Pub Date : 2025-01-01Epub Date: 2025-11-11DOI: 10.1016/j.cccb.2025.100520
Joakim Ölmestig , Kristian N. Mortensen , Marie B. Thomas , Birgitte Fagerlund , Trevor W. Robbins , Nadia Naveed , Mette M. Nordling , Hanne Christensen , Helle K. Iversen , Mai B. Poulsen , Hartwig R. Siebner , Christina Kruuse
Background
Cerebral small vessel disease (CSVD) is the dominant cause of vascular cognitive impairment and dementia. We aimed to test whether continuous daily treatment with the vasoactive phosphodiesterase 5 inhibitor tadalafil improved cognitive performance in patients with CSVD.
Methods
This is a pre-registered sub-study on cognitive outcomes from the ETLAS-2 trial, a randomized, placebo-controlled, double-blind, parallel study investigating 3 months of daily tadalafil (20 mg) treatment against placebo in patients with CSVD and previous stroke or transient ischemic attack. Outcomes were assessed twice, at baseline and after 3 months of treatment. The primary outcomes were changes in the cognitive domains of processing speed, attention, memory, and executive functions assessed by the Symbol Digit Modalities test, digit span forward, and tests from the computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB).
Results
The per-protocol sub-study analysis comprised 60 participants, 28 of whom received tadalafil and 32 received placebo. Baseline cognitive impairments involved reduced processing speed and impaired visual learning and memory. At follow-up, we found a slower mean simple reaction time in the tadalafil group compared to placebo (28.8 ± 13.8 ms, p = 0.04). There were no differences between groups in any other primary or secondary outcome.
Conclusion
We found no overall difference in cognitive outcomes between groups over 3-month treatment. In the tadalafil group, a slower reaction time in a single test was observed, which may be a spurious finding. A longer treatment time may be required to identify potential effects on cognitive outcomes, which could be secondary to improved blood flow.
背景：脑血管病（CSVD）是血管性认知障碍和痴呆的主要原因。我们的目的是测试持续每日服用血管活性磷酸二酯酶5抑制剂他达拉非是否能改善CSVD患者的认知能力。方法：这是一项预先注册的etas -2试验的认知结局亚研究，etas -2试验是一项随机、安慰剂对照、双盲、平行研究，调查了患有CSVD和既往卒中或短暂性脑缺血发作的患者每日接受他达拉非（20mg）治疗3个月的安慰剂对照。在基线和治疗3个月后对结果进行两次评估。主要结果是在处理速度、注意力、记忆和执行功能的认知领域的变化，这些变化由符号数字模态测试、数字前展和基于计算机的剑桥神经心理测试自动化电池（CANTAB）进行评估。每个方案的子研究分析包括60名参与者，其中28人服用他达拉非，32人服用安慰剂。基线认知障碍包括处理速度降低、视觉学习和记忆受损。在随访中，我们发现他达拉非组的平均简单反应时间比安慰剂组慢（28.8±13.8 ms, p = 0.04）。两组之间在其他主要或次要结果上没有差异。结论治疗3个月后，两组患者的认知功能无明显差异。在他达拉非组中，在单次测试中观察到较慢的反应时间，这可能是一个虚假的发现。可能需要更长的治疗时间来确定对认知结果的潜在影响，这可能是血液流动改善的次要影响。临床试验注册网址：https://www.clinicaltrials.gov，唯一标识符：NCT05173896。
{"title":"Cognitive outcomes after tadalafil treatment in patients with cerebral small vessel disease: ETLAS-2 sub-study","authors":"Joakim Ölmestig , Kristian N. Mortensen , Marie B. Thomas , Birgitte Fagerlund , Trevor W. Robbins , Nadia Naveed , Mette M. Nordling , Hanne Christensen , Helle K. Iversen , Mai B. Poulsen , Hartwig R. Siebner , Christina Kruuse","doi":"10.1016/j.cccb.2025.100520","DOIUrl":"10.1016/j.cccb.2025.100520","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral small vessel disease (CSVD) is the dominant cause of vascular cognitive impairment and dementia. We aimed to test whether continuous daily treatment with the vasoactive phosphodiesterase 5 inhibitor tadalafil improved cognitive performance in patients with CSVD.</div></div><div><h3>Methods</h3><div>This is a pre-registered sub-study on cognitive outcomes from the ETLAS-2 trial, a randomized, placebo-controlled, double-blind, parallel study investigating 3 months of daily tadalafil (20 mg) treatment against placebo in patients with CSVD and previous stroke or transient ischemic attack. Outcomes were assessed twice, at baseline and after 3 months of treatment. The primary outcomes were changes in the cognitive domains of processing speed, attention, memory, and executive functions assessed by the Symbol Digit Modalities test, digit span forward, and tests from the computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB).</div></div><div><h3>Results</h3><div>The per-protocol sub-study analysis comprised 60 participants, 28 of whom received tadalafil and 32 received placebo. Baseline cognitive impairments involved reduced processing speed and impaired visual learning and memory. At follow-up, we found a slower mean simple reaction time in the tadalafil group compared to placebo (28.8 ± 13.8 ms, <em>p</em> = 0.04). There were no differences between groups in any other primary or secondary outcome.</div></div><div><h3>Conclusion</h3><div>We found no overall difference in cognitive outcomes between groups over 3-month treatment. In the tadalafil group, a slower reaction time in a single test was observed, which may be a spurious finding. A longer treatment time may be required to identify potential effects on cognitive outcomes, which could be secondary to improved blood flow.</div></div><div><h3>Clinical trial registration</h3><div>URL: <span><span>https://www.clinicaltrials.gov</span><svg><path></path></svg></span>, Unique identifier: NCT05173896.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100520"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578584","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: 2025-02-11DOI: 10.1016/j.cccb.2025.100378
Arunima Kapoor , Shubir Dutt , Amy Nguyen , Trevor Lohman , Aimée Gaubert , John Paul M. Alitin , Isabel J Sible , Anisa Marshall , Fatemah Shenasa , Allison C Engstrom , David Robert Bradford , Kathleen Rodgers , Daniel A Nation
APOE4 carriers at genetic risk for Alzheimer's disease exhibit early cerebrovascular dysfunction, which may be triggered by endothelial dysfunction. Endothelial progenitor cells (EPCs) represent cell populations involved in promoting angiogenesis and facilitating vascular repair in response to injury. We examined whether elevated EPCs are associated with lower cerebral small vessel disease burden in APOE4 carriers prior to cognitive decline. Independently living older adults (N = 109, mean age = 70.5 years; SD = 7.9; 34.9 % male) free of dementia or clinical stroke underwent brain MRI and venipuncture. Small vessel disease was determined using a validated scale. White matter hyperintensity (WMH) volume was determined using the lesion segmentation toolbox. PBMCs were cultured and EPCs were defined as number of colony forming units in vitro. Regression analysis revealed an association between average number of EPC colonies and lower small vessel disease load (p = .026) and WMH volume (p = .002), in APOE4 carriers. Findings suggest that EPC colony count may indicate activation of mechanisms which protect cerebrovascular function in APOE4 carriers prior to the development of cognitive decline.
{"title":"Endothelial progenitor cells and cerebral small vessel disease in APOE4 carriers","authors":"Arunima Kapoor , Shubir Dutt , Amy Nguyen , Trevor Lohman , Aimée Gaubert , John Paul M. Alitin , Isabel J Sible , Anisa Marshall , Fatemah Shenasa , Allison C Engstrom , David Robert Bradford , Kathleen Rodgers , Daniel A Nation","doi":"10.1016/j.cccb.2025.100378","DOIUrl":"10.1016/j.cccb.2025.100378","url":null,"abstract":"<div><div><em>APOE4</em> carriers at genetic risk for Alzheimer's disease exhibit early cerebrovascular dysfunction, which may be triggered by endothelial dysfunction. Endothelial progenitor cells (EPCs) represent cell populations involved in promoting angiogenesis and facilitating vascular repair in response to injury. We examined whether elevated EPCs are associated with lower cerebral small vessel disease burden in <em>APOE4</em> carriers prior to cognitive decline. Independently living older adults (<em>N</em> = 109, mean age = 70.5 years; SD = 7.9; 34.9 % male) free of dementia or clinical stroke underwent brain MRI and venipuncture. Small vessel disease was determined using a validated scale. White matter hyperintensity (WMH) volume was determined using the lesion segmentation toolbox. PBMCs were cultured and EPCs were defined as number of colony forming units in vitro. Regression analysis revealed an association between average number of EPC colonies and lower small vessel disease load (<em>p</em> = .026) and WMH volume (<em>p</em> = .002), in <em>APOE4</em> carriers. Findings suggest that EPC colony count may indicate activation of mechanisms which protect cerebrovascular function in <em>APOE4</em> carriers prior to the development of cognitive decline.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100378"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419271","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}
Atherosclerosis is a leading contributor to cardiovascular disease and mortality worldwide, influenced by both genetic and environmental factors. Educational attainment, as a key socioeconomic indicator, has been consistently associated with cardiovascular risk in observational studies. However, the causal nature of this relationship remains uncertain. This study aimed to investigate the potential causal association between educational attainment and the risk of atherosclerosis using Mendelian randomization (MR) methods.
Methods
We performed a two-sample MR analysis using genome-wide association study (GWAS) summary statistics. Educational attainment, measured as college completion and years of schooling, was used as the exposure, and atherosclerosis, coronary artery disease, and cerebral atherosclerosis were the outcomes. Causal estimates were obtained using inverse variance weighting (IVW), MR-Egger, and weighted median approaches. Sensitivity analyses, including pleiotropy and heterogeneity tests, were conducted to validate the robustness of the results.
Results
Using the inverse variance weighted (IVW) method, genetically predicted higher educational attainment (college completion) was associated with a lower risk of atherosclerosis (OR = 0.43, 95 % CI: 0.32–0.57, P = 1.79E-08) and coronary artery disease (OR = 0.57, 95 % CI: 0.46–0.71, P = 6.62E-07). Additionally, an inverse association was observed between genetically predicted years of education and coronary artery disease risk (OR = 0.95, 95 % CI: 0.93–0.97, P = 2.85E-06). No significant association was found with cerebral atherosclerosis (P > 0.05). Sensitivity analyses indicated no evidence of horizontal pleiotropy or substantial bias. Although the associations did not reach statistical significance in MR-Egger or weighted mode analyses, the odds ratios remained below 1 across these methods, suggesting consistent protective trends and supporting the robustness of the findings.
Conclusion
Our findings provide genetic evidence supporting a potential causal association between educational attainment and the risk of atherosclerosis, particularly coronary artery disease. These associations likely reflect indirect effects mediated by socioeconomic and behavioral pathways. Future research should investigate the mechanisms underlying these associations and explore how educational inequalities contribute to cardiovascular health disparities.
{"title":"The impact of educational attainment on the risk of three types of atherosclerosis: A two-sample mendelian randomization analysis","authors":"Cong Ding, Haifeng Chen, Chunlan Li, Tianyuan Fang, Guancheng Chen","doi":"10.1016/j.cccb.2025.100403","DOIUrl":"10.1016/j.cccb.2025.100403","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis is a leading contributor to cardiovascular disease and mortality worldwide, influenced by both genetic and environmental factors. Educational attainment, as a key socioeconomic indicator, has been consistently associated with cardiovascular risk in observational studies. However, the causal nature of this relationship remains uncertain. This study aimed to investigate the potential causal association between educational attainment and the risk of atherosclerosis using Mendelian randomization (MR) methods.</div></div><div><h3>Methods</h3><div>We performed a two-sample MR analysis using genome-wide association study (GWAS) summary statistics. Educational attainment, measured as college completion and years of schooling, was used as the exposure, and atherosclerosis, coronary artery disease, and cerebral atherosclerosis were the outcomes. Causal estimates were obtained using inverse variance weighting (IVW), MR-Egger, and weighted median approaches. Sensitivity analyses, including pleiotropy and heterogeneity tests, were conducted to validate the robustness of the results.</div></div><div><h3>Results</h3><div>Using the inverse variance weighted (IVW) method, genetically predicted higher educational attainment (college completion) was associated with a lower risk of atherosclerosis (OR = 0.43, 95 % CI: 0.32–0.57, P = 1.79E-08) and coronary artery disease (OR = 0.57, 95 % CI: 0.46–0.71, P = 6.62E-07). Additionally, an inverse association was observed between genetically predicted years of education and coronary artery disease risk (OR = 0.95, 95 % CI: 0.93–0.97, P = 2.85E-06). No significant association was found with cerebral atherosclerosis (P > 0.05). Sensitivity analyses indicated no evidence of horizontal pleiotropy or substantial bias. Although the associations did not reach statistical significance in MR-Egger or weighted mode analyses, the odds ratios remained below 1 across these methods, suggesting consistent protective trends and supporting the robustness of the findings.</div></div><div><h3>Conclusion</h3><div>Our findings provide genetic evidence supporting a potential causal association between educational attainment and the risk of atherosclerosis, particularly coronary artery disease. These associations likely reflect indirect effects mediated by socioeconomic and behavioral pathways. Future research should investigate the mechanisms underlying these associations and explore how educational inequalities contribute to cardiovascular health disparities.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100403"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145528143","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.2025.100472
Meenakshi Umar, Saifudeen Ismael, Gregory Bix
Introduction
SARS-CoV-2 can cause acute or chronic neurological complications in many COVID-19 patients. These neurological complications are often associated with cerebrovascular dysfunction and metabolic deregulation. In addition, genetic variations in MTHFR, a very common occurrence in the general population, are linked to an increased risk of vascular dementia and Parkinson’s disease and mice deficient in Mthfr exhibit cognitive impairments and cerebrovascular deficits. Therefore, we investigated the combined effect of SARS-CoV-2 infection and Mthfr deficiency on cerebrovascular dysfunction and metabolic dysregulation.
Methods
10-month-old Mthfr± and wild type mice (WT) were administered intranasally with either a mock (PBS) or the mouse-adapted (MA)10 strain of SARS-CoV-2 (1 × 104 PFU). At three days post-infection (3 dpi), the mice were euthanized, and lung and brain tissues were collected for quantitative PCR (qPCR) and histopathological analysis to evaluate markers of blood-brain barrier (BBB) disruption, inflammation, and the dopaminergic system. Plasma samples were processed for untargeted metabolomics analysis.
Results
Mthfr± and WT mice showed similar lung viral titer but no detectable virus in brain. However, qPCR and immunostaining revealed significantly lower levels of ZO-1 (BBB tight junction protein) in the brains of Mthfr±-infected mice. MA10 infection also increased brain IL-1β mRNA and cortical microglia in Mthfr± mice. Metabolomics analysis showed significantly reduced plasma dopamine and sarcosine (metabolites involved in cognitive function), and increased phenylacetyl glutamine (a metabolite associated with heightened platelet responsiveness and atherosclerosis) in Mthfr+/− infected mice. In addition, MA10 infection disrupted the dopaminergic system in Mthfr± mice as marked by significant reduction in tyrosine hydroxylase (TH) level, decreased TH+ dopaminergic neurons, and increased α-synuclein levels in the substantia nigra (SN).
Conclusions
SARS-CoV-2 infection causes experimental BBB disruption, neuroinflammation, dysregulated plasma metabolites as well as impairment in the SN dopaminergic system, particularly in mice with MTHFR deficiency, increasing their risk of cerebrovascular disorders and cognitive deficits. This is the first study to support a clear link between MTHFR deficiency, a common clinical occurrence, and increased risk of post- COVID neurological effects that merits further study.
{"title":"Exacerbated Cerebrovascular Dysfunction and Metabolic Alterations in a Combined Model of Mthfr Deficiency and SARS-CoV-2 Infection","authors":"Meenakshi Umar, Saifudeen Ismael, Gregory Bix","doi":"10.1016/j.cccb.2025.100472","DOIUrl":"10.1016/j.cccb.2025.100472","url":null,"abstract":"<div><h3>Introduction</h3><div>SARS-CoV-2 can cause acute or chronic neurological complications in many COVID-19 patients. These neurological complications are often associated with cerebrovascular dysfunction and metabolic deregulation. In addition, genetic variations in MTHFR, a very common occurrence in the general population, are linked to an increased risk of vascular dementia and Parkinson’s disease and mice deficient in Mthfr exhibit cognitive impairments and cerebrovascular deficits. Therefore, we investigated the combined effect of SARS-CoV-2 infection and Mthfr deficiency on cerebrovascular dysfunction and metabolic dysregulation.</div></div><div><h3>Methods</h3><div>10-month-old Mthfr± and wild type mice (WT) were administered intranasally with either a mock (PBS) or the mouse-adapted (MA)10 strain of SARS-CoV-2 (1 × 104 PFU). At three days post-infection (3 dpi), the mice were euthanized, and lung and brain tissues were collected for quantitative PCR (qPCR) and histopathological analysis to evaluate markers of blood-brain barrier (BBB) disruption, inflammation, and the dopaminergic system. Plasma samples were processed for untargeted metabolomics analysis.</div></div><div><h3>Results</h3><div>Mthfr± and WT mice showed similar lung viral titer but no detectable virus in brain. However, qPCR and immunostaining revealed significantly lower levels of ZO-1 (BBB tight junction protein) in the brains of Mthfr±-infected mice. MA10 infection also increased brain IL-1β mRNA and cortical microglia in Mthfr± mice. Metabolomics analysis showed significantly reduced plasma dopamine and sarcosine (metabolites involved in cognitive function), and increased phenylacetyl glutamine (a metabolite associated with heightened platelet responsiveness and atherosclerosis) in Mthfr+/− infected mice. In addition, MA10 infection disrupted the dopaminergic system in Mthfr± mice as marked by significant reduction in tyrosine hydroxylase (TH) level, decreased TH+ dopaminergic neurons, and increased α-synuclein levels in the substantia nigra (SN).</div></div><div><h3>Conclusions</h3><div>SARS-CoV-2 infection causes experimental BBB disruption, neuroinflammation, dysregulated plasma metabolites as well as impairment in the SN dopaminergic system, particularly in mice with MTHFR deficiency, increasing their risk of cerebrovascular disorders and cognitive deficits. This is the first study to support a clear link between MTHFR deficiency, a common clinical occurrence, and increased risk of post- COVID neurological effects that merits further study.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100472"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796572","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.2025.100418
Wei Ying Tan , Xiangyuan Huang , Jiannan Huang , Caroline Robert , Jiangbo Cui , Christopher Chen , Saima Hilal
Introduction
Cerebrovascular disease (CeVD) and cognitive impairment risk factors contribute to cognitive decline but the role of brain age gap (BAG) in mediating this relationship remains unclear, especially in Southeast Asian populations. This study investigated the influence of cognitive impairment risk factors on cognition and examined how BAG mediates this relationship, particularly in individuals with varying CeVD burden.
Methods
This cross-sectional study analyzed Singaporean community and memory clinic participants. Cognitive impairment risk factors were assessed using the Cognitive Impairment Scoring System (CISS), encompassing 11 sociodemographic and vascular factors. Cognition was assessed via a neuropsychological battery, evaluating global cognition and six cognitive domains: executive function, attention, memory, language, visuomotor speed, and visuoconstruction. Brain age was derived from structural MRI features using ensemble machine learning model. Propensity score matching balanced risk profiles between model training and the remaining sample. Structural equation modeling examined the mediation effect of BAG on CISS-cognition relationship, stratified by CeVD burden (high: CeVD+, low: CeVD–).
Results
The study included 1,437 individuals without dementia, with 646 in the matched sample (mean age 66.4±6.0 years, 47% female, 60% with no cognitive impairment).
Higher CISS was consistently associated with poorer cognitive performance across all domains, with the strongest negative associations in visuomotor speed (β=-2.70, p<0.001) and visuoconstruction (β=-3.02, p<0.001). Among CeVD+ group, BAG significantly mediated the relationship between CISS and global cognition (proportion mediated: 19.95%, p=0.01), with the strongest mediation effects in executive function (34.1%, p=0.03) and language (26.6%, p=0.008). BAG also mediated the relationship between CISS and memory (21.1%) and visuoconstruction (14.4%) in the CeVD+ group but these effects diminished after statistical adjustments.
Conclusions
Our findings suggest that BAG is a key intermediary linking cognitive impairment risk factors to cognitive function, particularly in individuals with high CeVD burden. This mediation effect is domain-specific, with executive function, language, and visuoconstruction being the most vulnerable to accelerated brain aging. Limitations of this study include the cross-sectional design, limiting causal inference, and the focus on Southeast Asian populations, limiting generalizability. Future longitudinal studies should verify these relationships and explore additional factors not captured in our model.
{"title":"The Role of Brain Age Gap as a Mediator in the Relationship between Cognitive Impairment Risk Factors and Cognition","authors":"Wei Ying Tan , Xiangyuan Huang , Jiannan Huang , Caroline Robert , Jiangbo Cui , Christopher Chen , Saima Hilal","doi":"10.1016/j.cccb.2025.100418","DOIUrl":"10.1016/j.cccb.2025.100418","url":null,"abstract":"<div><h3>Introduction</h3><div>Cerebrovascular disease (CeVD) and cognitive impairment risk factors contribute to cognitive decline but the role of brain age gap (BAG) in mediating this relationship remains unclear, especially in Southeast Asian populations. This study investigated the influence of cognitive impairment risk factors on cognition and examined how BAG mediates this relationship, particularly in individuals with varying CeVD burden.</div></div><div><h3>Methods</h3><div>This cross-sectional study analyzed Singaporean community and memory clinic participants. Cognitive impairment risk factors were assessed using the Cognitive Impairment Scoring System (CISS), encompassing 11 sociodemographic and vascular factors. Cognition was assessed via a neuropsychological battery, evaluating global cognition and six cognitive domains: executive function, attention, memory, language, visuomotor speed, and visuoconstruction. Brain age was derived from structural MRI features using ensemble machine learning model. Propensity score matching balanced risk profiles between model training and the remaining sample. Structural equation modeling examined the mediation effect of BAG on CISS-cognition relationship, stratified by CeVD burden (high: CeVD+, low: CeVD–).</div></div><div><h3>Results</h3><div>The study included 1,437 individuals without dementia, with 646 in the matched sample (mean age 66.4±6.0 years, 47% female, 60% with no cognitive impairment).</div><div>Higher CISS was consistently associated with poorer cognitive performance across all domains, with the strongest negative associations in visuomotor speed (β=-2.70, p<0.001) and visuoconstruction (β=-3.02, p<0.001). Among CeVD+ group, BAG significantly mediated the relationship between CISS and global cognition (proportion mediated: 19.95%, p=0.01), with the strongest mediation effects in executive function (34.1%, p=0.03) and language (26.6%, p=0.008). BAG also mediated the relationship between CISS and memory (21.1%) and visuoconstruction (14.4%) in the CeVD+ group but these effects diminished after statistical adjustments.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that BAG is a key intermediary linking cognitive impairment risk factors to cognitive function, particularly in individuals with high CeVD burden. This mediation effect is domain-specific, with executive function, language, and visuoconstruction being the most vulnerable to accelerated brain aging. Limitations of this study include the cross-sectional design, limiting causal inference, and the focus on Southeast Asian populations, limiting generalizability. Future longitudinal studies should verify these relationships and explore additional factors not captured in our model.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100418"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796647","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.2025.100448
Maede Sadat Etesami, Knut Hestad Ramune Grambaite
Introduction
The Norwegian COgnitive impairment After STroke (Nor-COAST) study investigates the prevalence and progression of psychiatric symptoms in stroke survivors over a 36-month period. This abstract presents descriptive and longitudinal findings from assessments conducted at 3, 18, and 36 months post-stroke.
Methods
A total of 815 stroke patients (mean age = 73.5 years; 55.1% male) were enrolled in a prospective multicenter cohort study. Psychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) and the Hospital Anxiety and Depression Scale (HADS). The NPI-Q measured the presence and severity of 12 symptom domains including delusions, apathy, depression, and nighttime behavioral disturbances. HADS provided both continuous and categorical scores for anxiety and depression, based on a clinical cut-off of 8. Reductions in symptom prevalence were measured across timepoints using categorical frequencies. Chi-square tests were applied to determine whether the observed changes were statistically significant.
Results
At baseline, 36.6% of participants lived alone, 42.5% had never smoked, and 85.5% abstained from alcohol. At 3 months, the most frequently reported symptoms were nighttime behavioral disturbances (19.4%), depressive symptoms (19.1%), apathy (13.5%), and anxiety (12.3%). The proportion of participants with at least one psychiatric symptom decreased from 46.3% at 3 months to 39.5% at 36 months. The percentage of individuals above the HADS threshold for anxiety declined from 58.2% to 39.3%, and for depression from 59.4% to 38.8%. NPI-Q severity scores followed a non-linear trajectory: 2.92 at 3 months, rising to 3.43 at 18 months, then returning to 2.94 at 36 months. However, none of these reductions were statistically significant (p > 0.83 for all).
Conclusions
Psychiatric symptoms are common in the aftermath of stroke, especially in the early recovery phase. While there is a general reduction in symptom burden over time, a considerable proportion of stroke survivors—approximately 40%—continue to experience symptoms up to three years post-stroke. These findings emphasize the importance of integrating long-term psychological assessment and support into stroke rehabilitation programs.
{"title":"Psychiatric Symptoms After Stroke: Longitudinal Findings from the Nor-COAST Study","authors":"Maede Sadat Etesami, Knut Hestad Ramune Grambaite","doi":"10.1016/j.cccb.2025.100448","DOIUrl":"10.1016/j.cccb.2025.100448","url":null,"abstract":"<div><h3>Introduction</h3><div>The Norwegian COgnitive impairment After STroke (Nor-COAST) study investigates the prevalence and progression of psychiatric symptoms in stroke survivors over a 36-month period. This abstract presents descriptive and longitudinal findings from assessments conducted at 3, 18, and 36 months post-stroke.</div></div><div><h3>Methods</h3><div>A total of 815 stroke patients (mean age = 73.5 years; 55.1% male) were enrolled in a prospective multicenter cohort study. Psychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) and the Hospital Anxiety and Depression Scale (HADS). The NPI-Q measured the presence and severity of 12 symptom domains including delusions, apathy, depression, and nighttime behavioral disturbances. HADS provided both continuous and categorical scores for anxiety and depression, based on a clinical cut-off of 8. Reductions in symptom prevalence were measured across timepoints using categorical frequencies. Chi-square tests were applied to determine whether the observed changes were statistically significant.</div></div><div><h3>Results</h3><div>At baseline, 36.6% of participants lived alone, 42.5% had never smoked, and 85.5% abstained from alcohol. At 3 months, the most frequently reported symptoms were nighttime behavioral disturbances (19.4%), depressive symptoms (19.1%), apathy (13.5%), and anxiety (12.3%). The proportion of participants with at least one psychiatric symptom decreased from 46.3% at 3 months to 39.5% at 36 months. The percentage of individuals above the HADS threshold for anxiety declined from 58.2% to 39.3%, and for depression from 59.4% to 38.8%. NPI-Q severity scores followed a non-linear trajectory: 2.92 at 3 months, rising to 3.43 at 18 months, then returning to 2.94 at 36 months. However, none of these reductions were statistically significant (p > 0.83 for all).</div></div><div><h3>Conclusions</h3><div>Psychiatric symptoms are common in the aftermath of stroke, especially in the early recovery phase. While there is a general reduction in symptom burden over time, a considerable proportion of stroke survivors—approximately 40%—continue to experience symptoms up to three years post-stroke. These findings emphasize the importance of integrating long-term psychological assessment and support into stroke rehabilitation programs.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100448"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796723","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.2025.100469
Adam Bentvelzen, The VASCOG-2-WSO Criteria Consortium
Introduction
Several sets of diagnostic criteria have been proposed for vascular cognitive impairment and dementia (VCID). The International Society for Vascular Behavioural and Cognitive Disorders (VASCOG) working group published comprehensive operationalised criteria in 2014. Considering subsequent advances in the field, an international expert group was established in 2023 to revise these criteria.
Methods
VASCOG criteria and other published diagnostic guidelines, aided by literature review of recent developments in VCID, were used as reference points for an online Delphi survey (minimum three rounds, ≥ 75% threshold for agreement) aimed at achieving consensus on diagnosis of VCID, including operationalization of criteria and guidance on potential biomarkers. Seventy international experts from diverse regions were invited to participate.
Results
Three survey rounds included 49-54 participants that agreed on VASCOG-2 diagnostic criteria for preclinical, mild and major/dementia levels of vascular cognitive impairment (under the overarching term VCID). Research guidelines, including the use of novel neuroimaging and fluid biomarkers, were also agreed upon. The World Stroke Organisation (WSO) endorsed the criteria, hence named VASCOG-2-WSO. The criteria are accompanied by a harmonised neuropsychological battery and standards for VCID, the VASCOG-2-NP.
Conclusions
The VASCOG-2-WSO criteria update the VASCOG criteria for the diagnosis of VCID, providing operationalisation and additional guidance on potential neuroimaging and fluid biomarkers. VASCOG-2-WSO should provide an international standard for VCID diagnosis, facilitating diagnostic consistency among clinicians and researchers. We will compare the VASCOG-2-WSO criteria to the original VASCOG criteria and other existing criteria, and will report preliminary findings from validating the criteria against neuropathological criteria for cerebrovascular disease.
{"title":"The VASCOG-2-WSO criteria diagnostic criteria for Vascular Cognitive Impairment and Dementia: Introduction, validation and future directions","authors":"Adam Bentvelzen, The VASCOG-2-WSO Criteria Consortium","doi":"10.1016/j.cccb.2025.100469","DOIUrl":"10.1016/j.cccb.2025.100469","url":null,"abstract":"<div><h3>Introduction</h3><div>Several sets of diagnostic criteria have been proposed for vascular cognitive impairment and dementia (VCID). The International Society for Vascular Behavioural and Cognitive Disorders (VASCOG) working group published comprehensive operationalised criteria in 2014. Considering subsequent advances in the field, an international expert group was established in 2023 to revise these criteria.</div></div><div><h3>Methods</h3><div>VASCOG criteria and other published diagnostic guidelines, aided by literature review of recent developments in VCID, were used as reference points for an online Delphi survey (minimum three rounds, ≥ 75% threshold for agreement) aimed at achieving consensus on diagnosis of VCID, including operationalization of criteria and guidance on potential biomarkers. Seventy international experts from diverse regions were invited to participate.</div></div><div><h3>Results</h3><div>Three survey rounds included 49-54 participants that agreed on VASCOG-2 diagnostic criteria for preclinical, mild and major/dementia levels of vascular cognitive impairment (under the overarching term VCID). Research guidelines, including the use of novel neuroimaging and fluid biomarkers, were also agreed upon. The World Stroke Organisation (WSO) endorsed the criteria, hence named VASCOG-2-WSO. The criteria are accompanied by a harmonised neuropsychological battery and standards for VCID, the VASCOG-2-NP.</div></div><div><h3>Conclusions</h3><div>The VASCOG-2-WSO criteria update the VASCOG criteria for the diagnosis of VCID, providing operationalisation and additional guidance on potential neuroimaging and fluid biomarkers. VASCOG-2-WSO should provide an international standard for VCID diagnosis, facilitating diagnostic consistency among clinicians and researchers. We will compare the VASCOG-2-WSO criteria to the original VASCOG criteria and other existing criteria, and will report preliminary findings from validating the criteria against neuropathological criteria for cerebrovascular disease.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100469"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796812","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.2025.100424
Oriane Marguet , Sanne van Winden , Yutong Chen , Lupei Cai , Marnix Maas , Anja van der Kolk , Anil Tuladhar , Daniel Tozer , Frank-Erik de Leeuw , Hugh S Markus
Introduction
Glymphatic failure is suggested to play a key role in many neurological conditions including cerebral small vessel disease (SVD). Preclinical studies have associated reduced fluid flow with enlarged perivascular spaces (PVS) in animal models of SVD. Direct measurement of glymphatic function requires intrathecal injection of contrast agents which is challenging in human research studies. However, non-invasive MRI techniques are now available to provide information on CSF dynamics. These include enlarged PVS (possibly reflecting waste accumulation), DTI-ALPS (a proxy measure of fluid flow alongside PVS), and choroid plexus volume (which might enlarge as compensation for poor flow). We examined whether these markers correlated with SVD severity.
Methods
We recruited 201 patients with symptomatic SVD defined as lacunar stroke, and/or cognitive impairment, and/or gait disorder with as a lacune seen on MRI from two sites in Cambridge and Nijmegen. Participants underwent a 3T-MRI scan. We segmented white matter hyperintensities (WMH) and counted cerebral microbleeds. We obtained PSMD from diffusion tensor imaging. We segmented PVS with an automatic algorithm and obtained the ratio of PVS volume in basal ganglia and in cerebral white matter per tissue volume. We segmented choroid plexuses with an automatic algorithm followed by manual correction and adjusted for intracranial volume. We obtained DTI-ALPS from diffusion tensor imaging and controlled for PSMD to control for any contribution of mean diffusivity to the DTI-ALPS signal. We conducted correlations or t-tests between markers of SVD severity (WMH volume) and CSF markers.
Results
DTI-ALPS associated with WMH volume (rs=-0.72, p<0.001) and presence of microbleeds (p<0.001). The PVS/basal ganglia ratio associated with WMH volume (rs=0.19, p=0.007) and presence of microbleeds (p=0.04). We found no relationship between SVD severity and choroid plexus volumes, nor with the PVS/cerebral white matter ratio.
Conclusions
Two markers of CSF dynamics, DTI-ALPS and the PVS/basal ganglia ratio, correlated with SVD severity. This would be consistent with glymphatic dysfunction playing a role in SVD, although longitudinal studies are required to see if these markers predict SVD progression.
{"title":"Is there a relationship between MRI markers of glymphatic dysfunction and cerebral small vessel disease severity?","authors":"Oriane Marguet , Sanne van Winden , Yutong Chen , Lupei Cai , Marnix Maas , Anja van der Kolk , Anil Tuladhar , Daniel Tozer , Frank-Erik de Leeuw , Hugh S Markus","doi":"10.1016/j.cccb.2025.100424","DOIUrl":"10.1016/j.cccb.2025.100424","url":null,"abstract":"<div><h3>Introduction</h3><div>Glymphatic failure is suggested to play a key role in many neurological conditions including cerebral small vessel disease (SVD). Preclinical studies have associated reduced fluid flow with enlarged perivascular spaces (PVS) in animal models of SVD. Direct measurement of glymphatic function requires intrathecal injection of contrast agents which is challenging in human research studies. However, non-invasive MRI techniques are now available to provide information on CSF dynamics. These include enlarged PVS (possibly reflecting waste accumulation), DTI-ALPS (a proxy measure of fluid flow alongside PVS), and choroid plexus volume (which might enlarge as compensation for poor flow). We examined whether these markers correlated with SVD severity.</div></div><div><h3>Methods</h3><div>We recruited 201 patients with symptomatic SVD defined as lacunar stroke, and/or cognitive impairment, and/or gait disorder with as a lacune seen on MRI from two sites in Cambridge and Nijmegen. Participants underwent a 3T-MRI scan. We segmented white matter hyperintensities (WMH) and counted cerebral microbleeds. We obtained PSMD from diffusion tensor imaging. We segmented PVS with an automatic algorithm and obtained the ratio of PVS volume in basal ganglia and in cerebral white matter per tissue volume. We segmented choroid plexuses with an automatic algorithm followed by manual correction and adjusted for intracranial volume. We obtained DTI-ALPS from diffusion tensor imaging and controlled for PSMD to control for any contribution of mean diffusivity to the DTI-ALPS signal. We conducted correlations or t-tests between markers of SVD severity (WMH volume) and CSF markers.</div></div><div><h3>Results</h3><div>DTI-ALPS associated with WMH volume (rs=-0.72, p<0.001) and presence of microbleeds (p<0.001). The PVS/basal ganglia ratio associated with WMH volume (rs=0.19, p=0.007) and presence of microbleeds (p=0.04). We found no relationship between SVD severity and choroid plexus volumes, nor with the PVS/cerebral white matter ratio.</div></div><div><h3>Conclusions</h3><div>Two markers of CSF dynamics, DTI-ALPS and the PVS/basal ganglia ratio, correlated with SVD severity. This would be consistent with glymphatic dysfunction playing a role in SVD, although longitudinal studies are required to see if these markers predict SVD progression.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100424"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796799","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.2025.100466
Minowoo Lee , Juneyoung Lee , Hee-Joon Bae
Introduction
Stroke survivors often face significant functional and cognitive impairments impacting their quality of life. Existing outcome measures, such as the modified Rankin Scale (mRS), inadequately capture cognitive aspects of recovery. This study aims to develop a comprehensive Brain Health Outcome Scale (BHOS) integrating both functional and cognitive assessments to address this critical gap.
Methods
Clinical data were drawn from the prospective stroke registry of two hospitals, involving 1,678 patients assessed with mRS, the Korean version of Mini-Mental State Examination (K-MMSE), and the Korean version of Instrumental Activities of Daily Living (K- IADL) scores. BHOS was created using a structured polyomino-based approach. A 24-cell grid was constructed by combining six groups derived from mRS scores (0 to 5, totaling six groups) and four standardized cognitive groups from K-MMSE scores using Z-scores (normal [-1≤Z], mild [-2≤Z<-1], moderate [-3≤Z<-2], severe [Z<-3]). Specific proximity and connectivity rules ensured each group comprised two to six adjacent squares, including permitted diagonal arrangements. Polyomino theory identified 110 candidate shapes, including dominoes, trominos, tetrominos, pentominos, hexominos, and diagonal configurations. Fifty-nine shapes anchored at the top-left corner yielded 408,500 unique configurations after redundancy reamoval. Cluster analysis using Welch’s F-statistic optimized intra-cluster homogeneity and inter-cluster differences in K-IADL scores in each group, refining the BHOS groupings
Results
From 408,500 configurations, the top 20 with the highest Welch’s F-statistic scores were selected. Among these, optimal grouping systems demonstrated clear differentiation regarding K-IADL scores, with no overlaps in their respective 95% confidence intervals. Furthermore, the selected configurations showed a consistent sequential ordering of groups from the top-left to the bottom-right areas of the grid, enhancing interpretability and practical utility.
Conclusions
The developed BHOS successfully integrates cognitive and functional measures, offering clear differentiation and intuitive interpretation of post-stroke brain health outcomes. Future studies are planned to evaluate whether BHOS scores correlate more closely with long-term outcomes including mortality, institutionalization, incident dementia and medical costs, compared to traditional measures such as mRS and K-MMSE.
{"title":"Development of the Brain Health Outcome Scale: A Polyomino-Based Integration of Functional and Cognitive Assessments After Stroke","authors":"Minowoo Lee , Juneyoung Lee , Hee-Joon Bae","doi":"10.1016/j.cccb.2025.100466","DOIUrl":"10.1016/j.cccb.2025.100466","url":null,"abstract":"<div><h3>Introduction</h3><div>Stroke survivors often face significant functional and cognitive impairments impacting their quality of life. Existing outcome measures, such as the modified Rankin Scale (mRS), inadequately capture cognitive aspects of recovery. This study aims to develop a comprehensive Brain Health Outcome Scale (BHOS) integrating both functional and cognitive assessments to address this critical gap.</div></div><div><h3>Methods</h3><div>Clinical data were drawn from the prospective stroke registry of two hospitals, involving 1,678 patients assessed with mRS, the Korean version of Mini-Mental State Examination (K-MMSE), and the Korean version of Instrumental Activities of Daily Living (K- IADL) scores. BHOS was created using a structured polyomino-based approach. A 24-cell grid was constructed by combining six groups derived from mRS scores (0 to 5, totaling six groups) and four standardized cognitive groups from K-MMSE scores using Z-scores (normal [-1≤Z], mild [-2≤Z<-1], moderate [-3≤Z<-2], severe [Z<-3]). Specific proximity and connectivity rules ensured each group comprised two to six adjacent squares, including permitted diagonal arrangements. Polyomino theory identified 110 candidate shapes, including dominoes, trominos, tetrominos, pentominos, hexominos, and diagonal configurations. Fifty-nine shapes anchored at the top-left corner yielded 408,500 unique configurations after redundancy reamoval. Cluster analysis using Welch’s F-statistic optimized intra-cluster homogeneity and inter-cluster differences in K-IADL scores in each group, refining the BHOS groupings</div></div><div><h3>Results</h3><div>From 408,500 configurations, the top 20 with the highest Welch’s F-statistic scores were selected. Among these, optimal grouping systems demonstrated clear differentiation regarding K-IADL scores, with no overlaps in their respective 95% confidence intervals. Furthermore, the selected configurations showed a consistent sequential ordering of groups from the top-left to the bottom-right areas of the grid, enhancing interpretability and practical utility.</div></div><div><h3>Conclusions</h3><div>The developed BHOS successfully integrates cognitive and functional measures, offering clear differentiation and intuitive interpretation of post-stroke brain health outcomes. Future studies are planned to evaluate whether BHOS scores correlate more closely with long-term outcomes including mortality, institutionalization, incident dementia and medical costs, compared to traditional measures such as mRS and K-MMSE.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100466"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796800","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.2025.100453
Shirine Moukaled , Vanessa Fonseca , Ileana De Anda-Duran , Jessica G. Woo , Elaine M. Urbina , Ganesh Baliga , Lydia A. Bazzano , David J. Libon
Introduction
Identifying individuals at risk before the onset of cognitive decline requires sensitive subclinical markers. Carotid intima-media thickness (cIMT), particularly at the carotid bulb—a region prone to early atherosclerotic change—has been consistently linked to cardiovascular disease outcomes later in life. Technology-based neurocognitive assessments, such as digital clock drawing tasks (DCT), provide scalable, precise measures of motor-cognitive integration that can capture subtle performance related to subclinical disease. This study investigated whether carotid bulb IMT was associated with performance on DCT in midlife adults.
Methods
We analyzed 168 participants from the Decades Study (mean age 55.5 ± 8.2 years; 80.4% female; 63.7% White, 34.5% Black). Carotid bulb IMT was measured by high- resolution B-mode ultrasound. Cognitive outcomes were derived from Linus Health DCT tasks. COMTotalTime was defined as the total time (seconds) to complete the command clock drawing, and COPTotalTime as the total time to complete the copy clock drawing, both from first pen touch to final lift. Multivariable linear regression models assessed associations of bulb IMT with COMTotalTime and COPTotalTime, adjusting for age, sex, race, hypertension, BMI, and education.
Results
Greater carotid bulb IMT was associated with slower motor-cognitive performance. In fully adjusted models, each unit increase in bulb IMT was linked to longer completion times for both COMTotalTime (β = 0.002, p < 0.05) and COPTotalTime (β = 0.004, p < 0.05). Effect sizes remained robust after adjusting for vascular risk factors, suggesting a specific contribution of subclinical carotid pathology to performance.
Conclusions
Carotid bulb IMT is linked to longer DCT drawing times in midlife, reflecting subtle slowing in motor-cognitive integration. These findings highlight the potential of combining vascular imaging with digital cognitive assessments to identify early vascular- related cognitive risk before cognitive decline is established. Integrating such approaches may improve prevention strategies by targeting at-risk individuals during midlife, when interventions are most likely to be effective.
{"title":"Carotid Bulb Intima-Media Thickness and Digital Clock Drawing in Midlife: Evidence from the DECADE Study","authors":"Shirine Moukaled , Vanessa Fonseca , Ileana De Anda-Duran , Jessica G. Woo , Elaine M. Urbina , Ganesh Baliga , Lydia A. Bazzano , David J. Libon","doi":"10.1016/j.cccb.2025.100453","DOIUrl":"10.1016/j.cccb.2025.100453","url":null,"abstract":"<div><h3>Introduction</h3><div>Identifying individuals at risk before the onset of cognitive decline requires sensitive subclinical markers. Carotid intima-media thickness (cIMT), particularly at the carotid bulb—a region prone to early atherosclerotic change—has been consistently linked to cardiovascular disease outcomes later in life. Technology-based neurocognitive assessments, such as digital clock drawing tasks (DCT), provide scalable, precise measures of motor-cognitive integration that can capture subtle performance related to subclinical disease. This study investigated whether carotid bulb IMT was associated with performance on DCT in midlife adults.</div></div><div><h3>Methods</h3><div>We analyzed 168 participants from the Decades Study (mean age 55.5 ± 8.2 years; 80.4% female; 63.7% White, 34.5% Black). Carotid bulb IMT was measured by high- resolution B-mode ultrasound. Cognitive outcomes were derived from Linus Health DCT tasks. COMTotalTime was defined as the total time (seconds) to complete the command clock drawing, and COPTotalTime as the total time to complete the copy clock drawing, both from first pen touch to final lift. Multivariable linear regression models assessed associations of bulb IMT with COMTotalTime and COPTotalTime, adjusting for age, sex, race, hypertension, BMI, and education.</div></div><div><h3>Results</h3><div>Greater carotid bulb IMT was associated with slower motor-cognitive performance. In fully adjusted models, each unit increase in bulb IMT was linked to longer completion times for both COMTotalTime (β = 0.002, p < 0.05) and COPTotalTime (β = 0.004, p < 0.05). Effect sizes remained robust after adjusting for vascular risk factors, suggesting a specific contribution of subclinical carotid pathology to performance.</div></div><div><h3>Conclusions</h3><div>Carotid bulb IMT is linked to longer DCT drawing times in midlife, reflecting subtle slowing in motor-cognitive integration. These findings highlight the potential of combining vascular imaging with digital cognitive assessments to identify early vascular- related cognitive risk before cognitive decline is established. Integrating such approaches may improve prevention strategies by targeting at-risk individuals during midlife, when interventions are most likely to be effective.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100453"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796928","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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