Comparison of plasma p-tau217/Aβ42, p-tau217, and Aβ42/Aβ40 biomarkers by race to detect Alzheimer's disease.

Introduction: In clinically and racially diverse training and test sets, we evaluated and validated Alzheimer's disease (AD) plasma biomarkers: phosphorylated tau-217 (p-tau217), amyloid beta 1-42/1-40 (Aβ42/Aβ40), and p-tau217/Aβ42.

Methods: Inclusion criteria were available plasma, race (people who self-identified as Black/African American [pBlack] or White [pWhite]), cognitive status (normal, mild cognitive impairment [MCI], dementia), and F-florbetaben or F-florbetapir positron emission tomography (PET) data. In the training set (n = 289; 28% pBlack), we used receiver-operating characteristic (ROC) analysis to calculate two cut points (0.

It is time to share Alzheimer biomarker results in dementia with Lewy bodies.

Unlabelled: There are increasing calls for sharing individual biomarker results with participants in dementia research. No studies investigate returning Alzheimer's disease (AD) biomarker results to individuals with syndromic dementia with Lewy bodies (DLB) even though most of these individuals have both pathologies. This perspective argues that AD biomarkers are valid, interpretable, and actionable, particularly relating to expected prognosis and treatment effects, in people with DLB.

Tau burden is best captured by magnitude and extent: Tau-MaX as a measure of global tau.

Introduction: Tau burden consists of both spatial spread and local accumulation, but no study has combined these measures into a single metric to capture overall global tau burden. Here we investigate a new measure combining magnitude and extent-Tau-MaX-as a marker of Alzheimer's disease (AD) severity.

Methods: A total of 1077 F-flortaucipir positron emission tomography scans were analyzed using Gaussian mixture models to identify tau+ regions and quantify magnitude of accumulation.

The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series.

Objective: A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders.

Blood α-Synuclein Separates Parkinson's Disease from Dementia with Lewy Bodies.

Objective: Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBDs), including Parkinson's disease (PD), and dementia with Lewy bodies (DLB) disease. Although evidence exists for aSyn "strains," conformations with distinct biological properties, biomarkers for PD versus DLB are lacking. Here, we used monoclonal antibodies selective for two different in vitro aSyn species - termed strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma.

Patient-reported outcomes for remote and in-person visits for genetic counseling in adult neurology.

At our center, we offer clinical genetic counseling (GC) visits for adults with a personal and/or family history of neurologic disease. Here, we report patient experience and outcomes from different visit modalities (e.g.

Tau Burden is Best Captured by Magnitude and Extent: Tau-MaX as a Measure of Global Tau.

Tau exhibits change in both spatial extent and density of pathology along the Alzheimer's disease (AD) spectrum with each aspect contributing to the overall burden of pathological tau. Nevertheless, studies using Tau PET have measured either magnitude using standardized uptake value ratios (SUVRs) or extent using number of Tau+ regions. We hypothesized that combining these two dimensions into a single measure of Magnitude and eXtent, Tau-MaX, would provide improved quantification of global tau burden as well as allowing for a region-agnostic measure of global tau burden that does not require a pre-specified region of interest (ROI) or meta-ROI.

An Open-Label Pilot Study to Examine the Safety, Tolerability and Efficacy of Deutetrabenazine in Isolated Dystonia.

Background: Dystonia may respond to VMAT2 inhibition.

Objectives: Providing pilot data on the safety, tolerability, and efficacy of deutetrabenazine in non dopa-responsive dystonia.

Methods: Deutetrabenazine was titrated by adults with isolated dystonia.

ADNI Biomarker Core: A review of progress since 2004 and future challenges.

Background: We describe the Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core major activities from October 2004 to March 2024, including biobanking ADNI cerebrospinal fluid (CSF), plasma, and serum biofluid samples, biofluid analyses for Alzheimer's disease (AD) biomarkers in the Biomarker Core and various non-ADNI laboratories, and continuous assessments of pre-analytics.

Results: Validated immunoassay and mass spectrometry-based assays were performed in CSF with a shift to plasma, a more accessible biofluid, as qualified assays became available. Performance comparisons across different CSF and plasma AD biomarker measurement platforms have enriched substantially the ADNI participant database enabling method performance determinations for AD pathology detection and longitudinal assessments of disease progression.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence exists for aSyn "strains" - conformations with distinct biological properties. However, biomarkers for PD vs.

Biomarker discovery in progressive supranuclear palsy from human cerebrospinal fluid.

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder often misdiagnosed as Parkinson's Disease (PD) due to shared symptoms. PSP is characterized by the accumulation of tau protein in specific brain regions, leading to loss of balance, gaze impairment, and dementia. Diagnosing PSP is challenging, and there is a significant demand for reliable biomarkers.

Parkinson's disease variant detection and disclosure: PD GENEration, a North American study.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease.

User and Usability Testing of a Web-Based Genetics Education Tool for Parkinson Disease: Mixed Methods Study.

Background: Genetic testing is essential to identify research participants for clinical trials enrolling people with Parkinson disease (PD) carrying a variant in the glucocerebrosidase (GBA) or leucine-rich repeat kinase 2 (LRRK2) genes. The limited availability of professionals trained in neurogenetics or genetic counseling is a major barrier to increased testing. Telehealth solutions to increase access to genetics education can help address issues around counselor availability and offer options to patients and family members.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain ( in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear.

Provider Impressions of Inpatient Teleneurology Consultation.

Background And Objectives: Teleneurology usage has increased during the severe acute respiratory syndrome coronavirus 2 pandemic. However, studies evaluating physician impressions of inpatient teleneurology are limited. We implemented a quality improvement initiative to evaluate neurologists' impression following individual inpatient teleneurology consultation at a satellite hospital of a large academic center with no in-person neurology coverage.

Genetic and phenotypic characterization of Parkinson's disease at the clinic-wide level.

Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale.

Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.

Introduction: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog).

Methods: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-.

GPNMB Biomarker Levels in GBA1 Carriers with Lewy Body Disorders.

Background: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease.

Objective: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype.

Disparities in Genetic Testing for Neurologic Disorders.

Background And Objectives: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions.

Evaluation of ATN Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease.

Background And Objectives: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ), phosphorylated tau 181 (p-tau), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ.

Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

Objective: Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia.

Methods: We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses.