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.

Cerebrospinal fluid levels of oxidative stress measured using diacron-reactive oxygen metabolites and biological antioxidant potential in patients with Parkinson's disease and progressive supranuclear palsy.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. Because no curative therapy is available for PD, elucidation of its pathophysiology is important to establish more effective treatments. Oxidative stress (OS) has gained attention and been investigated as one of the candidates involved in the pathogenesis of PD. This study aimed to evaluate OS in the cerebrospinal fluid (CSF) of patients with PD and progressive supranuclear palsy (PSP) using diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) tests, which can easily assess OS in liquid samples. Results were compared to the clinical background of patients and with those of the normal control (NC) group. CSF samples were obtained from 69 patients with PD, 14 patients with PSP, and 22 individuals in the NC group. OS levels and antioxidant capacity were measured using d-ROMs and BAP tests, respectively. CSF d-ROM levels were extremely low (<10 U.CARR) in all 3 groups than the plasma d-ROM levels. Antioxidant capacity was significantly higher in patients with PSP (1074 ± 79 µM) than in patients with PD (918 ± 350 µM) (p = 0.019). In the PD group, antioxidant capacity was significantly lower in patients with tremor (858 ± 269 µM) than in those without tremor (1132 ± 505 µM) (p = 0.004). Our study suggests that the CSF level of OS is under homeostatic control of antioxidative mechanisms in healthy individuals as well as those with neurodegenerative diseases, and increased antioxidant capacity can indicate the CSF level of OS. The lower CSF level of OS in the tremor dominant subtype of PD may be the reason for the benign clinical course.

Impaired metabolism of kynurenine and its metabolites in CSF of parkinson's disease.

AIM: The kynurenine (KYN) pathway plays an important role in degrading molecules responsible for oxidative stress in the central nervous system (CNS), but can also have neurotoxic effects. Both 3-hydroxykynurenine (3-HK) and quinolinic acid are neurotoxic metabolites produced from this pathway. In Parkinson's disease (PD), oxidative stress is suspected to represent a key pathogenic mechanism. This study aimed to investigate the function of the KYN pathway and interactions between oxidative stress and neuroinflammation in PD. METHODS: Participants comprised 20 patients with PD and 13 controls. Cerebrospinal fluid (CSF) levels of KYN and 3-HK were measured using high-performance liquid chromatography coupled with an electrochemical detector. CSF levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and interferon (IFN)-γ were measured with an enzyme-linked immunosorbent assay, and results were statistically compared between PD patients and controls. RESULTS: Median CSF levels of KYN and 3-HK were 49.0 nM and 4.25 nM in PD and 30.5 nM and 1.55 nM in controls, respectively, showing significantly higher levels in PD (p < 0.05). CSF levels of measured cytokines showed that TNF-α and IL-1ß were significantly higher in PD patients than in controls. No positive correlation between 3-HK and TNF-α was seen in PD. CONCLUSION: Dysfunction of the KYN pathway may induce oxidative stress in the CNS in PD, and may also induce cytokine-mediated neuroinflammation. Functional amelioration of the KYN pathway may facilitate modification of neurodegenerative processes in PD.

[A case of adult-onset mitochondrial encephalopathy due to m.4296G>A gene abnormality].

The case is a 30-year-old woman. From the age of 25 years, she had several episodes of cortical blindness and visited a local doctor. Mitochondrial disease was suspected based on findings of cerebral infarction-like imaging and a history of diabetes. However, serum and cerebrospinal fluid lactate levels were normal and no abnormal muscle pathology was found. At the age of 30 years, she visited our hospital with impaired consciousness, cortical blindness, and tremor-like involuntary movements in the neck and right fingers. Brain MRI showed abnormal signals in bilateral basal ganglia, with an increased lactate peak by magnetic resonance spectroscopy and high cerebrospinal fluid lactate levels. Mitochondrial gene analysis identified a m.4296G>A gene mutation. Consequently, we reached a diagnosis of mitochondrial encephalopathy. Adult-onset mitochondrial encephalopathy with m.4296G>A gene mutation is extremely rare. This case showed clinical features caused by damage of both the cerebral cortex and subcortical basal ganglia.