Tract-specific white matter hyperintensities and neuropsychiatric syndromes: a multicentre memory clinic study

Background White matter hyperintensities (WMH) have been implicated in the pathogenesis of neuropsychiatric symptoms of dementia but the functional significance of WMH in specific white matter (WM) tracts is unclear. We investigate whether WMH burden within major WM fibre classes and individual WM tracts are differentially associated with different neuropsychiatric syndromes in a large multicentre study. Method Neuroimaging and neuropsychiatric data of seven memory clinic cohorts through the Meta VCI Map consortium were harmonised. Class-based analyses of major WM fibres (association, commissural and projection) and region-of-interest-based analyses on 11 individual WM tracts were used to evaluate associations of WMH volume with severity of hyperactivity, psychosis, affective and apathy syndromes. Results Among 2935 patients (50.4% women; mean age=72.2 years; 19.8% subjective cognitive impairment, 39.8% mild cognitive impairment, and 40.4% dementia), larger WMH volume within projection fibres (B=0.24, SE=0.10, p=0.013) was associated with greater apathy. Larger WMH volume within association (B=0.31, SE=0.12, p=0.009), commissural (B=0.47, SE=0.17, p=0.006) and projection (B=0.39, SE=0.16, p=0.016) fibres was associated with greater hyperactivity, driven by the inferior fronto-occipital fasciculus (B=0.50, SE=0.18, p=0.006), forceps major (B=0.48, SE=0.18, p=0.009) and anterior thalamic radiation (B=0.49, SE=0.19, p=0.011), respectively. Larger WMH volume in the uncinate fasciculus (B=1.82, SE=0.67, p=0.005) and forceps minor (B=0.61, SE=0.19, p=0.001) were additionally associated with greater apathy. No associations with affective and psychosis were observed. Conclusions Tract-syndrome specificity of WMH burden with apathy and hyperactivity suggests that disruption of strategic neuronal pathways may be a potential mechanism through which small vessel disease affects emotional and behavioural regulation in memory clinic patients.