Piura, Yoav D

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.

AbstractObjectivePrion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG‐PET) imaging for this purpose.MethodsFDG‐PET were performed in 40 clinic patients with prion disease. FDG‐PET images were projected onto latent factors generated in an external dataset to yield patient‐specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data‐driven clusters, which were compared by survival time.ResultsMedian age at FDG‐PET was 65.3 years (range 23–85). Median time from FDG‐PET to death was 3.7 months (range 0.3–19.0). Four data‐driven clusters were generated, termed “Neocortical” (n = 7), “Transitional” (n = 12), “Temporo‐parietal” (n = 13), and “Deep nuclei” (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG‐PET‐patterns were not associated with demographic (age and sex) or clinical (CSF total‐tau, 14‐3‐3) variables.InterpretationGreater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG‐PET informs large‐scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG‐PET may enrich multimodal prion disease prognostication models.