Charlotte Zerna, MD, MSc

Sagnier S, Catheline G, Dilharreguy B, Linck P-A, Coupé P, Munsch F, et al. Normal-Appearing White Matter Integrity Is a Predictor of Outcome After Ischemic Stroke. Stroke. 2020;51:449–456.

The relationship between normal-appearing white matter (NAWM) integrity and specific brain functions has been reported during aging and in patients with cerebral small vessel disease, suggesting that it might be a relevant area of cerebral plasticity. In this study, the authors wanted to evaluate the predictive value of NAWM integrity on different domains of post-stroke recovery.

Through the Brain Before Stroke study undertaken by the Bordeaux University Hospital, eligible patients (>18 years, ischemic supratentorial stroke diagnoses within 24 to 72 hours after symptom onset, NIHSS between 1-25, in the absence of pre-stroke dementia and pre-stroke disability (mRS ≥1)) were prospectively and consecutively recruited between June 2012 and February 2015.

An informant questionnaire established the pre-stroke cognitive state, whereas the modified Rankin Scale (mRS), Montreal Cognitive Assessment test, Isaacs set test, Zazzo cancelation task, the Hospital Anxiety and Depression scale and the 10-meter walk test were used to measure functional outcome, global cognition, executive function, processing speed/attention, mood, and walking speed/gait at 1 year, respectively. A 3 Tesla brain MRI was performed at baseline, and different masks were used to extract white matter hyperintensity (WMH) volume and NAWM volume. The alteration in NAWM integrity was investigated using diffusion tensor imaging (DTI), by the detection of decreases in fractional anisotropy (FA) and increased mean diffusivity (MD), as well as axial diffusivity and radial diffusivity. As water molecules more easily diffuse along the white matter tracts than perpendicular to them, these markers can indicate how intact the white matter tracts are in both NAWM, as well as in more macrostructural affected regions.

A total of 207 patients (mean age 66 years, 67% men) were included in this analysis. Even though the inclusion criteria were liberal in terms of accepted stroke severity, the majority suffered from mild to moderate strokes (median NIHSS 3) because of the inability of more severe patients to perform the clinical assessment or undergo the specified MRI protocol.

NAWM integrity was an independent predictor of disability one year after ischemic stroke in a clinicoradiological model. This association involved white matter tracts in widespread regions, suggesting an altered microstructural integrity both near and remote from the ischemic lesion itself. The altered microstructural integrity might inhibit compensatory mechanisms after ischemia like recruitment and reorganization of ipsilateral and contralateral regions during post-stroke recovery. Since diffusion tensor imaging measurements in NAWM, but also WMH volume itself, were associated with disability, the authors conclude that these measurements signify the presence of an underlying and invisible cerebrovascular disease on conventional MRI sequences as a first step toward macrostructural vascular brain injury. Indeed, other studies have shown that vascular dysfunction precedes macrostructural changes. For example, Sam et al. could show that lower cerebrovascular reactivity in NAWM preceded WMH development.1, 2 Increased blood-brain-barrier permeability was detected in NAWM, as well as tissue displaying WMH in patients with overt cerebral small vessel disease compared to controls in a study by Zhang and colleagues.3 This mounting evidence suggests a continuous process of white matter degradation including demyelination and axonal loss due to chronic ischemic vascular processes that occurs (long) before macrostructural lesions on common sequences of clinical MRI scans become obvious.

NAWM integrity should be considered as an important early neuroimaging marker that could help predict post-stroke functional outcomes in further research, as well as a potential target for future clinical trial eligibility to be able to recognize early stages of cerebral small vessel disease that are amenable to therapeutic interventions.


1.           Sam K, Conklin J, Holmes KR, Sobczyk O, Poublanc J, Crawley AP, et al. Impaired dynamic cerebrovascular response to hypercapnia predicts development of white matter hyperintensities. NeuroImage Clinical. 2016;11:796-801.

2.           Sam K, Crawley AP, Conklin J, Poublanc J, Sobczyk O, Mandell DM, et al. Development of White Matter Hyperintensity Is Preceded by Reduced Cerebrovascular Reactivity. Annals of Neurology. 2016;80:277-85.

3.           Zhang CE, Wong SM, van de Haar HJ, Staals J, Jansen JF, Jeukens CR, et al. Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease. Neurology. 2017;88:426-432.