Centrum Semiovale Perivascular Spaces Predict First Hemorrhagic Lesion in Asymptomatic Amyloid-Positive Individuals

Identification of cerebral amyloid angiopathy (CAA) before its hemorrhagic manifestations remains limited. We aimed to determine whether severe enlarged perivascular spaces in the centrum semiovale (EPVS-CSO) identify a prehemorrhagic stage of sporadic CAA by predicting the first appearance of CAA-related hemorrhagic lesions or incident cognitive decline in amyloid-positive, cognitively unimpaired, hemorrhage-free older adults.

We performed a secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, a phase 3 randomized study in cognitively unimpaired, amyloid-positive older adults. Participants with baseline hemorrhagic lesions were excluded. Baseline EPVS-CSO severity was dichotomized as severe versus nonsevere. Severe basal ganglia EPVS, more closely associated with hypertensive small vessel disease, was evaluated as a topographical negative-control exposure. The primary outcome was incident strictly lobar cerebral microbleeds or cortical superficial siderosis. The secondary outcome was longitudinal cognitive trajectories measured by the Preclinical Alzheimer Cognitive Composite.

Among 932 participants (mean age 71.7 ± 4.8 years; 61.3% female), 101 (10.8%) had severe EPVS-CSO at baseline. Over a median follow up of 5.1 years (IQR 3.3-5.5 years), 33.7% of those with severe EPVS-CSO developed incident CAA-related hemorrhagic lesions compared with 13.6% of those with nonsevere EPVS-CSO (adjusted HR 2.85, 95% CI 1.91-4.25; p < 0.0001). Severe basal ganglia EPVS was not associated with incident hemorrhagic lesions (adjusted HR 0.87, 95% CI 0.35-2.18; p = 0.77). Severe EPVS-CSO was not associated with early cognitive differences, and participants who developed incident hemorrhagic lesions showed more pronounced cognitive decline.

These findings identify severe EPVS-CSO as a strong predictor of first appearance of CAA-related hemorrhagic lesions in amyloid-positive individuals, supporting integration of amyloid biomarkers into magnetic resonance imaging-based Boston criteria. Identifying markers of the transition of CAA from a nonhemorrhagic to a hemorrhagic stage provides a potential foundation for approaching primary prevention of CAA-related hemorrhage. ANN NEUROL 2026.