Day, Gregory S

Abstract INTRODUCTION Plasma p‐tau217 and p‐tau217/Aβ42 reliably identify non‐Hispanic White individuals with symptomatic and pre‐clinical AD. However, performance across ethnoracially diverse groups remains unknown. METHODS Cognitively normal Black, Hispanic, and non‐Hispanic White participants completed cognitive evaluations, brain magnetic resonance imaging (MRI), amyloid and tau positron emission tomography (PET), and measures of kidney function. Plasma p‐tau217 and Aβ42 were measured using Fujirebio Lumipulse assays. Pre‐clinical AD detection was evaluated using symptomatic and cohort‐derived optimized cutoffs. RESULTS Among 191 participants (57 Black, 46 Hispanic White, 88 non‐Hispanic White), age‐adjusted plasma p‐tau217 and p‐tau217/Aβ42 performed similarly in detecting amyloid‐positive individuals (≥ 25 Centiloids), regardless of race/ethnicity. Both measures independently correlated with amyloid deposition, whereas estimated glomerular filtration rate (eGFR) correlated solely with p‐tau217. Pre‐clinical AD optimized cutoffs (p‐tau217 ≥ 0.132 pg/ml; p‐tau217/Aβ42 ≥ 0.0059) outperformed cutoffs established in symptomatic individuals (sensitivity: 83% vs. 57%; 77% vs. 63%; negative predictive value [NPV] > 93%). DISCUSSION Plasma biomarkers performed similarly across ethnoracially diverse cohorts. Optimized cutoffs may improve early detection and trial enrollment.

Abstract Objective This study was undertaken to examine acute and chronic electroencephalographic (EEG) and seizure characteristics in new onset refractory status epilepticus (NORSE). Methods Multicenter inpatient and follow‐up clinical and EEG data were analyzed using International League Against Epilepsy definitions and American Clinical Neurophysiology Society (ACNS) EEG terminology. Results Forty‐four patients were included from the Yale NORSE/FIRES Biorepository (median age = 29 years, 33 female, 38 cryptogenic). Nine hundred twenty inpatient EEG days were reviewed (median = 13.5 days/patient). Presenting status epilepticus (SE) types included 24 convulsive SE (CSE), five focal–motor (FMSE), and 15 nonconvulsive (NCSE). Of 39 patients with post discharge follow‐up (median = 14.7 months), 61.5% ( n = 24) had seizures and required more antiseizure medications than seizure‐free patients (median = 4 vs. 1, p < .001). Inpatient EEG captured epileptiform discharges in all and periodic discharges in 38 patients. Seizures were captured in 38 patients: 33 electrographic (11 only electrographic) and 27 electroclinical. Total seizure burden ranged 6.5–29 615.0 min (median = 50.7). Seizures fulfilling ACNS EEG criteria for SE were captured in 20 patients; two had CSE and the remainder NCSE with coma, nine of whom also had FMSE. Inpatient seizure days (median = 50.0 vs. 15.5%, p = .004) and seizure burden (median = 42.9 vs. 0 min, p = .009) were higher in the first half of monitored days. Interictal findings were equally present and did not predict postdischarge seizures, whereas electroclinical seizures (90.9% vs. 45.5%, p = .037), seizure burden (median = 116.8 vs. 32.5 min, p = .045), and proportion of seizure days (36.3% vs. 20.0%, p = .037) did. Among 12 patients with follow‐up EEGs (median = 19.6 months post onset), posterior‐dominant rhythm (PDR) returned in nine; five had periodic discharges, and three had seizure captured. Significance Seizures are most commonly convulsive upon presentation and nonconvulsive or clinically subtle throughout the inpatient course in NORSE. Inpatient seizures, but not interictal abnormalities, occur earlier in the inpatient course and presence of electroclinical seizures, seizure burden, and proportion of seizure days but not interictal findings are associated with postdischarge seizures. Although return of PDR reflects neurological recovery, seizure persistence and EEG abnormalities post‐NORSE are common.

ABSTRACT Early identification of patients with treatment‐responsive rapidly progressive dementia (RPD) is important as early treatment improves outcomes. The STAM 3 P score identifies treatment‐responsive RPD using “high risk” presenting features. We optimized performance by adding a time component (i.e., dementia within 3 months) and validated the modified “STAM3 m P score” in two independent cohorts ( n = 302). A STAM3 m P score ≥ 1 identified 96% of patients with treatment‐responsive RPD; ≥ 3 features were highly specific (98%). These data suggest that ≥ 1 STAM3 m P features effectively identifies treatment‐responsive RPD and may be used to prioritize investigations, whereas ≥ 3 STAM3 m P features are highly specific and may inform early treatment decisions.

ABSTRACT BACKGROUND Increasing evidence suggests that accurate prediction of Alzheimer’s disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) Aβ42/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring. METHODS We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD. FINDINGS NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values. INTERPRETATION Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development. FUNDING National Institute on Aging, Alzheimer’s Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.

Abstract INTRODUCTION Visual perceptual difficulties occur in dementia with Lewy bodies (DLB). Normative data and cut scores for DLB and mild cognitive impairment with Lewy bodies (MCI‐LB) are needed for the 20‐item Noise Pareidolia Task. METHODS Participants included 344 cognitively unimpaired (CU), 112 DLB, and 105 MCI‐LB. Cumulative percentile ranking was used for normative classification. Receiver operating characteristic analyses, convergent validity, and associations with visual hallucinations (VH) were assessed. RESULTS In CU participants, a perfect score was average, one error was low average, and two or more errors fell below average. A cut score of one or more errors optimally distinguished CU participants from DLB (Total score area under the curve [AUC]: 0.82, Noise score AUC: 0.77) and MCI‐LB (Total score AUC: 0.75, Noise score AUC: 0.74). A cut score of two or more errors lowered sensitivity but increased specificity to 94%. Performance was associated with VH in DLB, but not MCI‐LB. DISCUSSION Results establish normative data for the 20‐item Noise Pareidolia Task and support its use in DLB and MCI‐LB.