NPJ Parkinson's Disease最新文献

Transcranial direct current stimulation (tDCS) is a promising noninvasive intervention for Parkinson’s disease (PD). However, studies of its motor and cognitive effect have produced mixed results. We conducted a systematic review including 38 studies and meta-analysis of 12 randomized sham-controlled trials with 263 PD patients. No significant differences were found between active and sham tDCS in motor function (UPDRS-III: SMD = –0.14, p = 0.74), gait (SMD = 0.10, p = 0.513), attention and working memory (SMD = 0.24, p = 0.13), executive function (SMD = 0.03, p = 0.854), and memory and learning (SMD: −0.07, p = 0.758). The prediction intervals indicated substantial heterogeneity among studies. Meta-regression showed small positive effects in younger PD patients with milder symptoms. These findings are preliminary but suggest tDCS may benefit some PD patients while being neutral or harmful to others.

Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinson's disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human α-synuclein (Snca^+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca^+/+ rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes. However, only LPS Snca^+/+ rats showed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction in the release of evoked dopamine in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby α-synuclein and inflammation interact to promote neurodegeneration in PD.

Sleep difficulties affect up to 98% of Parkinson’s disease (PD) patients and are often not well treated. How globus pallidus internus (GPi)-DBS could help is less understood. We retrospectively analyzed sleep outcomes in 32 PD patients after GPi-DBS with a two-year follow-up. We observed high heterogeneity in sleep response to pallidal stimulation: 16 patients showed clinically meaningful improvement, 9 had minor changes, and 7 experienced worsened sleep quality, with no overall significant change on the Parkinson’s Disease Sleep Scale-2 (P = 0.19). Further analysis revealed that stimulation of the left sensorimotor GPi was significantly associated with sleep improvement. Fiber tracts from the left sensorimotor GPi to the bilateral sensorimotor cortex, right GPi, brainstem, and bilateral cerebellum were linked to better sleep, while projections to the left hippocampus correlated with worsened sleep. These findings may guide personalized GPi-DBS lead placement to optimize sleep outcomes in PD.

The voluntary nature of decision-making is fundamental to human behavior. The subthalamic nucleus is important in reactive decision-making, but its role in voluntary decision-making remains unclear. We recorded from deep brain stimulation subthalamic electrodes time-locked with acute stimulation using a Go/Nogo task to assess voluntary action and inaction. Beta oscillations during voluntary decision-making were temporally dissociated from motor function. Parkinson's patients showed an inaction bias with high beta and intermediate physiological states. Stimulation reversed the inaction bias highlighting its causal nature, and shifting physiology closer to reactive choices. Depression was associated with higher alpha during Voluntary-Nogo characterized by inaction or inertial status quo maintenance whereas apathy had higher beta-gamma during voluntary action or impaired effortful initiation of action. Our findings suggest the human subthalamic nucleus causally contributes to voluntary decision-making, possibly through threshold gating or toggling mechanisms, with stimulation shifting towards voluntary action and suggest biomarkers as potential clinical predictors.

Cognitive impairment (CI) is common in α-synucleinopathies, i.e., Parkinson's disease, Lewy bodies dementia, and multiple system atrophy. We summarize data from systematic reviews/meta-analyses on neuroimaging, neurophysiology, biofluid and genetic diagnostic/prognostic biomarkers of CI in α-synucleinopathies. Diagnostic biomarkers include atrophy/functional neuroimaging brain changes, abnormal cortical amyloid and tau deposition, and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers, cortical rhythm slowing, reduced cortical cholinergic and glutamatergic and increased cortical GABAergic activity, delayed P300 latency, increased plasma homocysteine and cystatin C and decreased vitamin B12 and folate, increased CSF/serum albumin quotient, and serum neurofilament light chain. Prognostic biomarkers include brain regional atrophy, cortical rhythm slowing, CSF amyloid biomarkers, Val66Met polymorphism, and apolipoprotein-E ε2 and ε4 alleles. Some AD/amyloid/tau biomarkers may diagnose/predict CI in α-synucleinopathies, but single, validated diagnostic/prognostic biomarkers lack. Future studies should include large consortia, biobanks, multi-omics approach, artificial intelligence, and machine learning to better reflect the complexity of CI in α-synucleinopathies.

Pathological forms of α-synuclein contribute to synucleinopathies, including Parkinson’s disease (PD). Most cases of PD arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms in animal models. We quantitatively profiled nearly 630 metabolites in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice, compared to wild-type (WT) animals, and comparing germ-free (GF) to specific pathogen-free (SPF) animals (n = 5 WT-SPF; n = 6 ASO-SPF; n = 6 WT-GF; n = 6 ASO-GF). Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. The microbial metabolite trimethylamine N-oxide (TMAO) strongly correlates from the gut to the plasma to the brain in mice, notable since TMAO is elevated in the blood and cerebrospinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and microbiome in a mouse model of PD.

Alpha-synuclein (α-syn) inclusions in the brain are hallmarks of so-called Lewy body diseases. Lewy bodies contain mainly aggregated α-syn together with some other proteins. Monomeric α-syn lacks a well-defined three-dimensional structure, but it can aggregate into oligomeric and fibrillar amyloid species, which can be detected using specific antibodies. Here we investigate the aggregate specificity of monoclonal MJFR14-6-4-2 antibodies. We conclude that partial masking of epitope in unstructured monomer in combination with a high local concentration of epitopes is the main reason for MJFR14-6-4-2 selectivity towards aggregates. Based on the structural insight, we produced mutant α-syn that when fibrillated is unable to bind MJFR14-6-4-2. Using these fibrils as a tool for seeding cellular α-syn aggregation, provides superior signal/noise ratio for detection of cellular α-syn aggregates by MJFR14-6-4-2. Our data provide a molecular level understanding of specific recognition of toxic amyloid oligomers, which is critical for the development of inhibitors against synucleinopathies.

Numerous studies proposed methods to detect Parkinson's disease (PD) via speech analysis. However, existing corpora often lack prodromal recordings, have small sample sizes, and lack longitudinal data. Speech samples from celebrities who publicly disclosed their PD diagnosis provide longitudinal data, allowing the creation of a new corpus, ParkCeleb. We collected videos from 40 subjects with PD and 40 controls and analyzed evolving speech features from 10 years before to 20 years after diagnosis. Our longitudinal analysis, focused on 15 subjects with PD and 15 controls, revealed features like pitch variability, pause duration, speech rate, and syllable duration, indicating PD progression. Early dysarthria patterns were detectable in the prodromal phase, with the best classifiers achieving AUCs of 0.72 and 0.75 for data collected ten and five years before diagnosis, respectively, and 0.93 post-diagnosis. This study highlights the potential for early detection methods, aiding treatment response identification and screening in clinical trials.

The impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on neuropsychiatric fluctuations in Parkinson´s disease (PD) remains unclear. The Neuropsychiatric Fluctuations Scale (NFS) can help to fill this gap, directly measuring fluctuations between the OFF- and ON-medication conditions. The NFS provides NFS-plus (hyperdopaminergic) and NFS-minus (hypodopaminergic) sub-scores. Based on these, the NFS global scores express the overall magnitude of neuropsychiatric symptoms in both the OFF- and ON-medication states. The total fluctuation score (TFS) represents the difference between ON- vs. OFF-medication NFS global scores, thus assessing fluctuations amplitude. The NFS was used to evaluate changes in neuropsychiatric fluctuations between the OFF- and ON-medication conditions before and 1-year after bilateral STN-DBS in 45 PD patients (32 males; mean age, 61.3 ± 7.2 years; PD duration, 10.2 ± 3.0 years). After surgery, the amplitude of neuropsychiatric fluctuations was significantly reduced (p < 0.001), confirming the efficacy of STN-DBS on these symptoms.

Deep brain stimulation (DBS) with electric field steering may avoid areas responsible for side effects. This prospective randomized cross-over trial compared omnidirectional (OS) and directional (DS) subthalamic DBS in 19 patients. Electromyographically measured rigidity was the primary outcome. Motor and non-motor scores were secondary outcomes. There were no significant differences between OS and DS. In the acute setting, both conditions improved motor scores compared to no stimulation. Motor symptoms improved after 3 weeks of OS relative to acute measurements, whereas they worsened under DS. The more ventral the active contact, and the less the motor improvement sweet spot was stimulated, the greater the benefit of DS over OS for executive function. Accurate OS of the dorsal subthalamic nucleus ensures motor and non-motor improvements. While DS can mitigate executive decline stemming from off-target stimulation, it may lead to worse motor outcomes. Larger, long-term studies are needed to confirm these findings. (Registration: subthalamic steering for therapy optimization in Parkinson’s Disease ClinicalTrials.gov: NCT03548506, 2018-06-06).