In a recent Viewpoint article (. 2024;81:789‒90), Okubadejo et al. raised concerns regarding two recent proposals for biological definitions and staging systems for synucleinopathies (the Neuronal Synuclein Disease Integrated Staging System and SynNeurGe system).
View Article and Find Full Text PDFThe Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline.
View Article and Find Full Text PDFBackground: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without evidence of alpha-synuclein aggregates.
View Article and Find Full Text PDFParkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life.
View Article and Find Full Text PDFThis series of studies characterized [F]T-008, a PET radiotracer for imaging cholesterol 24-hydroxylase (CH24H), in healthy volunteers (ClinicalTrials.gov identifier NCT02497235). Assessments included radiation dosimetry, kinetic modeling, test-retest variability (TRT) evaluation, and a dose occupancy evaluation using soticlestat, a selective CH24H inhibitor.
View Article and Find Full Text PDFThere is disagreement in the literature whether olfaction may show specific impairments in Parkinson Disease (PD) and if olfactory tests comprised of selected odors could be more specific for diagnosis. We sought to validate previously proposed subsets of the University of Pennsylvania Smell Identification Test (UPSIT) odors for predicting conversion to PD in an independent, prodromal cohort. Conversion to PD was assessed in 229 participants in the Parkinson At Risk Study who completed baseline olfactory testing with the UPSIT and up to 12 years of clinical and imaging evaluations.
View Article and Find Full Text PDFBackground: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD).
Objective: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD.
Methods: Two randomized, double-blind, placebo-controlled studies were completed.
Parkinsonism Relat Disord
November 2022
Background: The Parkinson Associated Risk Syndrome (PARS) study was designed to evaluate whether screening with olfactory testing and dopamine transporter (DAT) imaging could identify participants at risk for developing Parkinson's disease (PD).
Objective: Hyposmia on a single test has been associated with increased risk of PD, but, taken alone, lacks specificity. We evaluated whether repeating olfactory testing improves the diagnostic characteristics of this screening approach.
Mutations in leucine-rich repeat kinase 2 () are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD.
View Article and Find Full Text PDFMultiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) in the pathogenesis of fragile X syndrome (FXS), the most commonly known single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Nevertheless, animal and human studies regarding the link between FMRP and mGluR5 expression provide inconsistent or conflicting findings about the nature of those relationships. Since multiple clinical trials of glutamatergic agents in humans with FXS did not demonstrate the amelioration of the behavioral phenotype observed in animal models of FXS, we sought measure if mGluR5 expression is increased in men with FXS to form the basis for improved clinical trials.
View Article and Find Full Text PDFGlutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR) in knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR expression in humans with FXS exposed to NAMs might help in that effort.
View Article and Find Full Text PDFObjective: The Systemic Synuclein Sampling Study (S4) measured α-synuclein in multiple tissues and biofluids within the same patients with Parkinson disease (PD) vs healthy controls (HCs).
Methods: S4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and nonmotor measures and dopamine transporter SPECT were obtained.
Background And Objectives: The PARS (Parkinson Associated Risk Syndrome) study was designed to test whether screening for hyposmia followed by dopamine transporter imaging can identify risk for conversion to clinical PD, and to evaluate progression markers during the prodromal period.
Methods: Subjects with hyposmia completed annual clinical evaluations and biennial [ I]ß-CIT single-photon emission computed tomography scans. Subjects were categorized as normal (>80% age-expected tracer uptake; n = 134), indeterminate (>65-80%; n = 30), and dopamine transporter deficit (≤65%; n = 21) by their baseline scan, and survival analysis was used to compare risk of conversion to motor PD.
As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability.
View Article and Find Full Text PDFObjective: To determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC).
Background: Cerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery effort in PD with still limited data on safety and feasibility of serial LPs in PD participants.
Design/methods: Parkinson's Progression Marker Initiative (PPMI) is a longitudinal observation study designed to identify PD progression biomarkers.
Objective: The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials.
Methods: A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging.
Background: α-synuclein is a lead Parkinson's disease (PD) biomarker. There are conflicting reports regarding accuracy of α-synuclein in different tissues and biofluids as a PD biomarker, and the within-subject anatomical distribution of α-synuclein is not well described. The Systemic Synuclein Sampling Study (S4) aims to address these gaps in knowledge.
View Article and Find Full Text PDFImmunohistochemical (IHC) α-synuclein (Asyn) pathology in peripheral biopsies may be a biomarker of Parkinson disease (PD). The multi-center Systemic Synuclein Sampling Study (S4) is evaluating IHC Asyn pathology within skin, colon and submandibular gland biopsies from 60 PD and 20 control subjects. Asyn pathology is being evaluated by a blinded panel of specially trained neuropathologists.
View Article and Find Full Text PDFPlasma total and nervous system derived exosomal (NDE) α-synuclein have been determined as potential biomarkers of Parkinson's disease (PD). To explore the utility of plasma α-synuclein in the prodromal phase of PD, plasma total and NDE α-synuclein were evaluated in baseline and 2-year follow-up samples from 256 individuals recruited as part of the Parkinson's Associated Risk Syndrome (PARS) study. The results demonstrated that baseline and longitudinal increases in total α-synuclein predicted progression of cognitive decline in hyposmic individuals with dopamine transporter (DAT) binding reduction.
View Article and Find Full Text PDFObjective: The objective of this study was to assess longitudinal change in clinical and dopamine transporter imaging outcomes in early, untreated PD.
Methods: We describe 5-year longitudinal change of the MDS-UPDRS and other clinical measures using results from the Parkinson's Progression Markers Initiative, a longitudinal cohort study of early Parkinson's disease (PD) participants untreated at baseline. We also provide data on the longitudinal change in dopamine transporter 123-I Ioflupane striatal binding and correlation between the 2 measures.
Background: Prospective data on cognition in prodromal Parkinson's disease are limited. The objectives of this study were to assess in prodromal PD (1) if baseline cognition predicts conversion to clinical PD, (2) if baseline dopamine transporter binding predicts longitudinal changes in cognition, and (3) if impaired olfaction predicts future cognitive decline.
Methods: Prodromal participants were 136 hyposmic individuals enrolled in the Parkinson Associated Risk Study.