Pub Date : 2025-01-01DOI: 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 : 2025-01-01DOI: 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 : 2025-01-01DOI: 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 : 2025-01-01DOI: 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 : 2025-01-01DOI: 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 : 2025-01-01DOI: 10.1016/j.cccb.2025.100503
Lauren Hannam , Dan Jobson , Louise Allan , Gan Han , Newman SK Sze , Raj Kalaria
Introduction
Introduction: Ageing is associated with the pathological accumulation of damaged proteins (termed proteinopathies) that affect the cardiovascular system and the brain. Spontaneous chemical reactions such as deamidation lead to degenerative protein modifications (DPMs), including the formation of isoAsp-Gly-Arg (isoDGR) motifs. These DPMs can cause toxic gain-of-function effects, promote inflammation, and can contribute to chronic conditions such as vascular cognitive impairment and dementia. The burden of isoDGR in relation to neurofibrillary pathology however is not known across the dementias.
Methods
Methods: We systematically assessed isoDGR and phosphorylated-Tau (pTau) immunoreactivites in terms of densities and co-localisation frequencies across a range of dementia disorders including: post-stroke dementia, vascular dementia (VaD) and Alzheimer’s disease (AD), Mixed dementia as well as in post-stroke survivors without dementia and normal ageing control subjects (n=60; age range 73-99; male 52%).
Results
Results: We found that isoDGR and pTau immunoreactivities were similar across all assessed hippocampal regions including CA1, CA2/CA3 and entorhinal cortex (p=0.71), but isoDGR burden differed across disorder groups in all regions (CA1: p=0.008; CA2/3: p<0.001; entorhinal cortex: p=0.05). VaD had higher isoDGR concentrations in all hippocampal regions and was the only group with strong positive correlations between isoDGR and pTau levels (r=.86, p<0.01). AD subjects showed significantly higher levels of pTau and co-localisations in all regions. However, isoDGR exceeded pTau quantity in all hippocampal regions.
Conclusions
Conclusions: We noted isoDGR to be significantly high in VaD in the general absence of pTau or neurofibrillary pathology. While isoDGR may be used as a potential biomarker for this subtype of dementia, greater concentrations of isoDGR compared to pTau suggests it may precede and promote neurofibrillary pathology. This also highlights anti-isoDGR as a potential therapeutic target in dementia.
{"title":"Degenerative Protein Modifications in the Hippocampal Formation in Vascular Dementia","authors":"Lauren Hannam , Dan Jobson , Louise Allan , Gan Han , Newman SK Sze , Raj Kalaria","doi":"10.1016/j.cccb.2025.100503","DOIUrl":"10.1016/j.cccb.2025.100503","url":null,"abstract":"<div><h3>Introduction</h3><div>Introduction: Ageing is associated with the pathological accumulation of damaged proteins (termed proteinopathies) that affect the cardiovascular system and the brain. Spontaneous chemical reactions such as deamidation lead to degenerative protein modifications (DPMs), including the formation of isoAsp-Gly-Arg (isoDGR) motifs. These DPMs can cause toxic gain-of-function effects, promote inflammation, and can contribute to chronic conditions such as vascular cognitive impairment and dementia. The burden of isoDGR in relation to neurofibrillary pathology however is not known across the dementias.</div></div><div><h3>Methods</h3><div>Methods: We systematically assessed isoDGR and phosphorylated-Tau (pTau) immunoreactivites in terms of densities and co-localisation frequencies across a range of dementia disorders including: post-stroke dementia, vascular dementia (VaD) and Alzheimer’s disease (AD), Mixed dementia as well as in post-stroke survivors without dementia and normal ageing control subjects (n=60; age range 73-99; male 52%).</div></div><div><h3>Results</h3><div>Results: We found that isoDGR and pTau immunoreactivities were similar across all assessed hippocampal regions including CA1, CA2/CA3 and entorhinal cortex (p=0.71), but isoDGR burden differed across disorder groups in all regions (CA1: p=0.008; CA2/3: p<0.001; entorhinal cortex: p=0.05). VaD had higher isoDGR concentrations in all hippocampal regions and was the only group with strong positive correlations between isoDGR and pTau levels (r=.86, p<0.01). AD subjects showed significantly higher levels of pTau and co-localisations in all regions. However, isoDGR exceeded pTau quantity in all hippocampal regions.</div></div><div><h3>Conclusions</h3><div>Conclusions: We noted isoDGR to be significantly high in VaD in the general absence of pTau or neurofibrillary pathology. While isoDGR may be used as a potential biomarker for this subtype of dementia, greater concentrations of isoDGR compared to pTau suggests it may precede and promote neurofibrillary pathology. This also highlights anti-isoDGR as a potential therapeutic target in dementia.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100503"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796635","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 : 2025-01-01DOI: 10.1016/j.cccb.2025.100446
Si Han , Jesper de Jong , Fariba Ahmadizar
Introduction
While hypertension and type 2 diabetes (T2D) are widely acknowledged contributors to cardiovascular and cerebrovascular diseases, blood pressure variability (BPV) has emerged as an important, but less studied risk factor. BPV reflects visit-to-visit blood pressure fluctuations, indicating possible vascular instability and autonomic dysfunction. Its impact on neurovascular outcomes and mortality, especially in relation to glycemic status, remains unclear. This study investigates the association between visit-to- visit BPV and the risks of dementia subtypes (all-cause dementia, Alzheimer’s disease (AD), vascular dementia), stroke (all-cause stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage), and all-cause mortality across glycemic states, and evaluates whether the Apolipoprotein E (ApoE) ε4 genotype modifies these associations.
Methods
BPV was calculated for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using absolute and directional variability metrics. Time-to-event analyses included Fine & Gray competing risk regression for dementia and stroke, and Cox proportional hazards models for all-cause mortality. All models were adjusted for sociodemographic, lifestyle, clinical, and genetic factors. Additionally, ApoE genotype was added as a modifier to investigate its role in the associations between BPV and the mentioned outcomes.
Results
The study included 41,737 participants from the UK Biobank. Higher BPV was consistently associated with an increased risk of all-cause mortality across all glycemic groups, with the strongest associations observed in individuals with prediabetes and T2D groups. High directional MAP variability in the prediabetes group was associated with a significantly increased mortality risk (HR: 1.46, 95% CI: 1.19-1.80). Associations with dementia and stroke were less consistent. Among normoglycemic individuals, higher directional variability in DBP and MAP was linked to an increased risk of AD (DBP HR: 1.42; 95% CI: 1.11-1.83; MAP HR: 1.37; 95% CI: 1.06-1.77). BPV was also associated with subarachnoid hemorrhagic stroke in the normoglycemia group. The ApoE ε4 genotype showed interaction effects with BPV on dementia risk in the prediabetes subgroup.
Conclusions
Visit-to-visit BPV is a robust predictor of all-cause mortality and may increase the risk of dementia and stroke. Monitoring and stabilizing BPV could be a key strategy in preventing adverse health outcomes, particularly in individuals with prediabetes and T2D.
{"title":"Visit-to-Visit Blood Pressure Variability, Glycemic Status and the Risk of Dementia, Stroke, and All-Cause Mortality: A UK Biobank Cohort Study","authors":"Si Han , Jesper de Jong , Fariba Ahmadizar","doi":"10.1016/j.cccb.2025.100446","DOIUrl":"10.1016/j.cccb.2025.100446","url":null,"abstract":"<div><h3>Introduction</h3><div>While hypertension and type 2 diabetes (T2D) are widely acknowledged contributors to cardiovascular and cerebrovascular diseases, blood pressure variability (BPV) has emerged as an important, but less studied risk factor. BPV reflects visit-to-visit blood pressure fluctuations, indicating possible vascular instability and autonomic dysfunction. Its impact on neurovascular outcomes and mortality, especially in relation to glycemic status, remains unclear. This study investigates the association between visit-to- visit BPV and the risks of dementia subtypes (all-cause dementia, Alzheimer’s disease (AD), vascular dementia), stroke (all-cause stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage), and all-cause mortality across glycemic states, and evaluates whether the Apolipoprotein E (ApoE) ε4 genotype modifies these associations.</div></div><div><h3>Methods</h3><div>BPV was calculated for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using absolute and directional variability metrics. Time-to-event analyses included Fine & Gray competing risk regression for dementia and stroke, and Cox proportional hazards models for all-cause mortality. All models were adjusted for sociodemographic, lifestyle, clinical, and genetic factors. Additionally, ApoE genotype was added as a modifier to investigate its role in the associations between BPV and the mentioned outcomes.</div></div><div><h3>Results</h3><div>The study included 41,737 participants from the UK Biobank. Higher BPV was consistently associated with an increased risk of all-cause mortality across all glycemic groups, with the strongest associations observed in individuals with prediabetes and T2D groups. High directional MAP variability in the prediabetes group was associated with a significantly increased mortality risk (HR: 1.46, 95% CI: 1.19-1.80). Associations with dementia and stroke were less consistent. Among normoglycemic individuals, higher directional variability in DBP and MAP was linked to an increased risk of AD (DBP HR: 1.42; 95% CI: 1.11-1.83; MAP HR: 1.37; 95% CI: 1.06-1.77). BPV was also associated with subarachnoid hemorrhagic stroke in the normoglycemia group. The ApoE ε4 genotype showed interaction effects with BPV on dementia risk in the prediabetes subgroup.</div></div><div><h3>Conclusions</h3><div>Visit-to-visit BPV is a robust predictor of all-cause mortality and may increase the risk of dementia and stroke. Monitoring and stabilizing BPV could be a key strategy in preventing adverse health outcomes, particularly in individuals with prediabetes and T2D.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100446"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796646","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 : 2025-01-01DOI: 10.1016/j.cccb.2025.100474
Duygu Kilinc , Eline J. Vinke , Wiesje van der Flier , Meike W. Vernooij , Geert Jan Biessels
Introduction
Age and sex norm-referenced small vessel disease (SVD) MRI scores may provide a more precise and comprehensible individualized indication of the abnormality of SVD burden in a clinical setting. We recently created such referenced data from the population-based Rotterdam Study. Here we assessed the distribution of norm-referenced SVD burden and the relation with cognitive functioning in memory clinic patients with possible vascular cognitive impairment.
Methods
830 patients from the TRACE-VCI memory clinic cohort, all with vascular injury on MRI, were included. White matter hyperintensity (WMH) volumes were converted to norm-referenced percentile scores. Lacune and microbleed counts were expressed as “Number Needed to Scan (NNS)”, i.e. 1/ lesion count probabilities in the general population. We assessed the distribution of these norm-referenced SVD scores in the patients, as well as cross-sectional associations with cognitive functioning (i.e. neuropsychological assessment-derived domain z-scores and clinical dementia rating (CDR)) using unadjusted regression models. As a frame of reference, regression analyses were repeated with conventional SVD metrics, adjusted for age and sex.
Results
Mean baseline age was 67.7 years, 54% were men. TRACE-VCI patients showed a higher SVD burden compared to norm-referenced data. For WMH, 29.1% had WMH percentile scores above the 90th, and 66.8% above the 50th percentile. High lacune burden (NNS scores ≥21) was observed in 16% of TRACE-VCI patients compared to 3% in the Rotterdam Study; for microbleeds, this was 23% versus 6%. Higher WMH percentile scores were significantly associated with worse cognitive performance across all domains (memory, attention and executive functioning, processing speed; all p<0.01) and with increased CDR (OR = 1.27, 95% CI: 1.14-1.42). Lacune and microbleed NNS scores showed no significant associations with cognition. The regression models with just the SVD burden scores by themselves, showed similar associations with cognition as a model with non- referenced WMH volumes combined with age and sex and outperformed Fazekas scores.
Conclusions
Norm-referenced MRI scores enable clinicians to determine the degree of abnormality of an individual patient’s SVD burden according to age and sex. These scores retain their intrinsic association with cognition and are at least as informative as conventional metrics on that aspect.
{"title":"Norm-referenced small vessel disease MRI scores and their association with cognition in patients with vascular cognitive impairment","authors":"Duygu Kilinc , Eline J. Vinke , Wiesje van der Flier , Meike W. Vernooij , Geert Jan Biessels","doi":"10.1016/j.cccb.2025.100474","DOIUrl":"10.1016/j.cccb.2025.100474","url":null,"abstract":"<div><h3>Introduction</h3><div>Age and sex norm-referenced small vessel disease (SVD) MRI scores may provide a more precise and comprehensible individualized indication of the abnormality of SVD burden in a clinical setting. We recently created such referenced data from the population-based Rotterdam Study. Here we assessed the distribution of norm-referenced SVD burden and the relation with cognitive functioning in memory clinic patients with possible vascular cognitive impairment.</div></div><div><h3>Methods</h3><div>830 patients from the TRACE-VCI memory clinic cohort, all with vascular injury on MRI, were included. White matter hyperintensity (WMH) volumes were converted to norm-referenced percentile scores. Lacune and microbleed counts were expressed as “Number Needed to Scan (NNS)”, i.e. 1/ lesion count probabilities in the general population. We assessed the distribution of these norm-referenced SVD scores in the patients, as well as cross-sectional associations with cognitive functioning (i.e. neuropsychological assessment-derived domain z-scores and clinical dementia rating (CDR)) using unadjusted regression models. As a frame of reference, regression analyses were repeated with conventional SVD metrics, adjusted for age and sex.</div></div><div><h3>Results</h3><div>Mean baseline age was 67.7 years, 54% were men. TRACE-VCI patients showed a higher SVD burden compared to norm-referenced data. For WMH, 29.1% had WMH percentile scores above the 90th, and 66.8% above the 50th percentile. High lacune burden (NNS scores ≥21) was observed in 16% of TRACE-VCI patients compared to 3% in the Rotterdam Study; for microbleeds, this was 23% versus 6%. Higher WMH percentile scores were significantly associated with worse cognitive performance across all domains (memory, attention and executive functioning, processing speed; all p<0.01) and with increased CDR (OR = 1.27, 95% CI: 1.14-1.42). Lacune and microbleed NNS scores showed no significant associations with cognition. The regression models with just the SVD burden scores by themselves, showed similar associations with cognition as a model with non- referenced WMH volumes combined with age and sex and outperformed Fazekas scores.</div></div><div><h3>Conclusions</h3><div>Norm-referenced MRI scores enable clinicians to determine the degree of abnormality of an individual patient’s SVD burden according to age and sex. These scores retain their intrinsic association with cognition and are at least as informative as conventional metrics on that aspect.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100474"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796568","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}
Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. While conventional MRI markers (e.g., white matter hyperintensities, lacunes) reflect late-stage pathology, diffusion MRI can detect earlier microstructural tissue alterations. The diffusion MRI marker "peak width of skeletonized mean diffusivity" (PSMD) has been widely used in SVD research. We introduce PSMD-2, a new version optimised for longitudinal studies such as clinical trials. Key improvements (Fig.1) include (1) skeletonization using free-water corrected diffusion maps, (2) reduced cerebrospinal fluid (CSF) contamination through an improved skeleton mask and free water-based CSF elimination, (3) creation of a within-subject template with a unified white matter skeleton across timepoints, and (4) support for multiple diffusion metrics (e.g., mean diffusivity, free water).
Methods
PSMD-2 was developed using data from 120 CADASIL patients of the DiViNAS study (3T, Philips, 2-year follow-up). Validation was performed in two independent cohorts: 17 CADASIL patients from the VASCAMY study (3T, Siemens, 18-month follow-up) and 72 patients with sporadic SVD from the SCANS study (1.5T, GE, 2-year follow-up). We benchmarked PSMD-2 against the original PSMD by estimating required sample sizes for a hypothetical clinical trial (power=80%, α=0.05, mean change=30%). Instrumental validation in MarkVCID involved assessment of scan-rescan repeatability in 43 sporadic SVD patients who underwent two MRI scans within 14 days, as well as inter-scanner reproducibility in 17 sporadic SVD patients scanned on three different 3 T MRI scanners (Philips Achieva, Siemens Trio, Siemens Prisma).
Results
PSMD-2 consistently tracked disease progression in all cohorts. Compared to the original PSMD method, PSMD-2 reduced required sample sizes by 24.3% (DiViNAS), 31.0% (VASCAMY), and 18.6% (SCANS). Instrumental validation demonstrated excellent repeatability for all assessed markers (ICC>0.95), with PSMD-2 showing superior reproducibility across scanners (ICC≤0.92) compared to the original PSMD (ICC=0.76).
Conclusions
PSMD-2 improves sensitivity to longitudinal change in SVD-related white matter injury and improves statistical power in clinical trials. Its robust longitudinal design, excellent repeatability, and superior reproducibility position PSMD-2 as a compelling surrogate endpoint candidate for clinical trials targeting SVD. PSMD-2 will be made freely available to the community.
{"title":"PSMD-2: A Longitudinal Diffusion MRI Marker for Monitoring Cerebral Small Vessel Disease Progression","authors":"Dewenter , Gesierich , Lesnik Oberstein , Rutten , Gravesteijn , Kopczak , Franzmeier , Tozer , Markus , Duering","doi":"10.1016/j.cccb.2025.100423","DOIUrl":"10.1016/j.cccb.2025.100423","url":null,"abstract":"<div><h3>Introduction</h3><div>Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. While conventional MRI markers (e.g., white matter hyperintensities, lacunes) reflect late-stage pathology, diffusion MRI can detect earlier microstructural tissue alterations. The diffusion MRI marker \"peak width of skeletonized mean diffusivity\" (PSMD) has been widely used in SVD research. We introduce PSMD-2, a new version optimised for longitudinal studies such as clinical trials. Key improvements (Fig.1) include (1) skeletonization using free-water corrected diffusion maps, (2) reduced cerebrospinal fluid (CSF) contamination through an improved skeleton mask and free water-based CSF elimination, (3) creation of a within-subject template with a unified white matter skeleton across timepoints, and (4) support for multiple diffusion metrics (e.g., mean diffusivity, free water).</div></div><div><h3>Methods</h3><div>PSMD-2 was developed using data from 120 CADASIL patients of the DiViNAS study (3T, Philips, 2-year follow-up). Validation was performed in two independent cohorts: 17 CADASIL patients from the VASCAMY study (3T, Siemens, 18-month follow-up) and 72 patients with sporadic SVD from the SCANS study (1.5T, GE, 2-year follow-up). We benchmarked PSMD-2 against the original PSMD by estimating required sample sizes for a hypothetical clinical trial (power=80%, α=0.05, mean change=30%). Instrumental validation in MarkVCID involved assessment of scan-rescan repeatability in 43 sporadic SVD patients who underwent two MRI scans within 14 days, as well as inter-scanner reproducibility in 17 sporadic SVD patients scanned on three different 3 T MRI scanners (Philips Achieva, Siemens Trio, Siemens Prisma).</div></div><div><h3>Results</h3><div>PSMD-2 consistently tracked disease progression in all cohorts. Compared to the original PSMD method, PSMD-2 reduced required sample sizes by 24.3% (DiViNAS), 31.0% (VASCAMY), and 18.6% (SCANS). Instrumental validation demonstrated excellent repeatability for all assessed markers (ICC>0.95), with PSMD-2 showing superior reproducibility across scanners (ICC≤0.92) compared to the original PSMD (ICC=0.76).</div></div><div><h3>Conclusions</h3><div>PSMD-2 improves sensitivity to longitudinal change in SVD-related white matter injury and improves statistical power in clinical trials. Its robust longitudinal design, excellent repeatability, and superior reproducibility position PSMD-2 as a compelling surrogate endpoint candidate for clinical trials targeting SVD. PSMD-2 will be made freely available to the community.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100423"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796710","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 : 2025-01-01DOI: 10.1016/j.cccb.2025.100481
Dalal Alasousi , Kawthar Braysh , Leora D'Souza , Dana Altarrah , Fawaz Alzaid , Mohammed Al-Onaizi
Introduction
Type 2 diabetes (T2D) is increasingly recognized as a contributor to vascular cognitive impairment through mechanisms involving chronic metabolic dysfunction, microvascular damage, and neuroinflammation. The db/db mouse model recapitulates key features of diabetic vasculopathy, including cerebrovascular dysfunction and cognitive decline. ARA 290, a non-erythropoietic analogue of erythropoietin (EPO), has shown promise in reducing vascular inflammation and promoting neuroprotection in Alzheimer’s disease (AD), yet its potential to ameliorate vascular cognitive impairment in T2D remains untested. Here, we aimed to evaluate whether ARA 290 improves cognitive performance in db/db mice, with a focus on visuospatial learning and cognitive flexibility—domains often compromised by vascular pathology in diabetes.
Methods
Male db/db mice (n = 9) and lean controls (n = 10) were tested using the touchscreen-based Pairwise Visual Discrimination (PVD) task to assess visuospatial learning (Acquisition 1) and cognitive flexibility through contingency reversal (Reversal 1). Following baseline testing, mice received ARA 290 (0.7 nmol/kg), and were retested (Acquisition 2 and Reversal 2). Outcome measures included trials to criterion, number of errors, correction trials, and response latencies. Statistical analysis involved Student’s t-tests and repeated measures ANOVA.
Results
db/db mice demonstrated mild impairments in visuospatial acquisition and significant deficits in reversal learning, consistent with impaired cognitive flexibility due to diabetic vascular pathology. ARA 290 administration did not yield significant improvements in any cognitive domain tested in either group.
Conclusions
Our findings support the notion that T2D impairs specific cognitive domains via vascular mechanisms. Although ARA 290 shows neuroprotective efficacy in AD, it did not improve cognition in this model of diabetic vasculopathy, underscoring the need for disease-specific interventions targeting vascular contributions to cognitive impairment.
{"title":"Exploring the Efficacy of the Non-Erythropoietic Peptide ARA 290 on Visuospatial Learning and Cognitive Flexibility in a Mouse Model of Diabetic Vasculopathy","authors":"Dalal Alasousi , Kawthar Braysh , Leora D'Souza , Dana Altarrah , Fawaz Alzaid , Mohammed Al-Onaizi","doi":"10.1016/j.cccb.2025.100481","DOIUrl":"10.1016/j.cccb.2025.100481","url":null,"abstract":"<div><h3>Introduction</h3><div>Type 2 diabetes (T2D) is increasingly recognized as a contributor to vascular cognitive impairment through mechanisms involving chronic metabolic dysfunction, microvascular damage, and neuroinflammation. The db/db mouse model recapitulates key features of diabetic vasculopathy, including cerebrovascular dysfunction and cognitive decline. ARA 290, a non-erythropoietic analogue of erythropoietin (EPO), has shown promise in reducing vascular inflammation and promoting neuroprotection in Alzheimer’s disease (AD), yet its potential to ameliorate vascular cognitive impairment in T2D remains untested. Here, we aimed to evaluate whether ARA 290 improves cognitive performance in db/db mice, with a focus on visuospatial learning and cognitive flexibility—domains often compromised by vascular pathology in diabetes.</div></div><div><h3>Methods</h3><div>Male db/db mice (n = 9) and lean controls (n = 10) were tested using the touchscreen-based Pairwise Visual Discrimination (PVD) task to assess visuospatial learning (Acquisition 1) and cognitive flexibility through contingency reversal (Reversal 1). Following baseline testing, mice received ARA 290 (0.7 nmol/kg), and were retested (Acquisition 2 and Reversal 2). Outcome measures included trials to criterion, number of errors, correction trials, and response latencies. Statistical analysis involved Student’s t-tests and repeated measures ANOVA.</div></div><div><h3>Results</h3><div>db/db mice demonstrated mild impairments in visuospatial acquisition and significant deficits in reversal learning, consistent with impaired cognitive flexibility due to diabetic vascular pathology. ARA 290 administration did not yield significant improvements in any cognitive domain tested in either group.</div></div><div><h3>Conclusions</h3><div>Our findings support the notion that T2D impairs specific cognitive domains via vascular mechanisms. Although ARA 290 shows neuroprotective efficacy in AD, it did not improve cognition in this model of diabetic vasculopathy, underscoring the need for disease-specific interventions targeting vascular contributions to cognitive impairment.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100481"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796714","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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