Citations

Objective To determine the clinical features that identify patients with suspected rapidly progressive dementia (RPD) who will develop RPD. Methods Patients with suspected RPD were enrolled and followed at Mayo Clinic (Jacksonville, FL; January 2020 to October 2023) and Washington University (Saint Louis, MO; June 2016 to December 2019). Two dementia specialists independently reviewed clinical data and assigned diagnoses. Patients were diagnosed with RPD if they developed dementia within 1 year or incapacitation within 2 years of symptom onset. The associations between clinical features and causes and outcomes were explored via univariate and multivariate comparisons. Results Of 248 patients with suspected RPD, 185 (74.6%) met criteria for RPD. Patients with RPD were older (62.6 ± 14.5 vs 55.2 ± 18.1 years; p < 0.001), and more frequently diagnosed with Alzheimer's disease or related dementias (OR 3.13, 95% CI 1.40, 7.31) or Creutzfeldt–Jakob disease (OR 4.67, 95% CI 1.38, 15.75). Visual agnosia (15/183; 8.2%), substantial brain atrophy (27/182; 14.8%), and periodic epileptiform discharges (11/151; 7.3%) were exclusively detected in patients with RPD. After controlling for age, intensive care unit admission (OR 4.77, 95% CI 1.61, 14.12), lack of seizures (OR 2.47, 95% CI 1.15, 5.31), abnormal brain magnetic resonance imaging (OR 2.01, 95% CI 0.997, 4.05), and cerebrospinal fluid white blood cell count ≤5 cells/mm 3 (OR 3.30, 95% CI 1.60, 6.82) were also independently associated with RPD. Patients with RPD were more likely to die or develop severe dementia (mean time to outcome, 36.1 months; 95% CI 31.2–41.0). Interpretation Selected clinical features may identify patients with suspected RPD who are likely to continue to decline. Early recognition of these features may improve diagnostic accuracy and inform prognosis. ANN NEUROL 2025;98:764–776

Abstract INTRODUCTION Plasma biomarkers of Alzheimer's disease (AD) represent accessible alternatives to positron emission tomography (PET) and cerebrospinal fluid (CSF)‐based biomarkers in well‐characterized cohorts. It remains to be determined whether performance is maintained in outpatient clinics comprised of patients with multiple causes of cognitive impairment. METHODS Plasma phosphorylated tau217 (p‐tau217) and amyloid beta (Aβ) 42/40 were measured in 509 patients evaluated in a tertiary‐care memory clinic. Biomarker performance was compared across diagnoses, referencing established cutpoints for positive and negative biomarkers. RESULTS Plasma p‐tau217 distinguished patients with diagnoses of symptomatic AD with 95% sensitivity and 82% specificity. Integration of Aβ42 measurements (p‐tau217/Aβ42) incrementally improved specificity (86%). Plasma p‐tau217 and p‐tau217/Aβ42 concentrations closely associated with established CSF biomarkers of AD (area under the curve [AUC]: 0.94 and 0.96, respectively). Reduced kidney function associated with elevated plasma p‐tau217 and p‐tau217/Aβ42 concentrations in patients without AD (referencing CSF biomarkers). DISCUSSION Plasma p‐tau217 and p‐tau217/Aβ42 concentrations demonstrated robust diagnostic performance in a heterogeneous clinical cohort; interpretation requires consideration of kidney function. Highlights Plasma phosphorylated tau217 (p‐tau217) reliably identified clinic patients with Alzheimer's disease. A two‐cutpoint strategy yielded definitive results in 86% of patients. Integration of plasma amyloid beta (Aβ; p‐tau217/Aβ42) minimally improved diagnostic performance. Plasma p‐tau217 levels were increased in patients with kidney dysfunction.

AbstractBackgroundPatients with rapid progressive Alzheimer disease and related dementias (rpAD/ADRD) develop dementia within 1 year or incapacitation within 2 years of symptom onset. We previously showed that selected CSF biomarkers of neuronal injury (NfL, VILIP‐1), AD neuropathology (p‐tau181), and neuroinflammation (GFAP, MCP‐1, sTREM2) measured at presentation associated with etiologic diagnoses and reliably differentiated patients with treatment‐responsive causes of rapid progressive dementia. However, no differences were identified between CSF biomarkers in patients with rapid and typical progressive forms of AD/ADRD, leaving key questions unanswered concerning the mechanisms that drive rpAD/ADRD. Blood‐based biomarkers may inform the systemic factors that contribute to rpAD/ADRD, including the systemic inflammation, metabolic function, and vascular injury.MethodsBiomarkers of systemic inflammation (Eotaxin‐3, IFN‐γ, IL‐1b, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TARC, TNF‐α), metabolic function (A2M, B2M, FABP‐3, FVII, I‐309, IL‐18, PPY, TNC, TPO), and vascular injury (CRP, SAA, sICAM‐1, sVCAM‐1) were measured in plasma obtained at presentation from patients with rpAD/ADRD (n=29) and age‐ and sex‐ similar participants with typical progressive AD/ADRD (n=39) enrolled in prospective studies of memory and aging at Mayo Clinic in Florida. Biomarker measures were completed at the University of North Texas Institute for Translational Research using Meso Scale Discovery multiplexed assays. Biomarker concentrations were compared between groups using univariate analyses; potential predictors (p<0.05) were further evaluated via step‐wise multivariate logistic regression.ResultsMarkers of vascular injury (SAA, CRP, sICAM‐1), metabolic function (I‐309, TPO), and systemic inflammation (Eotaxin‐3, TARC, TNF‐α) were increased in patients with rapid versus typical progressive AD/ADRD (p<0.05). Eotaxin‐3, I‐309, and SAA were independently associated with rpAD/ADRD in multivariable model after controlling for age and sex. The overall model correctly characterized 86.8% of patients, with an area under the curve of 0.864 (95%CI: 0.777‐0.950; p<0.001).ConclusionBlood‐based biomarkers of systemic inflammation, metabolic function, and vascular injury were elevated at presentation in patients with rapid vs typical AD/ADRD. These findings may provide additional insights into the mechanisms that drive rpAD/ADRD. Longitudinal measures from larger cohorts are needed to decipher the relationship between candidate biomarkers and rpAD/ADRD.