Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.

A metabolic profile of polyamines in parkinson disease: A promising biomarker.

OBJECTIVE: Aging is the highest risk factor for Parkinson disease (PD). Under physiological conditions, spermidine and spermine experimentally enhance longevity via autophagy induction. Accordingly, we evaluated the ability of each polyamine metabolite to act as an age-related, diagnostic, and severity-associated PD biomarker. METHODS: Comprehensive metabolome analysis of plasma was performed in Cohort A (controls, n = 45; PD, n = 145), followed by analysis of 7 polyamine metabolites in Cohort B (controls, n = 49; PD, n = 186; progressive supranuclear palsy, n = 19; Alzheimer disease, n = 23). Furthermore, 20 patients with PD who were successively examined within Cohort B were studied using diffusion tensor imaging (DTI). Association of each polyamine metabolite with disease severity was assessed according to Hoehn and Yahr stage (H&Y) and Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). Additionally, the autophagy induction ability of each polyamine metabolite was examined in vitro in various cell lines. RESULTS: In Cohort A, N8-acetylspermidine and N-acetylputrescine levels were significantly and mildly elevated in PD, respectively. In Cohort B, spermine levels and spermine/spermidine ratio were significantly reduced in PD, concomitant with hyperacetylation. Furthermore, N1,N8-diacetylspermidine levels had the highest diagnostic value, and correlated with H&Y, UPDRS-III, and axonal degeneration quantified by DTI. The spermine/spermidine ratio in controls declined with age, but was consistently suppressed in PD. Among polyamine metabolites, spermine was the strongest autophagy inducer, especially in SH-SY5Y cells. No significant genetic variations in 5 genes encoding enzymes associated with spermine/spermidine metabolism were detected compared with controls. INTERPRETATION: Spermine synthesis and N1,N8-diacetylspermidine may respectively be useful diagnostic and severity-associated biomarkers for PD. ANN NEUROL 2019;86:251-263.

Shared Metabolic Profile of Caffeine in Parkinsonian Disorders.

OBJECTIVE: The objective of this study was to determine comprehensive metabolic changes of caffeine in the serum of patients with parkinsonian disorders including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) and to compare this with healthy control serum. METHODS: Serum levels of caffeine and its 11 downstream metabolites from independent double cohorts consisting of PD (n = 111, 160), PSP (n = 30, 19), MSA (n = 23, 17), and healthy controls (n = 43, 31) were examined by liquid chromatography-mass spectrometry. The association of each metabolite with clinical parameters and medication was investigated. Mutations in caffeine-associated genes were investigated by direct sequencing. RESULTS: A total of 9 metabolites detected in more than 50% of participants in both cohorts were decreased in 3 parkinsonian disorders compared with healthy controls without any significant association with age at sampling, sex, or disease severity (Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale motor section) in PD, and levodopa dose or levodopa equivalent dose in PSP and MSA. Of the 9 detected metabolites, 8 in PD, 5 in PSP, and 3 in MSA were significantly decreased in both cohorts even after normalizing to daily caffeine consumption. No significant genetic variations in CYP1A2 or CYP2E1 were detected when compared with controls. CONCLUSION: Serum caffeine metabolic profiles in 3 parkinsonian diseases show a high level of overlap, indicative of a common potential mechanism such as caffeine malabsorption from the small intestine, hypermetabolism, increased clearance of caffeine, and/or reduced caffeine consumption. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Metabolomic analysis revealed mitochondrial dysfunction and aberrant choline metabolism in MPP+-exposed SH-SY5Y cells.

1-Methyl-4-phenylpyridinium (MPP+)-treated human neuroblastoma SH-SY5Y cells have been generally accepted as a cellular model for Parkinson's disease. To understand comprehensive metabolic disturbances in this model, both cell lysates and culture supernatants were subjected to metabolomic analysis. As expected from the fact that MPP+ inhibits mitochondrial complex I, a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis was indicated by an increase in extracellular lactic acid and a parallel depletion of pyruvic acid. In cell lysates, the metabolic shift was supported by consistent decreases in TCA cycle intermediates. Metabolomic analysis also revealed aberrant choline metabolism. Choline in the culture supernatant was elevated 8.5- and 17-fold by 30 and 300 µM MPP+ exposure, respectively; therefore, extracellular choline might be a metabolic biomarker for Parkinson's disease.

Neuromelanin imaging and midbrain volumetry in progressive supranuclear palsy and Parkinson's disease.

Background Nigral degeneration patterns differ between PSP and PD. However, the relationship between nigral degeneration and midbrain atrophy in PSP remains unclear. Objective We analyzed differences and relationships between nigral degeneration and midbrain atrophy in PSP and PD. Methods Neuromelanin-sensitive MRI and midbrain volumetry were performed in 11 PSP patients, 24 PD patients, and 10 controls to measure the neuromelanin-sensitive SNpc area and midbrain volume. Results The neuromelanin-sensitive SNpc area and midbrain volume were significantly smaller in PSP patients compared with PD patients and controls. Motor deficits were inversely correlated with neuromelanin-sensitive SNpc area in PD, but not PSP patients. There was no significant correlation between neuromelanin-sensitive SNpc area and midbrain volume in either disease group. Midbrain volumetry discriminated PSP from PD. Diagnostic accuracy was improved when neuromelanin-sensitive MRI analysis was added. Conclusions Neuromelanin-sensitive MRI and midbrain volumetry may reflect the clinical and pathological characteristics of PSP and PD. Combining neuromelanin-sensitive MRI and midbrain volumetry may be useful for differentiating PSP from PD. © 2018 International Parkinson and Movement Disorder Society.

Limb-Shaking Transient Ischemic Attack Induced by Middle Cerebral Artery Dissection after Lung Surgery.

We report a case of limb-shaking transient ischemic attack (TIA) caused by a dissection of the middle cerebral artery (MCA) following lung surgery under general anesthesia. An 81-year-old male patient who underwent lobectomy for lung cancer suddenly developed transient shaking movements of the neck and the left upper distal limb on postoperative day 1. On the basis of the double-barrel appearance of the right M1 segment of the MCA, a diagnosis of MCA dissection was made. Physicians should be aware that limb-shaking TIA is sometimes caused by MCA dissection and could be precipitated by any condition, including lung surgery under general anesthesia.

Cerebral infarction in a case of Parry-Romberg syndrome.

Our objective is to report a rare coexistence of Parry-Romberg disease and ischemic stroke. Here, we report the case of a 34-year-old woman with Parry-Romberg syndrome who developed cerebral infarction. This patient developed sudden left-sided weakness and was admitted to our hospital. Magnetic resonance imaging revealed acute cerebral infarction in the posterior limb of the right internal capsule. The patient had been diagnosed with Parry-Romberg syndrome at the age of 12, and she had a history of migraine without aura. Transesophageal echocardiography revealed a patent foramen ovale, but no atrial septal aneurysm or deep vein thrombosis was observed in the lower extremities. She was treated with 200 mg of aspirin and 10 mg of atorvastatin. Her symptoms gradually improved, and she was discharged 10 days after admission. Parry-Romberg syndrome is a rare disease of progressive hemifacial atrophy with unknown etiology. The potential risk factors for ischemic stroke in Parry-Romberg syndrome include ipsilateral cerebrovascular abnormality or migraine. In addition, patent foramen ovale was identified as a concomitant risk factor in our case.

Efficacy and Safety of Elobixibat in Parkinson's Disease with Chronic Constipation: CONST-PD Study.

BACKGROUND: Chronic constipation is a common digestive complication of Parkinson's disease (PD). OBJECTIVES: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD. METHODS: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed. RESULTS: The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported. CONCLUSIONS: Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation. TRIAL REGISTRATION INFORMATION: Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).

Midbrain atrophy in pathologically diagnosed Lewy body disease and clinically diagnosed Parkinson's disease.

OBJECTIVE: Midbrain atrophy is considered specific to progressive supranuclear palsy (PSP) compared with Parkinson's disease (PD). We aimed to determine how often midbrain atrophy is observed in pathologically diagnosed Lewy body disease (LBD) and clinically diagnosed PD and the robustness of midbrain atrophy assessed by the One-Line Method previously developed for the diagnosis of PSP. METHODS: We studied two separate cohorts with MRI: the first pathologically diagnosed cohort consisted of patients with LBD (n = 13), PSP (n = 6), multiple system atrophy (MSA, n = 7), and corticobasal degeneration (CBD, n = 2); the second cohort consisted of patients with PD (n = 122). Midbrain length was measured using the One-Line Method and FreeSurfer estimated volumes of the subcortical nuclei. RESULTS: The area under the curve of midbrain length differentiating PSP from LBD, MSA, and CBD in a pathologically diagnosed cohort was 0.91. Midbrain length with cut-off values of 10.5 mm and 9.5 mm had a sensitivity of 100% and 67% and a specificity of 68% and 96%, respectively. In the first cohort, 7.7% and 23.0% of patients with LBD showed midbrain lengths <9.5 mm and 10.5 mm, respectively, and in the second cohort, 4.9% and 19.7% showed midbrain lengths <9.5 mm and 10.5 mm, respectively. INTERPRETATION: Midbrain length measured using the One-Line Method is helpful in the diagnosis of PSP. Some cases of pathologically diagnosed LBD and clinically diagnosed PD present with midbrain atrophy.

Factor analysis for construct validity of a trunk impairment scale in Parkinson's disease: a cross-sectional study.

Objectives: To investigate the construct validity of the Trunk Impairment Scale (TIS), which was developed to assess trunk impairment in patients with stroke, in patients with Parkinson's disease (PD). Design: This retrospective, cross-sectional study enrolled consecutive PD inpatients. Correlation analysis was performed to clarify whether the TIS assessment was related to other balance functions, lower extremity muscle strength, or walking ability. Factor analysis was performed to see how the background factors of TIS differ from balance function, lower limb muscle strength, and walking ability. Results: Examining the data of 471 patients with PD, there were relationships between TIS and the Mini-Balance Evaluation Systems Test (r = 0.67), Barthel Index (r = 0.57), general lower limb extension torque (r = 0.51), two-minute walk test (r = 0.54), Hoehn and Yahr stage (r = -0.61), and Movement Disorder Society Unified Parkinson's Disease Rating Scale part III total points (r = -0.59). Factor analysis showed that TIS items were divided into three factors (an abdominal muscles and righting reflex component; a perception and verticality component; and a rotational component), differing from other scales that included clinical assessment items. Conclusion: The TIS can be useful for assessing the underlying trunk impairment as a basis for activities of daily living, gait function, and balance ability in patients with PD.

Analytical and clinical validity of wearable, multi-sensor technology for assessment of motor function in patients with Parkinson's disease in Japan.

Continuous, objective monitoring of motor signs and symptoms may help improve tracking of disease progression and treatment response in Parkinson's disease (PD). This study assessed the analytical and clinical validity of multi-sensor smartwatch measurements in hospitalized and home-based settings (96 patients with PD; mean wear time 19 h/day) using a twice-daily virtual motor examination (VME) at times representing medication OFF/ON states. Digital measurement performance was better during inpatient clinical assessments for composite V-scores than single-sensor-derived features for bradykinesia (Spearman |r|= 0.63, reliability = 0.72), tremor (|r|= 0.41, reliability = 0.65), and overall motor features (|r|= 0.70, reliability = 0.67). Composite levodopa effect sizes during hospitalization were 0.51-1.44 for clinical assessments and 0.56-1.37 for VMEs. Reliability of digital measurements during home-based VMEs was 0.62-0.80 for scores derived from weekly averages and 0.24-0.66 for daily measurements. These results show that unsupervised digital measurements of motor features with wrist-worn sensors are sensitive to medication state and are reliable in naturalistic settings.Trial Registration: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI): JapicCTI-194825; Registered June 25, 2019.

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson's disease.

Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson's disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology.

Investigating the efficacy and safety of elobixibat, an ileal bile acid transporter inhibitor, in patients with Parkinson's disease with chronic constipation: a multicentre, placebo-controlled, randomised, double-blind, parallel-group stud (CONST-PD).

INTRODUCTION: Chronic constipation worsens the quality of life (QOL) of patients with Parkinson's disease (PD). Elobixibat, an ileal bile acid transporter inhibitor, is a useful laxative, but its effect on chronic constipation in patients with PD remains unclear. Therefore, we designed a placebo-controlled, randomised, double-blind study to investigate the efficacy and safety of elobixibat in patients with PD with chronic constipation. METHODS AND ANALYSIS: The study will consist of 2-week observation and 4-week treatment periods. Patients with clinically established PD will record the status of spontaneous bowel movements and use of rescue medications/concomitant medications in a Bowel Movement Diary from the start of the observation period at visit 1 (week -2). At visit 2 (week 0), patients will be assessed for final registration based on the diary records and physical examinations, and allocated to either the elobixibat or placebo group. Daily intake of the investigational drug will be recorded in the diary. Patients will undergo laboratory tests and answer constipation-related, PD-related and QOL-related questionnaires at visits 2 and 4 (week 4). Subjective symptoms and objective findings will be collected at visits 2, 3 (week 2) and 4. Since patients' motor function might be improved by treatment of constipation, the use of dopamine preparations will also be monitored. Bowel movement data and other parameters will be compared between groups.Safety information will be collected as adverse events, specifically focusing on those occurring in association with study conduct. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the Helsinki Declaration, the Clinical Trials Act of the Japan Ministry of Health, Labour and Welfare, and related laws and regulations. The study was approved by the Juntendo University Certified Review Board. The results will be disseminated through an online study registry (Japan Registry of Clinical Trials), presented at scientific conferences, and published in medical journals. TRIAL REGISTRATION NUMBER: JPRN-jRCTs031200172; Pre-results.

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 2: Acquired Disorders.

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these "imaging pearls" into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.

Metabolomic analysis data of MPP+-exposed SH-SY5Y cells using CE-TOFMS.

1-Methyl-4-phenylpyridinium (MPP+)-treated human neuroblastoma SH-SY5Y cells have been generally accepted as a cellular model for Parkinson's disease. This article contains metabolic analysis data of not only cell lysate but also culture supernatants to understand comprehensive metabolic disturbances in this model. Metabolic analysis employed by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Data obtained by CE-TOFMS were processed to extract peak information including m/z, peak area, and migration time. The data provided in this manuscript have been analyzed and discussed in the research article entitled "Metabolomic analysis revealed mitochondrial dysfunction and aberrant choline metabolism in MPP+-exposed SH-SY5Y cells" [1].

Diffusion MRI Captures White Matter Microstructure Alterations in PRKN Disease.

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.