Tipton, Philip W.

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

ObjectiveTo improve the timely recognition of patients with treatment‐responsive causes of rapidly progressive dementia (RPD).MethodsA total of 226 adult patients with suspected RPD were enrolled in a prospective observational study and followed for up to 2 years. Diseases associated with RPD were characterized as potentially treatment‐responsive or non‐responsive, referencing clinical literature. Disease progression was measured using Clinical Dementia Rating® Sum‐of‐Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Findings informed the development of a clinical criterion optimized to recognize patients with potentially treatment‐responsive causes of RPD early in the diagnostic evaluation.ResultsA total of 155 patients met defined RPD criteria, of whom 86 patients (55.5%) had potentially treatment‐responsive causes. The median (range) age‐at‐symptom onset in patients with RPD was 68.9 years (range 22.0–90.7 years), with a similar number of men and women. Seizures, tumor (disease‐associated), magnetic resonance imaging suggestive of autoimmune encephalitis, mania, movement abnormalities, and pleocytosis (≥10 cells/mm3) in cerebrospinal fluid at presentation were independently associated with treatment‐responsive causes of RPD after controlling for age and sex. Those features at presentation, as well as age‐at‐symptom onset <50 years (ie, STAM3P), captured 82 of 86 (95.3%) cases of treatment‐responsive RPD. The presence of ≥3 STAM3P features had a positive predictive value of 100%.InterpretationSelected features at presentation reliably identified patients with potentially treatment‐responsive causes of RPD. Adaptation of the STAM3P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with suspected RPD. ANN NEUROL 2024;95:237–248

Autoimmune movement disorders are increasingly recognized, but isolated tremor is extremely rare. We describe a 70‐year‐old male with rapidly progressive, severe postural and intention tremor and weight loss. His cerebrospinal fluid was inflammatory and harbored a neural tissue‐restricted antibody. The autoantigen was identified by immunoprecipitation and mass spectrometry and confirmed by antigen‐specific assays to be specific for tenascin‐R. He was investigated for cancer and diagnosed with follicular lymphoma that expressed tenascin‐R suggesting a paraneoplastic origin; cancer treatment and immunotherapy led to complete recovery. With this individualized patient approach and antibody discovery, we expand the spectrum of antibodies accompanying autoimmune hyperkinetic movement disorders. ANN NEUROL 2023;94:502–507