Diagnostic Utility of Cerebrospinal Fluid Biomarkers in Patients with Rapidly Progressive Dementia

Abstract

ObjectivesApply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD).BackgroundOverlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment‐responsive causes of RPD.MethodsBiomarkers of Alzheimer disease neuropathology (Aβ42/40, p‐tau181, p‐tau231), neuroaxonal/neuronal injury (NfL, VILIP‐1, total tau), neuroinflammation (YKL‐40, sTREM2, GFAP, MCP‐1), and synaptic dysfunction (SNAP‐25, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age‐ and sex‐ matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease.ResultsAlzheimer disease biomarkers associated with neurodegenerative causes of RPD. High NfL, sTREM2, YKL‐40, and low VILIP‐1 identified patients with autoimmune/inflammatory diseases. MCP‐1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP‐1, p‐tau181, and sTREM2 identified the 44 patients with treatment‐responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease.InterpretationSelected CSF biomarkers at presentation associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross‐sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear.This article is protected by copyright. All rights reserved.

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

“…Notably, overexpressing TREM2 in P301S tau transgenic mice has been shown to activate M2 microglia, which leads to a reduction in the release of pro-inflammatory cytokines, demonstrating TREM2’s therapeutic potential ( Neumann and Takahashi, 2007 ; Jiang et al, 2016 ). Furthermore, the levels of sTREM2 in CSF serve as a dynamic biomarker for AD progression, reflecting microglial states and their engagement in clearing amyloid plaques and regulating inflammation ( Kuchenbecker et al, 2024 ; Yin S. et al, 2024 ). This is particularly notable during the early symptomatic stages of AD.…”

Novel diagnostic and prognostic approach for rapidly progressive dementias: Indicators based on amyloid/tau/neurodegeneration (ATN) framework

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