Cerebral circulation - cognition and behavior最新文献

{"title":"Advantages and challenges of using arterial spin labelling MRI to monitor cerebral blood flow in multi-centre clinical trials of neurodegenerative disease: Experience from the RADAR study","authors":"Lina Jarutyte ,&nbsp;Jan Petr ,&nbsp;Nicholas Turner ,&nbsp;Patrick G. Kehoe ,&nbsp;Henk-Jan Mutsaerts ,&nbsp;David L. Thomas","doi":"10.1016/j.cccb.2024.100376","DOIUrl":"10.1016/j.cccb.2024.100376","url":null,"abstract":"<div><div>Arterial spin labelling (ASL) enables non-invasive quantification of regional brain perfusion using MRI. ASL was used in the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) multi-centre trial to pilot the assessment of the effects of the anti-hypertension drug losartan on cerebral blood flow (CBF). In the multi-centre setting, disparities in ASL implementation on scanners from different manufacturers lead to inherent differences in measured CBF and its associated parameters (e.g. spatial coefficient of variation (sCoV) of CBF, a proxy of arterial arrival times). In addition, differences in ASL acquisition parameter settings can also affect the measured quantitative perfusion values. In this study, we used data from the RADAR cohort as a case study to evaluate the site-dependent systematic differences of CBF and sCoV, and show that variations in the readout module (2D or 3D) and the post-labelling delay acquisition parameter introduced artifactual group differences. When accounting for this effect in data analysis, we show that it is still possible to combine ASL data across sites to observe the expected relationships between grey matter CBF and cognitive scores. In summary, ASL can provide useful information relating to CBF difference in multi-centre therapeutic trials, but care must be taken in data analysis to account for the inevitable inter-site differences in scanner type and acquisition protocol.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"8 ","pages":"Article 100376"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061234","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}

{"title":"Subclinical vascular risk composites and dementia imaging biomarkers 17–20 years later in the Multi-Ethnic Study of Atherosclerosis (MESA)","authors":"Marc D. Rudolph ,&nbsp;Jordan Tanley ,&nbsp;Jingzhong Ding ,&nbsp;Kiran K. Solingapuram Sai ,&nbsp;Haiying Chen ,&nbsp;Kathleen M. Hayden ,&nbsp;Yongmei Liu ,&nbsp;R. Nick Bryan ,&nbsp;Ilya M. Nasrallah ,&nbsp;Sudipto Dolui ,&nbsp;Mohamad Habes ,&nbsp;José A. Luchsinger ,&nbsp;Robert A. Koeppe ,&nbsp;Susan R. Heckbert ,&nbsp;Suzanne Craft ,&nbsp;Samuel N. Lockhart ,&nbsp;Timothy M. Hughes","doi":"10.1016/j.cccb.2025.100406","DOIUrl":"10.1016/j.cccb.2025.100406","url":null,"abstract":"<div><div>Cardiovascular disease (CVD) risk factors captured in midlife represent potentially modifiable features of CVD, stroke, dementia, and dementia-related neuropathology and are included in dementia risk scores. <em>Subclinical</em> measures of CVD represent degrees of subclinical vascular aging. We hypothesize that subclinical vascular measures associated with dementia may help identify specific structural and functional aspects underlying vascular contributions to cognitive impairment and dementia over and above conventional dementia risk scores. Utilizing a large (<em>n</em> = 1420), racially, ethnically, and regionally diverse group of older adults free from clinical CVD at baseline from the Multi-Ethnic Study of Atherosclerosis (MESA), we assessed relationships between factor composites representing subclinical CVD collected at baseline and neuroimaging biomarkers acquired ∼17–20 years later. Baseline subclinical factors were differentially associated with MRI measures at follow-up. Subclinical composites of arteriosclerosis and atherosclerosis exhibited the strongest associations with brain MRI, including reduced global and hippocampal gray matter volume, greater white matter hyperintensity burden, and to a lesser extent with higher amyloid PET deposition in both unadjusted and adjusted models. Cross-validated prediction models utilizing all subclinical measures demonstrated that baseline subclinical features best predicted MRI measures indexing global and regional gray matter atrophy. Individual measures representing subclinical arteriosclerosis (e.g., small artery elasticity, systemic vascular resistance, carotid distensibility) and subclinical atherosclerosis (e.g., common carotid intimal-media thickness, maximum intimal-media thickness) were most predictive across imaging outcomes assessed. Ultimately, our findings may highlight specific subclinical atherosclerosis and arteriosclerosis vascular pathways consistent with the vascular contributions to cognitive impairment and dementia.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100406"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145415888","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}

{"title":"Targeting biogenic amines to combat Alzheimer’s Disease","authors":"George Sideris-Lampretsas ,&nbsp;Meiting Mai ,&nbsp;David Attwell","doi":"10.1016/j.cccb.2025.100502","DOIUrl":"10.1016/j.cccb.2025.100502","url":null,"abstract":"<div><h3>Introduction</h3><div>Reduction in cerebral blood flow (CBF) is the first clinically detectable symptom of Alzheimer’s Disease (AD) and is sufficient to cause cognitive decline, highlighting its therapeutic potential. To study this, we focus on how neuronal activity regulates local blood flow in the brain capillary network and how this is perturbed in AD (PMID: 31221773). Biogenic amines are well established modulators of CBF, and serotonin (5HT) specifically is inversely correlated with Aβ deposition (PMID: 21873225). Hence, our initial aim was to establish the molecular mechanism by which 5HT regulates flow in physiology, and explore whether this pathway is perturbed in AD.</div></div><div><h3>Methods</h3><div>To address this, we follow a preclinical approach combining experiments on in vitro acute brain slices, with in vivo two-photon brain imaging of anaesthetised mice. To study amyloidosis, we are using the AppNL-G-F mouse model of AD, in which APP with a humanized Aβ region containing three AD-related mutations is knocked in to avoid artefacts associated with APP overexpression.</div></div><div><h3>Results</h3><div>Our preliminary results suggest that in healthy animals, 5HT increases calcium in astrocytes through 5HT2CR which in turn leads to pericyte contraction though the release of vasoactive lipids. To our surprise, AD mice not only show changes in 5HT axon density, but most importantly develop markedly enlarged neuronal processes termed axonal spheroids, whose effect on cortical interstitial 5HT level and circuit functions remains unknown. Similar structures can also be observed in cholinergic, noradrenergic and dopaminergic neurons, which differ dramatically from axonal spheroids in glutamatergic axons, with far more axon swelling closer to the plaque.</div></div><div><h3>Conclusions</h3><div>Conceivably, the peri-plaque environment is strongly dictated by the type of affected axons, and the clinically used acetylcholinesterase and monoamine reuptake inhibitors restore peri-plaque neurotransmitter concentrations in the cortex. We are currently investigating how the presence of cholinergic and monoaminergic axonal spheroids affects local circuit activity, microglial responses and blood flow.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100502"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796628","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}

{"title":"Inflammatory driven remodelling of the brain endothelial glycocalyx","authors":"Anna L Gray,&nbsp;Ingo Schiessl,&nbsp;Adam Greenstein","doi":"10.1016/j.cccb.2025.100499","DOIUrl":"10.1016/j.cccb.2025.100499","url":null,"abstract":"<div><h3>Introduction</h3><div>Leukocyte migration is central to our ability to fight infection. One critical component of the leukocyte recruitment cascade that has been overlooked is the endothelial glycocalyx, composed of a complex network of proteoglycans, glycoproteins, and glycosaminoglycans (GAGs). The glycocalyx lines the luminal surface of blood vessels and in a healthy context precludes interactions between circulating leukocytes and the endothelium. In conditions such as small vessel disease and post-ischemic stroke, leukocyte recruitment into the brain can be excessive and contributes to pathology. The glycocalyx is thought to be remodelled during inflammation to enable leukocyte:endothelial cell interaction, however the details of this process remain unclear. We hypothesise that these modifications contribute significantly to disease mechanisms, driving transendothelial migration of immune cells.</div></div><div><h3>Methods</h3><div>We have established a system to effectively analyse glycocalyx composition and vascular permeability, and to monitor changes in response to inflammatory mediators.</div></div><div><h3>Results</h3><div>We demonstrate that glycocalyx composition differs between vessel types, and comparisons between brain and peripheral vasculature reveal context-dependent variability. These findings suggest that targeted modulation of specific glycocalyx components may be required in a disease-specific manner. Inflammatory challenge significantly increases both vascular permeability and leukocyte adhesion. Additionally, photothrombotic stroke induces substantial disruption of the endothelial glycocalyx and enhances leukocyte recruitment. We have developed an IMARIS image analysis pipeline to quantify glycocalyx thickness.</div></div><div><h3>Conclusions</h3><div>Here we build on the limited knowledge of glycocalyx structure and composition in vivo. We present a reliable technique using chronic cranial window implantation and high resolution intravital imaging, to examine the glycocalyx. This research represents an under-studied biological challenge, with therapeutic significance to a multitude of diseases.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100499"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796570","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}

{"title":"Higher cardiovascular risk measured with SCORE2-OP is associated with lower global cognitive level in older adults","authors":"Malva Hillman,&nbsp;Johan Skoog,&nbsp;Lina Rydén,&nbsp;Ingmar Skoog","doi":"10.1016/j.cccb.2025.100449","DOIUrl":"10.1016/j.cccb.2025.100449","url":null,"abstract":"<div><h3>Introduction</h3><div>Several cardiovascular risk factors, including hypertension and smoking, are also risk factors for dementia. Cardiovascular risk can be measured with different risk scores, like the Systematic Coronary Risk Evaluation 2-Older Persons (SCORE2-OP), which estimates the 10-year percentual risk of fatal or nonfatal cardiovascular events in individuals over the age of 70. This project aims to study whether higher SCORE2-OP is associated with worse cognitive performance.</div></div><div><h3>Methods</h3><div>Participants were drawn from the Gothenburg H70 Birth Cohort Studies (n=1263), aged 70 years at baseline and 75–78 at follow-up. SCORE2-OP was calculated based on geographical risk region, age, sex, diabetes, current smoking, systolic blood pressure, and total and HDL cholesterol, at baseline. Cognitive performance was measured through a cognitive test battery at baseline and follow-up. Z-scores were calculated for ten cognitive tests; the tests were divided into five cognitive domains and averaged to yield a domain score. Finally, the domain scores were averaged to provide a global cognitive score. Linear mixed-effect analyses were conducted wherein by-subject intercept (random effect) and fixed effects (SCORE2-OP, Swedish as first language, post-secondary education, and time-point) were evaluated in their ability to affect cognitive level and change. An interaction term between time and SCORE2-OP was tested in a separate model to study the association between SCORE2-OP and cognitive change. Sensitivity analyses were performed after excluding individuals with cardiovascular disease, dementia, or missing follow-up data.</div></div><div><h3>Results</h3><div>SCORE2-OP was associated with lower global cognitive level (β=-0.016, p≤.001), see Figure 1, but not cognitive decline (interaction term time*SCORE2-OP p =.163). The exclusion of individuals with cardiovascular disease, dementia, and no follow- up did not alter the results.</div></div><div><h3>Conclusions</h3><div>These findings suggest an association between higher cardiovascular risk, measured with SCORE2-OP, and lower global cognitive level but not decline. To further evaluate the relationship between SCORE2-OP and cognitive decline, cognitive performance should be assessed at more time-points with a longer follow-up. Future research should investigate whether associations vary across cognitive domains and to assess potential interactions between cardiovascular risk and neurodegenerative disorders. In summary, the findings indicate that cardiovascular health and cognition are connected, and treating cardiovascular risk factors could be helpful for cognitive health.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100449"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796720","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}

{"title":"Characterization of brain barrier fluorescent reporter mouse models of cerebral amyloid angiopathy","authors":"Urban Deutsch,&nbsp;Britta Engelhardt,&nbsp;Steven T. Proulx,&nbsp;Linh Tran","doi":"10.1016/j.cccb.2025.100491","DOIUrl":"10.1016/j.cccb.2025.100491","url":null,"abstract":"<div><h3>Introduction</h3><div>There is renewed interest in how central nervous system (CNS) fluids and barriers contribute to neurological disorders, including cerebral amyloid angiopathy (CAA). Evidence suggests that impaired clearance of amyloid-β (Aβ) plays a role in CAA formation, highlighting the need to better understand brain fluid clearance mechanisms. Nonetheless, the mechanisms for fluid circulation and solute exchange in the brain remain debated, and many studies overlook the brain’s compartmentalizing barriers. To address this gap, we developed new transgenic mouse models to visualize key CNS barriers.</div></div><div><h3>Methods</h3><div>We have developed two dual-reporter mouse strains: a Vascular reporter (Claudin5-GFP for cerebral vessels, Prox1-tdTom for lymphatics) and a Border reporter (Aqp4-mRuby3 for astrocytic glia limitans, VE-cadherin-GFP for leptomeninges and blood vessels). These two strains were crossed with the ArcAβ transgenic line, yielding two triple- transgenic models of cerebral amyloidosis. We analyzed Aβ deposition at different disease stages and examined solute distribution after parenchymal tracer infusion using ex vivo imaging of decalcified skulls and fixed brains.</div></div><div><h3>Results</h3><div>Aβ deposition patterns and tracer studies revealed multiple drainage pathways that are dependent on the region of the brain and the size of the solute. These include transport along white matter tracts and across the glia limitans—findings that diverge from the popular “glymphatic” model of perivascular bulk flow. Aβ was found to accumulate at the leptomeninges in a pattern that was not always associated with pial blood vessels. The potential links between Aβ accumulation and changes in barrier integrity are under further investigation.</div></div><div><h3>Conclusions</h3><div>Our novel reporter models provide powerful tools to study CNS barriers and solute clearance in CAA. These findings offer new insights into alternative drainage mechanisms besides glymphatic flow. The involvement of each pathway upon the onset of Aβ deposition remains to be elucidated and we speculate that certain types of deposition result from the rerouting of clearance due to the failure of other pathways. Future validation with in vivo imaging techniques, such as two-photon microscopy and synchrotron X-ray imaging, will further elucidate the spatial and functional dynamics of fluid movement in the diseased brain.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100491"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796797","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}

{"title":"A novel amyloid-to-integrin interaction underlies the reduction in brain blood flow in early Alzheimer's disease","authors":"Ella M Hastings ,&nbsp;Katy R Walsh ,&nbsp;Junzhe Zha ,&nbsp;Lowri E Evans ,&nbsp;Thea G E Danby ,&nbsp;Harry A T Pritchard ,&nbsp;Martin J Humphries ,&nbsp;Ingo Schiessl ,&nbsp;Mark T Nelson ,&nbsp;Adam S Greenstein","doi":"10.1016/j.cccb.2025.100486","DOIUrl":"10.1016/j.cccb.2025.100486","url":null,"abstract":"<div><h3>Introduction</h3><div>The reduction in brain blood flow seen in patients with early Alzheimer's disease is a therapeutic target to slow progression. We recently identified Amyloid-β(1-40) (Aβ1-40) as the molecular culprit responsible for this reduction in flow, due to induction of pro-contractile Ca2+ waves within vascular smooth muscle cells (VSMC) of pial arteries, mimicking the phenotype of 18-month old APP23 mice. Here, we present the molecular mechanism by which Aβ1-40 induces this vascular pathology, inviting imminent drug development.</div></div><div><h3>Methods</h3><div>9 month APP23 and WT mice were studied using Laser Speckle Contrast imaging to quantify cerebral blood flow and behaviourally, the Y-maze. Pial arteries from these and 12 week C57Bl6/J mice were studied using pressure myography and high-speed spinning disc confocal microscopy to image VSMC Ca2+ events. Biacore Surface Plasmon Resonance (SPR) and Electron Microscopy quantified Aβ1-40 binding to VSMC integrins.</div></div><div><h3>Results</h3><div>At 9 months of age, APP23 mice showed reduced cerebral blood flow compared with WT mice, although behaviour was equivalent. There was an excess of pathological Ca2+ waves in APP23 mice (APP23: 0.07±0.01 vs WT: 0.026±0.05, p&lt;0.001: waves/cell/s), indicating an Aβ1-40-induced intermediate ‘vascular phenotype’. Aβ1-40 very strongly bound integrins of pial artery VSMC (KD: 2.8E-10M to αVβ5 integrin). A single amino acid substitution within a previously undetected RGD-like domain within Aβ1-40: Aspartate 7 to Alanine 7 (henceforth: Ala-7) prevented binding to αVβ5 integrin (KD: undetectable), although fibril formation remained normal. Similarly, Ala-7, did not induce pathological Ca2+ waves (10nM Aβ1-40: 0.2±0.03 vs 10nM Ala-7: 0.01±0.006, p&lt;0.001: waves/cell/s). Further single point substitutions within Aβ1-40 indicated both intact fibril and preservation of the RGD-like domain were needed for integrin binding and Ca2+ wave initiation.</div><div>Similarly, 10nM Aβ1-40 constricted pial arteries with stable myogenic tone by 10.9±2.07%, significantly greater than Ala7 (2.2±0.95%, p=0.005,) or a scrambled Aβ1-40 peptide (2.2±1.96%, p=0.007). Pre-incubation with Cilengitide, a specific integrin antagonist, prevented both Aβ1-40-induced Ca2+ waves and constriction of the arteries.</div></div><div><h3>Conclusions</h3><div>An RGD-like domain within Aβ1-40 binds VSMC integrins to initiate pro- contractile Ca2+ waves, accounting for reduction in cerebral blood flow. This intermediate phenotype, preceding cognitive dysfunction, is a novel druggable target.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100486"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796927","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}

{"title":"Neurofilament Light and GFAP as prognostic biomarkers of cognitive outcomes after stroke: a 5-year prospective multi-centre cohort study","authors":"Jule Filler ,&nbsp;Marco Duering ,&nbsp;Michael Goertler ,&nbsp;Silke Wunderlich ,&nbsp;Inga Zerr ,&nbsp;Matthias Endres ,&nbsp;Gabor Petzold ,&nbsp;Martin Dichgans ,&nbsp;Steffen Tiedt","doi":"10.1016/j.cccb.2025.100412","DOIUrl":"10.1016/j.cccb.2025.100412","url":null,"abstract":"<div><h3>Introduction</h3><div>Cognitive impairment is a common consequence of stroke, yet early identification of patients at risk remains challenging. Blood-based biomarkers of neuroaxonal and astroglial injury, such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), may improve risk stratification, but evidence on their prognostic value for long-term cognitive outcomes is limited.</div></div><div><h3>Methods</h3><div>We conducted a prospective cohort study of dementia-free patients with ischaemic or haemorrhagic stroke admitted to six German tertiary stroke centres between May 2011 and January 2019 (DEMDAS; NCT01334749). Baseline blood samples were collected at a median of 3 days (IQR 2–5) post-stroke, and plasma NfL and GFAP were measured using the Simoa platform. Neuropsychological assessments were performed at 6, 12, 36, and 60 months. The primary outcome was post-stroke cognitive impairment (PSCI), defined as ≥1 domain &lt;-1.5 SD. Secondary outcomes included global cognitive performance and domain-specific impairments. Associations of baseline biomarkers with outcomes over 5 years were estimated using generalized estimating equations, adjusted for demographics, stroke severity, acute-phase cognition, vascular risk factors, imaging parameters, and time to sampling. We also assessed model improvement and subgroup effects.</div></div><div><h3>Results</h3><div>Among 558 patients with baseline biomarker data, higher NfL was significantly associated with PSCI (OR=1.57, 95% CI 1.28–1.91, p&lt;0.0001), while GFAP was not. NfL also predicted worse global cognitive performance (β=–0.11, 95% CI –0.20 to –0.03, p=0.007) and impairments in the attention (OR=1.90, 1.38–2.60) and executive (OR=1.30, 1.04–1.62) domains. NfL improved model fit for PSCI and cognitive performance beyond clinical predictors, although gains in explained variance and discrimination were modest.</div><div>The prognostic value of NfL was particularly pronounced in patients with poorer performance on acute-phase Montreal Cognitive Assessment (MoCA).</div></div><div><h3>Conclusions</h3><div>Baseline plasma NfL was independently associated with cognitive outcomes over five years after stroke, especially in domains that are commonly affected by vascular pathology. Future studies should explore the benefits of longitudinal NfL monitoring for timely risk stratification and its potential to guide patient selection for clinical trials targeting post-stroke cognitive impairment.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100412"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797091","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}

{"title":"Multi-trait Genome-wide analysis of Vascular Dementia and Related Endophenotypes Reveals Shared Etiology and Novel Genetic Loci","authors":"Jingxian Huang ,&nbsp;Fotios Koskeridis ,&nbsp;Devendra Meena ,&nbsp;Abbas Dehghan ,&nbsp;Ioanna Tzoulaki","doi":"10.1016/j.cccb.2025.100451","DOIUrl":"10.1016/j.cccb.2025.100451","url":null,"abstract":"<div><h3>Introduction</h3><div>Vascular dementia (VaD), the second most common form of dementia after Alzheimer's disease, arises from a complex interplay between genetic predisposition and vascular risk factors. Genome-wide association studies (GWAS) have so far identified only a small number of genetic variants linked to VaD, mainly due to insufficient power and the heterogeneity in disease pathology which cannot be fully captured by single-trait GWAS.</div></div><div><h3>Methods</h3><div>We applied LD Score regression and multi-trait analyses of GWAS (MTAG) to map shared genetic architecture and pleiotropic loci between VaD and related endophenotypes (small-vessel stroke, cerebral infarction and microbleeds, MRI markers of white matter hyperintensities, and extensive perivascular space (PVS) burden). We further performed genetic colocalization and fine mapping to pinpoint potential genetic risk factors with pleiotropic effects shared across VaD, different vascular pathologies of VaD, tissue- specific gene expression, and circulating levels of plasm proteome, in the corresponding risk loci identified through the MTAG.</div></div><div><h3>Results</h3><div>We found that VaD demonstrated moderate genetic correlations with small-vessel stroke (rg = 0.50), mean diffusivity (rg = 0.43), and extensive PVS burden at basal ganglia (PVS-BG; rg = 0.49). Across the pairwise bivariate MTAG, we identified three distinct genetic loci associated with VaD at genome-wide significance level (PMTAG &lt; 5 × 10-8), representing 42 unique signals. Of these, PRDM16 (rs2455132) was a novel locus for VaD. In addition, we identified 33 distinct loci associated with different VaD endophenotypes, and CENPA (rs714447) was identified as a novel locus for PVS-BG (PMTAG = 9.79 × 10-9).</div><div>Genetic colocalization prioritized 15 regions where ≥ 2 phenotypes show evidence of colocalization (posterior probability &gt; 0.5). In 5 of the regions (PRDM16, CENPA, AL662890.1, TCF25, and APOC1-APOE-PVRL2), we found that VaD colocalized with at least one endophenotypes and further with gene expression level. In the novel VaD locus (PRDM16), VaD colocalized with small-vessel stroke and PRDM16-DT expression in tibial artery.</div></div><div><h3>Conclusions</h3><div>Our findings provide novel insights into the understanding of genetic pleiotropy and potential shared mechanisms between VaD and different vascular pathologies captured by endophenotypes, with implications for future prevention and therapeutic strategies.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100451"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797092","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}

{"title":"The role of race or residence on the burden and risk factors for cerebral small vessel disease in individuals with incident stroke or transient ischemic attack","authors":"Oluchi Ekenze ,&nbsp;Russell P. Sawyer ,&nbsp;Liang Niu ,&nbsp;Hugo J. Aparicio ,&nbsp;Sudha Seshadri ,&nbsp;Virginia J. Howard ,&nbsp;George Howard ,&nbsp;Jose R. Romero ,&nbsp;Hyacinth I. Hyacinth","doi":"10.1016/j.cccb.2025.100441","DOIUrl":"10.1016/j.cccb.2025.100441","url":null,"abstract":"<div><h3>Introduction</h3><div>Cerebral small vessel disease (CSVD) is associated with a higher risk of stroke, cognitive impairment, and dementia. We examined the association of race (Black vs. White) and/or residence (stroke belt vs non-stroke belt), with the total or regional brain burden of CSVD markers including cerebral microbleeds, (CMB), enlarged perivascular spaces (ePVS), and white matter hyperintensity volume (WMHV), among participants in the REason for Geographic And Racial Differences in Stroke study.</div></div><div><h3>Methods</h3><div>CMB and ePVS were visually rated using the STRIVE criteria and WMHV was estimated using the unidentified bright object detector software pipeline. Presence or absence of CMB was classified whole brain (any CMB), non-lobar only, lobar only, mixed CMB (non-lobar and lobar) and we recorded total CMB count. ePVS was rated in the basal ganglia (BG) and centrum semiovale (CSO) and classified as high (grade ≥2 in the BG or ≥3 in CSO) or low (grade &lt;2) burden. Exposures were race or residence. Our data analysis used multivariable logistic (for CMB presence/location and ePVS burden), negative binomial (for CMB count), and linear (for WMHV) regression. Models were adjusted for relevant demographic and vascular risk factors, socioeconomic status and APOE (for WMHV analysis) genotype.</div></div><div><h3>Results</h3><div>Our sample sizes are 808 for CMB, 1108 for ePVS, and 1094 for WMHV. Prevalence of CMBs and high ePVS burden in the BG and CSO were 26% and 82 and 67% respectively. Stroke belt residents with CMB and/or high ePVS burden in the BG or CSO were younger compared to non-stroke belt residents. Black participants with CMBs and/or high ePVS burden in the BG or CSO ePVS were also younger compared to White participants irrespective of residence. Overall, Black participants had higher risk of any CMB (1.72, 1.22–2.43), larger WMHV in the whole brain (β=0.36, p&lt;0.001), periventricular (β=0.35, p&lt;0.001) and deep (β=0.42, p&lt;0.001) regions. Irrespective of race, stroke-belt residency was associated with a lower risk of CMB burden and counts. No significant interaction effect was observed.</div></div><div><h3>Conclusions</h3><div>The relationship between race or stroke belt residence and CSVD burden was marker related. Future studies using the overall CSVD burden are ongoing in this population.</div></div>","PeriodicalId":72549,"journal":{"name":"Cerebral circulation - cognition and behavior","volume":"9 ","pages":"Article 100441"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797157","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}