Abstract / Summary
Abstract Background and Objectives Cerebral microhaemorrhages influence eligibility and monitoring for anti-amyloid therapies. Emerging evidence and expert opinion suggest that subcortical microhaemorrhages may be less closely related to cerebral amyloidosis than lobar lesions and may therefore warrant separate consideration in anti-amyloid treatment eligibility criteria. Using longitudinal MRI data from cognitively unimpaired individuals with preclinical Alzheimer disease in the A4 study, we hypothesised that lobar and subcortical microhaemorrhages would show distinct location-specific patterns of progression and associated risk profiles. Methods We conducted a retrospective longitudinal cohort analysis of centrally assessed MRI data from A4 study participants with at least two evaluable MRI examinations. Baseline and follow-up were defined as the first and last evaluable scans, respectively. Participants were classified according to the anatomical distribution of baseline microhaemorrhages as lobar or subcortical, and subsequent location-specific lesion accumulation was examined. Multivariable logistic regression was used to assess whether baseline lobar and subcortical microhaemorrhage counts were independently associated with the development of additional lobar and subcortical microhaemorrhages. Results Among 1,146 participants followed for a mean of 4.55 years (SD = 1.78), 38 had subcortical-only and 157 had lobar-only microhaemorrhages at baseline. Subsequent lesions preferentially accumulated in the same anatomical compartment. Baseline subcortical microhaemorrhage count was associated with additional subcortical lesions (OR 3.60, 95% CI 2.00-6.47), but not with additional lobar lesions (OR 1.25, 95% CI 0.73-2.15). Conversely, baseline lobar microhaemorrhage count was associated with additional lobar lesions (OR 2.74, 95% CI 2.06-3.64), but not with additional subcortical lesions (OR 1.08, 95% CI 0.77-1.53). White matter hyperintensity burden was associated with subcortical progression, while APOE4 homozygosity and greater cerebral amyloid burden were associated with lobar progression. Systolic blood pressure was directionally positive but not associated with lobar microhaemorrhage accumulation in either analysis. Discussion Our findings support the emerging view that subcortical and lobar microhaemorrhages exhibit distinct longitudinal patterns and associated risk profiles. Longitudinal studies in patients receiving contemporary plaque-clearing therapies are needed to determine whether microhaemorrhages should be considered differently according to anatomical location in treatment eligibility and monitoring guidelines.