Decreased heart rate variability in sympathetic dominant states in Parkinson's disease and isolated REM sleep behavior disorder.

INTRODUCTION: Parkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in parasympathetic dominant states. In this study, we aimed to examine whether HRV in sympathetic dominant states during the head-up tilt table test (HUT) serves as a marker of autonomic dysfunction in PD and isolated REM sleep behavior disorder (iRBD). METHODS: We retrospectively assessed 102 patients with PD, 10 patients with iRBD, and 43 healthy controls. We then measured the coefficient of variation of RR intervals as an HRV parameter in sympathetic dominant states (CVRR-S) and parasympathetic dominant states (CVRR-P). Furthermore, we evaluated parameters of cardiac autonomic function, including HUT and the heart-to-mediastinum (H/M) ratio of cardiac metaiodobenzylguanidine scintigraphy. RESULTS: Patients with iRBD and PD at Hoehn and Yahr stage I exhibited a significantly decreased CVRR-S compared to healthy controls (controls vs. iRBD vs. PD; 1.82 ± 0.64 % vs. 1.13 ± 0.41 % vs. 1.15 ± 0.51 %, p < 0.001), although no further deterioration was observed in PD at more severe Hoehn and Yahr stages. CVRR-S showed a significant correlation with the H/M ratio in PD (r = 0.51, p < 0.001). Additionally, receiver operating characteristic (ROC) analysis revealed a larger area under the ROC curve in CVRR-S compared to that in CVRR-P for discriminating PD or iRBD from healthy controls. CONCLUSION: HRV in sympathetic dominant states shows the potential to be a marker of autonomic dysfunction in iRBD and early-stage PD, aiding in early diagnosis and patient stratification.

Meta-analysis of shotgun sequencing of gut microbiota in Parkinson's disease.

We aimed to identify gut microbial features in Parkinson's disease (PD) across countries by meta-analyzing our fecal shotgun sequencing dataset of 94 PD patients and 73 controls in Japan with five previously reported datasets from USA, Germany, China1, China2, and Taiwan. GC-MS and LC-MS/MS assays were established to quantify fecal short-chain fatty acids (SCFAs) and fecal polyamines, respectively. α-Diversity was increased in PD across six datasets. Taxonomic analysis showed that species Akkermansia muciniphila was increased in PD, while species Roseburia intestinalis and Faecalibacterium prausnitzii were decreased in PD. Pathway analysis showed that genes in the biosyntheses of riboflavin and biotin were markedly decreased in PD after adjusting for confounding factors. Five out of six categories in carbohydrate-active enzymes (CAZymes) were decreased in PD. Metabolomic analysis of our fecal samples revealed that fecal SCFAs and polyamines were significantly decreased in PD. Genes in the riboflavin and biotin biosyntheses were positively correlated with the fecal concentrations of SCFAs and polyamines. Bacteria that accounted for the decreased riboflavin biosynthesis in Japan, the USA, and Germany were different from those in China1, China2, and Taiwan. Similarly, different bacteria accounted for decreased biotin biosynthesis in the two country groups. We postulate that decreased SCFAs and polyamines reduce the intestinal mucus layer, which subsequently facilitates the formation of abnormal α-synuclein fibrils in the intestinal neural plexus in PD, and also cause neuroinflammation in PD.

Formation Processes of a Solid Electrolyte Interphase at a Silicon/Sulfide Electrolyte Interface in a Model All-Solid-State Li-Ion Battery.

Understanding the electrochemical reactions at the interface between a Si anode and a solid sulfide electrolyte is essential in improving the cycle stabilities of Si anodes in all-solid-state batteries (ASSBs). Highly dense Si films with very low roughnesses of <1 nm were fabricated at room temperature via cathodic arc plasma deposition, which led to the formation of a Si/sulfide electrolyte model interface. Li (de)alloying through the model interface hardly occurred during the first cycle, whereas it proceeded stably in subsequent cycles. Hard X-ray photoelectron spectroscopy and neutron reflectometry directly revealed that the reduction or oxidation of the interfacial component or Li3PS4 electrolyte occurred during the first cycle. Consequently, an interfacial layer with a thickness of 13 nm and primarily composed of Li2S, SiS2, and P2S5 glasses was formed during the first cycle. The interfacial layer acted as a Li-conductive, electron-insulating solid electrolyte interphase (SEI) that provided reversible (de)lithiation. Our model interface directly demonstrates the electrochemical reaction processes at the Si/Li3PS4 interface and provides insights into the structures and electrochemical properties of SEIs to activate the (de)lithiation of Si anodes using a sulfide electrolyte.

Stable Photoelectrochemical Reactions at Solid/Solid Interfaces toward Solar Energy Conversion and Storage.

Electrochemistry has extended from reactions at solid/liquid interfaces to those at solid/solid interfaces. However, photoelectrochemistry at solid/solid interfaces has been hardly reported. In this study, we achieve a stable photoelectrochemical reaction at the semiconductor-electrode/solid-electrolyte interface in a Nb-doped anatase-TiO2 (a-TiO2:Nb)/Li3PO4 (LPO)/Li all-solid-state cell. The oxidative currents of a-TiO2:Nb/LPO/Li increase upon light irradiation when a-TiO2:Nb is located at a potential that is more positive than its flat-band potential. This is because the photoexcited electrons migrate to the current collector due to the bending of the conduction band minimum toward the negative potential. The photoelectrochemical reaction at the semiconductor/solid-electrolyte interface is driven by the same principle as those at semiconductor/liquid-electrolyte interfaces. Moreover, oxidation under light irradiation exhibits reversibility with reduction in the dark. Thus, we extend photoelectrochemistry to all-solid-state systems composed of solid/solid interfaces. This extension would enable us to investigate photoelectrochemical phenomena uncleared at solid/liquid interfaces because of low stability and durability.

Relationship Between Sleep Quality and Constipation Severity in Patients With Parkinson Disease: A Cross-sectional Study.

ABSTRACT: BACKGROUND: Constipation in patients with Parkinson disease (PD) adversely affects motor symptoms, making defecation management critical. Sleep disturbance is another common complaint in patients with PD (PWP). Associations between sleep disturbances and constipation have been reported in recent studies on PD. If improving sleep quality is useful for managing constipation in PWP, it might serve as a new method of constipation management that is less physically and mentally distressing than laxatives. This study aimed to examine the relationship between sleep quality and constipation severity in PWP. METHODS: We administered a questionnaire on sleep and constipation to 1048 PWP. Constipation severity was assessed using Constipation Assessment Scale Japanese version 2 (CAS). General sleep quality was estimated using the Japanese versions of the Pittsburgh Sleep Quality Index (PSQI) and Athens Insomnia Scale. Sleep quality due to PD-specific nighttime problems was estimated using the Parkinson's Disease Sleep Scale-2 Japanese version (PDSS-2). We conducted a multiple regression analysis using the forced entry method to identify the variables that influenced CAS. RESULTS: We analyzed 350 PWP. Overall, 94.9% of PWP had constipation symptoms. The percentages of PWP with poor sleep were as follows: PSQI, 74.7%; Athens Insomnia Scale, 69.8%; and PDSS-2, 73.8%. Furthermore, 17.6% of the patients with constipation and 35.3% with sleep problems did not consult a healthcare provider. Multivariate analysis revealed that CAS was significantly associated only with PDSS-2 (standardized partial regression coefficient, 0.217; 95% confidence interval, 0.030-0.111). CONCLUSION: Poor sleep quality, related to PD-specific nighttime problems, was found be associated with worsening constipation severity. Nursing activities that help PWP with PD-specific nighttime problems have a more comfortable night's sleep would be key to alleviating constipation severity.

A lithium superionic conductor for millimeter-thick battery electrode.

No design rules have yet been established for producing solid electrolytes with a lithium-ion conductivity high enough to replace liquid electrolytes and expand the performance and battery configuration limits of current lithium ion batteries. Taking advantage of the properties of high-entropy materials, we have designed a highly ion-conductive solid electrolyte by increasing the compositional complexity of a known lithium superionic conductor to eliminate ion migration barriers while maintaining the structural framework for superionic conduction. The synthesized phase with a compositional complexity showed an improved ion conductivity. We showed that the highly conductive solid electrolyte enables charge and discharge of a thick lithium-ion battery cathode at room temperature and thus has potential to change conventional battery configurations.

Gastrointestinal disorders in Parkinson's disease and other Lewy body diseases.

Parkinson's disease (PD) is pathologically characterized by the abnormal accumulation of α-synuclein fibrils (Lewy bodies) in the substantia nigra and other brain regions, although the role of Lewy bodies remains elusive. Constipation usually precedes the motor symptoms in PD, which is in accordance with the notion that α-synuclein fibrils start from the intestinal neural plexus and ascend to the brain in at least half of PD patients. The gut microbiota is likely to be involved in intestinal and brain pathologies. Analyses of the gut microbiota in PD, rapid-eye-movement sleep behavior disorder, and dementia with Lewy bodies suggest three pathological pathways. First, Akkermansia, which is increased in PD, degrades the intestinal mucus layer and increases intestinal permeability, which triggers inflammation and oxidative stress in the intestinal neural plexus. Second, decreased short-chain fatty acids (SCFAs)-producing bacteria in PD reduce the number of regulatory T cells. Third, SCFAs also aggravate microglial activation with an unelucidated pathway. In addition, in dementia with Lewy bodies (DLB), which is another form of α-synucleinopathies, increased genera, Ruminococcus torques and Collinsella, may mitigate neuroinflammation in the substantia nigra by increasing secondary bile acids. Interventions for the gut microbiota and their metabolites may potentially delay or mitigate the development and progression of PD and other Lewy body diseases.

Cervicovaginal microbiome in patients with recurrent pregnancy loss.

There have been few studies concerning an association between unexplained recurrent pregnancy loss (RPL) and the microbiome. A recent study including 67 patients demonstrated that an increase in Ureaplasma species in the endometrium raised the risk of miscarriage with an euploid karyotype. While endometrial sampling is invasive, cervicovaginal sampling is not. We compared vaginal and cervical microbiomes with a 16 S ribosomal RNA sequence between 88 patients with unexplained RPL and 17 healthy women with no history of miscarriage. We prospectively assessed risk factors for maternal colonization at a subsequent miscarriage without an aneuploid karyotype in patients. Cervicovaginal bacteria were dominated by Lactobacillus iners, Gardnerella vaginalis, Atopobium vaginae and Bifidobacterium breve in Japanese population. The proportions of Delftia and unknown bacteria in the cervix were significantly higher in patients with RPL than in controls. Streptococcus, Microbacterium, Delftia, Anaerobacillus and Chloroplast in the cervix were significantly higher in patients with a history of chorioamnionitis compared to the controls. The abundance of Cutibacterium and Anaerobacillus in the cervix was significantly higher in patients who had subsequently miscarried compared to those who gave birth. The miscarriage rate in patients with higher proportions of both Cutibacterium and Anaerobacillus (66.7%, 2/3) was significantly greater than that of patients who lacked these bacteria (9.2%, 6/65, adjusted odds ratio 16.90, 95% confidence interval 1.27-225.47, p = 0.032). The presence of certain bacteria could be a predictor of subsequent miscarriage without an aneuploid karyotype. The cervicovaginal microbiome might be useful for investigating a possible cause of RPL.

Serum neurofilament light chain in patients with epilepsy and cognitive impairment.

BACKGROUND: The neurofilament light chain (NfL) is receiving increased attention as a biomarker of neurological diseases, as NfL concentration elevated in the blood and cerebrospinal fluid after neuronal damage. However, few studies have addressed NfL in epilepsy. We aimed to investigate the alteration of serum NfL in adult patients with epilepsy, and the association between this biomarker and cognitive impairment. METHODS: A total of 38 consecutive patients with epilepsy and 24 controls underwent cross-sectional measurement of serum NfL levels and cognitive testing using the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), the Frontal Assessment Battery (FAB), the Trail-Making Test, and the Stroop Color-Word Test. Statistical analysis was performed with Student's t-test to compare serum NfL levels between the epilepsy group and the control group, and with Spearman's correlation and age-corrected partial correlation analyses to evaluate the association between serum NfL level and cognitive impairment in epilepst patients. RESULTS: There was no difference in serum NfL levels between the epilepsy and control groups (epilepsy [mean ± SD]: 17.3 ± 13.9 pg/mL; control: 17.7 ± 11.5 pg/mL; p = .92); however, the MoCA-J scores were lower in the epilepsy group (26.6 ± 3.1 vs. 28.1 ± 1.6; p = .03). The age-corrected partial correlation analysis showed a correlation between serum NfL level and cognitive test scores in the epilepsy group (MMSE: rs = -.63, p < .01; MoCA-J: rs = -.54, p < .01; FAB: rs = -.68, p < .01), whereas serum NfL levels were correlated exclusively with MMSE scores in the control group (rs = .44, p = .04). SIGNIFICANCE: In adult epilepsy patients, the serum NfL level was not significantly elevated, but was correlated with cognitive test scores. Our findings suggest that serum NfL concentration could be an indicator of cognitive function in epilepsy patients.

Gut microbiota in dementia with Lewy bodies.

Gut microbiota and fecal bile acids were analyzed in 278 patients with α-synucleinopathies, which were comprised of 28 patients with dementia with Lewy bodies (DLB), 224 patients with Parkinson's disease (PD), and 26 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Similarly to PD, short-chain fatty acids-producing genera were decreased in DLB. Additionally, Ruminococcus torques and Collinsella were increased in DLB, which were not changed in PD. Random forest models to differentiate DLB and PD showed that high Ruminococcus torques and high Collinsella, which presumably increase intestinal permeability, as well as low Bifidobacterium, which are also observed in Alzheimer's disease, were predictive of DLB. As Ruminococcus torques and Collinsella are also major secondary bile acids-producing bacteria, we quantified fecal bile acids and found that the production of ursodeoxycholic acid (UDCA) was high in DLB. Increased UDCA in DLB may mitigate neuroinflammation at the substantia nigra, whereas neuroinflammation may not be critical at the neocortex. Theraeutic intervention to increase Bifidobacteirum and its metabolites may retard the development and progression of DLB.

[Ascendance of Abnormal α-synuclein Fibrils Through the Vagal Nerve in Parkinson's Disease].

Parkinson's disease (PD) is caused by the abnormal accumulation of α-synuclein fibrils (Lewy bodies) in the substantia nigra. The α-synuclein fibrils behave like prions. Autopsy shows that α-synucleinopathy ascends from the brain stem to the substantia nigra. In patients with PD, the α-synuclein pathology is frequently observed in the intestinal neural plexus. In animal models, injection of α-synuclein fibrils in the gastric wall or the peritoneum caused immunostaining for aggregated α-synuclein fibrils in the substantia nigra. In Finland and Sweden, truncal vagotomy, but not partial vagotomy, reduced the chance of developing PD to 50% in 35 years. Of note, not all patients with PD show ascending α-synuclein pathology in the brain and that truncal vagotomy reduced the chance of developing PD to half. Thus, α-synucleinopathy is likely to start from the intestinal neural plexus and ascends through the vagal nerve to the substantia nigra in at least 50% of patients with PD. Additionally, short-chain fatty acids (SCFA)-producing intestinal bacteria are reduced in PD. Although the underlying mechanisms are currently under investigation, the vagal nerve also senses SCFA and transmits signals to the central nervous system. This pathway is likely to be compromised by gut dysbiosis in PD.

Examination of Abnormal Alpha-synuclein Aggregates in the Enteric Neural Plexus in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: Parkinson's disease (PD) is the second most neurodegenerative disease after Alzheimer's disease. Accumulating knowledge points to the notion that abnormal aggregation of alpha-synuclein (αSyn) starts in the gut and ascends to the substantia nigra via the vagus nerve in about a half of PD patients. Epidemiological studies revealed that ulcerative colitis (UC) increases a risk for PD 1.3 to 1.8-folds. However, it remains unknown whether αSyn is abnormally aggregated in the enteric neurons in UC patients. METHODS: We first inspected and optimized the immunostaining protocols with an anti-phosphorylated αSyn antibody, pSyn#64, using the brain and the gut of eight autopsied cases (five with PD and three without PD). Then, we examined abnormal αSyn aggregation in the enteric neurons in 23 and 18 colectomized patients with and without UC, respectively. Five or more sections were stained for αSyn in each of 87 and 25 paraffin- embedded blocks in patients with and without UC, respectively. RESULTS: Ten different protocols of epitope exposure appropriately stained aggregated αSyn in the brain, but only complete lack of epitope exposure stained aggregated αSyn in the colon with low background. Abnormal αSyn aggregates, which was confirmed by co-localization of p62, in the enteric neurons were detected in a single patient with UC but not in any patients without UC. CONCLUSIONS: Omission of epitope exposure enabled us to immunostain aggregated αSyn in the colon by pSyn#64 with low nonspecific staining, but the number of 23 UC patients was not high enough to discern whether abnormal αSyn aggregation in the colonic neural plexus was increased in UC or not.

Wearable sensor device-based detection of decreased heart rate variability in Parkinson's disease.

The evidence that heart rate variability (HRV) decreases during early Parkinson's disease (PD) largely depends on electrocardiogram data. In this study, we examined HRV in PD using wearable sensors and assessed various evaluation methods for detecting disease-related alterations. We evaluated 27 patients with PD and 23 disease controls. The wearable sensors POLAR V800 HR and POLAR H10 were used for the HRV measurements. The participants wore the two sensors for approximately 24 h, and long-term HRV data were acquired. We analyzed the standard deviation of normal R-R intervals (SDNN) and coefficient of variation of R-R intervals (CVRR) for every 100 consecutive beats. Focusing on the fluctuation of SDNN and CVRR, we extracted the minimum, first decile, first quartile, and median values of SDNN and CVRR. The area under the receiver operating characteristic curve (AUC) for each HRV parameter was calculated to differentiate PD from the disease controls. The minimum values of SDNN and CVRR had the highest AUC (SDNN: AUC 0.90, 95% confidence interval [CI] 0.78-0.96; CVRR: AUC 0.90, CI 0.76-0.96) among the evaluation methods tested. The minimum values of SDNN and CVRR were significantly decreased in PD (SDNN: 9.5 ± 4.0 ms vs. 4.4 ± 2.0 ms, p < 0.0001; CVRR: 1.15 ± 0.33% vs. 0.65 ± 0.24%, p < 0.0001). We detected decreased HRV in PD using wearable sensors. Analyzing the minimum values of the HRV parameter in long-term recordings appears to be appropriate for detecting the decrease in HRV in PD.

Short chain fatty acids-producing and mucin-degrading intestinal bacteria predict the progression of early Parkinson's disease.

To elucidate the relevance of gut dysbiosis in Parkinson's disease (PD) in disease progression, we made random forest models to predict the progression of PD in two years by gut microbiota in 165 PD patients. The area under the receiver operating characteristic curves (AUROCs) of gut microbiota-based models for Hoehn & Yahr (HY) stages 1 and 2 were 0.799 and 0.705, respectively. Similarly, gut microbiota predicted the progression of Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores in an early stage of PD with AUROC = 0.728. Decreases of short-chain fatty acid-producing genera, Fusicatenibacter, Faecalibacterium, and Blautia, as well as an increase of mucin-degrading genus Akkermansia, predicted accelerated disease progression. The four genera remained unchanged in two years in PD, indicating that the taxonomic changes were not the consequences of disease progression. PD patients with marked gut dysbiosis may thus be destined to progress faster than those without gut dysbiosis.

Periosteum-derived podoplanin-expressing stromal cells regulate nascent vascularization during epiphyseal marrow development.

Bone marrow development and endochondral bone formation occur simultaneously. During endochondral ossification, periosteal vasculatures and stromal progenitors invade the primary avascular cartilaginous anlage, which induces primitive marrow development. We previously determined that bone marrow podoplanin (PDPN)-expressing stromal cells exist in the perivascular microenvironment and promote megakaryopoiesis and erythropoiesis. In this study, we aimed to examine the involvement of PDPN-expressing stromal cells in postnatal bone marrow generation. Using histological analysis, we observed that periosteum-derived PDPN-expressing stromal cells infiltrated the cartilaginous anlage of the postnatal epiphysis and populated on the primitive vasculature of secondary ossification center. Furthermore, immunophenotyping and cellular characteristic analyses indicated that the PDPN-expressing stromal cells constituted a subpopulation of the skeletal stem cell lineage. In vitro xenovascular model cocultured with human umbilical vein endothelial cells and PDPN-expressing skeletal stem cell progenies showed that PDPN-expressing stromal cells maintained vascular integrity via the release of angiogenic factors and vascular basement membrane-related extracellular matrices. We show that in this process, Notch signal activation committed the PDPN-expressing stromal cells into a dominant state with basement membrane-related extracellular matrices, especially type IV collagens. Our findings suggest that the PDPN-expressing stromal cells regulate the integrity of the primitive vasculatures in the epiphyseal nascent marrow. To the best of our knowledge, this is the first study to comprehensively examine how PDPN-expressing stromal cells contribute to marrow development and homeostasis.

Anomalously High Ionic Conductivity of Li2SiS3-Type Conductors.

Solid-state electrolytes that exhibit high ionic conductivities at room temperature are key materials for obtaining the next generation of safer, higher-specific-energy solid-state batteries. However, the number of currently available crystal structures for use as superionic conductors remains limited. Here, we report a lithium superionic conductor, Li2SiS3, with tetragonal crystal symmetry, which possesses a new three-dimensional framework structure consisting of isolated edge-sharing tetrahedral dimers. This species exhibits an anomalously high ionic conductivity of 2.4 mS cm-1 at 298 K, which is 3 orders of magnitude higher than the reported ionic conductivity for its orthorhombic polymorph. The framework of this conductor consists mainly of silicon, which is abundant in natural resources, and its further optimization may lead to the development of new solid-state electrolytes for large-scale applications.

Reaction Mechanism of Li2MnO3 Electrodes in an All-Solid-State Thin-Film Battery Analyzed by Operando Hard X-ray Photoelectron Spectroscopy.

Li2MnO3 is a promising cathode candidate for Li-ion batteries because of its high discharge capacity; however, its reaction mechanism during cycling has not been sufficiently explicated. Observations of Mn and O binding energy shifts in operando hard X-ray photoelectron spectroscopy measurements enabled us to determine the charge-compensation mechanism of Li2MnO3. The O 1s peak splits at an early stage during the first charge, and the concentration of lower-valence O changes reversibly with cycling, indicating the formation of a low-valence O species that intrinsically participates in the redox reaction. The O 1s peak-splitting behavior, which indicates the number of valences of O in Li2MnO3, is supported by the computational results for an O3 to O1 structural transition. This is in agreement with the results of our previous study, wherein we confirmed this O3 to O1 transition based on in situ surface X-ray diffraction analysis, X-ray photoelectron spectroscopy, and first-principles formation energy calculations.

Li10GeP2S12-Type Structured Solid Solution Phases in the Li9+δP3+δ'S12-kOk System: Controlling Crystallinity by Synthesis to Improve the Air Stability.

Understanding the fast Li ionic conductors of oxygen-substituted thiophosphates is useful for developing all-solid-state batteries because these compounds possess a high electrochemical stability and thus may be applied as solid electrolytes. In this study, we synthesized the Li9+δP3+δ'S12-kOk series of solid solution phases with the same structure as the Li10GeP2S12 superionic conductor and characterized their crystallinity, solid solution range, and chemical stabilities. Two methods (mechanochemical and melt quenching) were used for sample synthesis. Mechanochemical synthesis was used to obtain samples within a wide range of sulfur/oxygen substitution degrees, and the solid solution range was determined to be 0 < k ≤ 3.6 based on their lattice parameter variation. Meanwhile, the melt-quenched Li9P3S9O3 phase exhibited a high degree of crystallinity up to its particle surface and was thus selected for neutron crystal structure analysis, which revealed the oxygen distribution related to the solubility limit. The highly crystalline melt-quenched Li9P3S9O3 showed better stability in the air atmosphere compared to the mechanochemically synthesized counterpart with a low crystallinity, implying that sample crystallinity is an important parameter in evaluating the air stability of thiophosphates. The promising electrochemical properties of the solid solution series were demonstrated by the stable charge-discharge cycling of an all-solid-state lithium metal cell using the Li9+δP3+δ'S12-kOk electrolyte with k = 0.9 and a conductivity of >1 × 10-3 S cm-1 at 300 K.

Altered gut microbiota in Parkinson's disease patients with motor complications.

INTRODUCTION: Parkinson's disease (PD) is associated with gut dysbiosis. However, whether gut dysbiosis can cause motor complications is unclear. METHODS: Subjects were enrolled from four independent movement disorder centers in Japan. We performed 16S ribosomal RNA gene sequence analysis of gut microbiota. Relative abundance of gut microbiota and relationships between them and clinical characteristics were statistically analyzed. Analysis of co-variance (ANCOVA) was used to assess altered gut microbiota associated with wearing-off or dyskinesia. RESULTS: We enrolled 223 patients with PD. Wearing-off was noted in 47.5% of patients and dyskinesia in 21.9%. We detected 98 genera of bacteria. Some changes in the gut microbiota were observed in patients with PD and motor complications. After Bonferroni correction, patients with wearing-off showed decreased relative abundance of Lachnospiraceae Blautia (p < 0.0001) and increased relative abundance of Lactobacillaceae Lactobacillus (p < 0.0001), but patients with dyskinesia no longer showed significant changes in the gut microbiota. Adjustment with two models of confounding factors followed by ANCOVA revealed that age (p < 0.0001), disease duration (p = 0.01), and wearing-off (p = 0.0004) were independent risks for the decreased relative abundance of Lachnospiraceae Blautia, and wearing-off (p = 0.009) was the only independent risk factor for the increased relative abundance of Lachnospiraceae Lactobacillus. CONCLUSION: Relative abundance of Lachnospiraceae Blautia and Lactobacillaceae Lactobacillus was significantly decreased and increased, respectively, in the gut microbiota of PD patients with motor complications. This indicates that an altered gut microbiota is associated with the development of motor complications in patients with advanced PD.