Pub Date : 2025-01-01Epub Date: 2025-03-13DOI: 10.1016/j.cccb.2025.100381
Rupal I. Mehta, Ana W. Capuano, Roshni Biswas, David A. Bennett, Zoe Arvanitakis
Permutations of cerebrovascular pathologies (CVP) in persons with diabetes mellitus (DM) have not been comprehensively investigated. Here, we examine diverse postmortem CVP outcomes, including permutations of single or mixed CVP, in 2163 older adults with or without DM who were followed in longitudinal studies of aging. Annual clinical evaluations included data to classify DM status by medical history (DM diagnosis), direct medication inspection (anti-diabetic therapy), and hemoglobin A1C level (≥6.5 %). Upon death, neuropathological examinations were performed and included evaluation for CVP (considering vessel pathologies and brain infarcts) and Alzheimer's disease neuropathologic change (AD-NC). Among all participants [mean age, 89.49 ± 6.89 years (SD)], single CVP were more common than mixed CVP. Logistic regression was used to analyze the association of DM with CVP permutations, controlling for age at death, sex, education, and AD-NC, and revealed increased odds of microinfarcts alone (odds ratio, 1.56 [95 %CI, 1.03–2.35]) and mixed microinfarcts and macroinfarcts (odds ratio, 1.90 [95 %CI, 1.16–3.13]). These associations remained after adjusting for demographic factors and cohort or vascular comorbidities including stroke, heart disease, hypertension, claudication, smoking, and systolic blood pressure. Furthermore, after controlling for demographic factors as well as AD-NC and APOE type, mixed microinfarcts and macroinfarcts were associated with approximate threefold increased risk of dementia (odds ratio, 2.95 [95 %CI, 1.13–7.70]) in participants with DM. Evidence suggests that older adults living with DM have higher odds of microinfarcts and mixed microinfarcts and macroinfarcts in the absence of intracranial vessel pathologies that cannot be explained by vascular comorbidities, and in this population mixed microinfarcts and macroinfarcts are associated with higher odds of dementia.
{"title":"Permutations of cerebrovascular pathologies in older adults with and without diabetes","authors":"Rupal I. Mehta, Ana W. Capuano, Roshni Biswas, David A. Bennett, Zoe Arvanitakis","doi":"10.1016/j.cccb.2025.100381","DOIUrl":"10.1016/j.cccb.2025.100381","url":null,"abstract":"<div><div>Permutations of cerebrovascular pathologies (CVP) in persons with diabetes mellitus (DM) have not been comprehensively investigated. Here, we examine diverse postmortem CVP outcomes, including permutations of single or mixed CVP, in 2163 older adults with or without DM who were followed in longitudinal studies of aging. Annual clinical evaluations included data to classify DM status by medical history (DM diagnosis), direct medication inspection (anti-diabetic therapy), and hemoglobin A1C level (≥6.5 %). Upon death, neuropathological examinations were performed and included evaluation for CVP (considering vessel pathologies and brain infarcts) and Alzheimer's disease neuropathologic change (AD-NC). Among all participants [mean age, 89.49 ± 6.89 years (SD)], single CVP were more common than mixed CVP. Logistic regression was used to analyze the association of DM with CVP permutations, controlling for age at death, sex, education, and AD-NC, and revealed increased odds of microinfarcts alone (odds ratio, 1.56 [95 %CI, 1.03–2.35]) and mixed microinfarcts and macroinfarcts (odds ratio, 1.90 [95 %CI, 1.16–3.13]). These associations remained after adjusting for demographic factors and cohort or vascular comorbidities including stroke, heart disease, hypertension, claudication, smoking, and systolic blood pressure. Furthermore, after controlling for demographic factors as well as AD-NC and APOE type, mixed microinfarcts and macroinfarcts were associated with approximate threefold increased risk of dementia (odds ratio, 2.95 [95 %CI, 1.13–7.70]) in participants with DM. Evidence suggests that older adults living with DM have higher odds of microinfarcts and mixed microinfarcts and macroinfarcts in the absence of intracranial vessel pathologies that cannot be explained by vascular comorbidities, and in this population mixed microinfarcts and macroinfarcts are associated with higher odds of dementia.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100381"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143682581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-10-04DOI: 10.1016/j.cccb.2025.100401
Brittany Monte , Judianne Davis , Xiaoyue Zhu , Feng Xu , Mark Majchrzak , Matthew J. Cabral , Waela M. Van Nostrand , Bethany Healey , Sunil Koundal , Hedok Lee , John K. Robinson , Helene Benveniste , William E. Van Nostrand
Background
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) is a rare hereditary cerebral small vessel disease associated with loss-of-function mutations in the High Temperature Requirement Serine Protease 1 (HTRA1). While previous mouse models have provided insight into the functions of HTRA1, they have incompletely replicated the pathogenesis of CARASIL.
Methods
A novel gene-edited rat model of CARASIL (designated CRHTRA1) was generated containing the loss-of-function Htra1 mutation p.R302Q. Quantitative cognitive, physiological, pathological and transcriptomic analyses were conducted to assess the CARASIL phenotype.
Results
At 12 months, histopathological analyses revealed marked thickening of the cerebral arteriolar walls with concomitant lumen stenosis. Changes in elastic composition, vascular smooth muscle cells and extracellular matrix proteins were identified in cerebral arteries. Downstream pathological remodeling of vasculature is implicated in increased capillary tortuosity and changes in capillary coverage in specific brain regions. Focal hyperintensity regions associated with enlarged perivascular spaces were identified locally by in vivo proton density weighted MRI. Region-specific reductions of fractional anisotropy were identified using diffusion tensor imaging and correlated with a reduction in neuronal densities. Behavioral testing in CRHTRA1 rats revealed significant cognitive deficit and gait disturbances. Micro-computed tomography of spinal vertebrae revealed pronounced increases in osteophyte formation. Global cerebral RNA sequencing revealed changes in signaling pathways associated with the loss-of-function HTRA1 CARASIL mutation, including those associated with transforming growth factor-β signaling and extracellular matrix remodeling.
Conclusion
The CRHTRA1 rat recapitulates many pathological changes that are consistent with both clinical CARASIL pathology and studies of HTRA1 function in vitro.
{"title":"A novel gene edited rat model of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)","authors":"Brittany Monte , Judianne Davis , Xiaoyue Zhu , Feng Xu , Mark Majchrzak , Matthew J. Cabral , Waela M. Van Nostrand , Bethany Healey , Sunil Koundal , Hedok Lee , John K. Robinson , Helene Benveniste , William E. Van Nostrand","doi":"10.1016/j.cccb.2025.100401","DOIUrl":"10.1016/j.cccb.2025.100401","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) is a rare hereditary cerebral small vessel disease associated with loss-of-function mutations in the High Temperature Requirement Serine Protease 1 (HTRA1). While previous mouse models have provided insight into the functions of HTRA1, they have incompletely replicated the pathogenesis of CARASIL.</div></div><div><h3>Methods</h3><div>A novel gene-edited rat model of CARASIL (designated CRHTRA1) was generated containing the loss-of-function <em>Htra1</em> mutation p.R302Q. Quantitative cognitive, physiological, pathological and transcriptomic analyses were conducted to assess the CARASIL phenotype.</div></div><div><h3>Results</h3><div>At 12 months, histopathological analyses revealed marked thickening of the cerebral arteriolar walls with concomitant lumen stenosis. Changes in elastic composition, vascular smooth muscle cells and extracellular matrix proteins were identified in cerebral arteries. Downstream pathological remodeling of vasculature is implicated in increased capillary tortuosity and changes in capillary coverage in specific brain regions. Focal hyperintensity regions associated with enlarged perivascular spaces were identified locally by <em>in vivo</em> proton density weighted MRI. Region-specific reductions of fractional anisotropy were identified using diffusion tensor imaging and correlated with a reduction in neuronal densities. Behavioral testing in CRHTRA1 rats revealed significant cognitive deficit and gait disturbances. Micro-computed tomography of spinal vertebrae revealed pronounced increases in osteophyte formation. Global cerebral RNA sequencing revealed changes in signaling pathways associated with the loss-of-function HTRA1 CARASIL mutation, including those associated with transforming growth factor-β signaling and extracellular matrix remodeling.</div></div><div><h3>Conclusion</h3><div>The CRHTRA1 rat recapitulates many pathological changes that are consistent with both clinical CARASIL pathology and studies of HTRA1 function <em>in vitro</em>.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100401"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-02-25DOI: 10.1016/j.cccb.2025.100380
Claire Seigworth , Isabelle Grassl , Dawn F. Wolfgram
Introduction Cerebrovascular reactivity (CVR) can inform about cerebral vascular health and provide prognostic information on risk cerebral ischemic injury. Use of transcranial Doppler ultrasound (TCD) is a non-invasive and inexpensive method to measure CVR and often uses a stimulus of increase in arterial partial pressure of carbon dioxide (pCO2). We evaluate re-breathing and breath-hold to measure CVR in a medically complex hemodialysis cohort who are at risk for cerebral hypoperfusion due to circulatory stress of hemodialysis.
Methods CVR was measured using both a 30 s breath-hold and a re-breathing period. We used percent change in mean flow velocity of the middle cerebral artery, measured with TCD over the change in end-tidal CO2 to calculate CVR. Paired T-test was used to compare the parameters of CVR and Pearson correlation to evaluate relevant risk factors for lower CVR.
Results 16 participants completed both CVR measurements, with mean (SD) age of 64.2 (11.2) years. CVR measured from each technique was similar 3.4 (2.9) %/mmHg (breath-hold) vs 2.7 (1.6) %/mmHg, (re-breathing) p = 0.37. Older age and history of stroke were associated with lower CVR when measured with re-breathing but not with breath-hold technique.
Conclusions Re-breathing to increase pCO2 and measure CVR is well-tolerated by a frail older medically complex patient population and may be a way to measure cerebrovascular health.
{"title":"Measuring cerebrovascular reactivity in a hemodialysis cohort","authors":"Claire Seigworth , Isabelle Grassl , Dawn F. Wolfgram","doi":"10.1016/j.cccb.2025.100380","DOIUrl":"10.1016/j.cccb.2025.100380","url":null,"abstract":"<div><div>Introduction Cerebrovascular reactivity (CVR) can inform about cerebral vascular health and provide prognostic information on risk cerebral ischemic injury. Use of transcranial Doppler ultrasound (TCD) is a non-invasive and inexpensive method to measure CVR and often uses a stimulus of increase in arterial partial pressure of carbon dioxide (pCO<sub>2</sub>). We evaluate re-breathing and breath-hold to measure CVR in a medically complex hemodialysis cohort who are at risk for cerebral hypoperfusion due to circulatory stress of hemodialysis.</div><div>Methods CVR was measured using both a 30 s breath-hold and a re-breathing period. We used percent change in mean flow velocity of the middle cerebral artery, measured with TCD over the change in end-tidal CO<sub>2</sub> to calculate CVR. Paired T-test was used to compare the parameters of CVR and Pearson correlation to evaluate relevant risk factors for lower CVR.</div><div>Results 16 participants completed both CVR measurements, with mean (SD) age of 64.2 (11.2) years. CVR measured from each technique was similar 3.4 (2.9) %/mmHg (breath-hold) vs 2.7 (1.6) %/mmHg, (re-breathing) <em>p</em> = 0.37. Older age and history of stroke were associated with lower CVR when measured with re-breathing but not with breath-hold technique.</div><div>Conclusions <em>Re</em>-breathing to increase pCO<sub>2</sub> and measure CVR is well-tolerated by a frail older medically complex patient population and may be a way to measure cerebrovascular health.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100380"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143519720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-03-24DOI: 10.1016/j.cccb.2025.100383
Naomi Vlegels , Hilde van den Brink , Anna Kopczak , Tine Arts , Stanley D.T. Pham , Jeroen C.W. Siero , Benno Gesierich , Alberto De Luca , Marco Duering , Jaco J.M. Zwanenburg , Martin Dichgans , Geert Jan Biessels
In cerebral small vessel disease (cSVD), vascular dysfunction has been associated with cSVD-lesions across the brain. Here we further explore the relation between vascular dysfunction and cSVD-related brain injury. We tested two hypotheses: (1) that complementary measures of abnormal small vessel function relate to decreased white matter integrity, and (2) that local variance in vascular dysfunction relates to local variance in white matter integrity within individual patients.
We included 23 patients with monogenic cSVD (i.e. CADASIL) and 46 patients with sporadic cSVD. With whole-brain analyses, we tested if small vessel flow velocity and reactivity measures from 7T-MRI were associated with global peak-width-of-skeletonized-mean-diffusivity (PSMD). We also tested voxel-wise correlations between reactivity to hypercapnia and mean diffusivity (MD) in white matter.
Whole-brain analyses showed a negative association between blood flow velocity and PSMD for the perforating arteries in the centrum semiovale in CADASIL (p = 0.04) and in the basal ganglia in sporadic cSVD (p = 0.002). Global white matter reactivity to hypercapnia was not associated with PSMD. Within patients, both in CADASIL and sporadic cSVD, we observed significant voxel-wise negative correlations for endothelial-independent vascular reactivity and MD in the white matter.
These findings confirm our hypothesis that small vessel dysfunction in patients with cSVD is associated with microstructural white matter alterations, also at voxel level. The latter may reflect a direct relationship between local small vessel dysfunction and tissue injury.
{"title":"The relation between cerebral small vessel function and white matter microstructure in monogenic and sporadic small vessel disease - the ZOOM@SVDs study","authors":"Naomi Vlegels , Hilde van den Brink , Anna Kopczak , Tine Arts , Stanley D.T. Pham , Jeroen C.W. Siero , Benno Gesierich , Alberto De Luca , Marco Duering , Jaco J.M. Zwanenburg , Martin Dichgans , Geert Jan Biessels","doi":"10.1016/j.cccb.2025.100383","DOIUrl":"10.1016/j.cccb.2025.100383","url":null,"abstract":"<div><div>In cerebral small vessel disease (cSVD), vascular dysfunction has been associated with cSVD-lesions across the brain. Here we further explore the relation between vascular dysfunction and cSVD-related brain injury. We tested two hypotheses: (1) that complementary measures of abnormal small vessel function relate to decreased white matter integrity, and (2) that local variance in vascular dysfunction relates to local variance in white matter integrity within individual patients.</div><div>We included 23 patients with monogenic cSVD (i.e. CADASIL) and 46 patients with sporadic cSVD. With whole-brain analyses, we tested if small vessel flow velocity and reactivity measures from 7T-MRI were associated with global peak-width-of-skeletonized-mean-diffusivity (PSMD). We also tested voxel-wise correlations between reactivity to hypercapnia and mean diffusivity (MD) in white matter.</div><div>Whole-brain analyses showed a negative association between blood flow velocity and PSMD for the perforating arteries in the centrum semiovale in CADASIL (<em>p</em> = 0.04) and in the basal ganglia in sporadic cSVD (<em>p</em> = 0.002). Global white matter reactivity to hypercapnia was not associated with PSMD. Within patients, both in CADASIL and sporadic cSVD, we observed significant voxel-wise negative correlations for endothelial-independent vascular reactivity and MD in the white matter.</div><div>These findings confirm our hypothesis that small vessel dysfunction in patients with cSVD is associated with microstructural white matter alterations, also at voxel level. The latter may reflect a direct relationship between local small vessel dysfunction and tissue injury.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100383"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-04-05DOI: 10.1016/j.cccb.2025.100384
Esther M.C. Vriend , Mathijs B.J. Dijsselhof , Thomas A. Bouwmeester , Oscar H. Franco , Henrike Galenkamp , Didier Collard , Aart J. Nederveen , Bert-Jan H. van den Born , Henk J.M.M. Mutsaerts
Background
Cardiovascular (CV) risk factors are associated with cerebrovascular damage and cognitive decline in late-life. However, it is unknown how different ethnic CV risk profiles relate to cerebral haemodynamics in mid-life. We aimed to investigate associations of CV risk factors with cerebral haemodynamics at two timepoints and examine the impact of ethnicity on these measures.
Methods
From the HELIUS study (53.0 years, 44.8 % female), participants of Dutch (n = 236), Moroccan (n = 122), or South-Asian Surinamese (n = 173) descent were included. Cerebral blood flow (CBF) and its spatial coefficient of variation (sCoV, an ASL-label arrival measure of macrovascular efficiency) were obtained in grey (GM) and white matter (WM). CV risk factors were assessed 8.4 years [7.4–9.5] (first visit) and 2.2 years [1.8–2.6] (second visit) prior to MRI. Associations of CV risk factors, WM hyperintensities (WMH), and carotid plaques with cerebral haemodynamics were investigated using linear regressions.
Results
CBF and sCoV differed per ethnicity. Only at the second visit associations were found, without an interaction with ethnicity; history of CV disease with lower GM CBF and higher WM sCoV, higher total cholesterol and lower WMH volume with lower WM CBF, smoking with higher WM sCoV, and higher SBP with lower GM sCoV.
Conclusions
These findings suggest that cerebral haemodynamics differ between ethnic groups in midlife. Although no interaction with ethnicity was found in the associations of CV risk factors, the observed differences in CBF and sCoV highlight the need to further explore how ethnic-specific risk profiles may contribute to cerebrovascular pathology over time.
{"title":"Mid-life association between cardiovascular risk factors and cerebral blood flow in a multi-ethnic population","authors":"Esther M.C. Vriend , Mathijs B.J. Dijsselhof , Thomas A. Bouwmeester , Oscar H. Franco , Henrike Galenkamp , Didier Collard , Aart J. Nederveen , Bert-Jan H. van den Born , Henk J.M.M. Mutsaerts","doi":"10.1016/j.cccb.2025.100384","DOIUrl":"10.1016/j.cccb.2025.100384","url":null,"abstract":"<div><h3>Background</h3><div>Cardiovascular (CV) risk factors are associated with cerebrovascular damage and cognitive decline in late-life. However, it is unknown how different ethnic CV risk profiles relate to cerebral haemodynamics in mid-life. We aimed to investigate associations of CV risk factors with cerebral haemodynamics at two timepoints and examine the impact of ethnicity on these measures.</div></div><div><h3>Methods</h3><div>From the HELIUS study (53.0 years, 44.8 % female), participants of Dutch (<em>n</em> = 236), Moroccan (<em>n</em> = 122), or South-Asian Surinamese (<em>n</em> = 173) descent were included. Cerebral blood flow (CBF) and its spatial coefficient of variation (sCoV, an ASL-label arrival measure of macrovascular efficiency) were obtained in grey (GM) and white matter (WM). CV risk factors were assessed 8.4 years [7.4–9.5] (first visit) and 2.2 years [1.8–2.6] (second visit) prior to MRI. Associations of CV risk factors, WM hyperintensities (WMH), and carotid plaques with cerebral haemodynamics were investigated using linear regressions.</div></div><div><h3>Results</h3><div>CBF and sCoV differed per ethnicity. Only at the second visit associations were found, without an interaction with ethnicity; history of CV disease with lower GM CBF and higher WM sCoV, higher total cholesterol and lower WMH volume with lower WM CBF, smoking with higher WM sCoV, and higher SBP with lower GM sCoV.</div></div><div><h3>Conclusions</h3><div>These findings suggest that cerebral haemodynamics differ between ethnic groups in midlife. Although no interaction with ethnicity was found in the associations of CV risk factors, the observed differences in CBF and sCoV highlight the need to further explore how ethnic-specific risk profiles may contribute to cerebrovascular pathology over time.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100384"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-12DOI: 10.1016/j.cccb.2024.100374
Lars Nyberg
We still know relatively little about how the human brain supports intelligence. I this personal view I argue that adopting the framework of neurocognitive component processes (NCP) might advance the current state of knowledge. Integration of information processing across distributed brain regions is proposed as a potential NCP, and some possible clinical implications of adopting the NCP framework are outlined.
{"title":"Where in the brain is human intelligence?✰","authors":"Lars Nyberg","doi":"10.1016/j.cccb.2024.100374","DOIUrl":"10.1016/j.cccb.2024.100374","url":null,"abstract":"<div><div>We still know relatively little about how the human brain supports intelligence. I this personal view I argue that adopting the framework of neurocognitive component processes (NCP) might advance the current state of knowledge. Integration of information processing across distributed brain regions is proposed as a potential NCP, and some possible clinical implications of adopting the NCP framework are outlined.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100374"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-12-14DOI: 10.1016/j.cccb.2025.100473
Hope Han , Gabriele Rocha , Lara Robinson Hannah Sleven , Anandhakumar Chandran , Cesar Medina , Robert Kitchen , Zam Cader
Introduction
Cardiovascular disorders including hypertension and diabetes are major risk factors that accelerate cognitive decline and increase the risk of neurodegenerative disease. However, the cellular and molecular mechanisms underlying their effects on the human brain remain poorly defined. Uncovering these mechanism may offer new approaches to protect the brain.
Methods
We employed single-nucleus RNA sequencing (snRNA-seq) of post-mortem prefrontal cortex tissue from 48 individuals hypertension and/or diabetes, alongside matched controls, to delineate cell-type-specific effects on the brain. We peformed single dissociation into vascular and parenchymal fractions followed by Split-Seq barcoding of extacted nuclei, library preparation and sequencing. Cell types were annotated to produce a prefrontal cortex single cell atlas. Downstream analysis included psuedobulk differential gene expresson, cell-type GWAS enrichement and cell-cell communication.
Results
We identify a striking enrichment of hypertension-associated genetic risk within brain vascular and glial cell populations, highlighting a potential causal role of brain cells in the development of hypertension. Furthermore, we find that despite having received antihypertensive treatment, hypertension continues to drive transcriptional alterations in brain vascular cells and astrocytes. Functional analyses reveal that these changes prominently involve genes implicated in synaptic structure and neuronal connectivity, suggesting an unanticipated role of these genes in vascular and glial cells. Co-expression network analysis further supports their functional importance, with a module of synaptic and axon guidance genes present in control tissue brain endothelial cells and specifically disrupted in hypertension.
Conclusions
Our findings suggest that conventional antihypertensive therapies, even blood-brain-barrier penetrant angiotensin targeted treatments, may be insufficient to counteract hypertension-driven neurovascular dysfunction. This highlights the need for new interventions that preserve glia-vascular in hypertension to mitigate cognitive decline.
{"title":"The effects of hypertension on the neurovasculature of the human prefrontal cortex at single cell resolution","authors":"Hope Han , Gabriele Rocha , Lara Robinson Hannah Sleven , Anandhakumar Chandran , Cesar Medina , Robert Kitchen , Zam Cader","doi":"10.1016/j.cccb.2025.100473","DOIUrl":"10.1016/j.cccb.2025.100473","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiovascular disorders including hypertension and diabetes are major risk factors that accelerate cognitive decline and increase the risk of neurodegenerative disease. However, the cellular and molecular mechanisms underlying their effects on the human brain remain poorly defined. Uncovering these mechanism may offer new approaches to protect the brain.</div></div><div><h3>Methods</h3><div>We employed single-nucleus RNA sequencing (snRNA-seq) of post-mortem prefrontal cortex tissue from 48 individuals hypertension and/or diabetes, alongside matched controls, to delineate cell-type-specific effects on the brain. We peformed single dissociation into vascular and parenchymal fractions followed by Split-Seq barcoding of extacted nuclei, library preparation and sequencing. Cell types were annotated to produce a prefrontal cortex single cell atlas. Downstream analysis included psuedobulk differential gene expresson, cell-type GWAS enrichement and cell-cell communication.</div></div><div><h3>Results</h3><div>We identify a striking enrichment of hypertension-associated genetic risk within brain vascular and glial cell populations, highlighting a potential causal role of brain cells in the development of hypertension. Furthermore, we find that despite having received antihypertensive treatment, hypertension continues to drive transcriptional alterations in brain vascular cells and astrocytes. Functional analyses reveal that these changes prominently involve genes implicated in synaptic structure and neuronal connectivity, suggesting an unanticipated role of these genes in vascular and glial cells. Co-expression network analysis further supports their functional importance, with a module of synaptic and axon guidance genes present in control tissue brain endothelial cells and specifically disrupted in hypertension.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that conventional antihypertensive therapies, even blood-brain-barrier penetrant angiotensin targeted treatments, may be insufficient to counteract hypertension-driven neurovascular dysfunction. This highlights the need for new interventions that preserve glia-vascular in hypertension to mitigate cognitive decline.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100473"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-12-14DOI: 10.1016/j.cccb.2025.100458
Jessica Lebenberg , Laura Tintore-Carbonell , Louis Lambert , Mohamed Saichi , Hugues Chabriat
Introduction
CADASIL is a severe monogenic cerebral small vessel disease leading to stroke, motor impairment, gait disturbances and cognitive decline. On cerebral MRI, several markers are observed during the disease course, including cerebral microbleeds (CMBs).
Although not directly correlated with clinical severity, CMBs reflect significant underlying vessel wall pathology, suggesting potential predictive value for disease progression.
However, as they are observed in only 1/3 of patients and test-retests showed a low reliable counting when their number increases, the factors associated with their appearance and increase remain poorly investigated. We searched its predictors in a large French cohort of patients.
Methods
In addition to the CMBs counted visually in 517 CADASIL patients recruited at the National Referral Centre in France, we collected for each individual age, sex, vascular risk factors, NOTCH3 mutation location and other biological and neuroimaging markers. To investigate the predictors of both the presence and burden of CMBs, a Hurdle modeling approach was used based on two parts: 1) the presence of CMBs was analyzed using a logistic regression model; 2) among individuals with CMBs, the total count was studied using a truncated negative binomial regression model to account for the overdispersion and absence of zero counts. All continuous predictors were standardized prior to analysis. A univariate screening step was first applied to exclude variables with weak associations with CMBs (p > 0.3).
Results
The distribution of CMBs in our study was zero-inflated, with approximately 2/3 of participants without any lesion, positively skewed, with a small subset exhibiting more than 50 CMBs. Older age and higher number of lacunes were revealed as significant predictors of the presence of CMBs. In contrast, male sex and higher LDL cholesterol levels were found associated with a larger burden of CMBs among individuals with such lesions (Fig1).
Conclusions
Our results suggest that the predictors of the emergence and increase of CMBs differ in CADASIL. These findings support that the mechanisms underlying their appearance may change over time and that other factors, as the disease progresses, may contribute to an increase in their number. Further studies are needed to confirm these results in other cohorts and settings.
{"title":"Predictors of microbleed emergence and increase may differ in CADASIL","authors":"Jessica Lebenberg , Laura Tintore-Carbonell , Louis Lambert , Mohamed Saichi , Hugues Chabriat","doi":"10.1016/j.cccb.2025.100458","DOIUrl":"10.1016/j.cccb.2025.100458","url":null,"abstract":"<div><h3>Introduction</h3><div>CADASIL is a severe monogenic cerebral small vessel disease leading to stroke, motor impairment, gait disturbances and cognitive decline. On cerebral MRI, several markers are observed during the disease course, including cerebral microbleeds (CMBs).</div><div>Although not directly correlated with clinical severity, CMBs reflect significant underlying vessel wall pathology, suggesting potential predictive value for disease progression.</div><div>However, as they are observed in only 1/3 of patients and test-retests showed a low reliable counting when their number increases, the factors associated with their appearance and increase remain poorly investigated. We searched its predictors in a large French cohort of patients.</div></div><div><h3>Methods</h3><div>In addition to the CMBs counted visually in 517 CADASIL patients recruited at the National Referral Centre in France, we collected for each individual age, sex, vascular risk factors, NOTCH3 mutation location and other biological and neuroimaging markers. To investigate the predictors of both the presence and burden of CMBs, a Hurdle modeling approach was used based on two parts: 1) the presence of CMBs was analyzed using a logistic regression model; 2) among individuals with CMBs, the total count was studied using a truncated negative binomial regression model to account for the overdispersion and absence of zero counts. All continuous predictors were standardized prior to analysis. A univariate screening step was first applied to exclude variables with weak associations with CMBs (p > 0.3).</div></div><div><h3>Results</h3><div>The distribution of CMBs in our study was zero-inflated, with approximately 2/3 of participants without any lesion, positively skewed, with a small subset exhibiting more than 50 CMBs. Older age and higher number of lacunes were revealed as significant predictors of the presence of CMBs. In contrast, male sex and higher LDL cholesterol levels were found associated with a larger burden of CMBs among individuals with such lesions (Fig1).</div></div><div><h3>Conclusions</h3><div>Our results suggest that the predictors of the emergence and increase of CMBs differ in CADASIL. These findings support that the mechanisms underlying their appearance may change over time and that other factors, as the disease progresses, may contribute to an increase in their number. Further studies are needed to confirm these results in other cohorts and settings.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100458"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-12-14DOI: 10.1016/j.cccb.2025.100501
Gan Han , Erika Kitajima , Ashley Suwanda , Dan Jobson , Louise Allan , Masafumi Ihara , Newman S K Sze , Yoshiki Hase , Tuomo Polvikoski , Raj Kalaria
Introduction
Carotid artery disease (CAD) is a recognised important cause of stroke. However, its relationship with cerebral small vessel disease (SVD) and dementia remains unclear. We hypothesized that CAD in older individuals significantly affects cerebral perfusion, and leads to cerebral SVD.
Methods
We performed a clinicopathological study in patients from the Cognitive Function After Stroke (CogFAST) study and prospectively recruited dementia patients with evidence of cerebral SVD. In addition to brain tissues, we collected postmortem samples of the internal carotid arteries (ICA) from these cohorts in the Newcastle Brain Tissue Resource. Standard neuropathological examination was performed for diagnosis and assignment of the cases per current diagnostic criteria for vascular and neurodegenerative dementias and assessed for presence of types of vascular pathology including the degree of stenosis and sclerosis in vascular tissues.
Results
We evaluated a total of 159 ICA samples and brain tissues from all cases with evidence of SVD. Severity of ICA stenosis and sclerotic index correlated strongly with both clinical stroke and brain infarction (P<0.0001). More than 90% of the subjects had one subtype of ICA lesion in the order: intimal thickening >fibrocalcific >fibrous cap (thick) >fibrous cap (thin) >thrombus group with a strong inflammatory reaction in fibrocalcific atheromas. Linear regression analysis showed that ICA stenosis was positively correlated to both SVD pathology scores and total number of vascular lesions (P<0.034). We found that severity of stenosis was related to anterior circulation involvement and small infarcts in the subcortical structures including the white matter (WM) rather than the cortex. Total intracranial artery scores were correlated with ICA stenosis and sclerosis (P<0.001). In the CogFAST group analysis, the smallest lesions in the WM but not in the cortex or basal ganglia, and thalamus were associated with severity of ICA stenosis (P<0.05)
Conclusions
Carotid atherosclerosis promotes cerebral SVD types of changes and influences the cerebral arterial system. Our observations also suggest extracranial ICA athology impacts on the perfusion and integrity of the deep WM.
{"title":"Carotid Artery Disease in Cerebral Small Vessel Disease and Dementia","authors":"Gan Han , Erika Kitajima , Ashley Suwanda , Dan Jobson , Louise Allan , Masafumi Ihara , Newman S K Sze , Yoshiki Hase , Tuomo Polvikoski , Raj Kalaria","doi":"10.1016/j.cccb.2025.100501","DOIUrl":"10.1016/j.cccb.2025.100501","url":null,"abstract":"<div><h3>Introduction</h3><div>Carotid artery disease (CAD) is a recognised important cause of stroke. However, its relationship with cerebral small vessel disease (SVD) and dementia remains unclear. We hypothesized that CAD in older individuals significantly affects cerebral perfusion, and leads to cerebral SVD.</div></div><div><h3>Methods</h3><div>We performed a clinicopathological study in patients from the Cognitive Function After Stroke (CogFAST) study and prospectively recruited dementia patients with evidence of cerebral SVD. In addition to brain tissues, we collected postmortem samples of the internal carotid arteries (ICA) from these cohorts in the Newcastle Brain Tissue Resource. Standard neuropathological examination was performed for diagnosis and assignment of the cases per current diagnostic criteria for vascular and neurodegenerative dementias and assessed for presence of types of vascular pathology including the degree of stenosis and sclerosis in vascular tissues.</div></div><div><h3>Results</h3><div>We evaluated a total of 159 ICA samples and brain tissues from all cases with evidence of SVD. Severity of ICA stenosis and sclerotic index correlated strongly with both clinical stroke and brain infarction (P<0.0001). More than 90% of the subjects had one subtype of ICA lesion in the order: intimal thickening >fibrocalcific >fibrous cap (thick) >fibrous cap (thin) >thrombus group with a strong inflammatory reaction in fibrocalcific atheromas. Linear regression analysis showed that ICA stenosis was positively correlated to both SVD pathology scores and total number of vascular lesions (P<0.034). We found that severity of stenosis was related to anterior circulation involvement and small infarcts in the subcortical structures including the white matter (WM) rather than the cortex. Total intracranial artery scores were correlated with ICA stenosis and sclerosis (P<0.001). In the CogFAST group analysis, the smallest lesions in the WM but not in the cortex or basal ganglia, and thalamus were associated with severity of ICA stenosis (P<0.05)</div></div><div><h3>Conclusions</h3><div>Carotid atherosclerosis promotes cerebral SVD types of changes and influences the cerebral arterial system. Our observations also suggest extracranial ICA athology impacts on the perfusion and integrity of the deep WM.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100501"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-12-14DOI: 10.1016/j.cccb.2025.100454
Vanessa Fonseca Lomeli , Ileana De Anda-Duran , Shirine Moukaled , Jessica G. Woo , Elaine M. Urbina , Ganesh Baliga , David J. Libon , Lydia A. Bazzano
Introduction
Age, sex, race, and education are well-established determinants of cognitive performance in traditional testing, yet their impact on novel digital measures is less understood. Digital assessments offer scalable, precise evaluation of cognition and may reveal subtle demographic differences important for early risk detection. Leveraging three distinct cohorts from the Disparities and Equity in Childhood Cardiovascular Exposures and Alzheimer’s Dementia (DECADES) project, we examined demographic influences on two digital cognitive tools.
Methods
Participants included 236 community-dwelling adults (age 38-69 years; 79.5% female; 68.3% White) drawn from three midlife DECADES cohorts, each with distinct racial/ethnic and socioeconomic profiles. Demographic predictors of interest were age, sex, and race; obesity and hypertension were also considered, given their cognitive relevance. Cognitive performance was measured using two tablet-based instruments: (1) the Rowan Digital Cancellation Test (RDCT), which includes letter, symbol, and mixed conditions with outcomes of accuracy and processing speed, and (2) the Linus Digital Clock Drawing Task, which includes command and copy conditions with metrics of latency, stroke conformity, speed, and total completion time. Standardized protocols were used for administration across sites. One-way ANOVA models were used to test differences between demographic variables and digital outcomes. Significant differences were further examined with pairwise post hoc comparisons to delineate group differences.
Results
Older participants demonstrated slower processing across RDCT and clock tasks (letter speed F=36.5, p<0.001; mixed speed F=29.8, p<0.001). Women outperformed men on RDCT speed (letter F=22.9, p<0.001; symbol F=9.6, p=0.002) and on clock copy time (F=4.9, p=0.027). Black participants exhibited longer clock command latencies (F=22.7, p<0.001), more stroke errors (F=6.9, p<0.001), and slower cancellation performance (letter speed F=10.5, p=0.001). Obesity was associated with slower digital processing, as indicated by reduced performance on clock average speed (F = 4.83, p = 0.02) and cancellation average speed (F = 4.82, p = 0.029), whereas hypertension did not show a significant association.
Conclusions
Demographic factors—including age, sex, and race—exert a strong influence on digital cognitive performance in midlife, paralleling traditional neuropsychological test findings. RDCT and digital clock drawing are sensitive to sociodemographic differences, underscoring their potential as scalable tools to identify at-risk groups before clinical symptoms emerge.
{"title":"Demographic and Cardiovascular Risk Factors Influence Midlife Cognitive Function: Evidence from the i3C DECADE Study","authors":"Vanessa Fonseca Lomeli , Ileana De Anda-Duran , Shirine Moukaled , Jessica G. Woo , Elaine M. Urbina , Ganesh Baliga , David J. Libon , Lydia A. Bazzano","doi":"10.1016/j.cccb.2025.100454","DOIUrl":"10.1016/j.cccb.2025.100454","url":null,"abstract":"<div><h3>Introduction</h3><div>Age, sex, race, and education are well-established determinants of cognitive performance in traditional testing, yet their impact on novel digital measures is less understood. Digital assessments offer scalable, precise evaluation of cognition and may reveal subtle demographic differences important for early risk detection. Leveraging three distinct cohorts from the Disparities and Equity in Childhood Cardiovascular Exposures and Alzheimer’s Dementia (DECADES) project, we examined demographic influences on two digital cognitive tools.</div></div><div><h3>Methods</h3><div>Participants included 236 community-dwelling adults (age 38-69 years; 79.5% female; 68.3% White) drawn from three midlife DECADES cohorts, each with distinct racial/ethnic and socioeconomic profiles. Demographic predictors of interest were age, sex, and race; obesity and hypertension were also considered, given their cognitive relevance. Cognitive performance was measured using two tablet-based instruments: (1) the Rowan Digital Cancellation Test (RDCT), which includes letter, symbol, and mixed conditions with outcomes of accuracy and processing speed, and (2) the Linus Digital Clock Drawing Task, which includes command and copy conditions with metrics of latency, stroke conformity, speed, and total completion time. Standardized protocols were used for administration across sites. One-way ANOVA models were used to test differences between demographic variables and digital outcomes. Significant differences were further examined with pairwise post hoc comparisons to delineate group differences.</div></div><div><h3>Results</h3><div>Older participants demonstrated slower processing across RDCT and clock tasks (letter speed F=36.5, p<0.001; mixed speed F=29.8, p<0.001). Women outperformed men on RDCT speed (letter F=22.9, p<0.001; symbol F=9.6, p=0.002) and on clock copy time (F=4.9, p=0.027). Black participants exhibited longer clock command latencies (F=22.7, p<0.001), more stroke errors (F=6.9, p<0.001), and slower cancellation performance (letter speed F=10.5, p=0.001). Obesity was associated with slower digital processing, as indicated by reduced performance on clock average speed (F = 4.83, p = 0.02) and cancellation average speed (F = 4.82, p = 0.029), whereas hypertension did not show a significant association.</div></div><div><h3>Conclusions</h3><div>Demographic factors—including age, sex, and race—exert a strong influence on digital cognitive performance in midlife, paralleling traditional neuropsychological test findings. RDCT and digital clock drawing are sensitive to sociodemographic differences, underscoring their potential as scalable tools to identify at-risk groups before clinical symptoms emerge.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100454"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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