Changes in White Matter Microstructure Over 3 Years in People With and Without Stroke

Background and Objectives: Cerebral white matter health can be estimated by MRI-derived indices of microstructure. White matter dysfunction is increasingly recognized as a contributor to neurodegenerative disorders affecting cognition and to functional outcomes after stroke. Reduced indices of white matter microstructure have been demonstrated cross-sectionally in stroke survivors compared to stroke-free participants, but longitudinal changes in the structure of white matter after stroke remain largely unexplored. We aimed to characterise white matter micro- and macrostructure over 3 years after stroke and study associations with white matter metrics and cognitive functions.

Methods: Patients with first-ever or recurrent ischemic stroke of any etiology in any vascular territory were compared with stroke-free age- and sex-matched controls. Those diagnosed with hemorrhagic stroke, transient ischemic attack, venous infarction, or significant medical comorbidities, psychiatric and neurodegenerative disorders, substance abuse, or history of dementia were excluded. Diffusion-weighted MRI data at 3, 12 and 36 months were analysed using a longitudinal “fixel”-based analysis, sensitive to fiber tract-specific differences within a voxel. It was used to examine whole-brain white matter degeneration in stroke compared to control participants. We studied microstructural differences in fiber density and macrostructural changes in fiber-bundle cross-section, in relation to cognitive performance. Analyses were performed controlling for age, intracranial volume, and education (FWE-corrected p<0.05, non-parametric testing over 5000 permutations).

Results: We included 71 stroke (age 66±12, 22 women) and 36 control participants (age 69±5, 13 women). We observed extensive white matter structural degeneration across the whole brain, particularly affecting the thalamic, cerebellar, striatal, and superior longitudinal tracts, and corpus callosum. Importantly, follow up regression analyses in 72 pre-defined tracts showed that the decline in fiber density and cross-section from 3 months to 3 years was associated with worse cognitive performance at 3 years after stroke, especially affecting visuospatial processing, processing speed, language, and recognition memory.

Discussion: We conclude that white matter neurodegeneration in ipsi- and contra-lesional- thalamic, striatal and cerebellar tracts continues to be greater in stroke survivors compared to stroke-free controls. White matter degeneration persists even years after stroke and is associated with post-stroke cognitive impairment.