Inflamed Microglia like Macrophages in the Central Nervous System of Prodromal Parkinson's Disease.

We investigated the role of inflammation in the pathogenesis of prodromal Parkinson's Disease (PD), performing single-cell RNAseq analysis of cerebrospinal fluid (CSF) and blood from 111 individuals, comparing control subjects with early prodromal PD and later PD to patients with multiple sclerosis (MS). Surprisingly, we identified a pleocytosis in the CSF, most pronounced in patients with early PD. Single-cell RNAseq revealed increases in CSF-specific microglia-like macrophages expressing JAK-STAT and TNFα signaling signatures in prodromal PD, with a lack of T cell activation in the CSF.

Characterizing Parkinson's Disease Clinical and Biomarker Interactions in REM Sleep Behavior Disorder.

Background: REM Sleep Behavior Disorder (RBD), marked by dream enactment due to loss of REM-related muscle atonia, is a prominent prodromal indicator of synucleinopathies, particularly Parkinson's Disease (PD).

Objectives: This study aimed to investigate the interplay among key PD biomarkers- α-synuclein seed amplification assay (SAA), hyposmia, and dopamine transporter (DaT) SPECT imaging - in individuals with RBD. Additionally, we evaluated how phenoconversion events and Movement Disorder Society (MDS)-Prodromal PD probability scores relate to clinical symptoms and biomarker profiles in an incident RBD population.

The effect of polygenic risk score on PD risk and phenotype in G2019S and carriers.

BackgroundWhile and variants are associated with Parkinson's disease (PD), most carriers will not develop the disease.ObjectiveTo test if polygenic risk score (PRS) modifies disease risk and phenotypes in G2019S carriers, carriers, and non-carriers (NC).MethodsWe genotyped 786 participants using Illumina's NeuroBooster-array (NBA) and sequenced the genome of 244, all of Ashkenazi ancestry (AJ), and calculated PRS to test its effects on clinically- and biologically-defined disease risk and phenotypes (n = 715).

Quantification of cinpanemab (BIIB054) binding to α-synuclein in cerebrospinal fluid of phase 1 single ascending dose samples.

Through its pathological and genetic association with Parkinson disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Although published studies from some immunotherapy trials have demonstrated engagement in plasma, none has shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system. Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low-affinity binding to monomeric forms.

Radiological markers of CSF α-synuclein aggregation in Parkinson's disease patients.

Alpha-synuclein (αS) aggregation is a widely regarded hallmark of Parkinson's disease (PD) and can be detected through synuclein amplification assays (SAA). This study investigated the association between cerebrospinal fluid (CSF) radiological measures in 41 PD patients (14 iPD, 14 GBA1-PD, 13 LRRK2-PD) and 14 age-and-sex-matched healthy controls. Quantitative measures including striatal binding ratios (SBR), whole-brain and deep gray matter volumes, neuromelanin-MRI (NM-MRI), functional connectivity (FC), and white matter (WM) diffusion-tensor imaging (DTI) were calculated.

Accelerating Parkinson's Disease drug development with federated learning approaches.

Parkinson's Disease is a progressive neurodegenerative disorder afflicting almost 12 million people. Increased understanding of its complex and heterogenous disease pathology, etiology and symptom manifestations has resulted in the need to design, capture and interrogate substantial clinical datasets. Herein we advocate how advances in the deployment of artificial intelligence models for Federated Data Analysis and Federated Learning can help spearhead coordinated and sustainable approaches to address this grand challenge.

Validating new symptom emergence as a patient-centric outcome measure for PD clinical trials.

Introduction: Tracking of emergent symptoms (ES) in de novo Parkinson Disease (PD) patients using Parts Ib and II of the MDS-UPDRS rating scale has been proposed as an outcome measure for PD clinical trials, based on observations in the Safety, Tolerability and Efficacy Assessment of Isradipine for PD (STEADY-PD3) clinical trial.

Methods: Individual item-level data was extracted from the SURE-PD3 study (coded as "PD-1018" in the C-path pooled dataset). We sought to confirm the observations made in the STEADY-PD3 dataset by analyzing data from a different Phase 3 clinical trial, the Phase 3 Study of Urate Elevation in Parkinson Disease (SURE-PD3), in which MDS-UPDRS was assessed more frequently than the 12-month intervals in STEADY-PD3, using similar methodology.

Validity of the Short Weekly Calendar Planning Activity in patients with Parkinson disease and nonmanifesting LRRK2 and GBA carriers.

Background And Purpose: Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short Weekly Calendar Planning Activity (WCPA-10)'s known-group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined.

Mild cognitive impairment among LRRK2 and GBA1 patients with Parkinson's disease.

Background: Mild cognitive impairment (MCI) is common in Parkinson's disease (PD). We aimed to assess the incidence of MCI among patients with PD, carriers of mutations in LRRK2 and GBA1 genes, based on the movement disorder society (MDS) criteria for the diagnosis of MCI in early-stage PD.

Methods: Patients with PD were included if they scored ≤2 on the Hoehn and Yahr and ≤6 years since motor symptom onset.

Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial.

Background And Objectives: Sensitive, reliable, and scalable biomarkers are needed to accelerate the development of therapies for Parkinson disease (PD). In this study, we evaluate the biomarkers of early PD diagnosis, disease progression, and treatment effect collected in the SPARK.

Methods: Cinpanemab is a human-derived monoclonal antibody binding preferentially to aggregated forms of extracellular α-synuclein.

Digital Mobility Measures: A Window into Real-World Severity and Progression of Parkinson's Disease.

Background: Real-world monitoring using wearable sensors has enormous potential for assessing disease severity and symptoms among persons with Parkinson's disease (PD). Many distinct features can be extracted, reflecting multiple mobility domains. However, it is unclear which digital measures are related to PD severity and are sensitive to disease progression.

Mapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early Parkinson's Disease.

Background: Adoption of new digital measures for clinical trials and practice has been hindered by lack of actionable qualitative data demonstrating relevance of these metrics to people with Parkinson's disease.

Objective: This study evaluated of relevance of WATCH-PD digital measures to monitoring meaningful symptoms and impacts of early Parkinson's disease from the patient perspective.

Methods: Participants with early Parkinson's disease (N = 40) completed surveys and 1:1 online-interviews.

Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson's Disease.

Background: Patient perspectives on meaningful symptoms and impacts in early Parkinson's disease (PD) are lacking and are urgently needed to clarify priority areas for monitoring, management, and new therapies.

Objective: To examine experiences of people with early-stage PD, systematically describe meaningful symptoms and impacts, and determine which are most bothersome or important.

Methods: Forty adults with early PD who participated in a study evaluating smartwatch and smartphone digital measures (WATCH-PD study) completed online interviews with symptom mapping to hierarchically delineate symptoms and impacts of disease from "Most bothersome" to "Not present," and to identify which of these were viewed as most important and why.

The Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease.

Background: Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the and genes are common among Ashkenazi Jews, with more severe phenotype reported for -PD.

Objective: To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status.

A qualitative evaluation of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) by the patient community: a web-based cross-sectional survey.

Objective: The revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is the most commonly used outcome measure in ALS studies. The aim of this study was to identify potential limitations of the ALSFRS-R from the perspective of people living with ALS and their caregivers.

Methods: A web-based survey was developed by investigators, people living with ALS, and their caregivers, and shared across social media.

Neuromelanin and T*-MRI for the assessment of genetically at-risk, prodromal, and symptomatic Parkinson's disease.

MRI was suggested as a promising method for the diagnosis and assessment of Parkinson's Disease (PD). We aimed to assess the sensitivity of neuromelanin-MRI and T* with radiomics analysis for detecting PD, identifying individuals at risk, and evaluating genotype-related differences. Patients with PD and non-manifesting (NM) participants [NM-carriers (NMC) and NM-non-carriers (NMNC)], underwent MRI and DAT-SPECT.

Trial of Cinpanemab in Early Parkinson's Disease.

Background: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease.

Methods: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks.

Application of longitudinal item response theory models to modeling Parkinson's disease progression.

The Movement Disorder Society revised version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts 2 and 3 reflect patient-reported functional impact and clinician-reported severity of motor signs of Parkinson's disease (PD), respectively. Total scores are common clinical outcomes but may obscure important time-based changes in items. We aim to analyze longitudinal disease progression based on MDS-UPRDS parts 2 and 3 item-level responses over time and as functions of Hoehn & Yahr (H&Y) stages 1 and 2 for subjects with early PD.

Tracking Emergence of New Motor and Non-Motor Symptoms Using the MDS-UPDRS: A Novel Outcome Measure for Early Parkinson's Disease?

Background: Summary scores of current clinical rating scales do not appear sensitive enough to quantify changes in disease progression in early Parkinson's disease (PD) clinical trials. An alternate approach might be to track the appearance of new or emergent symptoms (ES) over time as a measure of disease progression.

Objective: Explore the potential utility of patient reported ES as an outcome measure during the early phase of PD.

Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers.

Non-manifesting carriers (NMCs) of Parkinson's disease (PD)-related mutations such as LRRK2 and GBA are at an increased risk for developing PD. Dopamine transporter (DaT)-spectral positron emission computed tomography is widely used for capturing functional nigrostriatal dopaminergic activity. However, it does not reflect other ongoing neuronal processes; especially in the prodromal stages of the disease.

Considerations to address missing data when deriving clinical trial endpoints from digital health technologies.

Digital health technologies (DHTs) enable us to measure human physiology and behavior remotely, objectively and continuously. With the accelerated adoption of DHTs in clinical trials, there is an unmet need to identify statistical approaches to address missing data to ensure that the derived endpoints are valid, accurate, and reliable. It is not obvious how commonly used statistical methods to handle missing data in clinical trials can be directly applied to the complex data collected by DHTs.

Evaluating dopamine transporter imaging as an enrichment biomarker in a phase 2 Parkinson's disease trial.

Background: Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can quantify the functional integrity of the dopaminergic nerve terminals and has been suggested as an imaging modality to verify the clinical diagnosis of Parkinson's disease (PD). Depending on the stage of progression, approximately 5-15% of participants clinically diagnosed with idiopathic PD have been observed in previous studies to have normal DaT-SPECT patterns. However, the utility of DaT-SPECT in enhancing early PD participant selection in a global, multicenter clinical trial of a potentially disease-modifying therapy is not well understood.

Seeking progress in disease modification in Parkinson disease.

Objective: Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions.

Methods: The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD.