Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes

Abstract

Objective: To gain insight into different cerebral amyloid angiopathy (CAA) phenotypes and mechanisms, we investigated cortical superficial siderosis (CSS), a new imaging marker of the disease, and its relation with APOE genotype in patients with pathologically proven CAA, who presented with and without intracerebral hemorrhage (ICH).

Methods: MRI scans of 105 patients with CAA pathologic confirmation and MRI were analyzed for CSS (focal, ≤3 sulci; disseminates, ≥4 sulci) and other imaging markers. We compared pathologic, imaging, and APOE genotype data between subjects with vs without ICH, and investigated associations between CSS and APOE genotype.

Results: Our cohort consisted of 54 patients with CAA with symptomatic lobar ICH and 51 without ICH. APOE genotype was available in 53 patients. More than 90% of pathology samples in both groups had neuritic plaques, whereas neurofibrillary tangles were more commonly present in the patients without ICH (87% vs 42%, p < 0.0001). There was a trend for patients with CAA with ICH to more commonly have APOE ε2 (48.7% vs 21.4%, p = 0.075), whereas patients without ICH were more likely to be APOE ε4 carriers (85.7% vs 53.9%, p = 0.035). Disseminated CSS was considerably commoner in patients with ICH (33.3% vs 5.9%, p < 0.0001). In logistic regression, disseminated CSS was associated with APOE ε2 (but not APOE ε4) (odds ratio 5.83; 95% confidence interval 1.49-22.82, p = 0.011).

Conclusions: This neuropathologically defined CAA cohort suggests that CSS and APOE ε2 are related to the hemorrhagic expression of the disease; APOE ε4 is enriched in nonhemorrhagic CAA. Our study emphasizes the concept of different CAA phenotypes, suggesting divergent pathophysiologic mechanisms.

Figure. Representative MRIs of patients with pathologic evidence of cerebral amyloid angiopathy with and without symptomatic intracerebral hemorrhage

(A) A 73-year-old woman with cerebral amyloid angiopathy (CAA)–intracerebral hemorrhage (ICH) and disseminated cortical superficial siderosis on T2*-weighted gradient-recalled echo (T2*-GRE) (left). Her APOE genotype was ε2/ε4. (B) Multiple strictly lobar cerebral microbleeds (but no siderosis) on T2*-GRE MRI (left) in a 73-year-old woman with cognitive impairment and ε4/ε4 APOE genotype. Note the comparable white matter hyperintensities burden on fluid-attenuated inversion recovery MRI (middle panels) and centrum semiovale perivascular spaces on T2-weighted images (right panels) in the 2 patients. Both cases had severe CAA with vasculopathic changes (vessel-within-vessel appearance) on pathology.