Publications by authors named "Nobutaka Hattori"

779 Publications

Effects of safinamide adjunct therapy on pain in patients with Parkinson's disease: Post hoc analysis of a Japanese phase 2/3 study.

J Neurol Sci 2021 Sep 4;429:118070. Epub 2021 Sep 4.

Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan. Electronic address:

Introduction: The non-dopaminergic and dopaminergic actions of safinamide may alleviate pain in patients with Parkinson's disease (PD). We investigated the efficacy of safinamide for pain when administered as an adjunct to levodopa in Japanese patients with PD.

Methods: This was a post hoc analysis of a phase 2/3 clinical study of safinamide in Japanese patients with PD who were experiencing wearing-off. Pain was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part II 'sensory symptoms' item 17, on a scale of 0-4, and the 39-item Parkinson's Disease Questionnaire (PDQ-39) 'bodily discomfort' domain score. Subgroup analyses, according to baseline symptoms and concomitant medications, were also performed.

Results: Least square (LS) mean changes in the UPDRS item 17 score from baseline to Week 24 in the placebo, safinamide 50-mg and safinamide 100-mg groups during the OFF phase were 0.08, -0.15 (p = 0.0133 vs placebo) and -0.18 (p = 0.0054), respectively, and during the ON phase were 0.04, -0.08 (p = 0.0529) and -0.08 (p = 0.0505), respectively. Changes from baseline to Week 24 in PDQ-39 'bodily discomfort' scores were not significantly different in safinamide groups vs placebo. The presence of moderate-to-severe bradykinesia or early-morning dystonia at baseline resulted in numerically greater effect sizes in UPDRS item 17 scores during the OFF phase.

Conclusions: Safinamide 50 mg and 100 mg reduced the UPDRS item 17 score in patients with PD, especially during the OFF phase. Patients with moderate-to-severe bradykinesia and early-morning dystonia may benefit from safinamide treatment.
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http://dx.doi.org/10.1016/j.jns.2021.118070DOI Listing
September 2021

Elevated mycobacterium avium subsp. paratuberculosis (MAP) antibody titer in Japanese multiple sclerosis.

J Neuroimmunol 2021 Aug 25;360:577701. Epub 2021 Aug 25.

Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, International University of Health and Welfare, Fukuoka, Japan; Translational Neuroscience Center, Graduate School of Medicine, School of Pharmacy at Fukuoka, International University of Health and Welfare, Fukuoka, Japan. Electronic address:

To investigate whether antibody production against mycobacterium avium subsp. paratuberculosis (MAP) is related to clinical characteristics of multiple sclerosis (MS) and human leukocyte antigen (HLA) alleles, IgG antibody against three MAP peptides and two human peptides homologous to MAP were measured in sera from 103 MS patients and 50 healthy controls (HCs). MS patients had higher IgG levels against MAP2694 (MAP2694-IgG) than HCs, while the other antibodies were comparable. Multivariate analysis demonstrated that higher MAP2694-IgG titers were associated with higher EDSS scores, but not with HLA alleles or dairy product consumption. Immune response against MAP may worsen MS disability.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577701DOI Listing
August 2021

Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson's Disease: A Pooled Analysis of 8 Phase 2b/3 Trials.

J Parkinsons Dis 2021 Sep 1. Epub 2021 Sep 1.

Henry Ford Hospital, West Bloomfield, MI, USA.

Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson's disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor.

Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline.

Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline's FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor.

Results: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], -0.38 h [-0.61, -0.15]) and 40 mg/day (-0.45 h [-0.68, -0.22], p <  0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, -0.75 h [-1.10, -0.40]; 40 mg/day, -0.82 h [-1.17, -0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%).

Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.
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http://dx.doi.org/10.3233/JPD-212672DOI Listing
September 2021

Case Report: Chronic Adaptive Deep Brain Stimulation Personalizing Therapy Based on Parkinsonian State.

Front Hum Neurosci 2021 13;15:702961. Epub 2021 Aug 13.

Department of Neurology, School of Medicine, Juntendo University, Tokyo, Japan.

We describe the case of a 51-year-old man with Parkinson's disease (PD) presenting with motor fluctuations, who received bilateral subthalamic deep brain stimulation (DBS) with an adaptive DBS (aDBS) device, Percept™ PC (Medtronic, Inc. , Minneapolis, MN). This device can deliver electrical stimulations based on fluctuations of neural oscillations of the local field potential (LFP) at the target structure. We observed that the LFP fluctuations were less evident inside the hospital than outside, while the stimulation successfully adapted to beta oscillation fluctuations during the aDBS phase without any stimulation-induced side effects. Thus, this new device facilitates condition-dependent stimulation; this new stimulation method is feasible and provides new insights into the pathophysiological mechanisms of PD.
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http://dx.doi.org/10.3389/fnhum.2021.702961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414587PMC
August 2021

Comorbid alpha synucleinopathies in idiopathic normal pressure hydrocephalus.

J Neurol 2021 Sep 1. Epub 2021 Sep 1.

Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo Bynkyo-ku, Tokyo, 113-8421, Japan.

Objective: This study aimed to determine the prevalence and clinical features of Parkinson's disease (PD)/PD dementia (PD/PDD) or dementia with Lewy bodies (DLB) in idiopathic normal pressure hydrocephalus (iNPH).

Methods: Patients with iNPH who were admitted to the Department of Neurology, Juntendo University School of Medicine over the past 10 years have been retrospectively analyzed. The diagnosis of iNPH and concomitant PD/PDD or DLB was established using diagnostic criteria. Motor symptoms were assessed by the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III. I-ioflupane single-photon emission computed tomography (DaT-SPECT) and cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC)-based assay were performed for alpha synuclein aggregation.

Results: Overall, 79 patients met the criteria for iNPH, of which 34 developed iNPH without accompanying disorders (iNPHa; 43%), 23 developed iNPH with comorbid PD/PDD (iNPHc + PD/PDD; 29.1%), and 8 developed iNPH with comorbid DLB (iNPHc + DLB; 10.1%). Significant differences in facial expansion and upper-limb parkinsonism were observed with a comorbidity of either PD/PDD or DLB. The specific binding ratio (SBR) of DaTscan was reduced in iNPHa (p = 0.02), but it reduced further with comorbid PD/PDD (p < 0.01) or DLB (p < 0.01). RT-QuIC was positive for all 13 comorbid PD/PDD and negative for all 19 iNPHa.

Conclusion: These results highlight that synucleinopathies coexist with iNPH. These can be differentiated by performing DaTscan and RT-QuIC, which can affect its clinical features.
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http://dx.doi.org/10.1007/s00415-021-10778-1DOI Listing
September 2021

PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE).

J Neuroimmunol 2021 Oct 12;359:577694. Epub 2021 Aug 12.

Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8431, Japan. Electronic address:

Neuroinflammation plays an important role in the pathogenesis of several neurodegenerative disorders. To elucidate the effects of the mitophagy-related gene Parkin on neuroinflammation, we used a mouse model of experimental autoimmune encephalomyelitis (EAE). Female Parkin and female wild type control mice were immunized with myelin oligodendrocyte glycoprotein to develop active EAE. Compared to the wild type controls, the Parkin mice showed an earlier onset and greater severity of EAE with a greatly increased number of CD8αβTCRαβ T cells in the spleen and brain as well as a stronger T-cell proliferative response and an altered cytokine secretion in splenocytes. Furthermore, the Parkin mice showed massive recruitment of monocytes/macrophages and activated microglia in the spinal cord during the acute phase of the disease. They also showed accumulation of microglia co-expressing M1 and M2 markers in the brain and a strong over-expression of A1 reactive astrocytes in the spinal cord. Furthermore, the Parkin mice that developed persistent disease exhibited reduced glial cell numbers and abnormalities in mitochondrial morphology. Our study sheds light on the role of PARKIN protein in modulating peripheral immune cells-mediated immunity during EAE, highlighting its importance in neuroinflammation, and thus elucidating its potential in the development of novel neuroprotective therapies.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577694DOI Listing
October 2021

Potential of PINK1 and PARKIN Proteins as Biomarkers for Active Multiple Sclerosis: A Japanese Cohort Study.

Front Immunol 2021 4;12:681386. Epub 2021 Aug 4.

Department of Neurology, Juntendo University, Tokyo, Japan.

Background: Mitochondrial dysfunction has been suggested to play an important role in all stages of multiple sclerosis (MS).

Objective: To determine the expression of two mitophagy-related proteins, PTEN-induced kinase 1 (PINK1) and PARKIN, in a cohort of Japanese patients with different neuroinflammatory disorders.

Methods: Protein concentrations were measured using commercial ELISA in paired cerebrospinal fluid (CSF) and serum samples from patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), and from age- and sex-matched controls.

Results: CSF and serum concentrations of PINK1 were higher in patients with MS than in patients with NMOSD ( = 0.004 and < 0.001, respectively), MOGAD ( = 0.008 and = 0.011, respectively), and controls ( = 0.021 and = 0.002, respectively). CSF and concentrations of PARKIN were elevated in patients with MS in comparison with those in controls ( = 0.016 and = 0.05, respectively).

Conclusions: Our study highlighted the importance of mitophagy in MS and suggested the potential application of PINK1 and PARKIN as biomarkers to predict disease activity.
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http://dx.doi.org/10.3389/fimmu.2021.681386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371632PMC
August 2021

Multiple sclerosis plaques may undergo continuous myelin degradation: a cross-sectional study with myelin and axon-related quantitative magnetic resonance imaging metrics.

Neuroradiology 2021 Aug 12. Epub 2021 Aug 12.

Department of Radiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Purpose: We hypothesize that myelin is more susceptible to damage over time than axons. We investigated the association between the estimated duration from the onset of multiple sclerosis (MS) plaques and myelin- and axon-related quantitative synthetic magnetic resonance imaging (SyMRI) and neurite orientation dispersion and density imaging (NODDI) metrics.

Methods: We analyzed 31 patients with MS with 73 newly appeared plaques. Simple linear regression analysis was performed to assess the association between the estimated duration from the onset of plaques and quantitative MRI metrics. These metrics included the myelin volume fraction (MVF), axon volume fraction, and g-ratio in plaque and normal-appearing white matter.

Results: MS plaques with a longer estimated duration from onset were significantly correlated with a lower MVF (slope =  - 0.0070, R = 0.0970), higher g-ratio (slope = 0.0078, R = 0.0842) (all P values < 0.05).

Conclusion: These results suggested that myelin in plaques undergoes continuous damage, more so than axons. Myelin imaging with SyMRI and NODDI may be useful for the quantitative assessment of temporal changes in MS plaques.
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http://dx.doi.org/10.1007/s00234-021-02781-0DOI Listing
August 2021

Effectiveness of Long-Term Physiotherapy in Parkinson's Disease: A Systematic Review and Meta-Analysis.

J Parkinsons Dis 2021 Aug 4. Epub 2021 Aug 4.

Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: Long-term physiotherapy is acknowledged to be crucial to manage motor symptoms for Parkinson's disease (PD) patients, but its effectiveness is not well understood.

Objective: This systematic review and meta-analysis aimed to assess the evidence regarding the effectiveness of long-term physiotherapy to improve motor symptoms and reduce antiparkinsonian medication dose in PD patients.

Methods: Pubmed, Cochrane, PEDro, and CINAHL were searched for randomized controlled trials before August 31, 2020 that investigated the effectiveness of physiotherapy for 6 months or longer on motor symptoms and levodopa-equivalent dose (LED) in PD patients with Hoehn and Yahr stage 1- 3. We performed random effects meta-analyses for long-term physiotherapy versus no/control intervention and estimated standard mean differences with 95% confidence intervals (CIs). Levels of evidence were rated by the Grading of Recommendation Assessment, Development and Evaluation approach.

Results: From 2,940 studies, 10 studies involving 663 PD patients were assessed. Long-term physiotherapy had favorable effects on motor symptoms in off medication state [- 0.65, 95% CI - 1.04 to - 0.26, p = 0.001] and LED [- 0.49, 95% CI - 0.89to - 0.09, p = 0.02]. Subgroup analyses demonstrated favorable effects on motor symptoms in off medication state by aerobic exercise [- 0.42, 95% CI - 0.64 to - 0.20, p <  0.001] and LED by multidisciplinary rehabilitation of primarily physiotherapy [- 1.00, 95% CI - 1.44 to - 0.56, p <  0.001]. Quality of evidence for aerobic exercise and multidisciplinary rehabilitation were low and very low.

Conclusion: This review provided evidence that long-term physiotherapy has beneficial impact on motor symptoms and antiparkinsonian medication dose in PD patients and could motivate implementation of long-term physiotherapy.
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http://dx.doi.org/10.3233/JPD-212782DOI Listing
August 2021

White matter alterations in Parkinson's disease with levodopa-induced dyskinesia.

Parkinsonism Relat Disord 2021 Jul 24;90:8-14. Epub 2021 Jul 24.

Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan. Electronic address:

Introduction: Levodopa-induced dyskinesia is a complication of levodopa therapy and negatively impacts the quality of life of patients. We aimed to elucidate white matter alterations in Parkinson's disease with levodopa-induced dyskinesia using advanced diffusion magnetic resonance imaging techniques.

Methods: The enrolled subjects included 26 clinically confirmed Parkinson's disease patients without levodopa-induced dyskinesia, 25 Parkinson's disease patients with levodopa-induced dyskinesia, and 23 healthy controls. Subjects were imaged using a 3-T magnetic resonance scanner. Diffusion tensor imaging, diffusion kurtosis imaging, and neurite orientation dispersion and density imaging findings were compared between groups with a group-wise whole brain approach and a region-of-interest analysis for each white matter tract. Additionally, logistic regression analysis was used to calculate odds ratios for levodopa-induced dyskinesia.

Results: Group-wise tract-based spatial statistical analysis revealed significant white matter differences in isotropic diffusion, complexity, or heterogeneity, and neurite density between healthy controls and Parkinson's disease patients without levodopa-induced dyskinesia and between patients with and without levodopa-induced dyskinesia. Region-of-interest analysis revealed similar alterations using a group-wise whole-brain approach in the external capsule, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus. These tracts had an odds ratio of approximately 2.3 for the presence of levodopa-induced dyskinesia.

Conclusions: Our findings suggest that Parkinson's disease with levodopa-induced dyskinesia produces less white matter microstructural disruption, especially in temporal lobe fibers, than Parkinson's disease without levodopa-induced dyskinesia. These fibers has a more than 2-fold odds ratio for the presence of levodopa-induced dyskinesia and might be associated with the pathogenesis of the sequela.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.021DOI Listing
July 2021

Randomized double-blind placebo-controlled trial of hydrogen inhalation for Parkinson's disease: a pilot study.

Neurol Sci 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Background: Oxidative stress is involved in the progression of Parkinson's disease (PD). Recent studies have confirmed that molecular hydrogen (H) functions as a highly effective antioxidant in animal models of PD. A placebo-controlled, randomized, double-blind, parallel-group clinical pilot study was conducted to assess the efficacy of hydrogen gas inhalation in Japanese patients with PD on treatment with levodopa.

Methods: Twenty participants fulfilling the Movement Disorder Society criteria were enrolled. Participants inhaled 6.5 (0.1) vol% hydrogen gas in 2 L/min of mixed air or placebo air for 16 weeks, twice a day for 1 h.

Results: Five participants were excluded due to deviation from the protocol of the total duration of inhalation < 112 h. No significant differences were seen in the change in the total Movement Disorder Society Unified Parkinson's Disease Rating Scale score from baseline to the 16 week between the group that inhaled hydrogen gas and the group that inhaled placebo air (Mann-Whitney U test, p > 0.05). No adverse events were seen. The compliance to the protocol-based duration of inhalation time in all participants decreased with the elderly participants, the higher daily dose of levodopa, and the higher PDQ-39 items on emotions (n = 20, p < 0.05).

Conclusion: This pilot study revealed that the inhalation of molecular hydrogen gas was safe, but did not show any beneficial effects in patients with PD.

Trial Registration: UMIN ID: 000,039,217 (October 6, 2018).
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http://dx.doi.org/10.1007/s10072-021-05489-4DOI Listing
July 2021

Defined serum-free culture of human infant small intestinal organoids with predetermined doses of Wnt3a and R-spondin1 from surgical specimens.

Pediatr Surg Int 2021 Jul 3. Epub 2021 Jul 3.

Department of Research and Development for Organoids, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Purpose: Refinement of organoid technology is important for studying physiology and disease of the intestine. We aimed to optimize defined serum-free conditions for human infant small intestinal (SI) organoid culture with predetermined doses of Wnt3a and Rspo1 from surgical specimens. We further assessed whether intestinal specimens could be stored before use as a source of organoids.

Methods: Different doses of Wnt3a and Rspo1 in a serum-free medium were tested to establish a condition in which surgically resected SI cells grew as organoids over multiple passages. The expression of marker genes for stem and differentiated cells was assessed by quantitative polymerase chain reaction. We also investigated the organoid-forming efficiency of cells in degenerating intestines stored at 4 °C for various intervals post-resection.

Results: We determined the doses of Wnt3a and Rspo1 required for the continuous growth of infant SI organoids with multi-differentiation potential. We revealed that, despite the time-dependent loss of stem cells, tissues stored for up to 2 days preserved cells capable of generating amplifiable organoids.

Conclusion: SI cells can be grown as organoids under defined conditions. This could provide a reproducible and customizable method of using surgical specimens for the study of intestinal maturation and their relevance to pediatric diseases.
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http://dx.doi.org/10.1007/s00383-021-04957-4DOI Listing
July 2021

Fiber-specific white matter alterations in early-stage tremor-dominant Parkinson's disease.

NPJ Parkinsons Dis 2021 Jun 25;7(1):51. Epub 2021 Jun 25.

Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Using a fixel-based analysis (FBA), we assessed the fiber-specific white matter (WM) alterations in nonmedicated patients with early-stage Parkinson's disease (PD) with tremor-dominant (TD; n = 53; mean age, 61.7 ± 8.7 years) and postural instability and gait disorder (PIGD; n = 27; mean age, 57.8 ± 8.1 years) motor subtypes and age- and sex-matched healthy controls (HC; n = 43; mean age, 61.6 ± 9.2 years) from Parkinson's Progression Markers Initiative dataset. FBA revealed significantly increased macrostructural fiber cross section and a combination of fiber density and cross section metrics within the corticospinal tract in patients with TD-PD compared with HC. Nonetheless, no significant changes in FBA-derived metrics were found in patients with PIGD-PD compared with HC or patients with TD-PD. Our results may provide evidence of WM neural compensation mechanisms in patients with TD-PD marked by increases in fiber bundle size and the ability to relay information between brain regions.
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http://dx.doi.org/10.1038/s41531-021-00197-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233424PMC
June 2021

Role of the Gut Microbiota in Stroke Pathogenesis and Potential Therapeutic Implications.

Ann Nutr Metab 2021 Jun 9:1-9. Epub 2021 Jun 9.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Background: Major advances have been made in stroke treatment and prevention in the past decades. However, the burden of stroke remains high. Identification of novel targets and establishment of effective interventions to improve stroke outcomes are, therefore, needed. Recent research highlights the contribution of the gut microbiota to stroke pathogenesis.

Summary: Compositional and functional alterations of the gut microbiota, termed dysbiosis, are linked to stroke risk factors, such as obesity, metabolic diseases, and atherosclerosis. In acute cerebral ischemia, the gut microbiota plays a key role in bidirectional interactions between the gut and brain, referred to as the microbiota-gut-brain axis. Gut dysbiosis prior to ischemic stroke affects outcomes. Additionally, the brain affects the gut microbiota during acute ischemic brain injury, which in turn impacts outcomes. Interactions between the gut microbiota and stroke pathogenesis are mediated by several factors including bacterial components (e.g., lipopolysaccharide), gut microbiota-related metabolites (e.g., short-chain fatty acids and trimethylamine N-oxide), and the immune and nervous systems. Clinical studies have reported that patients with acute ischemic stroke exhibit gut dysbiosis, which is associated with host metabolism and inflammation, as well as functional outcomes. Modulation of the gut microbiota or its metabolites improves conditions related to stroke pathogenesis, including inflammation, cardiometabolic disease, atherosclerosis, and thrombosis. Key Messages: Accumulating evidence indicates that the gut microbiota plays a possible role in stroke pathogenesis. Modulation of the gut microbiota may provide a novel therapeutic strategy for the treatment and prevention of stroke.
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http://dx.doi.org/10.1159/000516398DOI Listing
June 2021

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

J Stroke Cerebrovasc Dis 2021 Aug 6;30(8):105892. Epub 2021 Jun 6.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan. Electronic address:

Objective: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score.

Materials And Methods: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis.

Results: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores.

Conclusions: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105892DOI Listing
August 2021

Association of Orthostatic Hypotension With Cerebral Atrophy in Patients With Lewy Body Disorders.

Neurology 2021 08 7;97(8):e814-e824. Epub 2021 Jun 7.

From the Neurology Unit (A. Pilotto, A.S., B.B., A.L., A. Padovani), Department of Clinical and Experimental Sciences, and Neuroradiology Unit (R.G.), Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia; Parkinson's Disease Rehabilitation Centre (A. Pilotto, M.C.R.), FERB ONLUS-S. Isidoro Hospital, Trescore Balneario, Bergamo; Department of Neuroscience "Rita Levi Montalcini" (A.R., E.M., L.L.) and Autonomic Unit (S.M.), Department of Medical Sciences, University of Turin, Italy; Department of Medicine (Neurology) (M.M., C.O.-L., S.E.B.), University of Toronto; Hurvitz Brain Sciences Program (M.M., C.O.-L., S.E.B.), Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Neurology (Y.S., R.T., K.Y., T.H., N.H.), Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Neuroscience Imaging and Clinical Sciences (L.B., S.D.P.), University G. d'Annunzio of Chieti-Pescara, Chieti, Italy; Department of Medicine and Neuroscience and Mental Health Institute (R.C., M.G.), University of Alberta, Edmonton, Canada; Department of Radiology (L.L.W.), and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Department of Neurology, University of Cincinnati, OH; Department of Molecular and Translational Medicine (A.K.D.), Texas Tech University Health Sciences Center, El Paso; Parkinson and Other Movement Disorders Center (K.L., I.L.), Department of Neurosciences, University of California, San Diego, La Jolla; Department of Neurology (F.R.-P.), Medical University of South Carolina, Charleston; Imaging Research Center (M.D), Department of Radiology, Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine (M.D.), OH; Department of Neurology (J.A.V.), Emory University, Atlanta, GA; ASST Spedali Civili Hospital (R.G.), Brescia, Italy; and Department of Neurology (A.M.), The Ohio State University, Columbus .

Objective: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).

Methods: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales.

Results: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy ( = 0.004) and regional atrophy involving the anterior-temporal ( = 0.001) and mediotemporal ( = 0.001) regions, greater in severe vs nonsevere OH ( = 0.001). The WMH burden was similar in those with and without OH ( = 0.49). SH was not associated with brain atrophy ( = 0.59) or WMH ( = 0.72).

Conclusions: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.
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http://dx.doi.org/10.1212/WNL.0000000000012342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397588PMC
August 2021

Genetic analysis of ATP10B for Parkinson's disease in Japan.

Parkinsonism Relat Disord 2021 Jul 29;88:10-12. Epub 2021 May 29.

Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan; Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. Electronic address:

Compound heterozygosity of ATP10B is thought to be a risk factor for young-onset Parkinson's disease (PD). We genetically screened 245 patients with young-onset sporadic PD and 33 patients with autosomal recessive PD for ATP10B. All 13 identified gene variants were heterozygous with little evidence of the pathogenicity.
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http://dx.doi.org/10.1016/j.parkreldis.2021.05.020DOI Listing
July 2021

Measurement of GCase Activity in Cultured Cells.

Methods Mol Biol 2021 ;2322:47-52

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Glucocerebrosidase (GCase), which is encoded by the GBA1 gene, has lysosomal glycoside hydrolase activity that hydrolyzes glucosylceramide. Defects in GCase lead to the accumulation of glucosylceramide, which causes the development of the lysosomal storage disease known as Gaucher's disease. Loss-of-function mutations in the GBA1 gene are the most important genetic risk factor for synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. Recent studies on PD genes associated with lysosomal function suggest that GCase activity is decreased in cell models of PD and in neurons derived from PD patients. In this chapter, we describe a protocol to measure GCase activity in cultured cells.
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http://dx.doi.org/10.1007/978-1-0716-1495-2_5DOI Listing
August 2021

Analysis of α-Synuclein in Exosomes.

Methods Mol Biol 2021 ;2322:41-45

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Alpha synuclein (α-Syn), a presynaptic protein with unknown function, is accumulated in Lewy bodies/neurites that are one of the hallmark pathologies of Parkinson's disease (PD). Missense or multiplication mutations in SNCA, which codes α-Syn, result in a genetic form of PD, further indicating the involvement of α-Syn in PD pathogenesis. Recent pathological and experimental studies suggest that α-Syn possesses a secretory feature, as it is detected in the culture media, in the cerebrospinal fluid, and even in the blood. Secreted α-Syn can spread throughout the body and invade the CNS, disseminating the α-Syn associated pathology. Exosomes are small extracellular vesicles that carry many proteins, lipids, or miRNA. We and others have discovered α-Syn in exosomes and revealed that exosomes may regulate intracellular α-Syn levels by transporting outside the cells. In this chapter, we describe a protocol to measure α-Syn levels in exosomes.
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http://dx.doi.org/10.1007/978-1-0716-1495-2_4DOI Listing
August 2021

α-Synuclein Seeding Assay Using Cultured Cells.

Methods Mol Biol 2021 ;2322:27-39

Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.

α-Synuclein, a presynaptic protein, is involved in synaptic vesicle dynamics in response to neuronal activity. Mutations of the α-synuclein gene and the neuronal deposition of α-synuclein, called Lewy bodies, are linked to the development of Parkinson's disease. α-Synuclein has a prion-like property that converts its physiological protein conformation to a pathogenic one, forming disease-causing fibrils. Aggregation of these fibrils and subsequent inclusion formation are suggested to interfere with vesicular trafficking and organelle function in neurons. Thus, detection of a prion-like property of α-synuclein and the evaluation of its modifying factors are required to understand the pathogenesis of Parkinson's disease and to develop new therapies. In this chapter, we describe a cell-based assay for detecting α-synuclein propagation.
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http://dx.doi.org/10.1007/978-1-0716-1495-2_3DOI Listing
August 2021

α-Synuclein Seeding Assay Using RT-QuIC.

Methods Mol Biol 2021 ;2322:3-16

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein (αSyn). They include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In each disease, it has been proposed that aggregates of αSyn represent different conformational strains of αSyn, leading to self-propagation and spreading from cell to cell. It has been considered that αSyn aggregates grow by seeded polymerization mechanisms. Previously, the mechanism of seed conversion in prion protein aggregation has been exploited by real-time quaking-induced conversion (RT-QuIC) assay. It was further refined by incorporating the fluorescent dye thioflavin-T, which enabled the real-time monitoring of kinetic changes with a highly sensitive detection of seed aggregates present at an extremely low level. In an application for diagnostics, it has been reported that αSyn RT-QuIC exhibits specificity between 82% and 100%, while its sensitivity varies between 70% and 100%, on the basis of a study in which this assay was performed at multiple different laboratories. Furthermore, it has been suggested that the αSyn RT-QuIC method can be applied to study the biochemical characteristics of different αSyn strains among synucleinopathies. In this article, we describe the detailed protocols for αSyn RT-QuIC assays.
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http://dx.doi.org/10.1007/978-1-0716-1495-2_1DOI Listing
August 2021

Cerebrovascular diseases in two patients with entire NSD1 deletion.

Hum Genome Var 2021 May 24;8(1):20. Epub 2021 May 24.

Department of human genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.

We describe two patients with NSD1 deletion, who presented with early-onset, or recurrent cerebrovascular diseases (CVDs). A 39-year-old female showed developmental delay and abnormal gait in infancy, and developed slowly-progressive intellectual disability and movement disorders. Brain imaging suggested recurrent parenchymal hemorrhages. A 6-year-old male had tremor as a neonate and brain imaging revealed subdural hematoma and brain contusion. This report suggests possible involvement of CVDs associated with NSD1 deletion.
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http://dx.doi.org/10.1038/s41439-021-00151-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144564PMC
May 2021

Possible Neuroprotective Effects of l-Carnitine on White-Matter Microstructural Damage and Cognitive Decline in Hemodialysis Patients.

Nutrients 2021 Apr 14;13(4). Epub 2021 Apr 14.

Department of Neurology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan.

Although l-carnitine alleviated white-matter lesions in an experimental study, the treatment effects of l-carnitine on white-matter microstructural damage and cognitive decline in hemodialysis patients are unknown. Using novel diffusion magnetic resonance imaging (dMRI) techniques, white-matter microstructural changes together with cognitive decline in hemodialysis patients and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent dMRI and laboratory and neuropsychological tests, which were compared across seven patients each in two groups according to duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment (NSTLC), and (2) long-term l-carnitine treatment (LTLC). Ten age- and sex-matched controls were enrolled. Compared to controls, microstructural disorders of white matter were widely detected on dMRI of patients. An autopsy study of one patient in the NSTLC group showed rarefaction of myelinated fibers in white matter. With LTLC, microstructural damage on dMRI was alleviated along with lower levels of high-sensitivity C-reactive protein and substantial increases in carnitine levels. The LTLC group showed better achievement on trail making test A, which was correlated with amelioration of disorders in some white-matter tracts. Novel dMRI tractography detected abnormalities of white-matter tracts after hemodialysis. Long-term treatment with l-carnitine might alleviate white-matter microstructural damage and cognitive impairment in hemodialysis patients.
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http://dx.doi.org/10.3390/nu13041292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070822PMC
April 2021

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson's Disease Affects LRRK2 Protein Levels.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.

() is a major causative gene of late-onset familial Parkinson's disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of associated with PD exhibit increased kinase activity. We herein report a novel variant-p.G2294R-located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient's peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.
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http://dx.doi.org/10.3390/ijms22073708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038167PMC
April 2021

Intrajejunal Infusion of Levodopa/Carbidopa for Advanced Parkinson's Disease: A Systematic Review.

Mov Disord 2021 08 25;36(8):1759-1771. Epub 2021 Apr 25.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28595DOI Listing
August 2021

Diffusion MRI Captures White Matter Microstructure Alterations in PRKN Disease.

J Parkinsons Dis 2021 ;11(3):1221-1235

Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan.

Background: Although pathological studies usually indicate pure dopaminergic neuronal degeneration in patients with parkin (PRKN) mutations, there is no evidence to date regarding white matter (WM) pathology. A previous diffusion MRI study has revealed WM microstructural alterations caused by systemic oxidative stress in idiopathic Parkinson's disease (PD), and we found that PRKN patients have systemic oxidative stress in serum biomarker studies. Thus, we hypothesized that PRKN mutations might lead to WM abnormalities.

Objective: To investigate whether there are WM microstructural abnormalities in early-onset PD patients with PRKN mutations using diffusion tensor imaging (DTI).

Methods: Nine PRKN patients and 15 age- and sex-matched healthy controls were recruited. DTI measures were acquired on a 3T MR scanner using a b value of 1,000 s/mm2 along 32 isotropic diffusion gradients. The DTI measures were compared between groups using tract-based spatial statistics (TBSS) analysis. Correlation analysis was also performed between the DTI parameters and several serum oxidative stress markers obtained in a previously conducted metabolomic analysis.

Results: Although the WM volumes were not significantly different, the TBSS analysis revealed a corresponding decrease in fractional anisotropy and an increase in mean diffusivity and radial diffusivity in WM areas, such as the anterior and superior corona radiata and uncinate fasciculus, in PRKN patients compared with controls. Furthermore, 9-hydroxystearate, an oxidative stress marker, and disease duration were positively correlated with several parameters in PRKN patients.

Conclusion: This pilot study suggests that WM microstructural impairments occur in PRKN patients and are associated with disease duration and oxidative stress.
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http://dx.doi.org/10.3233/JPD-202495DOI Listing
January 2021

High-fat diet-induced activation of SGK1 promotes Alzheimer's disease-associated tau pathology.

Hum Mol Genet 2021 Aug;30(18):1693-1710

Department of Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate of Medicine, Tokyo, Japan.

Type 2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer's disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that serum-/glucocorticoid-regulated kinase 1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.
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http://dx.doi.org/10.1093/hmg/ddab115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411983PMC
August 2021
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