Search

Background: The 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. Methods: Established 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). Results: Alzheimer 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). Conclusion: Selected 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. [ABSTRACT FROM AUTHOR]

Background: Rapidly progressive dementia (RPD) includes patients with less than two years from the onset of cognitive impairment to incapacitation due to dementia. Although RPD is often associated with fatal neurodegenerative diseases, including early‐onset Alzheimer disease or Creutzfeldt‐Jakob disease, treatable forms of RPD are increasingly recognized. Early recognition of patients with potentially treatable causes of RPD is key to the timely provision of therapies required to achieve the best possible long‐term outcomes. Method: 155 patients with RPD were prospectively enrolled from February 2016 to August 2022 via two tertiary care centers. Etiologic diagnoses were independently assigned by two neurologists with good agreement (>90%). Causes of RPD were further classified as treatment‐responsive or nonresponsive, referencing the extant literature. Demographic, clinical, and paraclinical features associated with treatable causes of RPD were identified using stepwise multivariate logistic regression and validated with 5‐fold cross validation. Result: 87/155 patients (56.1%) had a potentially treatable cause of RPD, including autoimmune/inflammatory disease (n = 52, 59.8%), vasculitis (n = 13, 14.9%), primary psychiatric disease (n = 4, 4.6%), or nutritional deficiency (n = 4, 4.6%). Multivariable analyses identified seven features that were independently associated with treatment‐responsiveness: age‐at‐symptom onset (OR: 0.62 per decade, 95%CI: 0.42‐0.93), seizures (OR: 9.81, 95%CI: 2.84‐33.89), MRI suggestive of autoimmune encephalitis (OR: 23.08, 95%CI: 2.28‐233.40), CSF white blood cell count ≥10 cells/mm3 (OR: 32.24, 95%CI:5.80‐179.21), movement abnormalities (OR: 4.99, 95%CI: 1.76‐14.10), presence of disease‐associated tumor (OR: 13.82, 95%CI: 2.25‐85.11), and mania (OR: 18.47, 95%CI: 1.76‐193.61). Model performance was excellent (c‐statistic = 0.88, 95%CI: 0.82‐0.94; p<0.001): 71 patients (81.6%) with potentially treatable causes of RPD and 56 patients (82.4%) with non‐treatable causes of RPD were correctly classified (PPV = 85.5%; NPV = 77.8%). Conclusion: Treatment‐responsive causes of RPD were common in our series. Younger age, seizures, movement abnormalities, or mania at presentation, and paraclinical tests suggesting inflammation (MRI or CSF) or tumor in patients with RPD should prompt consideration of treatable causes of RPD and initiation of treatment when indicated. [ABSTRACT FROM AUTHOR]