Disconnectome Associated with Progressive Ischemic Periventricular White Matter Lesions

Periventricular white matter (PVWM) hyperintensities on T2-weighted MRI are ubiquitous in older adults and associated with dementia. Efforts to determine how PVWM lesions impact structural connectivity to impinge on brain function remain challenging in part because white matter tractography algorithms for diffusion tensor imaging (DTI) may lose fidelity in the presence of lesions. We used a 9virtual lesion9 approach to characterize the 9disconnectome9 associated with periventricular white matter (PVWM) lesions. We simulated progressive ischemic PVWM lesions using sub-threshold cerebral blood flow (CBF) masks derived from a previously published group-averaged map acquired from N=436 middle aged subjects in which the lowest CBF values were seen in PVWM and morphologically recapitulated the spatial pattern of PVWM hyperintensities seen in typical aging. We mimicked the age-dependent evolution of PVWM lesion burden by varying the threshold applied to the CBF map. We found that the optic radiations, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, corpus callosum, temporopontine tract and fornix were affected in early simulated PVWM lesion burdens, and that the connectivity of subcortical, cerebellar, and visual regions were significantly disrupted with increasing simulated PVWM lesion burdens. We also validated the use of virtual lesions to simulate the disconnectome due to WM hyperintensities in a cognitively normal elderly cohort (N=46) by evaluating correlations between structural and functional connectomes. The virtual lesion approach provides new insights into the spatial-temporal changes of the brain structural connectome under progressive PVWM burdens during normal aging.