Normal appearing white matter permeability: a marker of inflammation and information processing speed deficit among relapsing remitting multiple sclerosis patients.

Purpose: Blood-brain barrier breakdown (BBBB) occurs in relapsing remitting multiple sclerosis (RRMS). Relative recirculation (rR), a BBBB surrogate, may show inflammation undetectable by gadolinium. We compared normal appearing white matter (NAWM) rR in patients with and without disability measured with Symbol Digit Modalities Test and the Expanded Disability Status Scale (EDSS).
Methods: Thirty-nine RRMS patients were prospectively recruited and classified as impaired or non-impaired based on the SDMT and EDSS threshold ≥3. Significant demographic, MRI structural and regional rR characteristics were advanced into multivariate analysis to assess the association with impairment of cognition and EDSS. Bonferroni corrected p < 0.025 was applied to demographic and rR group comparisons; p < 0.05 was used in the final multivariate logistic regression.
Results: rR was higher in NAWM (p = 0.012), NAGM (p = 0.004), and basal ganglia (p = 0.007) in cognitively impaired versus non-impaired patients. The difference between NAWM and T2HL rR was significant in cognitively non-impaired patients and approximated that of T2HL in impairment (0.084 vs. 0.075, p = 0.008; 0.118 vs. 0.101, p = 0.091, respectively). After adjusting for confounders, rR elevation for NAWM (OR 1.777; 95% CI 1.068-2.956; p = 0.026), NAGM (OR 2.138; 1.100-4.157; p = 0.025), and basal ganglia (OR 2.192; 1.120-4.289; p = 0.022) remained significantly predictive of cognitive impairment. NAWM area under the curve (AUC) for cognitive impairment was 0.783. No significant group differences or associations were seen for rR and EDSS impairment. No NAGM and cortical lesion rR difference was present within any of the impaired or non-impaired groups.
Conclusion: rR elevation in NAWM, NAGM, and basal ganglia appears sensitive to cognitive impairment but not EDSS.