β-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy

Abstract

OBJECTIVE: To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of beta-amyloid (Abeta). METHODS: HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of Abeta40, Abeta42, total tau, and phosphorylated tau181 proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses. RESULTS: We included 10 symptomatic patients with HCHWA-D (mean age 55 +/- 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 +/- 13 years), 31 controls <50 years old (mean age 31 +/- 7 years), and 50 controls >/=50 years old (mean age 61 +/- 8 years). After correction for age, CSF Abeta40 and Abeta42 were significantly decreased in symptomatic carriers vs controls (median Abeta40 1,386 vs 3,867 ng/L, p < 0.001; median Abeta42 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Abeta40 3,501 vs 4,684 ng/L, p = 0.011; median Abeta42 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Abeta40 was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02). CONCLUSIONS: Decreased levels of CSF Abeta40 and Abeta42 occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Abeta species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Abeta40 and Abeta42 may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.