Cortical Superficial Siderosis In Community-Dwelling Subjects: The Framingham Heart And Rotterdam Studies

Background: Cortical superficial siderosis (cSS) is increasingly recognized as an imaging marker of cerebral amyloid angiopathy (CAA) in clinical settings. In these hospital-based cohorts, cSS seems to be a robust indicator of increased risk of future intracerebral hemorrhage (ICH). cSS is also described in community-dwelling individuals, but current understanding of underlying pathology and prognostic implications in this setting is limited. We characterized cSS, its determinants and consequences, compared with another MRI marker of CAA (lobar cerebral microbleeds [CMBs]) in community-dwelling older adults by combining individual-level data from two large population cohorts. Methods: We evaluated cSS in Framingham Original/Offspring Cohort and Rotterdam Study participants ≥ 55 years of age who underwent brain MRI allowing for cSS and CMB detection. In cross-sectional analysis, we compared vascular risk factors/medications, MRI markers of interest, apolipoprotein E (APOE) genotypes (e3/e3 as control), and clinical outcomes (ICH, ischemic stroke, transient ischemic attack, and mild cognitive impairment) amongst participants with cSS and those without cSS/CMBs, as well as individuals with strictly lobar CMBs (without cSS). Results: cSS was present in 0.4% (26) of 6049 participants and strictly lobar CMBs in 13% (776). In comparison to participants with neither cSS nor CMBs and to those with strictly lobar CMBs, participants with cSS were older (OR per year increase 1.1, 95% CI 1.1-1.1 and 1.1, 1.0-1.1, respectively), and had overrepresentation of APOE e4 (at least 1 e4 allele; age/sex adjusted OR 5.23, 2.1-13.3 and 3.5, 1.4-9.0), and ICH (42, 7-251 and 31, 3.8-253). There also existed a trend toward overrepresentation of the APOE e2 allele in participants with cSS (2.8, 0.9-8.8, p=0.08 and 2.7, 0.8-8.5, p=0.10). The association with ICH withstood additional adjustment for white matter hyperintensity volume and lacunes on MRI. Conclusions: In this large population-based study of cSS, the prevalence of cSS was low but presence of cSS was more strongly associated with markers of CAA, such as APOE genotype and ICH, than presence of lobar microbleeds without cSS, suggesting that cSS may reflect advanced CAA even in community-dwelling subjects.