Redefining Normal: The Importance of White Matter Microstructural Integrity in Poststroke Outcomes.

See related article, p 449 Structural injury to white matter represents an important type of cerebral small-vessel disease. Macrostructural white matter injury, in the form of white matter hyperintensities (WMH) of presumed vascular origin on T2 magnetic resonance imaging scans, has long stood in the spotlight as a recognized harbinger of poor ischemic stroke outcomes. WMH, ostensibly as a radiographic indicator of end-stage cerebral small-vessel disease, however, generally represents only injury to a minority of total brain white matter (even in severe cases) and often with predominantly periventricular distribution. A logical question therefore is how WMH burden contributes to poor functional outcomes after ischemic stroke? One hypothesis is that WMHs reflect more widespread white matter microstructural injury, that is, only a tip of the iceberg, and that studying the structural integrity of normal-appearing white matter (NAWM) could provide additional information on the mechanistic links of white matter structural injury to ischemic stroke outcomes. By examining the randomness (anisotropy) of water molecule dispersion in white matter, diffusion tensor imaging has shown utility for further characterization of white matter microstructural integrity. When white matter fibers are intact, water molecules diffuse relatively orderly along the predictable longitudinal paths; yet, with the loss of integrity (ie, structural disarray), the diffusion becomes unrestricted in all directions. What has become increasingly clear is that the microstructural integrity of NAWM, as the lion’s share of the brain’s white matter, is clinically relevant. NAWM microstructural integrity loss has been linked to WMH burden, precedes WMH development, and—in line with what has been reported for WMH—incident cognitive impairment and stroke risk. Pertinent to acute cerebral ischemia, NAWM microstructural integrity seems to be an independent predictor of early clinical deterioration and long-term functional outcomes. These findings suggest an important role of preexisting NAWM microstructural disarray in poststroke recovery and warrant investigations into the influences of NAWM structural integrity on various outcome domains and region-specific effects. In this stroke volume, Sagnier et al report on a prospective study of 207 patients with ischemic stroke who underwent high-resolution magnetic resonance imaging obtained at 24 to 72 hours from stroke onset and multidomain outcomes assessment at 12 months. The authors applied 2 regression models to determine the association between white matter integrity and stroke outcomes. A radiological model, including NAWM diffusivity anisotropy metrics and WMH volume, and a clinicoradiologic model (adding age, male sex, and educational level) were evaluated in relation to 1-year global cognitive, executive function, attention and processing speed, mood, walking speed, and global functional outcomes. In the radiological model, NAWM fractional anisotropy or mean diffusivity and WMH volume showed similar behaviors with the different outcome measures suggesting that increased white matter microand macrostructural injury were associated with worse outcomes at 1 year. In the clinicoradiological model, addition of age, male sex, and educational level attenuated the relationship between the white matter injury markers and outcomes measures at 1 year; however, NAWM fractional anisotropy and mean diffusivity were still independent predictors of global functional outcome, and WMH was associated with global cognitive and executive function. Using path analysis, the authors showed that NAWM fractional anisotropy and mean diffusivity had direct effects on functional outcomes, and also an indirect effect mediated via WMH volume. Last, they applied tract-based spatial statistics to show tract-specific associations with functional outcome and executive function in right hemispheric, but surprisingly not left hemispheric, stroke patients. The strength of this study is in its relatively large samplesize coupled with early high-resolution magnetic resonance imaging acquisition, which allowed for segmentation of the total white matter. Assessment of multiple distinct outcome domains rather than the standard global functional outcomes further strengthened the authors ability to interrogate the impact of diffuse microstructural white matter injury on metrics of poststroke functional recovery. The inclusion of global functional and cognitive outcome measures along with domain-specific measures greatly enhances the interpretation of the effect on outcomes and should be modeled in stroke clinical trials moving forward, potentially with the addition of patient-reported outcome measures. Important considerations about the overall interpretation, however, are that this was a study of patients with mild stroke severity (patients with Guest Editor for this article was Gregory W. Albers, MD. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston. Correspondence to Natalia S. Rost, MD, MPH, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, 175 Cambridge St, Suite 300, Boston, MA 02114. Email nrost@partners.org Redefining Normal The Importance of White Matter Microstructural Integrity in Poststroke Outcomes