CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders

Abstract

Objective: To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD).

Methods: Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine₁₈₁, and Aβ_1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN - AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves.

Results: SYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ_1-42 (mean difference -84.0 ± 22.9 g/mL) compared to SYN - AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R² = 0.15-0.16, p < 0.05, both) and lower Aβ_1-42 (R² = 0.43-0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ_1-42 (R² = 0.31, p < 0.001) and higher CSF t-tau/Aβ_1-42 ratio (R² = 0.27, p = 0.01). CSF t-tau/Aβ_1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ_1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage.

Conclusions: Higher antemortem CSF t-tau/Aβ_1-42 and lower Aβ_1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.

Figure 1. CSF biomarkers in neuropathologic groups of LBD

Graphs depict individual data points for natural log transformed values CSF (A) t-tau, (B) p-tau, (C) Aβ_1-42, (D) t-tau/Aβ_1-42 ratio, and (E) p-tau/Aβ_1-42 ratio for the normal control (green), SYN − AD (blue), SYN + AD (red), and AD (orange) groups. Bars represent median and interquartile range. Bar denotes p < 0.05. *p < 0.01, **p < 0.001 difference between groups. Aβ = β-amyloid; AD = Alzheimer disease; p-tau = phosphorylated tau; SYN = α-synuclein; t-tau = total tau.

Figure 2. Relationship between CSF biomarkers and postmortem pathology

Scatterplots depict individual patient data of CSF analyte levels plotted against global cerebral pathology scores coded for neuropathologic diagnosis. Fitted lines and R² values derived from linear regression models predicting CSF analytes. *p < 0.05, **p ≤ 0.01. Aβ = β-amyloid; AD = Alzheimer disease; p-tau = phosphorylated tau; SYN = α-synuclein.

Figure 3. Diagnostic accuracy of CSF biomarkers for AD pathology and neocortical LBD stage in LBD

Receiver operating curves for diagnostic accuracy of CSF biomarkers to predict (A) SYN + AD pathology or (B) neocortical LBD stage pathology. Tables list optimal cut point with sensitivity, specificity, AUC, and 95% CI derived from a random sampling procedure with 1,000 bootstrap samples. Aβ = β-amyloid; AD = Alzheimer disease; AUC = area under the curve; CI = confidence interval; LBD = Lew body disorders; p-tau = phosphorylated tau; SYN = α-synuclein; t-tau = total tau.