Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease

White matter hyperintensities and lacunes are among the most frequent abnormalities on brain magnetic resonance imaging. They are commonly related to cerebral small vessel disease and associated with both stroke and dementia. We examined the spatial relationships between incident lacunes and white matter hyperintensities and related these findings to information on vascular anatomy to study possible mechanistic links between the two lesion types. Two hundred and seventy-six patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetically defined small vessel disease with mutations in the NOTCH3 gene were followed with magnetic resonance imaging over a total of 633 patient years. Using difference images and Jacobian maps from registered images we identified 104 incident lacunes. The majority (n = 95; 91.3%) of lacunes developed at the edge of a white matter hyperintensity whereas few lacunes were found to develop fully within (n = 6; 5.8%) or outside (n = 3; 2.9%) white matter hyperintensities. Adding information on vascular anatomy revealed that the majority of incident lacunes developed proximal to a white matter hyperintensity along the course of perforating vessels supplying the respective brain region. We further studied the spatial relationship between prevalent lacunes and white matter hyperintensities both in 365 patients with CADASIL and in 588 elderly subjects from the Austrian Stroke Prevention Study. The results were consistent with the results for incident lacunes. Lesion prevalence maps in different disease stages showed a spread of lesions towards subcortical regions in both cohorts. Our findings suggest that the mechanisms of lacunes and white matter hyperintensities are intimately connected and identify the edge of white matter hyperintensities as a predilection site for lacunes. Our observations further support and refine the concept of the white matter hyperintensity penumbra.