Corpus callosum lesions are associated with worse cognitive performance in cerebral amyloid angiopathy

The impact of vascular lesions on cognition is location-dependent. Here, we assessed the contribution of small vessel disease lesions in the corpus callosum (CC) to vascular cognitive impairment in cerebral amyloid angiopathy, as a model for cerebral small vessel disease. 65 patients with probable cerebral amyloid angiopathy underwent 3 T MRI, including a diffusion tensor imaging scan, and neuropsychological testing. Microstructural white matter integrity was quantified by fractional anisotropy and mean diffusivity. Z-scores on individual neuropsychological tests were averaged into five cognitive domains: information processing speed, executive functioning, memory, language, and visuospatial ability. Corpus callosum lesions were defined as hemorrhagic (microbleeds or larger bleeds) or ischemic (microinfarcts, larger infarcts, diffuse fluid-attenuated inversion recovery hyperintensities). Associations between corpus callosum lesion presence, microstructural white matter integrity, and cognitive performance were examined with multiple regression models. The prevalence of corpus callosum lesions was confirmed in an independent cohort of memory clinic patients with and without cerebral amyloid angiopathy (n = 82). In parallel, we assessed corpus callosum lesions on ex vivo MRI in cerebral amyloid angiopathy patients (n = 19) and controls (n = 5) and determined associated tissue abnormalities with histopathology. A total number of 21 corpus callosum lesions was found in 19/65 (29%) cerebral amyloid angiopathy patients. Corpus callosum lesion presence was associated with reduced microstructural white matter integrity within the corpus callosum and in the whole brain white matter. Patients with corpus callosum lesions performed significantly worse on all cognitive domains except language, compared to those without corpus callosum lesions after correcting for age, sex, education, and time between MRI and neuropsychological assessment. This association was independent of presence of intracerebral hemorrhage, whole brain fractional anisotropy and mean diffusivity, and white matter hyperintensity volume and brain volume for the domains of information processing speed and executive functioning. In the memory clinic patient cohort, corpus callosum lesions were present in 14/54 (26%) patients with probable and 2/8 (25%) patients with possible cerebral amyloid angiopathy, and in 3/20 (15%) patients without cerebral amyloid angiopathy. In the ex vivo cohort, corpus callosum lesions were present in 10/19 (53%) patients and 2/5 (40%) controls. On histopathology, ischemic corpus callosum lesions were associated with tissue loss and demyelination, which extended beyond the lesion core. Together, these data suggest that corpus callosum lesions are a frequent finding in cerebral amyloid angiopathy, and that they independently contribute to cognitive impairment through strategic microstructural disruption of white matter tracts.