Diffusion MRI biomarkers were abnormal at least a decade before WMH abnormality in the population, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.
Abstract
Background: White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease (SVD) but reflect late-stage injury. Diffusion MRI biomarkers have been proposed to capture earlier SVD-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. Methods: We identified 2,077 participants from the population-based cohort study of Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50–101 years) collected between 05/2005 to 09/2024 with longitudinal neuroimaging. Using multi-output nonlinear mixed-effects models in those with at least two FLAIR-MRI and diffusion-MRI scans, we characterized the temporal progression of WMH, and four diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum (Genu-FA), peak width of skeletonized mean diffusivity (PSMD), free water (FW), and Arteriolosclerosis-score (ARTS) which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). Results: Study population had mean age of 78 years, 47% were women, 28% APOE ε4 allele carriers, 80% cognitively unimpaired with average 5.2 years (standard deviation=4.3 years) follow-up for FLAIR-MRI and 4.3 years (standard deviation=3.9 years) for diffusion MRI. ARTS, Genu-FA, FW, and PSMD became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH becomes abnormal (half-width of CI <1 year), respectively. Global markers (ARTS, FW, PSMD, WMH) were correlated, indicating shared substrates of widespread white matter injury. Genu-FA, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, Genu-FA, and ARTS abnormalities whereas males exhibited earlier PSMD and FW abnormalities. Conclusions: Diffusion MRI biomarkers were abnormal at least a decade before WMH abnormality in the population, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.
ASL-sCoV may serve as an important hemodynamic measure for identifying perfusion deficits tied to SVD burden and progression and could provide substantial insight into the longitudinal clinical consequences of SVD.
W. Robb, Ava M. Santner, Pan-Pan Zhang et al.· Stroke· 0 citations
Lesion composition may offer a more informative framework than global WMH burden for understanding cerebrovascular contributions to aging and neurodegeneration, with potential implications for risk stratification, clinical interpretation, and targeted interventions.
Raúl González-Gómez, Enzo Tagliazuchi, C. G. Campo et al.· Neurology· 0 citations
INTRODUCTION
White matter hyperintensities (WMH) are key radiographic biomarkers of cerebral small vessel disease (CSVD) and have been associated with worse outcomes after stroke. Since CSVD may involve blood-brain barrier disruption, we hypothesized that worse outcomes in those with WMH may be mediated through more severe cerebral edema and hemorrhagic transformation (HT).
METHODS
In this retrospective multicenter cohort study, we studied patients from four multinational stroke cohorts who presented within 12 h of anterior circulation large vessel occlusion (LVO) stroke and received at least one follow-up computed tomography (CT) between 12 and 48 h. WMH were rated on baseline CTs using a Fazekas-derived system, with a subset also assessed with Fazekas grading on magnetic resonance imaging (MRI). Automated image analysis measured cerebrospinal fluid displacement (ΔCSF) and lesional-to-contralateral hemispheric CSF volumes (CSF-ratio) as quantitative edema biomarkers. We analyzed the association between WMH presence and edema severity, hemorrhagic transformation, and poor functional outcome (mRS 3-6), adjusting for key covariates, overall and in the subgroup undergoing thrombectomy and those with successful reperfusion.
RESULTS
Of 1290 patients with LVO, 782 were eligible for analysis. Of these, 19% had WMH on CT. Patients with WMH were older, more often female, and had a history of hypertension and higher presenting systolic blood pressure and glucose levels. WMH presence was associated with worse functional outcome, adjusting for age and additional covariates [OR 1.84 (1.06-3.22), p = 0.04] but lower risk of any HT [OR 0.48 (0.25-0.88), p = 0.03]. However, WMH presence by CT or MRI was not associated with edema (ΔCSF, CSF ratio, or midline shift) in the whole population or thrombectomy/reperfusion subgroups. Reperfusion was associated with less edema and improved recovery.
CONCLUSIONS
Presence of CT-graded WMH was associated with worse outcome after LVO stroke, independent of age and other factors. However, this risk appears not to be mediated through greater risk of HT or cerebral edema formation.
Patients with WMH exhibit alterations in EEG microstate features that are significantly correlated with WMH burden and cognitive function, and classification models based on these microstate features show promise for practical application in WMH-related dementia.
Kai-Yan Feng, Jia-Xin Cai, Jian-Ming Lei et al.· Frontiers in Neuroscience· 0 citations
Diffusion tensor imaging (DTI) is a promising tool for early detection of white matter deterioration, but the optimal DTI marker for assessing risk of cognitive decline and dementia is undetermined. The aim of this study was to compare the predictive value of multiple diffusion measures for cognitive decline and dementia risk in a population-based study. We measured peak-width skeletonized mean diffusivity (PSMD), normal-appearing white matter mean diffusivity (MD), and fractional anisotropy (FA) in participants aged 45 years and older who underwent 1.5T MRI between 2006-2015 as part of the ongoing prospective population-based Rotterdam Study. In a head-to-head comparison between DTI markers, we determined risk of cognitive decline and dementia during follow-up, using linear regression and Cox proportional hazard models, respectively, that also include age, sex, education and presence of lacunes or microbleeds. Of 5230 participants (mean age: 65.0 years +/-10.9 [standard deviation], 55.8% women), 286 developed dementia during a median follow-up of 9.8 years. For dementia risk, PSMD and global MD were superior regarding model fit, with the highest hazard ratio for global MD (HR: 1.74 [95%CI: 1.53-1.98]). Similarly, PSMD and MD had the highest discriminatory value (C-statistic, for PSMD: 0.886, and for MD: 0.882), albeit differences with other measures were small. Of all participants, 4433 (84.3%) had complete data on all cognitive tests at baseline, of whom 2800 (63.2%) completed their follow-up visit after on average 5.6 years. For global cognition both at time of MRI and at follow-up, PSMD was superior in terms of model fit and showed the highest regression coefficients, followed by tract-specific measures of MD and FA. In conclusion, when directly comparing structural connectivity measures, PSMD is superior to MD and FA for prediction of cognition and cognitive decline, while PSMD and MD perform best with respect to dementia risk.
Mathijs T. Rosbergen, F. Wolters, M. A. Ikram et al.· Imaging Neuroscience· 0 citations
Background: White matter hyperintensities (WMH) are prevalent in dementia, but lesion volume does not capture their microstructural heterogeneity. The T1-weighted to fluid-attenuated inversion recovery (T1w/T2w-FLAIR) ratio is sensitive to myelin, gliosis, and tissue water. We tested whether lesion-specific T1w/T2w-FLAIR ratio, referenced to each participant's normal-appearing white matter (NAWM), differs by diagnosis and reflects distinct amyloid and vascular mechanisms in Alzheimer's disease (AD) and vascular dementia (VD). Methods: We analyzed 576 participants from the multicentre BICWALZS cohort (seven South Korean sites), spanning subjective cognitive impairment (SCI, n=71), mild cognitive impairment (n=270), AD (n=125) and VD (n=88). WMH T1w/T2w-FLAIR ratio was regressed on NAWM ratio, yielding standardized residuals as the outcome. Regression and mediation models tested diagnosis, plasma biomarkers, APOE genotype, amyloid PET and vascular risk burden, adjusting for age, sex, education and site. We conducted regression and mediation analyses after multiple imputation for missing variables. We adjusted for hierarchical models using Bonferroni correction. We tested for insensitivity to site effects by applying ComBat harmonization. Results: Older age, AD, VD, and high vascular risk burden were associated with higher residualized T1w/T2w-FLAIR ratios relative to SCI. Lower plasma amyloid-beta 42 (greater amyloid burden) was associated with lower T1w/T2w-FLAIR ratios. Greater vascular burden was associated with greater T1w/T2w-FLAIR ratios, which partially mediated the VD association with T1w/T2w-FLAIR. Lower amyloid-beta 42 (greater amyloid) was associated with lower T1w/T2w-FLAIR, which partially mediated the effect between AD and T1w/T2w-FLAIR ratio. Findings were robust to harmonization. Conclusions: Residualized WMH T1w/T2w-FLAIR ratio captures lesion-specific microstructural variation missed by volumetric measures, consistent with vascular-gliotic injury in VD and coexisting amyloid-linked demyelination in AD. Limitations include the cross-sectional design, no cognitively normal comparison group, and a predominantly Korean sample.
Rushil Srirambhatla, J. Campion, Thomas Desmidt et al.· medRxiv· 0 citations
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