NPJ Parkinson's Disease最新文献

VisionMD, an open-source software for automated video-based analysis of MDS-UPDRS Part III motor tasks, offers precise, objective, and scalable assessments of motor symptoms in Parkinson’s disease and other movement disorders. Leveraging deep learning, VisionMD tracks body movements to compute kinematic features that quantify symptoms severity and supports longitudinal monitoring. VisionMD’s user-friendly, customizable framework empowers clinicians and researchers to objectively evaluate motor symptoms in persons with movement disorders without specialized hardware.

The motor symptoms of Parkinson’s Disease are attributed to the degeneration of dopamine neurons in the substantia nigra pars compacta (SNc). Previous work in the MCI-Park mouse model has suggested that the loss of somatodendritic dopamine transmission predicts the development of motor deficits. In the current study, brain slices from MCI-Park mice were used to investigate dopamine signaling in the SNc prior to and through the onset of movement deficits. Electrophysiological properties were impaired by p30 and somatic volume was decreased at all time points. The D2 receptor activated potassium current evoked by quinpirole was present initially, but declined after p30. In contrast, D2-IPSCs were absent at all time points. The decrease in GPCR-mediated inhibition was met with increased spontaneous GABA_A signaling. Dendro-dendritic synapses are identified as an early locus of dysfunction in response to bioenergetic decline and suggest that dendritic release sites may contribute to the induction of degeneration.

Non-motor symptoms (NMS) in Parkinson’s disease (PD) significantly impact quality of life, especially in later stages. REM sleep behavior disorder (RBD) affects approximately 42% of all PD patients and frequently precedes motor PD symptoms. RBD is linked to increased rates of depression and cognitive decline. This study explores how early RBD can predict the development of NMS profiles in patients, comparing those with and without early RBD. We identified a unique NMS profile associated with early RBD. These patients had a higher rate of cognitive impairment (M² = 326.84, p < 0.001), apathy (M² = 332.93, p < 0.001), hallucinations (M² = 480.05, p < 0.001), depression (M² = 480.05, p < 0.0001), anxiety (corrected p < 0.01), impulse control disorders (M² = 77.577, p < 0.001), and autonomic dysfunction (F = 251.8, p < 0001). A survival analysis revealed an association between early RBD and faster progression to cognitive impairment. These NMS profiles may play a critical role in stratifying patients for targeted interventions.

Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which clinically useful biomarkers remain to be identified and validated. Here, we adopted an untargeted omics approach to disclose lipidomic, metabolomic and proteomic alterations in plasma and in dermal fibroblasts of PD patients carrying mutations in TMEM175 gene. We revealed a wide dysregulation of lysosome, autophagy, and mitochondrial pathways in these patients, supporting a role of this channel in regulating these cellular processes. The most significant altered lipid classes were Fatty acyls, Glycerophospholipids and Phosphosphingolipids. The plasma level of Phosphatidylcholines (PC) and Phosphatidylinositol (PI) 34:1 significantly correlated with an earlier age at onset of the disease in TMEM175 patients (p = 0.008; p = 0.006). In plasma we also observed altered amino acids metabolic pathways in PD patients. We highlighted that increased level of L-glutamate strongly correlated (p < 0.001) with the severity of motor and non-motor symptoms in PD_TMEM175 patients. In dermal fibroblasts, we disclosed alterations of proteins involved in lipids biosynthesis (PAG15, PP4P1, GALC, FYV1, PIGO, PGPS1, PLPP1), in the insulin pathway (IGF2R), in mitochondrial metabolism (ACD10, ACD11, ACADS) and autophagy (RAB7L). Interestingly, we quantified 43 lysosomal or lysosomal-related proteins, which were differentially modulated between TMEM175 patients and controls. Integrative correlation analysis of proteome and lipidome of PD_TMEM175 cellular models identified a strong positive correlation of 13 proteins involved in biosynthetic processes with PC and Ceramides. Altogether, these data provide novel insights into the molecular and metabolic alterations underlying TMEM175 mutations and may be relevant for PD prediction, diagnosis and treatment.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments only manage symptoms and lack the ability to slow or prevent disease progression. We utilized a systems genetics approach to identify potential risk genes and repurposable drugs for PD. First, we leveraged non-coding genome-wide association studies (GWAS) loci effects on five types of brain-specific quantitative trait loci (xQTLs, including expression, protein, splicing, methylation and histone acetylation) under the protein–protein interactome (PPI) network. We then prioritized 175 PD likely risk genes (pdRGs), such as SNCA, CTSB, LRRK2, DGKQ, and CD44, which are enriched in druggable targets and differentially expressed genes across multiple human brain-specific cell types. Integrating network proximity-based drug repurposing and patient electronic health record (EHR) data observations, we identified Simvastatin as being significantly associated with reduced incidence of PD (hazard ratio (HR) = 0.91 for fall outcome, 95% confidence interval (CI): 0.87–0.94; HR = 0.88 for dementia outcome, 95% CI: 0.86–0.89) after adjusting for 267 covariates. In summary, our network-based systems genetics framework identifies potential risk genes and repurposable drugs for PD and other neurodegenerative diseases if broadly applied.

Neuromodulation therapy comprises a range of non-destructive and adjustable methods for modulating neural activity using electrical stimulations, chemical agents, or mechanical interventions. Here, we discuss how electrophysiological brain recording and imaging at multiple scales, from cells to large-scale brain networks, contribute to defining the target location and stimulation parameters of neuromodulation, with an emphasis on deep brain stimulation (DBS).

Biallelic intronic pentanucleotide repeat expansions, mainly (AAGGG)exp and/or (ACAGG)exp in RFC1, are detected in cerebellar ataxia, neuropathy and vestibular areflexia syndrome, late-onset ataxia, and in a wide disease spectrum including Charcot-Marie-Tooth disease, multiple system atrophy, and Parkinson’s disease (PD). However, the genotype-phenotype correlation and underlying mechanism are mostly unknown. We screened RFC1-repeat expansions in 1445 patients with parkinsonism. Comprehensive genetic and clinical, and pathological assessments were performed. We report two early-onset patients with PD carrying complex biallelic pentanucleotide repeat expansions in RFC1. Long-read sequencing revealed a novel repeat configuration of (AGGGG)exp(AAGGG)₁₄ and a possible somatic variant of (AAGGG)exp(AATGG)exp(AAGGG)exp in the (AAGGG)exp alleles in two RFC1-related PD patients. RNA foci were detected in the (AGGGG)exp-expressed HEK293T cell line as well as (AAGGG)exp and (ACAGG)exp, supporting (AGGGG)exp as a novel pathogenic repeat motif. This work revealed complex genotypes with novel repeat configuration of (AGGGG)exp and possible somatic (AATGG)exp insertion in RFC1-related PD.

This pilot randomized crossover study aimed to compare the effects of stimulating various transcranial direct current stimulation (tDCS) target sites to improve dual-task performance in patients with Parkinson’s disease (PD). Nineteen patients with idiopathic PD completed four sessions of 2 mA anodal tDCS for 20 min at randomly assigned sites: the primary motor cortex (M1), left dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex, and sham stimulation. Anodal M1 tDCS induced statistically significant improvements in single-task and cognitive dual-task timed up and go test. Additionally, enhancements were noted in the color-word Stroop test and trail-making test-Trail B following left DLPFC stimulation. However, none of the stimulation sites showed any significant changes in the dual-task effect. Overall, these results suggest that although tDCS targeting the M1 and DLPFC may immediately enhance motor and cognitive performances, respectively, neither has a significant effect on dual-task interference.

In Parkinson’s disease (PD), Lewy pathology deposits in the cerebral cortex, but how the pathology disrupts cortical circuit integrity and function remains poorly understood. To begin to address this question, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. We reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Specifically, αSyn aggregates-bearing intratelencephalic neurons (ITNs) showed hyperexcitability, increased input resistance, and decreased cell capacitance, which were associated with impaired HCN channel function. Morphologically, the αSyn aggregates-bearing ITNs showed shrinkage of cell bodies and loss of dendritic spines. Last, we showed that partial dopamine depletion is not sufficient to alter thalamocortical transmission to cortical pyramidal neurons. Our results provide a novel mechanistic understanding of cortical circuit dysfunction in PD.