CSF and Plasma Biomarkers in Patients With Iatrogenic Cerebral Amyloid Angiopathy

Abstract

Objectives: Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. β-Amyloid (Aβ) accumulation evidenced by amyloid PET positivity or CSF Aβ decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aβ and tau in iCAA and sCAA cohorts.

Methods: Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aβ40, Aβ42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse.

Results: 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aβ40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aβ42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aβ40 (p = 0.08, 95% CI 181-222), Aβ42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aβ40, 95% CI 153-193; Aβ42, 95% CI 6-7 and total tau, 95% CI 2-4).

Discussion: Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aβ and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.

Figure. Lumipulse CSF (A), SiMoA CSF (B), and SiMoA Plasma (C) Analysis

CSF concentrations of Aβ40, Aβ42, tau, and p-tau of patients with sCAA and iCAA were evaluated by Lumipulse G1200 (A) and SiMoA SRX (B) and expressed as pg/mL as indicated. (C) Plasma concentrations of Aβ40, Aβ42, and tau of patients with sCAA and iCAA were determined by SiMoA and expressed as pg/mL, as indicated. The number above bars indicates the means, and the error bars represent the SD. Each spot indicates an individual data point. Reference values of control patients are reported in light gray and indicated as “normal range”^, or “normal mean,”^, respectively. The statistical significance was calculated through the nonparametric Mann-Whitney U test. p Value <0.05 was considered statistically significant (ns; not significant). CAA = cerebral amyloid angiopathy; iCAA = iatrogenic CAA; sCAA = sporadic CAA.