scholarly journals Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

2022 ◽  
Vol 13 ◽  
Author(s):  
Mosi Li ◽  
Akihiro Kitamura ◽  
Joshua Beverley ◽  
Juraj Koudelka ◽  
Jessica Duncombe ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Stenosis ◽  
Molecular Layer ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Wild Type ◽  
Fluorescent Tracer ◽  
Pial Arteries ◽  
Dorsolateral Cortex ◽  
Large Vessel Disease

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

scholarly journals Pulsation changes link to impaired glymphatic function in a mouse model of vascular cognitive impairment

2021 ◽  
Author(s):  
Mosi Li ◽  
Akihiro Kitamura ◽  
Joshua Beverley ◽  
Juraj Koudelka ◽  
Jessica Duncombe ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Stenosis ◽  
Molecular Layer ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Spatial Learning And Memory ◽  
Pial Arteries ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Dorsolateral Cortex

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning and memory. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels using two-photon microscopy. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Since our findings show that BCAS may influence VCI by impaired glymphatic drainage and reduced vascular pulsation we propose that these additional targets need to be considered when treating VCI.

Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

2021 ◽  
pp. 0271678X2110395
Author(s):  
Emily C Peters ◽  
Michael T Gee ◽  
Lukas N Pawlowski ◽  
Allison M Kath ◽  
Felipe D Polk ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Arteries ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Pial Arteries ◽  
Aspartate Receptor ◽  
Model Of Alzheimer’S Disease ◽  
Intracellular Ca ◽  
Cerebral Amyloid

Transient increases in intracellular Ca2+ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid- β(1-40) accumulates around blood vessels. In neurons, amyloid- β impairs the Ca2+-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid- β(1-40) reduces NMDAR-elicited Ca2+ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca2+ influx through NMDAR ( NMDAR sparklets) and intracellular Ca2+ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca2+ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid- β(1-40) impairs NMDAR-elicited Ca2+ transients. Cerebral arteries incubated with amyloid- β(1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca2+ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid- β(1-40), as well as in a mouse model of Alzheimer’s disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca2+-dependent pathways, a process disrupted by amyloid- β(1-40) and impaired in 5x-FAD mice.

Neuronal Activity Topography Parameters as a Marker for Differentiating Vascular Cognitive Impairment in Carotid Stenosis

2014 ◽  
Vol 23 (9) ◽  
pp. 2384-2390 ◽  
Author(s):  
Takashi Shibata ◽  
Toshimitu Musha ◽  
Michiya Kubo ◽  
Yukio Horie ◽  
Takashi Asahi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Stenosis ◽  
Neuronal Activity ◽  
Vascular Cognitive Impairment

scholarly journals Heterogeneous Disease Progression in a Mouse Model of Vascular Cognitive Impairment

2020 ◽  
Vol 21 (8) ◽  
pp. 2820 ◽  
Author(s):  
Na Kyung Lee ◽  
Hunnyun Kim ◽  
Jehoon Yang ◽  
Jeyun Kim ◽  
Jeong Pyo Son ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Disease Progression ◽  
Treatment Options ◽  
Neuronal Loss ◽  
Vascular Cognitive Impairment ◽  
Wild Type ◽  
Heterogeneous Nature ◽  
Vascular Compromise ◽  
5Xfad Mice ◽  
The Right

Recently, an asymmetric vascular compromise approach that replicates many aspects of human vascular cognitive impairment (VCI) has been reported. The present study aimed to first investigate on the reproducibility in the disease progression of this newly reported VCI model using wild-type C57BL6/J mice. The second aim was to assess how this approach will affect the disease progression of transgenic Alzheimer’s disease (AD) 5XFAD mice subjected to VCI. C57BL6/J and 5XFAD mice were subjected to VCI by placing an ameroid constrictor on the right CCA and a microcoil on the left CCA. Infarcts and hippocampal neuronal loss did not appear predominantly in the right (ameroid side) as expected but randomly in both hemispheres. The mortality rate of C57BL6/J mice was unexpectedly high. Inducing VCI reduced amyloid burden in the hippocampi of 5XFAD mice. Since VCI is known to be complex and complicated, the heterogeneous disease progression observed from this current study shares close resemblance to the clinical manifestation of VCI. This heterogeneity, however, makes it challenging to test novel treatment options using this model. Further study is warranted to tackle the heterogeneous nature of VCI.

scholarly journals Detection and Prediction of Mild Cognitive Impairment in Alzheimer’s Disease Mice

2020 ◽  
Vol 77 (3) ◽  
pp. 1209-1221
Author(s):  
Surya Prakash Rai ◽  
Pablo Bascuñana ◽  
Mirjam Brackhan ◽  
Markus Krohn ◽  
Luisa Möhle ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Dysfunction ◽  
Age Of Onset ◽  
Amyloid Β ◽  
Current Approach ◽  
Classification Algorithm ◽  
Wild Type

Background: The recent failure of clinical trials to treat Alzheimer’s disease (AD) indicates that the current approach of modifying disease is either wrong or is too late to be efficient. Mild cognitive impairment (MCI) denotes the phase between the preclinical phase and clinical overt dementia. AD mouse models that overexpress human amyloid-β (Aβ) are used to study disease pathogenesis and to conduct drug development/testing. However, there is no direct correlation between the Aβ deposition, the age of onset, and the severity of cognitive dysfunction. Objective: To detect and predict MCI when Aβ plaques start to appear in the hippocampus of an AD mouse. Methods: We trained wild-type and AD mice in a Morris water maze (WM) task with different inter-trial intervals (ITI) at 3 months of age and assessed their WM performance. Additionally, we used a classification algorithm to predict the genotype (APPtg versus wild-type) of an individual mouse from their respective WM data. Results: MCI can be empirically detected using a short-ITI protocol. We show that the ITI modulates the spatial learning of AD mice without affecting the formation of spatial memory. Finally, a simple classification algorithm such as logistic regression on WM data can give an accurate prediction of the cognitive dysfunction of a specific mouse. Conclusion: MCI can be detected as well as predicted simultaneously with the onset of Aβ deposition in the hippocampus in AD mouse model. The mild cognitive impairment prediction can be used for assessing the efficacy of a treatment.

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.

Abstract P741: Elemental Calcium Influx Through Endothelial N-Methyl-D-Aspartate Receptors is Impaired by Acute Amyloid- β (1-40) in Cerebral Arteries

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Emily C Peters ◽  
Allison M Kath ◽  
Michael T Gee ◽  
Paulo W Pires
Keyword(s):  
Calcium Influx ◽  
Cerebral Arteries ◽  
Amyloid Β ◽  
Cyclopiazonic Acid ◽  
Time Lapse ◽  
Amyloid Angiopathy ◽  
Wild Type ◽  
Pial Arteries ◽  
Intracellular Ca ◽  
Nmdar Activation

Introduction: Cerebral amyloid angiopathy (CAA), the accumulation of amyloid- β (1-40) (A β ) around cerebral arteries, impairs endothelial function. Endothelium-dependent dilation is a consequence of transient increases in intracellular [Ca 2+ ] in endothelial cells (EC). The Ca 2+ permeable N-methyl-D-aspartate receptor (NMDAR) mediates endothelium-dependent dilation, although if these effects are dependent on Ca 2+ influx and transients, or if they are impaired by A β , remains undetermined. Hypothesis: A β inhibits endothelial NMDAR-mediated Ca 2+ influx and transients in murine pial arteries. Methods: We performed Ca 2+ time-lapse imaging of en face pial arteries from cdh5-GCaMP8 mice to quantify EC Ca 2+ events induced by NMDAR activation. Data are means ± SEM. Results: Elemental Ca 2+ entry through NMDAR, hereon called NMDAR sparklets , was assessed in arteries incubated with EGTA-AM and cyclopiazonic acid (CPA) to inhibit intracellular Ca 2+ transients. NMDA (10 μM) induced an increase in NMDAR sparklets frequency when compared to vehicle, an effect inhibited by the NMDAR antagonist D-APV (in Hz: 0.12±0.01 vs 0.44±0.05 vs 0.21±0.02, vehicle vs NMDA vs NMDA+D-APV, p<0.05). Further, pial arteries exposed to NMDA without EGTA-AM and CPA showed an increase in the frequency of intracellular Ca 2+ transients, also blocked by D-APV (in Hz: 0.24±0.05 vs 0.53±0.10 vs 0.28±0.05, vehicle vs NMDA vs NMDA+D-APV, p<0.05). We then tested the effects of A β on Ca 2+ events in pial artery EC. We observed that 30 minutes exposure to A β (5 μM) caused a significant reduction in NMDAR sparklets (in Hz: 0.62±0.07 vs 0.22±0.03, NMDA vs NMDA + A β , p<0.05) but did not significantly alter intracellular Ca 2+ transients (in Hz: 0.62±0.37 vs 0.27±0.07, NMDA vs NMDA + A β ). Lastly, we performed pressure myography on pial arteries of wild-type and 5x-FAD mice, a model of familial Alzheimer’s disease with rapid amyloid accumulation. 5x-FAD mice displayed impaired vasodilation to NMDA (vasodilation (%): 9.86±0.64 vs 4.22±2.76, wild-type vs 5x-FAD , p<0.05). Conclusion: These preliminary data suggest that A β impairs endothelial NMDAR-associated Ca 2+ influx events in cerebral arteries, which can impair blood flow in CAA patients, thus contributing to cognitive impairment.

scholarly journals Traumatic Brain Injury by Weight-Drop Method Causes Transient Amyloid-β Deposition and Acute Cognitive Deficits in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Hajime Shishido ◽  
Masaki Ueno ◽  
Kana Sato ◽  
Masahisa Matsumura ◽  
Yasunori Toyota ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cognitive Impairment ◽  
Brain Injury ◽  
Cognitive Deficits ◽  
Amyloid Β ◽  
Wild Type ◽  
Long Term Effects ◽  
Drop Method ◽  
Weight Drop

There has been growing awareness of the correlation between an episode of traumatic brain injury (TBI) and the development of Alzheimer’s disease (AD) later in life. It has been reported that TBI accelerated amyloid-β (Aβ) pathology and cognitive decline in the several lines of AD model mice. However, the short-term and long-term effects of TBI by the weight-drop method on amyloid-β pathology and cognitive performance are unclear in wild-type (WT) mice. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in wild-type C57BL6J mice. Five- to seven-month-old WT mice were subjected to either TBI by the weight-drop method or a sham treatment. Seven days after TBI, the WT mice exhibited significantly lower spatial learning than the sham-treated WT mice. However, 28 days after TBI, the cognitive impairment in the TBI-treated WT mice recovered. Correspondingly, while significant amyloid-β (Aβ) plaques and amyloid precursor protein (APP) accumulation were observed in the TBI-treated mouse hippocampus 7 days after TBI, the Aβ deposition was no longer apparent 28 days after TBI. Thus, TBI induced transient amyloid-β deposition and acute cognitive impairments in the WT mice. The present study suggests that the TBI could be a risk factor for acute cognitive impairment even when genetic and hereditary predispositions are not involved. The system might be useful for evaluating and developing a pharmacological treatment for the acute cognitive deficits.

Abstract WP488: Imaging Correlates of Vascular Cognitive Impairment After Recent Ischemia in Intracranial Atherosclerosis: Evidence From SAMMPRIS

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
David S Liebeskind ◽  
Jose G Romano ◽  
George A Cotsonis ◽  
Shadi Yaghi ◽  
Tristan Honda ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Cognitive Dysfunction ◽  
Vascular Cognitive Impairment ◽  
Large Vessel ◽  
Intracranial Atherosclerosis ◽  
Ischemic Lesion ◽  
Vessel Disease ◽  
Moca Score ◽  
Large Vessel Disease

Background: More than 50% of individuals with recently symptomatic intracranial atherosclerotic disease (ICAD) manifest cognitive dysfunction. The imaging correlates of such cognitive impairment due to large vessel disease remain largely unknown. We examined the degree of cognitive dysfunction associated with detailed quantification of MRI DWI and FLAIR lesions at baseline in the SAMMPRIS trial. Methods: Central, blinded, adjudication of baseline MRI included measurement of DWI and FLAIR lesions and corresponding volumes. Cognitive function was assayed with the Montreal Cognitive Assessment (MoCA) score (0-30). Statistical analyses were used to describe MRI lesion characteristics and the correlation with baseline MoCA score. Results: At enrollment in SAMMPRIS, baseline DWI was available in 309/451 (69%) subjects, with FLAIR in 293/451 (65%). Baseline MoCA was median 25.0 (10-30). Chronic ischemic lesion burden on FLAIR was median 2.7 cc (0-87.0), with greater extent in those older than 60 years (p=0.03) and those on anti-thrombotics (p=0.01). DWI lesion volume (median 1.45 cc, range 0-71.84) was associated with NIHSS score (p<0.01), antithrombotic use (p=0.01) and time from qualifying event to enrollment (p=0.05). The number of DWI lesions (median 9, range 1-69) correlated (r=0.63, p<0.01) with total volume of acute infarction and was associated with more than 7 days from qualifying event (15.3 vs. 10.7, p<0.01). Chronic FLAIR lesion burden was associated with worse cognitive function or lower MoCA (r=-0.18, p=0.01) at baseline. Importantly, the volume or number of acute DWI lesions was unrelated to MoCA. Conclusions: Cognitive impairment associated with recently symptomatic intracranial atherosclerosis reflects the underlying burden of chronic, not acute, ischemia. Routine MRI, including FLAIR may inform future studies of vascular cognitive impairment in large vessel disease.

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