NPJ Parkinson's Disease最新文献

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.

Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson's disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4-5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

Resting tremor (RT) is a Parkinson’s disease (PD) symptom with an unclear relationship to the dopaminergic system. We analysed data from 432 subjects from the Parkinson’s Progression Markers Initiative, 57 additional PD patients and controls and 86 subjects referred for dopamine transporter single-photon emission computed tomography (DaT-SPECT). Caudate binding ratio (CBR), but not putamen binding ratio, was higher in RT patients. Furthermore, higher baseline CBR was linked to RT development. In the smaller cohorts, a 4–6 Hz oscillation-based metric from inertial sensors correlated with RT amplitude, distinguished controls from patients with reduced DaT binding and correlated with CBR in the latter group. In silico modelling uncovered that higher CBR in RT patients explained correlations between RT and DaT-SPECT found in several datasets, supporting a spurious origin for ipsilateral correlations between CBR and RT. These results suggest that caudate dopaminergic terminals integrity is a feature of RT with potential pathophysiological implications.

To identify circRNAs associated with Parkinson’s disease (PD) we leveraged two of the largest publicly available studies with longitudinal clinical and blood transcriptomic data. We performed a cross-sectional study utilizing the last visit of each participant (N = 1848), and a longitudinal analysis that included 1166 participants with at least two time points. We identified 192 differentially expressed circRNAs, with effects that were sustained during disease, in mutation carriers, and diverse ancestry. The 192 circRNAs were leveraged to distinguish between PD and healthy participants with a ROC AUC of 0.797. Further, 71 circRNAs were sufficient to distinguish between genetic PD (AUC₇₁ = 0.954) and, at-risk participants (AUC₇₁ = 0.929) and healthy controls, supporting that circRNAs have the potential to aid the diagnosis of PD. Finally, we identified five circRNAs highly correlated with symptom severity. Overall, we demonstrated that circRNAs play an important role in PD and can be clinically relevant to improve diagnostic and monitoring.