Diagnostic Applications of Cerebrospinal Fluid Biomarkers in Patients with Rapidly Progressive Dementia
Gregory Day1, Lindsey Kuchenbecker2, Philip Tipton1, Yuka Martens2, Matthew Brier3, Nihal Satyadev1, Steven Dunham3, Evelyn Lazar4, Maxwell Dacquel2, Rachel Henson3, Guojun Bu2, Michael Geschwind5, John Morris3, Suzanne Schindler3, Elizabeth Herries3, Neill Graff-Radford1
1Neurology, 2Neuroscience, Mayo Clinic, 3Neurology, Washington University, 4Neurology, JFK Medical Center, 5Neurology, UCSF
Objective:
Apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy and recognition of patients with potentially treatment-responsive causes of rapidly progressive dementia (RPD).
Background:
Overlap 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.
Design/Methods:
Patients with RPD were enrolled and evaluated from 2016-2022 in inpatient and outpatient clinics at two tertiary care centers; CSF was obtained following the initial presentation and banked for research purposes. Biomarkers 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 from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex- matched patients with typical progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by treatment responsiveness, and between patients with typical and rapid progressive presentations of neurodegenerative disease.
Results:
Alzheimer 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 biomarker differences were observed between patients with typical and rapidly progressive presentations of neurodegenerative disease.
Conclusions:
Selected biomarkers associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD but did not inform the mechanisms that drive rapid progressive neurodegeneration. Biomarker panels may be adapted to improve etiologic diagnoses of RPD and recognition of patients with treatment-responsive causes of RPD early in the symptomatic course when diagnostic uncertainty and potential therapeutic responsiveness are highest.