Maria Del Carmen Valdes Hernandez

BACKGROUND: White matter hyperintensities (WMHs), the principal imaging manifestation of cerebral small vessel disease, lack an animal model that produces pathology of sufficient magnitude to validate potential therapeutics. We characterized white matter (WM) degeneration in a renovascular hypertension (RVH) rat model, interrogated its mechanism, and tested its relevance in patients. METHODS: RVH was induced by two-kidney, two-clip surgery and assessed by T2-weighted and diffusion MRI, myelin and axonal histology, and blood-brain barrier (BBB) leakage markers. The influence of angiotensin II (Ang II) on barrier function in brain endothelial cells was examined using transendothelial electrical resistance and reactive oxygen species (ROS) assays. Losartan was infused intracerebroventricularly to block brain AT1R (Ang II type 1 receptor) without systemic blood pressure reduction. WMH burden was compared between patients with and without renal artery stenosis, and WMH progression across antihypertensive classes was assessed in the CHALLENGE (Korea), MSS2 (UK), LBC1936 (UK), and SPRINT-MIND-MRI (US) cohorts. RESULTS: Approximately two-thirds of RVH rats developed WMHs that expanded between 7 and 9 weeks, accompanied by reduced fractional anisotropy, demyelination, axonal and mature oligodendrocyte loss, and glial activation. IgG, albumin, and fibrinogen leakage was confined to affected WM. Ang II impaired endothelial barrier function and generated ROS through AT1R. Intracerebroventricular losartan attenuated WM pathology and improved behavior while blood pressure remained comparably elevated. Patients with renal artery stenosis had higher WMH volumes (10.52 versus 6.52 mL; P = 0.035). Angiotensin receptor blocker use was associated with the slowest tertile of annual WMH progression in the Korean cohort (OR, 2.57 [95% CI, 1.20–5.61]) and among White participants in SPRINT-MIND-MRI (OR, 3.52 [95% CI, 1.05–12.29]). CONCLUSIONS: RVH produces prominent ischemic WM degeneration driven by AT1R signaling, identifying a blood pressure–independent therapeutic target with corroborating clinical evidence.

Ageing biomarkers quantify molecular, physiological or functional features that vary between individuals as they age and may improve prediction of health outcomes beyond chronological age. Recently, plasma proteomics have been used to estimate the biological ages of 11 human organs. Although accelerated organ ageing is associated with higher mortality risk, systematic benchmarking against established ageing biomarkers is lacking. Here, we pursued two complementary aims. First, we benchmarked proteomic organ clocks against multimodal ageing biomarkers for associations with 16‐year all‐cause mortality in the Lothian Birth Cohort 1936 (LBC1936) using Cox regression (861 participants; 444 deaths). Biomarkers included the epigenetic clock GrimAge2, telomere length, physical function (grip strength, walk time and respiratory function), neuroimaging and cognitive measures. Among proteomic clocks, accelerated liver (HR _perSD [95% CI] = 1.43 [1.30–1.58]), immune (1.42 [1.29–1.57]) and heart (1.38 [1.25–1.53]) ageing were most strongly associated with increased mortality risk. However, older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function and poorer cognition showed stronger associations with mortality (HR _perSD = 1.44–1.62). Second, survival analyses of 9703 plasma protein targets identified 368 candidates associated with mortality, with high‐risk proteins enriched for immune functions, and low‐risk proteins involved in genomic stability and cellular maintenance. GDF15 (HR _perSD [95% CI] = 1.56 [1.42–1.72]), WFDC2 (1.47 [1.33–1.62]) and TIMP1 (1.45 [1.29–1.62]) were the leading proteomic candidates associated with mortality. This study provides a systematic, cross‐modal benchmarking of proteomic organ clocks against established ageing biomarkers and identifies proteins and biological functions associated with mortality risk.

The role of physical fitness in cognitive reserve and brain maintenance remains unclear. We investigated the associations of muscular and aerobic fitness (VO ₂ max) with markers of brain health and cognition in 353 cognitively unimpaired older adults (mean age = 72.77 ± 7.95 years; 177 females). Muscular fitness comprised handgrip strength, appendicular skeletal muscle mass, and Timed-Up-and-Go performance. Blood biomarkers of Alzheimer’s pathology (Aβ _1–42 /Aβ _1–40 , p-tau ₂₁₇ , GFAP) and neuroplasticity (BDNF, VEGF, Cathepsin-B), gray matter (GM) volume and thickness, medial temporal lobe (MTL) tau burden ([¹⁸F]PI-2620 PET), white matter hyperintensities, and perivascular spaces (PVS) were assessed. Higher muscular capacity was associated with lower basal ganglia PVS volume, whereas aerobic fitness was related to greater MTL thickness and GM volume. Although fitness did not moderate pathology–cognition associations, VO₂max explained additional variance in verbal memory beyond tau. These findings indicate distinct associations of fitness with brain health, while providing limited support for cognitive reserve. Trial Registration: The study was registered in the German Clinical Trials Register (DRKS00032449; date of registration: 2025-05-07; recruiting ongoing).

Advancing the understanding of neuroimaging biomarkers in neurodevelopmental research requires structured, well-documented datasets to support reproducibility and comparative analyses. This dataset comprises diffusion MRI-derived measurements from the Autism Brain Imaging Data Exchange (ABIDE II) database—fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD)—across multiple brain regions for both ASD and control groups, associated with unique image identifiers. Data were generated using standardized image acquisition and computational processing pipelines, resulting in uniformly processed and reproducible quantitative region-specific metrics to facilitate cross-sectional comparative studies. The dataset is structured with explicit metadata, detailed variable descriptions, and complete case records to support programmatic access and automated workflows. Data visualization and harmonization codes accompany the dataset. This resource enables the investigation of white matter microstructural properties in relation to autism through different analytical approaches, including hypothesis testing, machine learning, and meta-analyses. The structured format and transparent documentation promote its reuse in other neuroimaging studies. FAIR ² Data Portal: https://www.doi.org/10.71728/senscience.dbrh-5zc8 .

BACKGROUND: Brain perivascular spaces (PVS) are emerging magnetic resonance imaging markers of microvascular function and waste metabolite clearance. Although PVS enlargement has been linked to aging and vascular risk, it remains unclear whether PVS morphometry reflects shared familial microvascular characteristics and how these are shaped by individual vascular, physiological, and neuropsychiatric factors. We investigated whether PVS morphometry captures these familial characteristics in addition to individual determinants. METHODS: We analyzed 1183 participants from the Stratifying Depression and Resilience Longitudinally family-based cohort, including 324 individuals with first-degree relatives. Automated magnetic resonance imaging segmentation quantified PVS volume, count, density, and median length in the centrum semiovale and basal ganglia. Linear mixed-effects models assessed associations with age, hypertension, hair cortisol, depressive symptom scores, and hand grip strength while accounting for familial clustering. RESULTS: In 1050 individuals (59.5% female; mean age, 59.3±10.1 years), PVS burden increased with age (PVSvolume%ROI, β=0.18 [95% CI, 0.11–0.26]; P P =0.009; BG, β=0.11 [0.043–0.18]; P =0.002; largely robust to false discovery rate correction), and with higher hair cortisol (PVS count β=0.08 [0.003–0.15]; P =0.041; borderline after false discovery rate correction) and weaker grip strength (PVSvolume%ROI β=−0.09 [−0.16 to −0.02]; P =0.013), in the centrum semiovale. Familial clustering was significant for PVS volume (β=0.22 [0.096–0.52]; P =0.013) and median length (β=0.28 [0.16−0.49]; P =0.0003), independent of other factors. CONCLUSIONS: PVS morphometry reflects shared familial microvascular phenotypes and neuropsychiatric influences beyond hypertension, highlighting both familial and individual determinants of PVS burden and morphology. These findings support PVS morphometry as a neuroimaging marker of cerebral microvascular health.

Background: Apolipoprotein E (APOE) has been implicated in blood-brain barrier (BBB) dysfunction and may influence ischaemic cerebrovascular disease and cerebral small-vessel disease (cSVD). This study examined associations between APOE genotype, BBB permeability, and infarct distribution in patients with mild ischemic stroke. Methods: We recruited patients with mild ischemic stroke who underwent structural and dynamic contrast-enhanced MRI (DCE-MRI) and APOE genotyping. Infarct type and location, white matter hyperintensities (WMH), and perivascular spaces (PVS) were assessed. BBB-related metrics were quantified using fractional plasma volume (vP) and permeability-surface area product (PS) across five brain regions of interest: deep grey matter (DGM), hippocampus, thalamus, normal-appearing white matter (NAWM), and WMH. Associations between genotype, BBB metrics, vascular risk factors, and age were evaluated using linear mixed-effects models. Binary logistic regression was also applied to assess the association between APOE status and infarct location by vascular territory (anterior vs posterior circulation). Results: Among 147 patients with APOE genotype and BBB measures, APOE4 carriers (n=44) demonstrated a greater proportion of posterior circulation infarcts than E3/E3 individuals (n=80; 56.4% versus 32.9%), including higher frequencies of posterior cerebral artery cortical, posterior borderzone, and thalamic infarcts. Mean PS and vP did not differ significantly by genotype. Increasing age was associated with lower PS across multiple regions and lower vP in WMH, while higher vascular risk burden was associated with lower vP in NAWM and WMH. Inclusion of regional BBB metrics did not substantially alter APOE4 effect estimates in infarct-location models. Conclusions: APOE4 carriers showed a posterior-predominant infarct distribution despite similar BBB permeability and vascularity measures. Age and vascular risk burden were more strongly associated with BBB-related imaging metrics than APOE genotype. These findings add to evidence suggesting that APOE genotype may influence regional cerebrovascular vulnerability and that this effect is unlikely to be fully explained by DCE-MRI-derived measures of BBB permeability and vascularity alone.

BACKGROUND: Stenosis and dolichoectasia of cranial arteries likely reflect distinct mechanisms. Their contributions to lacunar stroke and cerebral small-vessel disease (cSVD) remain contentious. We investigated the associations of large-artery stenosis (LAS) and arterial widening with stroke subtype, cSVD markers, incident infarcts, and clinical outcomes. METHODS: We prospectively recruited patients with lacunar or mild nonlacunar stroke, with demographic, stroke-related, cognitive, functional, and magnetic resonance imaging (index and incident infarcts, cSVD markers) assessments at baseline and 1 year. LAS was defined as ≥50% intracranial or cervical artery stenosis; basilar artery dolichoectasia was defined by basilar artery diameter, bifurcation height, and lateral displacement; and intracranial carotid and middle cerebral artery diameters were also measured. Associations were estimated from multivariable logistic, linear, and proportional odds regression models adjusted for age, sex, and vascular risk factors. We further conducted a systematic literature review to synthesize evidence on relationships between large-artery pathology and cSVD. RESULTS: Among 229 patients (mean age, 65.9±11.1 years; 131 [57.2%] lacunar stroke), LAS and basilar artery dolichoectasia were present in 20.5% and 15.7%, respectively. After adjustment, LAS (odds ratio, 0.49 [95% CI, 0.23–0.99]) and the presence of any embolic source were associated with lower odds of lacunar versus non-lacunar stroke, and not with cSVD markers or incident infarcts. In contrast, basilar artery dolichoectasia was strongly associated with lacunar stroke (odds ratio, 4.67 [95% CI, 1.87–13.14]), higher cSVD scores (ordinal analysis; odds ratio, 2.57 [95% CI, 1.28–5.25]), incident infarcts (75% subcortical; odds ratio, 2.29 [95% CI, 1.01–5.14]), and greater progression of white matter hyperintensities over 1 year (β, 0.15 [95% CI, 0.01–0.29] per log ₁₀ -transformed volume). Similar associations were observed for wider intracranial arteries. The systematic review supported these findings. CONCLUSIONS: cSVD, including lacunar stroke, was unrelated to LAS but strongly associated with dolichoectasia and wider arteries. These findings support a nonatheromatous, intrinsic microvascular pathology, particularly segmental arteriolar disorganization, as the principal mechanism of lacunar stroke and cSVD. Mechanism-specific diagnostic and therapeutic strategies are warranted.

Objective: Cranial artery stenosis and dilatation are distinct large artery phenotypes that often coexist with cerebral small vessel disease (cSVD), yet their downstream microvascular functional correlates remain unclear. Methods: In the prospective Mild Stroke Study 3, we recruited patients with lacunar or mild non-lacunar stroke. At baseline, large artery stenosis (LAS), basilar artery dolichoectasia (BADE), and intracranial arterial diameters were assessed. Multimodal MRI quantified cerebrovascular reactivity (CVR), blood-brain barrier (BBB) permeability, plasma volume fraction, and intracranial pulsatility. cSVD markers were evaluated at baseline and 1 year. Associations between large artery phenotypes and vascular function were examined with multivariable regression. Mediation analyses tested whether vascular dysfunction linked large artery pathology to cSVD progression. Results: Among 224 participants (mean age 66.0 ± 11.2 years; 66.5% men), BADE ( n =36, 16.1%) was independently associated with lower CVR in normal-appearing white matter (NAWM; β −0.01, 95% CI −0.016 to −0.004, P =0.003). Larger mean intracranial arterial diameter was associated with lower CVR in NAWM and white matter hyperintensities (WMH), while showing a U-shaped association with BBB permeability. LAS ( n =46, 20.5%) was unrelated to CVR, BBB permeability, or pulsatility, but was associated with higher plasma volume in WMH. CVR in NAWM partially mediated the association between BADE and both baseline cSVD burden and 1-year progression. Interpretation: Large artery dilatation may serve as a macroscopic signal of small-vessel dysfunction, being associated with lower CVR and altered BBB permeability. Reduced CVR in NAWM partially mediated the impact of dolichoectasia on cSVD progression and may represent a potential therapeutic target.

Chronic psychosocial stress (CPS) is associated with adverse brain and mental health outcomes. Effects on the cerebral microvasculature have been proposed as an underlying mechanism, although this remains to be established. Here, we examined the association between CPS and an early marker of microvascular dysfunction, magnetic resonance imaging (MRI)-visible perivascular spaces (PVS). Analyses were conducted in two cohorts of healthy young adults (N = 61; ages 18-43 years; 88% male) using high-resolution 3T MRI and an automated PVS quantification pipeline. CPS was assessed using the Perceived Stress Scale (PSS-10). We applied a two-step meta-analytic framework and controlled for known allostatic factors impacting PVS, including age, body mass index and mean arterial pressure. In accordance with our hypothesis, individuals with higher CPS had significantly higher fractional PVS volumes in the centrum semiovale (CSO), in particular in the frontal and occipital lobes (p _FDR < .05). No such effect was found in the basal ganglia, or in the CSO subdivision, parietal, and temporal lobes (p _FDR > .09). Our findings indicate that CPS may contribute to subtle, centrum semiovale specific microvascular alterations even in healthy young adults. Future multimodal research including inflammatory marker and blood-brain barrier measures may help to elucidate mechanistic pathways.