Prodromal features and risk of neurodegenerative disorders diagnosis in outpatients with REM sleep behavior disorder.

Study Objectives: Individuals with isolated REM sleep behavior disorder (iRBD) are at high risk of neurodegenerative parkinsonian disorders or dementia (NPD). Determining which characteristics predict greatest risk could improve clinical care. Our objectives were to utilize electronic health record (EHR) data to apply prodromal PD research diagnostic criteria to iRBD outpatients and determine their utility for identifying iRBD cases at high vs low risk for NPD diagnosis.

Nigrostriatal dopaminergic integrity in relation to prefrontal cortex activity and gait performance during dual-task walking in older adults.

Background: Walking automaticity facilitates maintenance of gait speed without prefrontal cortex (PFC) resources. Brain aging may cause shifts to attentional gait with greater engagement of the PFC. Nigrostriatal dopaminergic integrity likely facilitates walking automaticity and gait speed during attentional dual-tasks.

Cognitive Performance in Early Neuronal Synuclein Disease with Hyposmia but without Motor Disability: Association with Dopamine Deficiency and Isolated Rapid Eye Movement Sleep Behavior Disorder.

Objective: To determine the impact of dopamine deficiency and isolated rapid eye movement (REM) sleep behavior disorder (iRBD) on cognitive performance in early neuronal α-synuclein disease (NSD) with hyposmia but without motor disability.

Methods: Using Parkinson's Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) derived from robust healthy control (HC) norms. Performance was examined for participants with hyposmia in early NSD-Integrated Staging System (NSD-ISS), either stage 2A (cerebrospinal fluid α-synuclein seed amplification assay [SAA]+, dopamine transporter scan [DaTscan]-) or 2B (SAA+, DaTscan+).

Nigrostriatal dopaminergic neurotransmission and resilience to peripheral systemic risk factors for gait slowing upon transition to uneven surfaces in older adult.

Identifying mechanisms that compensate for slow gait speed in older adults is crucial. Dopaminergic neurotransmission curbs deleterious associations of cerebrovascular disease with gait, but whether it compensates for peripheral systemic risk factors (PSRF) for gait slowing has not been studied. In this cross-sectional study of community-dwelling older adults, we examined the relationship between nigrostriatal dopaminergic terminal integrity and gait speed in individuals with and without ≥ 1 PSRF for gait slowing: obesity, joint pain, or reduced muscle strength.

Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.

Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear. We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women).

Neuronal α-Synuclein Disease Stage Progression over 5 Years.

Background: Neuronal α-synuclein disease (NSD) is defined by the presence of an in vivo biomarker of neuronal alpha-synuclein (n-asyn) pathology. The NSD integrated staging system (NSD-ISS) for research describes progression across the disease continuum as stages 0 to 6.

Objective: The aim was to assess 5-year longitudinal change in NSD-ISS in early disease.

Fears and uncertainties of people with Parkinson's disease.

BackgroundThe patient experience of Parkinson's disease (PD) is heterogeneous, with limited prognostic tools to predict individual outcomes, leading to significant uncertainty for people with PD. Under-recognition of both psychosocial and biological drivers of fear and uncertainty in Parkinson's disease (PD) by clinicians may further contribute to patient distress.ObjectiveThe objective of the present study is to investigate fear and uncertainty in people with PD.

Carriers of pathogenic variants show a milder, anatomically distinct brain signature of Parkinson's disease.

gene variants are a major genetic risk factor for both familial and sporadic Parkinson's disease (PD), opening an unattended window on the disease's mechanisms and potential therapies. Investigating the influence of pathogenic variants in gene on brain structure is a crucial step toward enabling early diagnosis and personalized treatment. Yet, despite its significance, the ways in which genotype affects brain structure remain largely unexplored.

-associated parkinsonism with and without evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization.

Among -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 of follow-up, among -associated parkinsonism cases with and without evidence of alpha-synuclein aggregates.

Nigrostriatal dopaminergic integrity in relation to prefrontal cortex activity and gait performance during dual-task walking in older adults.

Greater walking automaticity facilitates maintenance of gait speed without prefrontal cortex (PFC) resources. Brain aging may cause shifts to more attentional gait with greater engagement of the PFC. Nigrostriatal dopaminergic integrity likely facilitates walking automaticity and maintenance of gait speed during attentional dual-tasks.

Effects of 6 months of endurance exercise on motor function, exercise capacity, and autonomic function based on presence of autonomic dysfunction in individuals with early Parkinson's disease.

BackgroundEndurance exercise improves aerobic capacity (VO) and motor symptoms in people with early Parkinson's disease (PD). Some people with PD exhibit signs of chronotropic incompetence (CI), which may impact exercise-induced benefits.ObjectiveWe investigated whether CI in people with early PD influences the change in motor signs, VO, and peak heart rate (HR) following 6 months of endurance exercise.

Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.

Elucidating the genetic contributions to Parkinson's disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases.

Concordance and test-retest consistency of sleep biomarker-based neurodegenerative disorder profiling.

Biomarkers that aid in early detection of neurodegeneration are needed to enable early symptomatic treatment and enable identification of people who may benefit from neuroprotective interventions. Increasing evidence suggests that sleep biomarkers may be useful, given the bi-directional relationship between sleep and neurodegeneration and the prominence of sleep disturbances and altered sleep architectural characteristics in several neurodegenerative disorders. This study aimed to demonstrate that sleep can accurately characterize specific neurodegenerative disorders (NDD).

Staged Screening Identifies People with Biomarkers Related to Neuronal Alpha-Synuclein Disease.

Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation.

Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis.

Impact of dopamine deficiency and REM sleep behavior disorder on cognition in early neuronal synuclein disease with hyposmia.

Objectives: To determine the impact of dopamine deficiency and isolated REM sleep behavior disorder (iRBD) on cognitive performance in early neuronal alpha-synuclein disease (NSD) with hyposmia.

Methods: Using Parkinson's Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) developed by applying regression-based internal norms derived from a robust healthy control (HC) group. Performance was examined for participants with hyposmia classified as NSD-Integrated Staging System (NSD-ISS) Stage 2, either Stage 2A (CSF alpha-synuclein seed amplification assay [SAA]+, SPECT dopamine transporter scan [DaTscan]-) or 2B (SAA+, DaTscan+).

Environmental Risk Factors for Parkinson's Disease: A Critical Review and Policy Implications.

The age-standardized prevalence of Parkinson's disease (PD) has increased substantially over the years and is expected to increase further. This emphasizes the need to identify modifiable risk factors of PD, which could form a logical entry point for the prevention of PD. The World Health Organization (WHO) has recommended reducing exposure to specific environmental factors that have been reported to be associated with PD, in particular pesticides, trichloroethylene (TCE), and air pollution.

REM Sleep Behavior Disorder Diagnostic Code Accuracy and Implications in the Real-World Setting.

Background And Objectives: Isolated REM sleep behavior disorder (iRBD) carries increased risk of neurodegenerative parkinsonian disorder or dementia (NPD) but is difficult to accurately screen for in the community. Health care data offer the opportunity to identify large numbers of iRBD cases among outpatients. We aimed to determine the positive predictive value (PPV) of an RBD (ICD) code for actual iRBD based on manual review of the electronic health record (EHR), examine risk of NPD diagnosis, and explore whether a statistical model developed using selected EHR data can identify individuals with the RBD ICD code who have high probability for actual iRBD.

Eleven Years of Change: Disease Progression in Biomarker-Defined Sporadic Parkinson's Disease.

Long-term longitudinal data on outcomes in sporadic Parkinson's Disease are limited, especially from cohorts with extensive biological characterization. Recent advances in biomarkers characterization of Parkinson's Disease necessitate an updated examination of long-term progression within contemporary cohorts like the Parkinson's Progression Markers Initiative, which enrolled individuals within 2 years of clinical diagnosis of Parkinson's Disease. Our study leverages the Neuronal Synuclein Disease framework, which defines the disease based on biomarker assessed presence of neuronal alpha-synuclein and dopamine deficit, rather than based on conventional clinical diagnostic criteria.

Neuronal alpha-Synuclein Disease integrated staging system performance in PPMI, PASADENA, and SPARK baseline cohorts.

The 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.

Higher Striatal Dopamine is Related With Lower Physical Performance Fatigability in Community-Dwelling Older Adults.

Background: Fatigability in community-dwelling older adults is highly prevalent and disabling, but lacks a treatment. Greater nigrostriatal dopaminergic signaling can ameliorate performance fatigability in healthy young adults, but its role in community-dwelling older adults is not known. We hypothesized that higher nigrostriatal dopaminergic integrity would be associated with lower performance fatigability, independent of cardiopulmonary and musculoskeletal energetics and other health conditions.