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Background: Biallelic variants in PARK7, which encodes protein-nucleic acid deglycase DJ-1, can cause early-onset Parkinson's disease (PD). Although many patients with PARK7 variants have been identified from European and Middle Eastern ethnic groups, there have been no reports in the Japanese population. Objectives: To determine the prevalence and clinical features of patients with PD harboring PARK7 variants in Japan. Methods: We performed a molecular genetic analysis of PD patients with PARK7 variants identified using comprehensive panel sequencing, to explore the details of variants. Moreover, clinical neurological features were investigated, including neuroimaging analyses. This study followed STROBE guidelines. Results: Four patients with biallelic rare variants of PARK7 were identified in the cohort. All four patients presented with levodopa-responsive parkinsonism, with an age at onset in the early 30s. Furthermore, two of the four patients had psychiatric complications. Dopamine transporter imaging revealed nigrostriatal pathway dysfunction. Conclusions: To our knowledge, this is the first report of Japanese patients with PARK7 variants. We identified a relatively low frequency of PARK7 variants in patients in Japan. As opposed to typical patients with sporadic PD, the identified patients developed the disease in their 30s and presented with a variety of non-motor symptoms and complications. Further studies are needed to identify the clinical features related to PARK7 variants in Japanese patients with PD, and to analyze the pathophysiology of how the variants identified in the present study might affect DJ-1 function.

Neuroinflammation contributes to the pathology and progression of Alzheimer's disease (AD), and it can be observed even with mild cognitive impairment (MCI), a prodromal phase of AD. Free water (FW) imaging estimates the extracellular water content and has been used to study neuroinflammation across several neurological diseases including AD. Recently, the role of gut microbiota has been implicated in the pathogenesis of AD. The relationship between FW imaging and gut microbiota was examined in patients with AD and MCI. Fifty-six participants underwent neuropsychological assessments, FW imaging, and gut microbiota analysis targeting the bacterial 16S rRNA gene. They were categorized into the cognitively normal control (NC) (n = 19), MCI (n = 19), and AD (n = 18) groups according to the neuropsychological assessments. The correlations of FW values, neuropsychological assessment scores, and the relative abundance of gut microbiota were analyzed. FW was higher in several white matter tracts and in gray matter regions, predominantly the frontal, temporal, limbic and paralimbic regions in the AD/MCI group than in the NC group. In the AD/MCI group, higher FW values in the temporal (superior temporal and temporal pole), limbic and paralimbic (insula, hippocampus and amygdala) regions were the most associated with worse neuropsychological assessment scores. In the AD/MCI group, FW values in these regions were negatively correlated with the relative abundances of butyrate-producing genera Anaerostipes, Lachnospiraceae UCG-004, and [Ruminococcus] gnavus group, which showed a significant decreasing trend in the order of the NC, MCI, and AD groups. The present study showed that increased FW in the gray matter regions related to cognitive impairment was associated with low abundances of butyrate producers in the AD/MCI group. These findings suggest an association between neuroinflammation and decreased levels of the short-chain fatty acid butyrate that is one of the major gut microbial metabolites having a potentially beneficial role in brain homeostasis.

Introduction: The reason why maximum tongue pressure (MTP) decreases in patients with Parkinson’s disease (PD) remains unclear. Repeated measurements of isometric force and MTP may be useful for analyzing muscle wasting and force generation. The purpose of this pilot study was to evaluate the clinical characteristics and temporal transition of MTP in PD and normal control (NC) groups. Methods: There were 18 participants in this study: 10 with PD and 8 NCs. The MTP was measured 20 times at regular intervals. The area under the curve of MTP temporal transitions, time to reach MTP, and total transition time of the tongue pressure (time to return to baseline) were compared between the groups. Results: MTP decreased from baseline in PD subjects. Unlike NCs, PD subjects showed diverse and inconsistent temporal transitions. The decrease in MTP and delays in time to reach MTP and time to return to baseline were significantly greater in PD subjects (p

Purpose: To develop a rigid real-time prospective motion-corrected multiparametric mapping technique and to test the performance of quantitative estimates. Methods: Motion tracking and correction were performed by integrating single-shot spiral navigators into a multiparametric imaging technique, three-dimensional quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS). The spiral navigator was optimized, and quantitative measurements were validated using a standard system phantom. The effect of motion correction on whole-brain T1 and T2 mapping under different types of head motion during the scan was evaluated in 10 healthy volunteers. Finally, six patients with Parkinson's disease, which is known to be associated with a high prevalence of motion artifacts, were scanned to evaluate the effectiveness of our method in the real world. Results: The phantom study demonstrated that the proposed motion correction method did not introduce quantitative bias. Improved parametric map quality and repeatability were shown in volunteer experiments with both in-plane and through-plane motions, comparable to the no-motion ground truth. In real-life validation in patients, the approach showed improved parametric map quality compared to images obtained without motion correction. Conclusions: Real-time prospective motion-corrected multiparametric relaxometry based on 3D-QALAS provided robust and repeatable whole-brain multiparametric mapping.

Many epidemiological studies have associated coffee consumption with a reduced Parkinson’s disease (PD) risk, but the molecular mechanisms remain unclear. In this study, systematic pharmacological and bioinformatics approaches were employed to explore the bioactive components and potential mechanisms mediated by coffee in PD. We identified 12 active compounds in coffee associated with 47 PD-related targets, which might exert synergism because some targets were enriched in multiple signaling pathways and biological processes. The compound–target network and protein–protein interaction network exemplified the multi-component and multi-target effect mediated by coffee in PD. Furthermore, a molecular docking assessment verified the great activity between active compounds identified in coffee and PD-related targets. These results showed that the bioactive components of coffee exerted synergistic effects against PD-associated targets through numerous pathways and provided a new perspective for scientific research exploring the multi-component and multi-target mechanisms mediated by coffee in PD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects extensive regions of the central nervous system. In this work, we evaluated the structural connectome of patients with PD, as mapped by diffusion-weighted MRI tractography and a multi-shell, multi-tissue (MSMT) constrained spherical deconvolution (CSD) method to increase the precision of tractography at tissue interfaces. The connectome was mapped with probabilistic MSMT-CSD in 21 patients with PD and in 21 age- and gender-matched controls. Mapping was also performed by deterministic single-shell, single tissue (SSST)-CSD tracking and probabilistic SSST-CSD tracking for comparison. A support vector machine was trained to predict diagnosis based on a linear combination of graph metrics. We showed that probabilistic MSMT-CSD could detect significantly reduced global strength, efficiency, clustering, and small-worldness, and increased global path length in patients with PD relative to healthy controls; by contrast, probabilistic SSST-CSD only detected the difference in global strength and small-worldness. In patients with PD, probabilistic MSMT-CSD also detected a significant reduction in local efficiency and detected clustering in the motor, frontal temporoparietal associative, limbic, basal ganglia, and thalamic areas. The network-based statistic identified a subnetwork of reduced connectivity by MSMT-CSD and probabilistic SSST-CSD in patients with PD, involving key components of the cortico–basal ganglia–thalamocortical network. Finally, probabilistic MSMT-CSD had superior diagnostic accuracy compared with conventional probabilistic SSST-CSD and deterministic SSST-CSD tracking. In conclusion, probabilistic MSMT-CSD detected a greater extent of connectome pathology in patients with PD, including those with cortico–basal ganglia–thalamocortical network disruptions. Connectome analysis based on probabilistic MSMT-CSD may be useful when evaluating the extent of white matter connectivity disruptions in PD. Keywords: Connectome, Diffusion MRI, Diffusion tensor imaging, Lewy bodies, Neurodegenerative disorders, Support vector machine

Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons. Although many reports have suggested that genetic factors are implicated in the pathogenesis of PD, molecular mechanisms underlying selective dopaminergic neuronal degeneration remain unknown. DJ-1 is a causative gene for autosomal recessive form of PARK7-linked early-onset PD. A number of studies have demonstrated that exogenous DJ-1 localizes within mitochondria and the cytosol, and functions as a molecular chaperon, as a transcriptional regulator, and as a cell protective factor against oxidative stress. However, the precise subcellular localization and function of endogenous DJ-1 are not well known. The mechanisms by which mutations in DJ-1 contributes to neuronal degeneration also remain poorly understood. Here we show by immunocytochemistry that DJ-1 distributes to the cytosol and membranous structures in a punctate appearance in cultured cells and in primary neurons obtained from mouse brain. Interestingly, DJ-1 colocalizes with the Golgi apparatus proteins GM130 and the synaptic vesicle proteins such as synaptophysin and Rab3A. Förster resonance energy transfer analysis revealed that a small portion of DJ-1 interacts with synaptophysin in living cells. Although the wild-type DJ-1 protein directly associates with membranes without an intermediary protein, the pathogenic L166P mutation of DJ-1 exhibits less binding to synaptic vesicles. These results indicate that DJ-1 associates with membranous organelles including synaptic membranes to exhibit its normal function.