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

Abstract

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.

The volume and the distribution of premorbid white matter hyperintensities: Impact on post‐stroke aphasia

“…A key finding of this research is the association between premorbid WMH load within the CC‐Fmin and early subacute comprehension impairments, when considered with other stroke lesion and demographic variables. This negative impact of callosal WMH on language in aphasia is consistent with converging evidence from ageing (Camerino et al, 2020 ; Freeze et al, 2022 ; Vemuri et al, 2021 ) and other stroke populations (Zhang et al, 2014 ) suggesting that WMH disrupts neural networks that underpin a range of cognitive functions, resulting in behavioural consequences. We found no relationship between the total volume of WMH and aphasia outcomes.…”

“…In research on cognitive ageing, the distribution of WMH within several segments of the CC, particularly the CC‐Fmin and the CC‐Fmaj, has been shown to independently explain the cognitive sequelae of WMH pathology, suggesting that callosal WMH may act as a surrogate marker of cognitive ageing processes (Freeze et al, 2022 ; Petersen et al, 2022 ; Vemuri et al, 2021 ). Our findings indicate that this may also be the case in pathological populations, such as post‐stroke aphasia.…”

“…With respect to the critical role of WMH spatial distribution, converging evidence from lesion-symptom mapping (LSM) studies have shown that some white matter tracts, such as the thalamic radiations and corpus callosum (CC) segments, are most commonly associated with cognitive deficits when affected by WMH (Biesbroek et al, 2016;Biesbroek et al, 2020;Camerino et al, 2020;Duering et al, 2011;Duering et al, 2014;Hilal et al, 2021;Jiang et al, 2018;Lampe et al, 2019;Zhao et al, 2018) (for a review, see Biesbroek et al, 2017). More recent studies specifically investigating the role of WMH lesion loads within the CC provide further evidence that callosal WMH lesions are independently associated with cognitive impairment in individuals with VCI and healthy ageing individuals (Freeze et al, 2022;Vemuri et al, 2021), suggesting that callosal connections are a strategic location within the white matter network.…”

White Matter Microstructural Alterations over the Year after Acute Ischemic Stroke in Patients with Baseline Impaired Cognitive Functions

“…The SLF is composed of long bidirectional frontal-parietal-temporal-occipital projections among the prefrontal, temporal, and occipital cortices via the posterior parietal cortex, and it is critical for visuospatial cognitive function and working memory performance [21]. The corpus callosum passes signals to various regions of the contralateral hemisphere cortex; corpus callosum lesion is associated with reduced cognitive performance in the domains of information processing speed, executive functioning, memory, and visuospatial processing [22]. The disruption of the CG can lead to the disruption of communication from the cingulate gyrus and hippocampus to the cerebral cortex, subsequently impairing episodic memory and other cognitive domains.…”

Peak width of skeletonized mean diffusivity (PSMD) as neuroimaging biomarker for vascular cognitive impairment in the context of cerebral amyloid angiopathy

“…47 The anatomical location of vascular lesions also plays an important role in the development of VCID and helps explain its heterogeneous neuropsychological manifestations. 4 Several studies point to strategic locations associated with global post-stroke cognitive deficits, such as: thalamus, internal capsule, basal ganglia, corpus callosum, 162 cingulate cortex, angular gyrus, frontal subcortical areas and specific white matter tracts of the left hemisphere. 163 Interestingly, cSVD lesions often affect centrally located and richly interconnected regions, which are responsible for the integration of information.…”