White matter hyperintensities as biomarkers in ALS: link to disease severity, progression, survival, and medication response

ImportanceWhile prior work in other neurodegenerative disorders link white matter hyperintensities (WMHs) to disease severity and progression, they remain unexplored in ALS. ObjectiveTo investigate the relationship between presence and progression of WMHs, disease severity, survival, and medication efficacy in ALS. DesignThis retrospective study uses data from the Canadian ALS Neuroimaging Consortium (CALSNIC), containing prospectively acquired multicentre longitudinal (three time points over one year) MRI and clinical assessments between 2014 and 2022. SettingMulticentre study across 9 North American sites. ParticipantsParticipants with a diagnosis of possible, probable, laboratory-supported probable or definite ALS and healthy controls were included. Participants with prior brain trauma were excluded; controls with cognitive impairment or stroke were also excluded. Main Outcome(s) and Measure(s)The main outcomes were differences in baseline and progression of WMHs in ALS patients compared to controls. Secondary outcomes included associations between WMH progression and ALS progression, and subgroup differences (short versus long survival, treatment vs non-treatment groups). ResultsFollowing exclusion criteria, 204 ALS (mean [SD] age, 59.7 [10.4] years; 71 females [34.8%]) and 165 control (mean [SD] age, 55.8 [9.64] years; 70 females [42.8%]) participants were included. ALS patients showed 35.7% greater WMH burden at baseline (p<0.005) and experienced 0.9 cubic centimeters (CCs) more WMH progression over one year (p<0.0001) compared to age and sex matched controls. ALS patients experienced 2 and 4 point drops in ALSFRS-R (p<0.0005) and ECAS-ALS (p<0.005) scores respectively for every 1 CC of WMH progression they experienced. The short survival group (N = 51) experienced faster WMH progression (0.690 CC per year, p<0.05) than the long survival group (N = 75). Patients taking edaravone (N = 181) and riluzole (N = 112) experienced slower WMH progression (0.764 and 0.924 CC per year, respectively, p<0.0005) than those who did not take these medications (N = 23 and N = 90, respectively). Conclusions and RelevanceWMH burden and progression were associated with ALS disease severity, progression, and survival. Edaravone and riluzole treatments were associated with slower WMH progression. Key PointsO_ST_ABSQuestionC_ST_ABSIs the burden of white matter hyperintensities (WMH), and their progression, linked to ALS diagnosis, clinical progression, survival, and medication treatment? FindingThis retrospective study revealed significantly greater WMH burden and progression in ALS compared to healthy controls, as well as links between WMH progression and clinical progression and differences across survival and treatment groups. MeaningWMHs may be utilized as a biomarker for ALS, and should be integrated into prognostic modeling and clinical trial design.