White matter hyperintensity burden in amyotrophic lateral sclerosis: motor and survival correlates

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration. Microvascular dysfunction has been implicated by recent research in ALS pathogenesis and motor neuron vulnerability. The aim of this study is to investigate whether MRI markers of white matter hyperintensities (WMHs), reflecting small-vessel disease, are associated with motor and cognitive impairment, disease staging and prognosis in ALS. In this retrospective cohort study MRI scans from 399 ALS patients were evaluated for periventricular and deep white matter hyperintensities (pvWMH and dWMH) using visual grading scales together with semi-automated volumetric quantification of relative WMH volume (WMHrv). The primary outcome was survival. Secondary outcomes included disease staging, functional impairment, motor and cognitive outcome measures. WMH burden was associated with more advanced King's topographic staging [pvWMH (P < 0.001), dWMH (P = 0.002)] and MiToS functional staging [pvWMH (P < 0.001), dWMH (P = 0.017)]. High pvWMH burden was associated with shorter survival [exp(β) = 3.503; 95% CI = 1.131, 10.832; P = 0.030] after adjustment for known prognostic factors. WMH measures correlated with greater functional impairment on ALSFRS-R score [pvWMH (P < 0.001), dWMH (P = 0.003), WMHrv (P = 0.008)]. WMH burden correlated with more severe lower, but not upper, motor neuron impairment, as measured with the MRC sum score [pvWMH (P = 0.002), dWMH (P = 0.024), WMHrv (p=0.030)] and lower motor neuron score [pvWMH (P < 0.001), dWMH (P = 0.001)]. WMH burden was also associated with cognitive deficits on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), as indicated by total [pvWMH (P = 0.007), dWMH (P = 0.009), WMHrv (P = 0.037)] and ALS-specific ECAS scores [pvWMH (P = 0.001), dWMH (P = 0.020), WMHrv (P = 0.022)]. This large-scale MRI study links small-vessel disease to clinical staging, survival and ALS-specific motor (distinctively LMN) and cognitive impairments. These results suggest that WMHs may reflect a diffuse neurovascular pathology spanning cortical and spinal regions and may be relevant to ALS progression. Routine MRI assessment of WMHs could aid patient stratification and inform trial designs. Longitudinal studies are needed to clarify causal relationships and neurovascular-targeted therapeutic implications.