Longitudinal alterations in brain microstructure surrounding subcortical ischemic stroke lesions detected by free-water imaging

Background Free-water imaging identifies subtle changes in white matter microstructure indicative of cellular and extracellular pathologies not visible on conventional stroke MRI. We explore the spatial extent and temporal trajectory of free-water changes in patients with subcortical stroke and their relationship to symptoms, as well as lesion evolution. Methods Twenty-seven patients with isolated subcortical infarct with mean age of 66.73 (SD 11.57) and median initial NIHSS score of 4 (IQR 4) received MRI 3-5 days, 1 month, 3 months and 12 months after symptom-onset. After lesion segmentation, 8 unique tissue shells (2 mm distance) surrounding stroke lesions were created. Extracellular freewater and fractional anisotropy of the tissue (FAT), derived from diffusion-weighted MRI, were averaged within tissue shells/stroke lesions, and normalized to corresponding contralateral regions. Linear mixed-effects models and t-tests were used for statistics. Baseline imaging measures were correlated with clinical outcomes 3 months after stroke. Results We found increased free-water and decreased FAT in the stroke lesion, as well as the surrounding tissue with a characteristic spatio-temporal distribution. Free-water and FAT changes were most prominent within the lesion and gradually became less with increasing distance from the lesion. Free-water elevations continuously increased over time and peaked after 12 months. In contrast, FAT decreases were most pronounced 1 month after stroke, after which there was a steady increase leading to similarly reduced FAT levels 12 months compared to 3-5 days after stroke. Higher perilesional free-water and higher lesional FAT at baseline were correlated with greater reductions in lesion size, while there were no associations with clinical measures. Conclusions Both free-water and FAT are altered beyond isolated subcortical stroke lesions. The spatial extent of these extracellular and cellular changes varies differentially over time indicating a dynamic parenchymal response to the initial insult characterized by vasogenic edema, cellular damage and white matter atrophy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 178316478 C2 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Landesaerztekammer Hamburg (State of Hamburg Chamber of Medical Practitioners) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors