Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta-analysis

Abstract

Objective: To perform a meta-analysis of 4 core CSF biomarkers (β-amyloid [Aβ]42, Aβ40, total tau [t-tau], and phosphorylated tau [p-tau]) to assess which of these are most altered in sporadic cerebral amyloid angiopathy (CAA).

Methods: We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting amyloid precursor protein metabolism (Aβ42, Aβ40), neurodegeneration (t-tau), and tangle pathology (p-tau) in symptomatic sporadic CAA cohorts vs controls and patients with Alzheimer disease (AD). Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations: (1) in patients with CAA vs healthy controls and (2) in patients with CAA vs patients with AD. RoM >1 indicates higher biomarker concentration in patients with CAA vs comparison population and RoM <1 indicates higher concentration in comparison groups.

Results: Three studies met inclusion criteria. These comprised 5 CAA patient cohorts (n = 59 patients) vs healthy controls (n = 94 cases) and AD cohorts (n = 158). Three core biomarkers differentiated CAA from controls: CSF Aβ42 (RoM 0.49, 95% confidence interval [CI] 0.38-0.64, p < 0.003), Aβ40 (RoM 0.70, 95% CI 0.63-0.78, p < 0.0001), and t-tau (RoM 1.54, 95% CI 1.15-2.07, p = 0.004); p-tau was marginal (RoM 1.24, 95% CI 0.99-1.54, p = 0.062). Differentiation between CAA and AD was strong for CSF Aβ40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001), but not Aβ42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For t-tau and p-tau, average CSF ratios in patients with CAA vs patients with AD were 0.63 (95% CI 0.54-0.74, p < 0.0001) and 0.60 (95% CI 0.50-0.71, p < 0.0001), respectively.

Conclusion: Specific CSF patterns of Aβ42, Aβ40, t-tau, and p-tau might serve as molecular biomarkers of CAA, but analyses in larger CAA cohorts are needed.

Figure 1. Flow chart of study selection

CAA = cerebral amyloid angiopathy.

Figure 2. Cerebral amyloid angiopathy (CAA) to control group (healthy controls or control group without amyloid-related brain disease) ratio for CSF Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau (p-tau)

Ratio for CSF Aβ42 (A), Aβ40 (B), t-tau (C), and p-tau (D). Outcome measures are given as the overall ratio between CAA patients and comparison groups. Individual study ratios and their corresponding 95% confidence intervals (CIs) are indicated by filled squares. The size of the square indicates the weight of the study. The overall pooled ratio and 95% CI is indicated by a diamond. The solid line indicates a ratio of 1 and the dotted line indicates the average ratio. RoM = ratio of means.

Figure 3. Cerebral amyloid angiopathy (CAA) to Alzheimer disease ratio for CSF Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau (p-tau)

CAA to Alzheimer disease ratio for CSF Aβ42 (A), Aβ40 (B), total tau (t-tau) (C), and phosphorylated tau(p-tau) (D). Outcome measures are given as the overall ratio between patients with CAA and comparison groups. Individual study ratios and their corresponding 95% confidence intervals (CIs) are indicated by filled squares. The size of the square indicates the weight of the study. The overall pooled ratio and 95% CI is indicated by a diamond. The solid line indicates a ratio of 1 and the dotted line indicates the average ratio. RoM = ratio of means.