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

Author:

Kuchenbecker Lindsey A.1ORCID,Tipton Philip W.2ORCID,Martens Yuka1,Brier Matthew R.3ORCID,Satyadev Nihal2ORCID,Dunham S. Richard3ORCID,Lazar Evelyn B.24,Dacquel Maxwell V.1,Henson Rachel L.3,Bu Guojun1,Geschwind Michael D.5,Morris John C.3,Schindler Suzanne E.3,Herries Elizabeth3,Graff‐Radford Neill R.2,Day Gregory S.2ORCID

Affiliation:

1. Department of Neuroscience Mayo Clinic Florida Jacksonville FL USA

2. Department of Neurology Mayo Clinic Florida Jacksonville FL USA

3. Department of Neurology Washington University School of Medicine Saint Louis MO USA

4. Hackensack Meridian JFK University Medical Center Edison NJ USA

5. Department of Neurology University of California, San Francisco San Francisco CA USA

Abstract

ObjectiveThis study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). 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.MethodsBiomarkers of Alzheimer disease neuropathology (amyloid‐β 42/40 ratio, phosphorylated tau [p‐tau181, p‐tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin‐like protein‐1 [VILIP‐1], total tau), neuroinflammation (chitinase‐3‐like protein [YKL‐40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein‐1 [MCP‐1]), and synaptic dysfunction (synaptosomal‐associated protein 25kDa, 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 were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and 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 were 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. ANN NEUROL 2024;95:299–313

Funder

National Institute on Aging

Publisher

Wiley

Subject

Neurology (clinical),Neurology

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