Charlotte Zerna, MD, MSc

Egorova N, Dhollander T, Khlif SM, Khan W, Werden E, Brodtmann. Pervasive White Matter Fiber Degeneration in Ischemic Stroke. Stroke. 2020;51:1507–1513.

Studies have shown that ischemic stroke does not only lead to focal tissue destruction, but can also result in the remote loss of gray matter and disruption of functional connectivity. However, less is known about the remote and regional white matter degeneration after ischemic stroke. Prior studies have been limited by using diffusion-tensor imaging metrics that are non-specific voxel-averaged measures and can lead to erroneous interpretations in locations where white matter fibers are crossing. The objective of the study by Egorova et al. was, therefore, to examine white matter degeneration in a cohort of participants at 3 months post-infarct using a novel fixel-based analysis (fiber population within an MRI voxel). This method allowed the authors to assess complex microstructural fiber geometry in greater detail.

Participants with ischemic stroke (confirmed both clinically and radiologically) were recruited within 6 weeks of their index event at 3 hospitals in Melbourne, Australia. Both patients with first ever (85.6%) and recurrent ischemic stroke (14.4%) in any vascular territory and of any etiology were considered. Age-matched controls (that were also comparable in sex and education status) were selected from a database of volunteers who had previously undertaken MRI research at one of the recruiting hospitals. Of the 165 recruited participants who completed scanning at 3 months, complete usable MRI diffusion data were available for 104 stroke and 40 control participants and could be used for analysis after successfully undergoing pre-processing.

The outcome measures of the study were fiber density (total intra-axonal volume of axons aligning with a specific fiber population in each voxel compartment), fiber bundle cross-section (individual differences in macroscopic fiber-bundle cross-sectional site), and their combined effect. The authors hypothesized that all 3 metrics would be decreased both globally and in the white matter tracts adjacent or connected to the lesion site in stroke patients at 3 months post-infarct compared to controls.

Stroke and control participants did not significantly differ in age, sex, or intracranial volume, but stroke participants had higher prevalence of hypertension, type 2 diabetes mellitus, atrial fibrillation, and hyperlipidemia, whereas control participants were better educated. Stroke severity was generally mild with a mean National Institutes of Health Stroke Scale score of 3.

Whole-brain analysis revealed significant white matter loss in stroke participants compared with control participants, manifesting both micro- and macrostructurally. The authors found evidence of typical Wallerian degeneration in the ipsilesional corticospinal tract and significant loss in the fiber density within inter-hemispheric connections. They also found a reduction in fiber bundle cross-section in the bilateral superior longitudinal fasciculi, with atrophy localized in the right hemisphere for participants with both left- and right-sided stroke. The superior longitudinal fasciculus is one of the major white matter tracts associated with behavioral deficits across multiple cognitive domains, and observed degeneration could be indicative of a mechanism explaining cognitive decline and increased risk of dementia after stroke. These findings suggest that white matter damage should be taken more into account when assessing treatment outcomes, as well as in future clinical trials and animal models of ischemic stroke.

The study was limited by assessing only one time-point post-stroke, and future studies should aim to track white matter changes longitudinally. Furthermore, the higher prevalence of hypertension, type 2 diabetes mellitus, atrial fibrillation, and hyperlipidemia in the stroke participants might suggest a higher small vessel disease burden that could have influenced the results. Finally, since stroke participants predominantly suffered from mild, middle cerebral artery strokes, the results might not apply to more severe strokes or strokes in the posterior circulation.