Clinical progression of Parkinson's disease in the early 21st century: Insights from the accelerating medicine partnership (AMP-PD) data.

Background: Parkinson's disease (PD) therapeutic strategies have evolved since levodopa introduction in mid 1900s. To understand their impact and research gaps, this study delineated the clinical progression of PD in recent years.

Methods: Using Accelerating Medicine Partnership-PD (AMP-PD) data harmonized from seven biomarker discovery studies (2010-2020), we extracted: overall [Schwab and England (S&E), PD Questionnaire (PDQ-39)]; motor [Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS)-II and -III and Hoehn & Yahr (HY)]; and non-motor [MDS-UPDRS-I, University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Epworth Sleepiness Scale (ESS)] scores.

Effects of mixed metal exposures on MRI diffusion features in the medial temporal lobe.

Background: Environmental exposure to metal mixtures is common and may be associated with increased risk for neurodegenerative disorders including Alzheimer's disease.

Objective: This study examined associations of mixed metal exposures with medial temporal lobe (MTL) MRI structural metrics and neuropsychological performance.

Methods: Metal exposure history, whole blood metal, and neuropsychological tests were obtained from subjects with/without a history of mixed metal exposure from welding fumes (42 exposed subjects; 31 controls).

Neuronally enriched microvesicle RNAs are differentially expressed in the serums of Parkinson's patients.

Background: Circulating small RNAs (smRNAs) originate from diverse tissues and organs. Previous studies investigating smRNAs as potential biomarkers for Parkinson's disease (PD) have yielded inconsistent results. We investigated whether smRNA profiles from neuronally-enriched serum exosomes and microvesicles are altered in PD patients and discriminate PD subjects from controls.

Dopamine D Agonists: First Potential Treatment for Late-Stage Parkinson's Disease.

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D agonist PF-06412562 to levodopa/carbidopa in six LsPD patients.

Higher hippocampal diffusivity values in welders are associated with greater R2* in the red nucleus and lower psychomotor performance.

Introduction: Chronic excessive welding exposure may be related to higher metal accumulation and structural differences in different subcortical structures. We examined how welding affected brain structures and their associations with metal exposure and neurobehavioral consequences.

Methods: Study includes 42 welders and 31 controls without a welding history.

Susceptibility Magnetic Resonance Imaging Correlates with Glial Density and Tau in the Substantia Nigra Pars Compacta.

Background: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration.

Objective: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden.

Synergic control in asymptomatic welders during multi-finger force exertion and load releasing while standing.

Motor synergies, i.e., neural mechanisms that organize multiple motor elements to ensure stability of actions, are affected by several neurological condition.

Frontostriatal and limbic contributions to cognitive decline in Parkinson's disease.

Background And Purpose: The circuitry underlying heterogenous cognitive profiles in Parkinson's disease (PD) remains unclear. The purpose of this study is to investigate whether structural changes in frontostriatal and limbic pathways contribute to different cognitive trajectories in PD.

Methods: We obtained clinical and multimodal MRI data from 120 control and 122 PD subjects without dementia or severe motor disability.

Dose-Dependent Regulation on Prefrontal Neuronal Working Memory by Dopamine D Agonists: Evidence of Receptor Functional Selectivity-Related Mechanisms.

Low doses of dopamine D agonists improve working memory-related behavior, but high doses eliminate the improvement, thus yielding an 'inverted-U' dose-response curve. This dose-dependency also occurs at the single neuron level in the prefrontal cortex where the cellular basis of working memory is represented. Because signaling mechanisms are unclear, we examined this process at the neuron population level.

Dopamine D receptor-mediated β-arrestin signaling: Insight from pharmacology, biology, behavior, and neurophysiology.

The awareness of the potential importance of functional selectivity/biased signaling has led to the discovery of biased compounds as both research tools and novel drugs. A major pan-receptor focus has been to identify GPCR-selective ligands that have bias in G protein-dependent vs. β-arrestin related signaling.

A Dopamine D Agonist Versus Methylphenidate in Modulating Prefrontal Cortical Working Memory.

Methylphenidate is used widely to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants has significant side effects. This study used a rodent model (spontaneously hypertensive rat) of spatial working memory (sWM) to compare the effects of methylphenidate with the novel dopamine D-like receptor agonist 2-methyldihydrexidine. Acute oral administration of methylphenidate (1.

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

Background: Higher nigral iron has been reported in Parkinson's disease (PD).

Objective: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment.

Methods: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PD ) and 87 drug-treated (PD ) PD patients.

Higher R2* in the Red Nucleus Is Associated With Lead Exposure in an Asymptomatic Welder Cohort.

Lead is a nonessential metal and may be a coexposure in welding fumes. Preclinical data indicate lead may affect iron regulation. The current study investigated blood lead concentrations and their association with brain iron accumulation in workers with chronic welding fume exposure, with a focus on iron-rich subcortical regions of the cerebellum and basal ganglia.

Subcortical Iron Accumulation Pattern May Predict Neuropsychological Outcomes After Subthalamic Nucleus Deep Brain Stimulation: A Pilot Study.

Background:: Neuropsychological outcomes after deep brain stimulation (DBS) are variable and may arise from the heterogeneous neuropathological processes in Parkinson’s disease (PD).

Objective:: To explore if brain iron accumulation patterns and its region-specific alterations relate to neuropsychological outcomes post-DBS.

Methods:: Thirty-two PD subjects were identified from our database with susceptibility MRI prior to bilateral subthalamic nucleus (STN) DBS between 2011–2016.

Choroidal Thickness Correlates with Clinical and Imaging Metrics of Parkinson's Disease: A Pilot Study.

Background: Parkinson's disease (PD) is marked clinically by motor symptoms and pathologically by Lewy bodies and dopamine neuron loss in the substantia nigra pars compacta (SNc). Higher iron accumulation, assessed by susceptibility MRI, also is observed as PD progresses. Recently, evidence has suggested that PD affects the retina.

Folded concave penalized learning of high-dimensional MRI data in Parkinson's disease.

Background: Brain MRI is a promising technique for Parkinson's disease (PD) biomarker development. Its analysis, however, is hindered by the high-dimensional nature of the data, particularly when the sample size is relatively small.

New Method: This study introduces a folded concave penalized machine learning scheme with spatial coupling fused penalty (fused FCP) to build biomarkers for PD directly from whole-brain voxel-wise MRI data.

HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers.

Paraquat is an herbicide whose use is associated with Parkinson's disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans.

Nigral MRI features of asymptomatic welders.

Introduction: Manganese (Mn)-induced parkinsonism involves motor symptoms similar to those observed in Parkinson's disease (PD). Previous literature suggests that chronic Mn- exposure may increase PD risk, although Mn-induced clinical syndromes are considered atypical for PD. This study investigated whether asymptomatic welders display differences in the substantia nigra (SN), the key pathological locus of PD.