow changes in models of hypoperfusion.
  • In another model an ameroid constrictor is applied to the right common carotid artery resulting in gradual occlusion of the vessel over 28 days, whereas placement of a microcoil to the left common carotid artery induces ∼50% arterial stenosis (43) .

Parenchymal alterations

  • Rat 2 vessel occlusion models have been extensively studied since they were first found to develop white matter rarefaction similar to that in humans (28) .
  • Paranodal septate-like junctions are damaged and axon-glial integrity is disrupted, as determined by spatial distribution of myelin-associated glycoprotein staining (46) .
  • In response to increasing durations of hypoperfusion, microglia gradually augment in parallel with the evolving damage to myelinated axons, resulting in a marked and sustained increase in microglial number, particularly in the white matter (36, 37, (45) (46) (47) .
  • Astrogliosis can also be observed but these changes appear to occur later than microglial alterations in BCAS models with diffuse white matter injury (48) .
  • Pathological changes in the gradual stenosis models are similar to the microcoil model but as expected these progress more slowly.

Small vessel and BBB changes

  • The BBB changes appear less prominent (51) .
  • Other studies, in which white matter damage appears more severe, showed earlier BBB disruption at 3 and 7 days after BCAS (52) .
  • A systematic study of the BBB, including tight junction proteins, across a range of times post-hypoperfusion in the different models is required to assess the dynamics of the BBB and whether these changes may be transient or sustained.
  • Sustained hypoperfusion can also induce morphological small vessel changes such as increased thickening and fibrosis of capillary walls, which are one of the characteristic features of human SVD (2).
  • In the gradual stenosis models, small vessel and BBB changes are yet to be described.

Brain atrophy

  • Clinical imaging studies have demonstrated both whole brain and regional brain atrophy in VCID (54, 55) .
  • Brain atrophy, in particular medial temporal lobe atrophy and subcortical atrophy, is associated with cognitive decline and can potentiate the effect of white matter lesions on cognition (54, 56) .
  • 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.
  • In agreement with this finding, hippocampal glucose uptake was also reduced when assessed with 18 F-FDG PET.
  • Together, these findings suggest that brain atrophy occurs at later time points following hypoperfusion, and are secondary to neuronal loss and white matter damage.

Cognitive impairments

  • It was proposed many years ago that chronic cerebral hypoperfusion leads to cognitive impairment (59) but human studies have shown at best a moderate association.
  • Interestingly, poor performance in the odour discrimination task suggests that cognitive functions related to olfaction are also impaired (64) , which is also seen as an early sign of cognitive impairment in patients with various neurodegenerative diseases, indicating the relevance of this model to human VCID.
  • The development of the BCAS mouse model demonstrated that chronic cerebral hypoperfusion causes deficits mainly in spatial working memory (45, 65-67) using a conventional 8-arm radial maze or Y-maze tests.
  • The authors highlighted that 1 month after BCAS, spatial working memory is impaired while reference memory remains intact, probably due to the select disruption of frontal-subcortical circuits (45) .
  • The emergence of deficits in both working and reference memory likely reflects the presence of white and grey matter pathology including whole brain and hippocampal atrophy (48, 70) .

Mechanisms of the hypoperfusion models

  • As indicated above, rodent models of hypoperfusion recapitulate some pathological features observed in VCID, such as disruption of white matter integrity, microvascular alterations and atrophy.
  • These alterations are related to cognitive deficits.
  • The precise molecular and cellular mechanisms that lead to such changes are currently being unravelled as outlined below:.

Hypoxia-induced white matter damage

  • Following vessel occlusion or carotid stenosis, cerebral perfusion is demonstrably reduced (28, 37) but it is less clear whether these changes affect tissue oxygen tension and whether there are differences between white matter and grey matter to account for their differential vulnerability.
  • Levels of pO2 are profoundly decreased in the corpus callosum at 3 days, 1 week and 6 weeks following BCAS surgery to levels consistent with hypoxic conditions.
  • Hypoxia, in addition to deleterious effects on oligodendrocytes, can also directly induce changes in BBB permeability (76) .
  • In the aged primate brain, microglial reactions predominate in the white matter and correlate with cognitive impairment (83) .
  • Higher numbers of microglial cells correlate with decreased nodal gap length and increased paranodal axon-glial disruption, supporting the idea that the structural alterations observed in response to hypoperfusion could be secondary to a pro-inflammatory environment.

Microvascular inflammation

  • Endothelial dysfunction is considered to be one of the pivotal mechanisms of the structural and functional cerebral vessel alterations in SVD (10, 11) leading to VCID.
  • Cerebral hypoperfusion upregulates the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), markers of endothelial cell activation (68, 86) .
  • Increased MMPs have been consistently shown in hypoperfusion models (90) (91) (92) and increased expression has been shown in the white matter (91, 92) localised to microglia and the endothelium (91) .
  • 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) .
  • Additionally, age, a key risk factor for VCID, is also associated with alterations in microglial phenotype and function (99) .

Neuro-glio-vascular function

  • Instead, disruption of the finely tuned interplay between cells of the neuro-glio-vascular unit (oligodendrocytes, endothelial cells, astrocytes and end-feet contacts, pericytes, microglia and neurons) (for review see 101) likely contributes to the pathophysiology.
  • Astrocytic activation has been detected in white matter at 7 days following BCAS surgery in mice (107) and has the potential to disrupt the contact between astrocytes and blood vessels.
  • Thus, the cellular interactions within the neuro-glio-vascular unit may be critically important for maintaining tissue health.
  • Taken together, hypoperfusion is likely to drive key pathways related to hypoxia, inflammation and BBB disruption, resulting in progressive deterioration of the neuro-gliovascular unit .

Interplay between cerebral hypoperfusion and co-morbidities

  • Post-mortem studies in brains from the elderly indicate the presence of a variety of pathological lesions or mixed pathologies (such as white matter changes, infarcts, microbleeds and amyloid pathology) (115) .
  • This would be important in identifying drug targets and as a basis for testing treatments.
  • White matter lesions were also exacerbated in the presence of occlusion and dietary factors (116) .
  • Since rodents do not naturally accumulate A most studies use transgenic models that harbour mutations in the amyloid precursor protein associated with rare familial forms of AD .
  • Thus, conceivably there may be an interplay between increased NOX and amyloid following hypoperfusion that exacerbates neurovascular dysfunction.

Pre-clinical investigation of drug targets

  • Assessment of pipeline drugs can be evaluated in preclinical models before clinical trials are initiated providing a translational opportunity.
  • In the BCAS model, pretreatment and post-treatment of cilostazol reduced endothelial activation, suppressed microglial proliferation and improved cognitive function without affecting resting CBF and white matter integrity (68) .
  • Other studies, in which white matter is damaged by cerebral hypoperfusion via unilateral occlusion (143) , two vessel occlusion (144) and in hypertensive stroke prone rats with two vessel occlusion (141) have also convincingly shown protective effects of minocycline.
  • A broad spectrum MMP inhibitor was also shown to protect against BBB opening in the mouse BCAS model and against the ensuing white matter pathology and cognitive deficits (52) .
  • Therefore, the implementation of even limited environmental enrichment may be beneficial for patients diagnosed with VCID.

Important considerations of the models; How can we close the gap between rodent models of chronic cerebral hypoperfusion and human VCID?

  • In order to effectively translate information generated from animal models such as cerebral hypoperfusion, the authors need to consider the general design, methodology and reporting of preclinical animal studies.
  • Additionally, monitoring blood flow alterations in the white matter would be important.
  • In some studies animals are allowed to recover between the placement of the first and second coils to allow restoration of cerebral haemodynamics (40, 44, (46) (47) (48) .
  • Application of microcoils or ligation of vessels may alter autoregulation, vascular stiffness or pulsatility and impact on the dynamics of cerebrospinal fluid circulation.
  • Several rodent models reflect aspects of human VCID and are pertinent to tease out specific questions that are impossible to readily address in human studies.

Figure legends:

  • Figure 1 Multiple experimental models have been developed in order to study disruption of cerebral blood flow.
  • Due to the severe reductions in flow typically observed in models of ischaemia and resultant ischaemic neuronal damage, new models have since been developed and refined in order to mimic the subtle yet chronic reductions in blood flow relevant to vascular cognitive impairment.
  • The levels of cortical surface cerebral blood flow (CBF) estimates at indicated time points (before, and 1, 3, 7, 14, and 28 days after each surgery) are shown as percentage of the baseline CBF.
  • B. At all times post-hypoperfusion, pO2 levels were significantly reduced to hypoxic levels (<10mmHg) ****p<0.0001 Figure 4 (B) Representative responses to whisker stimulation from sham and hypoperfused mice.

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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
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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

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Abstract: Advances in neuroimaging have enabled greater understanding of the progression of cerebral degenerative processes associated with ageing-related dementias. Leukoaraiosis or rarefied white matter (WM) originally described on computed tomography is one of the most prominent changes which occurs in older age. White matter hyperintensities (WMH) evident on magnetic resonance imaging have become commonplace to describe WM changes in relation to cognitive dysfunction, types of stroke injury, cerebral small vessel disease and neurodegenerative disorders including Alzheimer's disease. Substrates of WM degeneration collectively include myelin loss, axonal abnormalities, arteriolosclerosis and parenchymal changes resulting from lacunar infarcts, microinfarcts, microbleeds and perivascular spacing. WM cells incorporating astrocytes, oligodendrocytes, pericytes and microglia are recognized as key cellular components of the gliovascular unit. They respond to ongoing pathological processes in different ways leading to disruption of the gliovascular unit. The most robust alterations involve oligodendrocyte loss and astrocytic clasmatodendrosis with displacement of the water channel protein, aquaporin 4. These modifications likely precede arteriolosclerosis and capillary degeneration and involve tissue oedema, breach of the blood-brain barrier and induction of a chronic hypoxic state in the deep WM. Several pathophysiological mechanisms are proposed to explain how WM changes commencing with haemodynamic changes within the vascular system impact on cognitive dysfunction. Animal models simulating cerebral hypoperfusion in man have paved the way for several translational opportunities. Various compounds with variable efficacies have been tested to reduce oxidative stress, inflammation and blood-brain barrier damage in the WM. Our review demonstrates that WM degeneration encompasses multiple substrates and therefore more than one pharmacological approach is necessary to preserve axonal function and prevent cognitive impairment. This article is part of the Special Issue "Vascular Dementia".

139 citations


Cites background from "Chronic cerebral hypoperfusion: a k..."

  • ...Contribution of laboratory animal studies 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. 2017)....

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TL;DR: Several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.
Abstract: Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer's disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid β depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.

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TL;DR: The key finding indicates that WM capillaries are wider compared to those in the overlying neocortex in controls but they dilate further during dementia pathogenesis, which reflects compensatory changes to retain WM perfusion and integrity during hypoperfusive states in ageing-related dementias.
Abstract: Previous studies suggest white matter (WM) integrity is vulnerable to chronic hypoperfusion during brain ageing. We assessed ~ 0.7 million capillary profiles in the frontal lobe WM across several dementias comprising Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease with dementia, vascular dementia, mixed dementias, post-stroke dementia as well as post-stroke no dementia and similar age ageing and young controls without significant brain pathology. Standard histopathological methods were used to determine microvascular pathology and capillary width and densities in 153 subjects using markers of the basement membrane (collagen IV; COL4) and endothelium (glucose transporter-1; GLUT-1). Variable microvascular pathology including coiled, tortuous, collapsed and degenerated capillaries as well as occasional microaneurysms was present in all dementias. As expected, WM microvascular densities were 20–49% lower than in the overlying cortex. This differential in density between WM and cortex was clearly demonstrated by COL4, which was highly correlated with GLUT-1 densities (Spearman’s rho = 0.79, P = 0.000). WM COL4 immunopositive microvascular densities were decreased by ~ 18% across the neurodegenerative dementias. However, we found WM COL4 densities were increased by ~ 57% in post-stroke dementia versus ageing and young controls and other dementias. Using three different methods to measure capillary diameters, we found WM capillaries to be significantly wider by 19–45% compared to those in overlying neocortex apparent with both COL4 and GLUT-1. Remarkably, WM capillary widths were increased by ~ 20% across all dementias compared to ageing and young controls (P < 0.01). We also noted mean WM pathology scores incorporating myelin loss, arteriolosclerosis and perivascular spacing were correlated with COL4 immunopositive capillary widths (Pearson’s r = 0.71, P = 0.032). Our key finding indicates that WM capillaries are wider compared to those in the overlying neocortex in controls but they dilate further during dementia pathogenesis. We suggest capillaries undergo restructuring in the deep WM in different dementias. This reflects compensatory changes to retain WM perfusion and integrity during hypoperfusive states in ageing-related dementias.

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TL;DR: Different biomarkers including the ones of inflammatory responses to central nervous system tissue injuries, of coagulation and thrombosis and of circulating microRNA are analysed to set different combinations of biomarkers to use for differential diagnosis among types of dementia.
Abstract: Vascular pathology is the second most common neuropathology of dementia after Alzheimer’s disease (AD), with small vessels disease (SVD) being considered the major cause of vascular cognitive impairment and dementia (VCID). This review aims to evaluate pathophysiological pathways underlying a diagnosis of VCID. Firstly, we will discuss the role of endothelial dysfunction, blood-brain barrier disruption and neuroinflammation in its pathogenesis. Then, we will analyse different biomarkers including the ones of inflammatory responses to central nervous system tissue injuries, of coagulation and thrombosis and of circulating microRNA. Evidences on peripheral biomarkers for VCID are still poor and large-scale, prospectively designed studies are needed to translate these findings into clinical practice, in order to set different combinations of biomarkers to use for differential diagnosis among types of dementia.

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  • ...Cerebral hypoperfusion up-regulates the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), markers of endothelial cell activation [80]....

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  • ...It is not yet known whether inflammation is a primary driver of VCID and whether this neuroinflammation is triggered by intrinsic or systemic processes [80]....

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Frequently Asked Questions (16)
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. 

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). 

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. 

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). 

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

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). 

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

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

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. 

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). 

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. 

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). 

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. 

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. 

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). 

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.