scholarly journals 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

2017 ◽  
Vol 131 (19) ◽  
pp. 2451-2468 ◽  
Author(s):  
Jessica Duncombe ◽  
Akihiro Kitamura ◽  
Yoshiki Hase ◽  
Masafumi Ihara ◽  
Raj N. Kalaria ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Pathophysiological Mechanism ◽  
Rodent Models ◽  
Recent Refinement

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.

scholarly journals Lessons from a Mouse Model Characterizing Features of Vascular Cognitive Impairment with White Matter Changes

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Masafumi Ihara ◽  
Hidekazu Tomimoto
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Mouse Model ◽  
The Elderly ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Demographic Shift ◽  
White Matter Changes ◽  
Blood Brain Barrier Disruption

With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. Vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease and is frequently responsible for the cognitive decline of the elderly. It is characterized by cerebrovascular white matter changes; thus, in order to investigate the underlying mechanisms involved in white matter changes, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. The purpose of this paper is to provide a comprehensive summary of the achievements made with the model that shows good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion. Detailed characterization of this model may help to decipher the substrates associated with impaired memory and move toward a more integrated therapy of vascular cognitive impairment.

scholarly journals Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Zheng Zhu ◽  
Xiaomei Xie ◽  
Shuqin Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathways ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Stat3 Pathway ◽  
Stat3 Signaling

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

scholarly journals Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Zhao-Hui Yao ◽  
Xiao-li Yao ◽  
Shao-feng Zhang ◽  
Ji-chang Hu ◽  
Yong Zhang
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Long Term Potentiation ◽  
Chronic Cerebral Hypoperfusion ◽  
Synaptic Proteins ◽  
Cerebral Hypoperfusion ◽  
Spatial Learning And Memory ◽  
Pathophysiological Mechanism

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

scholarly journals Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

2020 ◽  
Vol 21 (6) ◽  
pp. 2176 ◽  
Author(s):  
Amelia Nur Vidyanti ◽  
Jia-Yu Hsieh ◽  
Kun-Ju Lin ◽  
Yao-Ching Fang ◽  
Ismail Setyopranoto ◽  
...  
Keyword(s):  
Animal Model ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Chronic Phase ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Hippocampal Atrophy ◽  
Tnf Α

The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30–50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.

scholarly journals Executive dysfunction and altered cerebrovascular activity in a rodent model of vascular cognitive impairment

2018 ◽  
Vol 45 (S1) ◽  
pp. S4-S5
Author(s):  
K.D. Langdon ◽  
C. Cordova ◽  
S. Granter-Button ◽  
J. Boyd ◽  
J. Peeling ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Small Vessel Disease ◽  
Executive Dysfunction ◽  
Vascular Cognitive Impairment ◽  
Cerebral Hypoperfusion ◽  
Small Vessel ◽  
Sprague Dawley ◽  
Middle Aged ◽  
Metabolic Disturbances ◽  
Vessel Disease

Most basic science research has focused on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease giving rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. This talk will describe a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant cerebral hypoperfusion experienced significant executive dysfunction. In Experiment 2, dietary influences on functional, physiological and anatomical parameters were assessed. We found significant hypertension, blockage of brain microvessels (2-photon microscopy) and white matter atrophy in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically-relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

scholarly journals Evaluation of Cerebral Blood Flow Measured by 3D PCASL as Biomarker of Vascular Cognitive Impairment and Dementia (VCID) in a Cohort of Elderly Latinx Subjects at Risk of Small Vessel Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Kay Jann ◽  
Xingfeng Shao ◽  
Samantha J. Ma ◽  
Steven Y. Cen ◽  
Lina D’Orazio ◽  
...  
Keyword(s):  
At Risk ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Vascular Cognitive Impairment ◽  
Small Vessel ◽  
Vessel Disease ◽  
Brain White Matter

Cerebral small vessel disease (cSVD) affects arterioles, capillaries, and venules and can lead to cognitive impairments and clinical symptomatology of vascular cognitive impairment and dementia (VCID). VCID symptoms are similar to Alzheimer’s disease (AD) but the neurophysiologic alterations are less well studied, resulting in no established biomarkers. The purpose of this study was to evaluate cerebral blood flow (CBF) measured by 3D pseudo-continuous arterial spin labeling (pCASL) as a potential biomarker of VCID in a cohort of elderly Latinx subjects at risk of cSVD. Forty-five elderly Latinx subjects (12 males, 69 ± 7 years) underwent repeated MRI scans ∼6 weeks apart. CBF was measured using 3D pCASL in the whole brain, white matter and 4 main vascular territories (leptomeningeal anterior, middle, and posterior cerebral artery (leptoACA, leptoMCA, leptoPCA), as well as MCA perforator). The test-retest repeatability of CBF was assessed by intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Absolute and relative CBF was correlated with gross cognitive measures and domain specific assessment of executive and memory function, vascular risks, and Fazekas scores and volumes of white matter hyperintensity (WMH). Neurocognitive evaluations were performed using Montreal Cognitive Assessment (MoCA) and neuropsychological test battery in the Uniform Data Set v3 (UDS3). Good to excellent test-retest repeatability was achieved (ICC = 0.77–0.85, wsCV 3–9%) for CBF measurements in the whole brain, white matter, and 4 vascular territories. Relative CBF normalized by global mean CBF in the leptoMCA territory was positively correlated with the executive function composite score, while relative CBF in the leptoMCA and MCA perforator territory was positively correlated with MoCA scores, controlling for age, gender, years of education, and testing language. Relative CBF in WM was negatively correlated with WMH volume and MoCA scores, while relative leptoMCA CBF was positively correlated with WMH volume. Reliable 3D pCASL CBF measurements were achieved in the cohort of elderly Latinx subjects. Relative CBF in the leptomeningeal and perforator MCA territories were the most likely candidate biomarker of VCID. These findings need to be replicated in larger cohorts with greater variability of stages of cSVD.

scholarly journals Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate

2019 ◽  
Vol 20 (24) ◽  
pp. 6176 ◽  
Author(s):  
Kazuo Washida ◽  
Yorito Hattori ◽  
Masafumi Ihara
Keyword(s):  
White Matter ◽  
Animal Models ◽  
Mouse Model ◽  
Carotid Arteries ◽  
Amyloid Β ◽  
Chronic Cerebral Hypoperfusion ◽  
Motor Dysfunction ◽  
Cerebral Hypoperfusion ◽  
Left Vertebral Artery ◽  
Vessel Occlusion

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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