NPJ Parkinson's Disease最新文献

In this study, heterozygous expression of a common Parkinson-associated GBA1 variant, the L444P mutation, was found to exacerbate α-synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system. These neurons were also shown to become more vulnerable to oxidative and nitrative stress after L444P expression. The latter paralleled neuronal formation of reactive oxygen species and led to a pronounced accumulation of nitrated α-synuclein. A causal relationship linked mutation-induced oxidative/nitrative stress to enhanced α-synuclein aggregation and spreading that could indeed be rescued by neuronal overexpression of mitochondrial superoxide dismutase 2. Further evidence supported a key involvement of mitochondria as sources of reactive oxygen species as well as targets of oxidative and nitrative damage within L444P-expressing neurons. These findings support the conclusion that enhanced vulnerability to mitochondrial oxidative stress should be considered an important mechanism predisposing to pathology conversion in carriers of GBA1 mutations.

Hyposmia (decreased smell function) is a common early symptom of Parkinson’s disease (PD). The shared genetic architecture between hyposmia and PD is unknown. We leveraged genome-wide association study (GWAS) results for self-assessment of ‘ability to smell’ and PD diagnosis to determine shared genetic architecture between the two traits. Linkage disequilibrium score (LDSC) regression found that the sense of smell negatively correlated at a genome-wide level with PD. Local Analysis of [co]Variant Association (LAVA) found negative correlations in four genetic loci near GBA1, ANAPC4, SNCA, and MAPT, indicating shared genetic liability only within a subset of prominent PD risk genes. Using Mendelian randomization, we found evidence for a strong causal relationship between PD and liability towards poorer sense of smell, but weaker evidence for the reverse direction. This work highlights the heritability of olfactory function and its relationship with PD heritability and provides further insight into the association between PD and hyposmia.

The vagus nerve (VN) is the main neural pathway linking the gut and brain in Parkinson’s disease (PD). In this study, we utilized high-resolution ultrasound to measure the VN cross-sectional area (CSA) in 96 healthy controls (HCs) and 75 PD patients. The PD group was further categorized into three subgroups: PD-preRBD, PD-postRBD, and PD-nonRBD. PD-preRBD was the body-first subtype, and PD-postRBD and PD-nonRBD were the brain-first subtype. The PD group had a significantly lower VN CSA than HCs. Subgroup analysis revealed that the PD-preRBD group tended to exhibit a smaller VN CSA than both the PD-postRBD and PD-nonRBD groups. The VN CSA, specifically the right VN, was significantly correlated with the body-first subtype and some components of PD-related assessment scales. Overall, these findings provide evidence of VN atrophy in PD, especially in body-first PD, suggesting that VN ultrasound could serve as an adjunctive diagnostic tool.

Idiopathic Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and postural instability. Magnetic Resonance-guided high-intensity focused ultrasound (MRgFUS) of the subthalamic nucleus (STN) is gaining recognition as a minimally invasive surgical option. This study assesses the safety and efficacy of unilateral MRgFUS subthalamotomy, aiming to create the smallest effective lesion. Between June 2021 and October 2023, twelve PD patients underwent the procedure, with primary outcomes focused on safety and motor improvements after six months. Results indicated significant motor improvements, with over 50% reduction in tremor, rigidity, and bradykinesia, while balance and gait remained stable. Quality of life also improved. Side effects were generally mild and transient, though some patients experienced involuntary movements, managed through medication adjustments. Despite limitations, this technique appears to offer a promising, less-invasive alternative for managing PD symptoms with a favorable risk-benefit profile. Further research is necessary to refine the procedure and assess long-term outcomes.

Parkinson’s disease (PD) is a complex neurological disorder characterized by dopaminergic neuron degeneration, leading to diverse motor and non-motor impairments. This variability complicates accurate progression modelling and early-stage prediction. Traditional classification methods based on clinical symptoms are often limited by disease heterogeneity. This study introduces an graph-based interpretable personalized progression method, utilizing data from the Parkinson’s Progression Markers Initiative (PPMI) and Stroke Parkinson’s Disease Biomarker Program (PDBP). Our approach integrates multimodal inter-individual and intra-individual data, including clinical assessments, MRI, and genetic information to make multi-dimension predictions. Validated using the PDBP dataset from 12 to 36 months, our AdaMedGraph method demonstrated strong performance, achieving AUC values of 0.748 and 0.714 for the 12-month Hoehn and Yahr Scale and Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III on the PPMI test set. Ablation analysis reveals the importance of baseline clinical assessment predictors. This novel framework improves personalized care and offers insights into unique disease trajectories in PD patients.

Treatment with L-3,4-dihydroxyphenylalanine (L-Dopa) compensates for decreased striatal dopamine (DA) levels and reduces Parkinson’s disease (PD) symptoms. However, during disease progression, L-Dopa-induced dyskinesia (LID) develops virtually in all PD patients, making the control of PD symptoms difficult. Thus, understanding the mechanisms underlying LID and the control of these motor abnormalities is a major issue in the care of PD patients. From experimental and clinical studies, a complex cascade of molecular and cellular events emerges, but the primary determinants of LID are still unclear. Here, with a translational approach, including four animal models and a wide cohort of PD patients, we show that striatal DA denervation is the major causal factor for the emergence of LID, while α-synuclein aggregates do not seem to play a significant role. Our data also support the concept that maladaptive basal ganglia plasticity is the main pathophysiological mechanism underlying LID.

α-Synuclein proximity ligation assay (PLA) has proved a sensitive technique for detection of non-Lewy body α-synuclein aggregate pathology. Here, we describe the MJF-14 PLA, a new PLA towards aggregated α-synuclein with unprecedented specificity, using the aggregate-selective α-synuclein antibody MJFR-14-6-4-2 (hereafter MJF-14). Signal in the assay correlates with α-synuclein aggregation in cell culture and human neurons, induced by α-synuclein overexpression or pre-formed fibrils. Co-labelling of MJF-14 PLA and pS129-α-synuclein immunofluorescence in post-mortem cases of dementia with Lewy bodies shows that while the MJF-14 PLA reveals extensive non-inclusion pathology, it is not sensitive towards pS129-α-synuclein-positive Lewy bodies. In Parkinson’s disease brain, direct comparison of PLA and immunohistochemistry with the MJF-14 antibody shows widespread α-synuclein pathology preceding the formation of conventional Lewy pathology. In conclusion, we introduce an improved α-synuclein aggregate PLA to uncover abundant non-inclusion pathology, which deserves future validation with brain bank resources and in different synucleinopathies.

To compare awake and asleep deep brain stimulation (DBS) surgery for Essential Tremor (ET), we conducted this retrospective cohort study of patients consecutively operated with DBS targeting the caudal Zona incerta (cZi). 37 underwent surgery awake and 55 asleep. Tremor before surgery and on/off stimulation one year after surgery were evaluated using the Essential Tremor Rating Scale (ETRS). Procedural time, electrode localization, stimulation parameters and adverse events were noted and compared. ETRS scores were similar at baseline between the groups except for contralateral arm tremor, which was slightly worse in the awake group. Total ETRS, contralateral arm tremor and activities of daily living scores showed no significant difference between the groups on-stimulation at one-year follow-up. Compared to the awake group, the asleep group had shorter procedural time and lower stimulation parameters. There were no intracranial haemorrhages nor surgery site-infections. Both groups showed a good improvement of tremor at one-year follow-up. Image-guided DBS surgery targeting the cZi enables safe and efficient asleep surgery for ET.

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.

Deep brain stimulation (DBS) can ameliorate motor symptoms in Parkinson’s disease (PD), but its mechanism remains unclear. This work constructs a multi-scale brain model using the fMRI data from 27 PD patients with subthalamic DBS and 30 healthy controls. The model fits microscopic coupling parameters in the cortico-basal ganglia-thalamic neural loop to match individual connectivity, finding the “push-pull” effect of basal ganglia network. Specifically, increased GABAergic projection into the thalamus from basal ganglia worsens rigidity, while reduced GABAergic projection within the cortex exacerbates bradykinesia, suggesting that the dopamine deficiency induces the chain coupling variations to “push” the network to an abnormal state. Conversely, DBS can alleviate rigidity by enhancing GABAergic projections within the basal ganglia, and improve bradykinesia by reducing cortical projections to basal ganglia, exhibiting that DBS “pulls” the network to a healthy state. This work combines the microscopic and macroscopic neural information for understanding PD and its treatment.