Mediators of cognitive impairment in cerebral amyloid angiopathy

Abstract

Background Cerebral amyloid angiopathy (CAA) is associated with cognitive decline. CAA has diverse impacts on brain structure and function; however, the brain lesions that mediate the association of CAA with cognition are not understood well. Aims To determine the degree to which CAA neuroimaging biomarkers mediate the association of CAA with cognitive dysfunction. Methods We analyzed cross-sectional data of patients with probable CAA and controls without cognitive impairment from the Functional Assessment of Vascular Reactivity study. Neuropsychological tests were grouped into domains of memory, executive function, and processing speed. Candidate CAA neuroimaging biomarkers were pre-specified based on prior literature, consisting of white matter hyperintensity volume, peak width of skeletonized mean diffusivity (PSMD) on diffusion tensor MRI, cerebrovascular reactivity (CVR), cortical thickness, and cortical thickness in a meta-region of interest typically affected by Alzheimer’s disease (AD). Cognitive scores and neuroimaging markers were standardized and reported in relation to values in controls. Mediation analysis was used to estimate the total effect of CAA on cognition and the proportion of the total effect that was mediated by neuroimaging biomarkers, controlling for age, sex, and education. Results There were 131 participants (67 CAA and 64 control). Mean age was 72.1 ± 7.7 years, and 54.2% were women. As expected, compared to controls CAA was associated with lower cognition. In mediation analyses, CAA had direct unmediated effects of 48%, 46%, and 52% on all three cognitive domains. The association of CAA with memory was mediated by CVR and PSMD, accounting for 18% and 36% of the total effect of CAA. The association of CAA with executive function was mediated by PSMD and mean cortical thickness in the AD meta-ROI, accounting for 33% and 31% of the total effect of CAA. The association of CAA with processing speed was mediated by CVR and PSMD, accounting for 8% and 34% of the total effect of CAA. Among CAA participants, the presence of cortical superficial siderosis was associated with lower processing speed. Conclusions Altered white matter diffusivity (i.e., PSMD), CVR, and atrophy, taken together, account for about half the effect of CAA on cognition. Data access statement Anonymized data will be shared by request from a qualified investigator.

Cerebral small vessel disease: Recent advances and future directions

“…A paper by Durrani in this month issue reports that altered white matter diffusivity, cerebrovascular reactivity, and atrophy, taken together, accounted for about half the effect of CAA on cognition. 9 While we have considerable data on risk factors for SVD itself, there are limited data on what are the risk factors for cognitive impairment in patients with SVD. A paper by Ohlmeier et al 35 also in this issue in almost 1000 lacunar stroke patients reports that diabetes mellitus (odds ratio (OR) = 1.98, 95% CI = (1.40-2.80), p < 0.001) and higher body mass index (BMI) (OR = 1.03, 95% CI = (1.00-1.05), p = 0.029) were independently associated with increased risk of VCI and years of full-time education with lower risk (OR = 0.92, 95% CI = (0.86-0.99), p = 0.018).…”

“…CAA is the primary cause of lobar ICH and an independent contributor to age-associated cognitive impairment. 8 – 10 …”

Three major global stroke challenges: Intracranial stenosis, atrial fibrillation, and cerebral small vessel disease

“…10 In patients with SVD, caused by both hypertension and CAA, a key mechanism appears to be disruption of white matter pathways underlying complex cortical-subcortical networks, which can be interrupted by the diverse pathologies occurring in SVD, including lacunar infarcts, white matter hyperintensities, more diffuse white matter damage seen on DTI, and cerebral microbleeds. 11,12 Such imaging markers are providing important…”

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

“…More recent studies, however, have failed to detect a significant association between WMHV and cognitive impairment in CAA. 53,93 1.2.5.1.5. Lobar lacunes Lacunes of presumed vascular origin represent cavities filled with fluid in the white matter or deep gray matter, that substitute tissue destroyed by ischemic or hemorrhagic injury, and are surrounded by reactive astrocytes, myelin and axonal loss, with significant perilesional tissue disruption.…”

“…112 A recent case-control study observed that, alongside CVR and a DWIbased marker, atrophy mediated the effect of CAA on cognition. 93 In a study comprising 158 non-demented probable CAA patients, medial temporal atrophy independently predicted conversion to dementia, indicating that there is likely a contributing role of AD pathology. 53 In a case-control study with 58 non-demented CAA patients and 138 cognitively normal controls, TBV was the only neuroimaging marker associated with executive function and processing speed.…”