Cerebrospinal fluid biomarkers at presentation associate with etiologic diagnosis and treatment responsiveness in patients with rapidly progressive dementia

Abstract

AbstractBackgroundThe causes of rapidly progressive dementia are heterogeneous, including neurodegenerative, vascular, and autoimmune/inflammatory diseases. Overlap in presenting symptoms and signs, results of cognitive testing, and findings on brain imaging and other common diagnostic tests confounds the etiologic diagnosis, contributing to diagnostic delays, missed opportunities for treatment, and poorer outcomes in patients with RPD. New tools and approaches are needed to improve diagnostic accuracy, with particular emphasis on improving early recognition of patients with potentially treatable causes of RPD.MethodsEstablished and emerging biomarkers of Alzheimer disease neuropathology (Aβ42/40, p‐tau181, p‐tau231), neuroaxonal and neuronal injury (neurofilament light [NfL], VILIP‐1, total tau), neuroinflammation (YKL‐40, sTREM2, GFAP, MCP‐1), and synaptic dysfunction (SNAP‐25, neurogranin) were measured in cerebrospinal fluid obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative (n = 35), vascular (n = 9), and autoimmune/inflammatory (n = 34) diseases, and 72 age‐ and sex‐similar cognitively normal individuals (controls). Causes of RPD were further classified as potentially treatment‐responsive or nonresponsive, referencing the extant literature. Biomarker levels were compared across etiologic diagnoses and by treatment responsiveness, referencing control values. Analyses were adjusted for the effects of age (ANCOVA).ResultsAlzheimer disease biomarkers (low Aβ42/40 and elevated p‐tau181 and p‐tau231) were associated with neurodegenerative causes of RPD (ANCOVA, p = 0.02 p = 0.30, p = 0.15), while high NfL (p = 0.61), low VILIP‐1 (p = 0.009), and elevated markers of inflammation (sTREM2, p = 0.009; YKL‐40, p<0.001) identified patients with autoimmune/inflammatory diseases (Figure). MCP‐1 levels were highest in patients with vascular causes of RPD (p = 0.08). 44 patients (56.4%) had potentially treatment‐responsive causes of RPD. Treatment responsiveness was associated with higher levels of CSF Aβ42/40 (p = 0.003), NfL (p<0.001), sTREM2 (p<0.001) and YKL‐40 (p<0.001); and lower levels of p‐tau‐181 and p‐tau231 (p<0.001, p<0.001) and VILIP‐1 (p<0.001).ConclusionSelected biomarkers measured in CSF at presentation associate with etiologic diagnosis and treatment responsiveness in patients with neurodegenerative, vascular, and autoimmune/inflammatory causes of RPD. Biomarker panels may be adapted to improve recognition of patients with treatment‐responsive causes of RPD early in the symptomatic course when treatments may be most effective.