Pub Date : 2025-01-01Epub Date: 2025-01-09DOI: 10.1016/j.cccb.2025.100377
Yunfei Li, Linus Jönsson
Brain disorders are prevalent across all age groups but particularly in the elderly, highlighting the importance of preserving brain health in ageing populations. There have been few previous studies to address the complete scope of burden of brain disorders, including direct and indirect costs as well as intangible costs from morbidity and mortality. We seek to illustrate the full health and economic impact of brain disorders by leveraging data from previous large-scale epidemiological and health economic studies to estimate the total direct, indirect and intangible cost of brain disorders in 2019. Two alternative methods were used to estimate indirect costs: the human capital (HC) method (data from the CBDE2010 study), and the willingness-to-pay (WTP) per DALY method (data from GBD2019). Less than 10% of the costs of Alzheimer's disease (AD) and other dementias are incurred by the health care system, while Alzheimer's disease and other dementias is the costliest condition using the HC approach and stroke is the costliest condition due to the large number of life-years lost, followed by AD using the WTP approach. Using per-capita GDP as a proxy for WTP, the indirect costs were nearly four times higher compared to the conventional HC approach. We found that Indirect costs of brain disorders outweigh the direct costs for diagnosis, treatment and care even in high-income countries with advanced, universally accessible systems in Europe. There is likely underinvestment in R&D for brain disorders, and health care systems may lack sufficient incentives to invest in their treatment and prevention.
{"title":"The health and economic burden of brain disorders: Consequences for investment in diagnosis, treatment, prevention and R&D","authors":"Yunfei Li, Linus Jönsson","doi":"10.1016/j.cccb.2025.100377","DOIUrl":"10.1016/j.cccb.2025.100377","url":null,"abstract":"<div><div>Brain disorders are prevalent across all age groups but particularly in the elderly, highlighting the importance of preserving brain health in ageing populations. There have been few previous studies to address the complete scope of burden of brain disorders, including direct and indirect costs as well as intangible costs from morbidity and mortality. We seek to illustrate the full health and economic impact of brain disorders by leveraging data from previous large-scale epidemiological and health economic studies to estimate the total direct, indirect and intangible cost of brain disorders in 2019. Two alternative methods were used to estimate indirect costs: the human capital (HC) method (data from the CBDE2010 study), and the willingness-to-pay (WTP) per DALY method (data from GBD2019). Less than 10% of the costs of Alzheimer's disease (AD) and other dementias are incurred by the health care system, while Alzheimer's disease and other dementias is the costliest condition using the HC approach and stroke is the costliest condition due to the large number of life-years lost, followed by AD using the WTP approach. Using per-capita GDP as a proxy for WTP, the indirect costs were nearly four times higher compared to the conventional HC approach. We found that Indirect costs of brain disorders outweigh the direct costs for diagnosis, treatment and care even in high-income countries with advanced, universally accessible systems in Europe. There is likely underinvestment in R&D for brain disorders, and health care systems may lack sufficient incentives to invest in their treatment and prevention.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100377"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-08-29DOI: 10.1016/j.cccb.2025.100393
Benno Gesierich , Lukas Pirpamer , Dominik S Meier , Michael Amann , Minne N Cerfontaine , Frank-Erik de Leeuw , Pauline Maillard , Sue Moy , Karl G. Helmer , Michael Kühne , Leo H Bonati , Julie W Rutten , Saskia A.J. Lesnik Oberstein , Marco Duering , Alzheimer’s Disease Neuroimaging Initiative
Introduction
White matter hyperintensities (WMH) on MRI are a hallmark of cerebral small vessel disease. Although numerous WMH segmentation tools exist, each presents relevant limitations that can impact their usability. This research aimed to develop, validate, and disseminate a novel WMH segmentation algorithm to address these limitations.
Methods
Using an intentionally heterogeneous dataset, we trained models based on the MD-GRU and nnU-Net deep learning algorithms. The new models were benchmarked in both technical and clinical validation against current state-of-the-art algorithms, utilizing datasets that were not included in the training data. For technical validation in patients, we assessed bias and precision against reference masks, scan-rescan repeatability and inter-scanner reproducibility in data from the MarkVCID consortium. Segmentation performance on 2D data was evaluated using the SWISS-AF dataset. For clinical validation, we determined percent volume change over a two-year follow-up in the DiViNAS study and calculated statistical power to detect treatment effects.
Results
The newly trained algorithms outperformed the benchmarking algorithms, demonstrating better agreement with reference volumes, as well as less bias and higher precision in the repeatability and reproducibility experiments. The nnU-Net algorithm exhibited the highest statistical power for detecting treatment effects, requiring a 41 % smaller sample size than the best-performing benchmarking algorithm.
Conclusion
We developed and systematically validated two novel WMH segmentation algorithms, which demonstrated excellent generalization capabilities. The comprehensive, user-friendly processing pipelines are publicly available as prebuilt software containers and can be applied to a wide range of datasets without re-training or modifications.
{"title":"Technical and clinical validation of a novel deep learning-based white matter hyperintensity segmentation tool","authors":"Benno Gesierich , Lukas Pirpamer , Dominik S Meier , Michael Amann , Minne N Cerfontaine , Frank-Erik de Leeuw , Pauline Maillard , Sue Moy , Karl G. Helmer , Michael Kühne , Leo H Bonati , Julie W Rutten , Saskia A.J. Lesnik Oberstein , Marco Duering , Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1016/j.cccb.2025.100393","DOIUrl":"10.1016/j.cccb.2025.100393","url":null,"abstract":"<div><h3>Introduction</h3><div>White matter hyperintensities (WMH) on MRI are a hallmark of cerebral small vessel disease. Although numerous WMH segmentation tools exist, each presents relevant limitations that can impact their usability. This research aimed to develop, validate, and disseminate a novel WMH segmentation algorithm to address these limitations.</div></div><div><h3>Methods</h3><div>Using an intentionally heterogeneous dataset, we trained models based on the MD-GRU and nnU-Net deep learning algorithms. The new models were benchmarked in both technical and clinical validation against current state-of-the-art algorithms, utilizing datasets that were not included in the training data. For technical validation in patients, we assessed bias and precision against reference masks, scan-rescan repeatability and inter-scanner reproducibility in data from the MarkVCID consortium. Segmentation performance on 2D data was evaluated using the SWISS-AF dataset. For clinical validation, we determined percent volume change over a two-year follow-up in the DiViNAS study and calculated statistical power to detect treatment effects.</div></div><div><h3>Results</h3><div>The newly trained algorithms outperformed the benchmarking algorithms, demonstrating better agreement with reference volumes, as well as less bias and higher precision in the repeatability and reproducibility experiments. The nnU-Net algorithm exhibited the highest statistical power for detecting treatment effects, requiring a 41 % smaller sample size than the best-performing benchmarking algorithm.</div></div><div><h3>Conclusion</h3><div>We developed and systematically validated two novel WMH segmentation algorithms, which demonstrated excellent generalization capabilities. The comprehensive, user-friendly processing pipelines are publicly available as prebuilt software containers and can be applied to a wide range of datasets without re-training or modifications.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100393"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007668","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.2025.100503
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 : 2025-01-01Epub Date: 2025-12-14DOI: 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 : 2025-01-01Epub Date: 2025-12-14DOI: 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}
Pub Date : 2025-01-01Epub Date: 2025-12-14DOI: 10.1016/j.cccb.2025.100447
Richard N.A. Henson , Richard A.I. Bethlehem , Kamen A. Tsvetanov , Yijin Fang
Introduction
Dementia is a multifactorial neurodegenerative disorder and primary global health concern, marked by progressive cognitive decline. Vascular health, especially blood pressure, is a key modifiable risk factor, yet most risk models focus on systolic blood pressure (SBP), overlooking the dynamic interplay between systolic and diastolic components. Pulse pressure (PP), reflecting the pulsatile component of blood flow, is a more informative vascular indicator of cognitive decline than SBP or mean arterial pressure (MAP), which captures steady-state flow. We hypothesised that PP contributes to dementia risk independent of other vascular factors.
Methods
Using UK Biobank data (N≈500,000), we investigated the associations between PP, MAP, and dementia through cross-sectional analysis using binomial logistic regression and Cox proportional hazards models. Covariates included education, sex, hearing, low- density lipoprotein, depression, traumatic brain injury, physical activity, diabetes, smoking, hypertension, BMI, and alcohol use.
Results
PP and MAP were positively associated with dementia when examined separately. When entered jointly, PP remained significant with a strengthened effect, while MAP reversed direction, suggesting that PP captures unique vascular variance. Adding age to the model substantially attenuated the effect of PP, indicating age-related overlap. An interaction term revealed that the PP-dementia association was stronger at older ages (b=0.052). In fully adjusted models including all covariates, each 10 mmHg increase in PP was associated with a 2.70% increase in dementia odds. The pattern held when MAP was replaced by SBP or total blood pressure (i.e. systolic + diastolic pressure).
Cox models confirmed the predictive value of PP. Both PP and MAP were positively associated with dementia hazard in adjusted single-exposure models. In a joint model, MAP again reversed direction. This directional shift and attenuation with age mirrored the cross- sectional findings. After adjusting for age and MAP and all covariates, each 10 mmHg increase in PP was associated with a 2.50% higher hazard of dementia. An interaction suggested PP’s effect was stronger at younger ages (b=-0.054).
Conclusions
Together, these results highlight pulse pressure as an independent and age- sensitive vascular marker of dementia risk. Despite differences in age interaction, consistent main effects across models support its inclusion in risk stratification to enhance early identification and targeted prevention.
{"title":"Pulse pressure and risk of dementia in UK Biobank","authors":"Richard N.A. Henson , Richard A.I. Bethlehem , Kamen A. Tsvetanov , Yijin Fang","doi":"10.1016/j.cccb.2025.100447","DOIUrl":"10.1016/j.cccb.2025.100447","url":null,"abstract":"<div><h3>Introduction</h3><div>Dementia is a multifactorial neurodegenerative disorder and primary global health concern, marked by progressive cognitive decline. Vascular health, especially blood pressure, is a key modifiable risk factor, yet most risk models focus on systolic blood pressure (SBP), overlooking the dynamic interplay between systolic and diastolic components. Pulse pressure (PP), reflecting the pulsatile component of blood flow, is a more informative vascular indicator of cognitive decline than SBP or mean arterial pressure (MAP), which captures steady-state flow. We hypothesised that PP contributes to dementia risk independent of other vascular factors.</div></div><div><h3>Methods</h3><div>Using UK Biobank data (N≈500,000), we investigated the associations between PP, MAP, and dementia through cross-sectional analysis using binomial logistic regression and Cox proportional hazards models. Covariates included education, sex, hearing, low- density lipoprotein, depression, traumatic brain injury, physical activity, diabetes, smoking, hypertension, BMI, and alcohol use.</div></div><div><h3>Results</h3><div>PP and MAP were positively associated with dementia when examined separately. When entered jointly, PP remained significant with a strengthened effect, while MAP reversed direction, suggesting that PP captures unique vascular variance. Adding age to the model substantially attenuated the effect of PP, indicating age-related overlap. An interaction term revealed that the PP-dementia association was stronger at older ages (b=0.052). In fully adjusted models including all covariates, each 10 mmHg increase in PP was associated with a 2.70% increase in dementia odds. The pattern held when MAP was replaced by SBP or total blood pressure (i.e. systolic + diastolic pressure).</div><div>Cox models confirmed the predictive value of PP. Both PP and MAP were positively associated with dementia hazard in adjusted single-exposure models. In a joint model, MAP again reversed direction. This directional shift and attenuation with age mirrored the cross- sectional findings. After adjusting for age and MAP and all covariates, each 10 mmHg increase in PP was associated with a 2.50% higher hazard of dementia. An interaction suggested PP’s effect was stronger at younger ages (b=-0.054).</div></div><div><h3>Conclusions</h3><div>Together, these results highlight pulse pressure as an independent and age- sensitive vascular marker of dementia risk. Despite differences in age interaction, consistent main effects across models support its inclusion in risk stratification to enhance early identification and targeted prevention.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100447"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796726","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.2025.100433
Eva Birgitte Aamodt , Ingvild Tina Saltvedt , Mona Kristiansen Beyer
Introduction
Allostatic load (AL) is a measure of chronic stress - the “wear and tear” of the body - and has been implicated in many diseases. There is emerging data on the impact of AL on stroke patients. We aimed to investigate the link between AL and cognitive status three months after acute stroke.
Methods
210 stroke survivors (age = 73.1 (10.9), women = 43.3%) were included from the ‘Norwegian Cognitive Impairment After Stroke’ (Nor-COAST) study. Clinical and neurocognitive data were collected three months after the acute stroke. The AL score was derived from 12 variables; metabolic: body mass index, waist-to-hip ratio, hemoglobin A1C (HbA1C), glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and creatinine. Inflammatory: C-reactive protein (CRP). Vascular: Systolic- and diastolic blood pressure, and pulse. Parameters were scored 1 if within the 75th percentile (25th for LDL), resulting in an AL score ranging from 0 to 12. Patients with AL score >4 were considered high AL. Dementia was defined as post-stroke neurocognitive disorder accompanied by dependency in Instrumental Activities of Daily Living (I-ADL), as per DSM-V guidelines. A multivariate logistic regression model was run, accounting for age, sex, years of education, and stroke severity as measured with National Institutes of Health Stroke Scale (NIHSS).
Results
High AL was found in 23.9% and dementia in 24.3% of the participants. We found a significant relationship between high AL and dementia (OR = 2.3, 95% CI [1.0 to 5.2], p = .038) three months post-stroke, with education and stroke severity also being significant contributing factors.
Conclusions
Chronic stress is linked to dementia three months after stroke.
适应负荷（AL）是衡量慢性压力——身体的“磨损”——的一种方法，与许多疾病有关。关于AL对脑卒中患者的影响有新的数据。我们的目的是研究急性脑卒中后三个月AL与认知状态之间的联系。方法纳入“挪威卒中后认知障碍”（Nor-COAST）研究的210名卒中幸存者（年龄 = 73.1(10.9%)，女性 = 43.3%）。急性脑卒中后3个月收集临床和神经认知数据。AL评分由12个变量导出；代谢：身体质量指数、腰臀比、血红蛋白A1C （HbA1C）、葡萄糖、总胆固醇、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）和肌酐。炎症：c反应蛋白（CRP）。血管：收缩压、舒张压、脉搏。如果在第75个百分位数内（LDL为第25个百分位数），则参数得分为1，导致AL评分范围为0至12。AL评分为>；4的患者被认为是高AL。根据DSM-V指南，痴呆被定义为卒中后神经认知障碍伴日常生活工具活动（I-ADL）依赖。采用多变量logistic回归模型，考虑年龄、性别、受教育年限和卒中严重程度（采用美国国立卫生研究院卒中量表（NIHSS）测量）。结果23.9%的人有高AL， 24.3%的人有痴呆。我们发现高AL与痴呆之间存在显著关系（OR = 2.3,95% CI [1.0 ~ 5.2], p = ）。[38]中风后3个月，教育程度和中风严重程度也是重要的影响因素。结论慢性应激与脑卒中后3个月痴呆有关。
{"title":"Chronic Stress is Associated with Dementia Three Months After Stroke","authors":"Eva Birgitte Aamodt , Ingvild Tina Saltvedt , Mona Kristiansen Beyer","doi":"10.1016/j.cccb.2025.100433","DOIUrl":"10.1016/j.cccb.2025.100433","url":null,"abstract":"<div><h3>Introduction</h3><div>Allostatic load (AL) is a measure of chronic stress - the “wear and tear” of the body - and has been implicated in many diseases. There is emerging data on the impact of AL on stroke patients. We aimed to investigate the link between AL and cognitive status three months after acute stroke.</div></div><div><h3>Methods</h3><div>210 stroke survivors (age = 73.1 (10.9), women = 43.3%) were included from the ‘Norwegian Cognitive Impairment After Stroke’ (Nor-COAST) study. Clinical and neurocognitive data were collected three months after the acute stroke. The AL score was derived from 12 variables; metabolic: body mass index, waist-to-hip ratio, hemoglobin A1C (HbA1C), glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and creatinine. Inflammatory: C-reactive protein (CRP). Vascular: Systolic- and diastolic blood pressure, and pulse. Parameters were scored 1 if within the 75th percentile (25th for LDL), resulting in an AL score ranging from 0 to 12. Patients with AL score >4 were considered high AL. Dementia was defined as post-stroke neurocognitive disorder accompanied by dependency in Instrumental Activities of Daily Living (I-ADL), as per DSM-V guidelines. A multivariate logistic regression model was run, accounting for age, sex, years of education, and stroke severity as measured with National Institutes of Health Stroke Scale (NIHSS).</div></div><div><h3>Results</h3><div>High AL was found in 23.9% and dementia in 24.3% of the participants. We found a significant relationship between high AL and dementia (OR = 2.3, 95% CI [1.0 to 5.2], p = .038) three months post-stroke, with education and stroke severity also being significant contributing factors.</div></div><div><h3>Conclusions</h3><div>Chronic stress is linked to dementia three months after stroke.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100433"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796729","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.2025.100481
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}
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 : 2025-01-01Epub Date: 2025-12-14DOI: 10.1016/j.cccb.2025.100413
Misha Ramesh , Royce Shakespeare , Roshan Welikala , Jiri Fajtl , Sarah A. Barman , Anthony P. Khawaja , Paul J. Foster , Alicja R. Rudnicka , Christopher G. Owen
Introduction
Retinal vasculometry (RV) offers a non-invasive window into microvascular health and has emerged as a potential biomarker for neurovascular and cognitive decline. While previous studies have explored RV in relation to cognitive function, the distinct contributions of smaller (<50µm) and larger (≥50µm) width retinal vessels remain unclear. This study investigates the associations between cognitive status and artificial intelligence (AI)-derived RV metrics across the spectrum of retinal vessel calibres.
Methods
Composite cognitive scores (G4) were derived, using principal component analysis, for UK Biobank participants who had completed four cognitive tests (“pairs matching”, “reaction time,” “prospective memory,” and “fluid intelligence”). RV features (width, area, tortuosity, and width-variance) were extracted from retinal images using the Quantitative Analysis of Retinal vessel Topology and siZe (QUARTZ) Deep Learning AI algorithm. Multilevel linear regression models estimated associations between RV measures and G4, adjusting for demographic, socioeconomic, and cardiometabolic covariates, with additional exclusion of participants with self-reported cardiovascular events.
Results
Data from 69,040 (78%) participants (mean age 57 years, 54.5% female) with 124,477 retinal images were included. A one standard deviation increase in G4 was associated with wider arterioles (0.11 µm, 95%CI 0.06, 0.17μm), greater arteriolar tortuosity (0.41%, 95%CI 0.405,0.412%), and increased arteriolar area (0.03mm², 95%CI 0.029,0.039mm²). Similar positive associations were found for venular width (0.48μm, 95%CI 0.35,0.61μm) and area (0.06mm², 95%CI 0.05,0.07mm²), particularly in the 50–59 age group. Conversely, venular tortuosity (-0.577%, 95%CI -0.575, -0.579%) and vessel width-variance were inversely associated with G4. Notably, lower cognitive scores were associated with narrower venules and reduced arteriolar tortuosity, across smaller and larger sized vessels. Arteriolar width, however, showed varied results between different sized vessels. Reductions in vessel area with lower G4 were more pronounced in larger vessels, suggesting vessel size-specific patterns of association.
Conclusions
AI-derived RV features are significantly associated with cognitive performance, reinforcing their potential as non-invasive biomarkers of neurovascular health. The observed differential associations across vessel sizes highlight the importance of analysing both smaller and larger retinal vessels in cognitive and neurodegenerative research. These findings support further exploration of RV metrics as early indicators of cognitive decline and potential tools in dementia risk stratification.
{"title":"Retinal Vasculometry and Cognitive Status: Insights from the UK Biobank","authors":"Misha Ramesh , Royce Shakespeare , Roshan Welikala , Jiri Fajtl , Sarah A. Barman , Anthony P. Khawaja , Paul J. Foster , Alicja R. Rudnicka , Christopher G. Owen","doi":"10.1016/j.cccb.2025.100413","DOIUrl":"10.1016/j.cccb.2025.100413","url":null,"abstract":"<div><h3>Introduction</h3><div>Retinal vasculometry (RV) offers a non-invasive window into microvascular health and has emerged as a potential biomarker for neurovascular and cognitive decline. While previous studies have explored RV in relation to cognitive function, the distinct contributions of smaller (<50µm) and larger (≥50µm) width retinal vessels remain unclear. This study investigates the associations between cognitive status and artificial intelligence (AI)-derived RV metrics across the spectrum of retinal vessel calibres.</div></div><div><h3>Methods</h3><div>Composite cognitive scores (G4) were derived, using principal component analysis, for UK Biobank participants who had completed four cognitive tests (“pairs matching”, “reaction time,” “prospective memory,” and “fluid intelligence”). RV features (width, area, tortuosity, and width-variance) were extracted from retinal images using the Quantitative Analysis of Retinal vessel Topology and siZe (QUARTZ) Deep Learning AI algorithm. Multilevel linear regression models estimated associations between RV measures and G4, adjusting for demographic, socioeconomic, and cardiometabolic covariates, with additional exclusion of participants with self-reported cardiovascular events.</div></div><div><h3>Results</h3><div>Data from 69,040 (78%) participants (mean age 57 years, 54.5% female) with 124,477 retinal images were included. A one standard deviation increase in G4 was associated with wider arterioles (0.11 µm, 95%CI 0.06, 0.17μm), greater arteriolar tortuosity (0.41%, 95%CI 0.405,0.412%), and increased arteriolar area (0.03mm², 95%CI 0.029,0.039mm²). Similar positive associations were found for venular width (0.48μm, 95%CI 0.35,0.61μm) and area (0.06mm², 95%CI 0.05,0.07mm²), particularly in the 50–59 age group. Conversely, venular tortuosity (-0.577%, 95%CI -0.575, -0.579%) and vessel width-variance were inversely associated with G4. Notably, lower cognitive scores were associated with narrower venules and reduced arteriolar tortuosity, across smaller and larger sized vessels. Arteriolar width, however, showed varied results between different sized vessels. Reductions in vessel area with lower G4 were more pronounced in larger vessels, suggesting vessel size-specific patterns of association.</div></div><div><h3>Conclusions</h3><div>AI-derived RV features are significantly associated with cognitive performance, reinforcing their potential as non-invasive biomarkers of neurovascular health. The observed differential associations across vessel sizes highlight the importance of analysing both smaller and larger retinal vessels in cognitive and neurodegenerative research. These findings support further exploration of RV metrics as early indicators of cognitive decline and potential tools in dementia risk stratification.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100413"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796925","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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