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 β-amyloid (Aβ). 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 Aβ(40), Aβ(42), total tau, and phosphorylated tau(181) 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 Aβ(40) and Aβ(42) were significantly decreased in symptomatic carriers vs controls (median Aβ(40) 1,386 vs 3,867 ng/L, p < 0.001; median Aβ(42) 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Aβ(40) 3,501 vs 4,684 ng/L, p = 0.011; median Aβ(42) 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Aβ(40) 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 Aβ(40) and Aβ(42) occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Aβ species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Aβ(40) and Aβ(42) may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.