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

Abstract

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). 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 Aβ₄₀, Aβ₄₂, 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. 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 Aβ₄₀ and Aβ₄₂ were significantly decreased in symptomatic carriers vs controls (median Aβ₄₀ 1,386 vs 3,867 ng/L, p < 0.001; median Aβ₄₂ 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Aβ₄₀ 3,501 vs 4,684 ng/L, p = 0.011; median Aβ₄₂ 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Aβ₄₀ 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). Decreased levels of CSF Aβ₄₀ and Aβ₄₂ 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 Aβ₄₀ and Aβ₄₂ may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.