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Background: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN‐induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear‐ and mitochondrial‐encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient‐derived neurons. Objectives: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level. Methods: We generated induced pluripotent stem cell (iPSC)–derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live‐cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single‐nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)‐treated iPSC‐derived neuron–microglia co‐cultures. Results: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin‐deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin‐deficient neuron–microglia co‐cultures elicited an enhanced immune response when exposed to mtDNA/LPS. Conclusions: Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: While mechanistic links between tau abnormalities and neurodegeneration have been proven in frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, variability of the tau pathogenesis and its relation to clinical progressions in the same MAPT mutation carriers are yet to be clarified.Objectives: The present study aimed to analyze clinical profiles, tau accumulations, and their correlations in 3 kindreds with frontotemporal dementia and parkinsonism linked to chromosome 17 attributed to the MAPT N279K mutation.Methods: Four patients with N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT underwent [11 C]PBB3-PET to estimate regional tau loads.Results: Haplotype assays revealed that these kindreds originated from a single founder. Despite homogeneity of the disease-causing MAPT allele, clinical progression was more rapid in 2 kindreds than in the other. The kindred with slow progression showed mild tau depositions, mostly confined to the midbrain and medial temporal areas. In contrast, kindreds with rapid progression showed profoundly increased [11 C]PBB3 binding in widespread regions from an early disease stage.Conclusions: [11 C]PBB3-PET can capture four-repeat tau pathologies characteristic of N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT. Our findings indicate that, in addition to the mutated MAPT allele, genetic and/or epigenetic modifiers of tau pathologies lead to heterogeneous clinicopathological features. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The National Institute of Neurological and Communicative Disorders and Stroke developed criteria for progressive supranuclear palsy (PSP) criteria in 1996,[1] which have played an important role in characterizing diagnosis in clinical and pathological research settings. New PSP criteria, included in "Clinical Diagnosis of Progressive Supranuclear Palsy: The Movement Disorder Society Criteria", were created by the Movement Disorder Society-endorsed PSP Study Group in 2017.[3] The new PSP criteria define the predominance type in detail using 4 core clinical features. Later, vertical supranuclear gaze palsy, apraxia, and frontal releasing sign was emerged, and the patient finally showed dysarthria and easy fall, making it impossible for the patient to stand by himself (year 5: probable PSP-RS). [Extracted from the article]

The anti-paraneoplastic (Ma2/Ta) antibody is related to testicular, lung and ovarian cancers, and might cause paraneoplastic neurological disorders. We present a 25-year-old woman presenting various neurological symptoms of myokymia, chronic widespread pain, tremor, excessive daytime sleepiness, impaired eye of movements, and seizures and autonomic symptoms related to anti-Ma2/Ta antibodies. Needle electromyography showed spontaneous multiplet and myokymic discharges in the left vestus lateralis. Thus, we diagnosed her as Morvan syndrome. After initiation of steroids, plasma exchange and dantrolene, her symptoms partially improved with decreasing intensity of the antigen of anti-Ma2/Ta antibodies, from moderate strong to borderline. The present case expands the clinical spectrum of anti-Ma2/Ta antibodies-related disorders to include the existence of neuroimmune activation and Morvan syndrome. [ABSTRACT FROM AUTHOR]

BACKGROUND: Oxidative stress is involved in the progression of Parkinson's disease (PD). Recent studies have confirmed that molecular hydrogen (H2 ) functions as a highly effective antioxidant in cultured cells and animal models. Drinking H2 -dissolved water (H2 -water) reduced oxidative stress and improved Parkinson's features in model animals. METHODS: In this a placebo-controlled, randomized, double-blind, parallel-group clinical pilot study, the authors assessed the efficacy of H2 -water in Japanese patients with levodopa-medicated PD. Participants drank 1,000 mL/day of H2 -water or pseudo water for 48 weeks. RESULTS: Total Unified Parkinson's Disease Rating Scale (UPDRS) scores in the H2 -water group (n=9) improved (median, -1.0; mean±standard deviation, -5.7±8.4), whereas UPDRS scores in the placebo group (n=8) worsened (median, 4.5; mean±standard deviation, 4.1±9.2). Despite the minimal number of patients and the short duration of the trial, the difference was significant (P<0.05). CONCLUSIONS: The results indicated that drinking H2 -water was safe and well tolerated, and a significant improvement in total UPDRS scores for patients in the H2 -water group was demonstrated. © 2013 Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background Oxidative stress is involved in the progression of Parkinson's disease (PD). Recent studies have confirmed that molecular hydrogen (H2) functions as a highly effective antioxidant in cultured cells and animal models. Drinking H2-dissolved water (H2-water) reduced oxidative stress and improved Parkinson's features in model animals. Methods In this a placebo-controlled, randomized, double-blind, parallel-group clinical pilot study, the authors assessed the efficacy of H2-water in Japanese patients with levodopa-medicated PD. Participants drank 1,000 mL/day of H2-water or pseudo water for 48 weeks. Results Total Unified Parkinson's Disease Rating Scale (UPDRS) scores in the H2-water group (n=9) improved (median, −1.0; mean±standard deviation, −5.7±8.4), whereas UPDRS scores in the placebo group (n=8) worsened (median, 4.5; mean±standard deviation, 4.1±9.2). Despite the minimal number of patients and the short duration of the trial, the difference was significant ( P<0.05). Conclusions The results indicated that drinking H2-water was safe and well tolerated, and a significant improvement in total UPDRS scores for patients in the H2-water group was demonstrated. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

SNCA duplication is a recognized cause of familial Parkinson's disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real-time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG-PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age-associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease-modifiers and may open novel avenues for future treatment. © 2009 Movement Disorder Society [ABSTRACT FROM AUTHOR]

We report on a male patient with Pick disease who had shown severe white matter atrophy and dilatation of the lateral ventricle in the frontal lobe from an early stage. Upon admission to our hospital 2 years after disease onset, the patient showed apathy, and MRI revealed severe atrophy of the cortex and white matter of the frontal lobe. He died at age 74, 11 years after disease onset. Autopsy revealed severe atrophy of the frontal and temporal lobes, severe loss of white matter in the frontal lobe, dilatation of the lateral ventricles, and cortical thinning. Histopathological examination showed severe loss of myelinated fibers in the frontal white matter and severe neuronal loss with gliosis in the frontal and temporal cortices. Many Pick bodies were seen. Our patient had a rare case of Pick disease predominantly affecting the frontal lobe with severe involvement of the white matter from an early stage. This case suggests that myelinated fibers in the white matter as well as cerebral neurons are primarily affected in Pick disease. [ABSTRACT FROM AUTHOR]

In the present case, a patient in whom limb apraxia and asymmetrical parkinsonism developed suggesting corticobasal degeneration, is reported. Neuropathologic examination revealed numerous tufted astrocytes in the precentral cortex in addition to the characteristic pathologic findings of PSP. Therefore, on the basis of clinicopathologic features, atypical progressive supranuclear palsy was diagnosed. In addition, the brain tissue of the present patient was investigated with an antibody specific for four-repeat tau (4R-tau). In the precentral cortex, numerous tau-positive tufted astrocytes, pretangles, and threads were positive for 4R-tau. Using a confocal microscopy we demonstrated that tufted astrocytes positive for 4R-tau were adjacent to astrocytes positive for GFAP. The present findings suggest that accumulation of four-repeat tau in astrocytes is a degenerative process rather than a reactive process. [ABSTRACT FROM AUTHOR]