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In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

Introduction: The King's Parkinson's Disease Pain Scale (KPPS)/King's Parkinson's Disease Pain Questionnaire (KPPQ) was developed as a tool to quantitatively assess pain in patients with Parkinson's disease (PwPD). Here, we conducted a Japanese multicenter validation study to verify the reliability of KPPS/KPPQ in Japanese PwPD., Methods: PwPD, ≥20 years, with unexplained pain were included; those with a definitive primary cause of pain other than PD were excluded. A total of 151 patients who fulfilled the criteria were analyzed, and test-retest reliability was investigated in 25 individuals., Results: The 151 patients included 101 women (66.9 %); mean age 68.3 ± 9.9 years, mean disease duration 9.2 ± 5.2 years. The most frequent pain type in the KPPS classification was musculoskeletal pain (82.8 %). There was a positive correlation between KPPS total score and the Non-Motor Symptoms Scale (NMSS) total score, NMSS item 27, the Parkinson's disease sleep scale-version 2 (PDSS-2) total score, PDSS-2 item 10, the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index and PDQ-8 item 7. Cronbach's alpha of KPPS was 0.626 (0.562-0.658) and the intraclass correlation coefficient of test-retest reliability was 0.740. Cronbach's alpha of KPPQ was 0.660 (0.617-0.705) and a test-retest reliability of kappa coefficient was 0.593 (0.0-1.0)., Conclusions: KPPS correlated well with other scales for assessing pain. KPPS correlated well with patients' quality of life, non-motor symptoms, and sleep disturbances. The reproducibility of KPPS/KPPQ makes it suitable for continuous evaluation of the same patient. On the other hand, the internal consistency of KPPS/KPPQ is rather low., Competing Interests: Declaration of competing interest We received financial support for this study by Eisai Co., Ltd., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca 2+ oscillations in the absence of the Ca 2+ -buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca 2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca 2+ oscillations, and (3) providing bioenergetic support.

Background: Parkinson's disease (PD) is associated with cognitive decline through multiple mechanisms, including Alzheimer's disease (AD) pathology and cortical Lewy body involvement. However, its underlying mechanisms remain unclear. Recently, AD-related plasma biomarkers have emerged as potential tools for predicting abnormal pathological protein accumulation. We aimed to investigate the association between AD-related plasma biomarkers and cognitive decline in PD patients., Methods: Plasma biomarkers were measured in 70 PD patients (49 with nondemented Parkinson's disease (PDND) and 21 with Parkinson's disease dementia (PDD)) and 38 healthy controls (HCs) using a single-molecule array. The study evaluated (1) the correlation between plasma biomarkers and clinical parameters, (2) receiver operating characteristic curves and areas under the curve to evaluate the discrimination capacity of plasma biomarkers among groups, and (3) a generalized linear model to analyze associations with Addenbrooke's Cognitive Examination-Revised and Montreal Cognitive Assessment-Japanese version scores., Results: Plasma glial fibrillary acidic protein significantly correlated with cognitive function tests, including all subdomains, with a notable increase in the PDD group compared with the HC and PDND groups, while plasma neurofilament light chain captured both cognitive decline and disease severity in the PDND and PDD groups. Plasma beta-amyloid 42/40 and pholphorylated-tau181 indicated AD pathology in the PDD group, but plasma beta-amyloid 42/40 was increased in the PDND group compared with HCs and decreased in the PDD group compared with the PDND group., Conclusions: AD-related plasma biomarkers may predict cognitive decline in PD and uncover underlying mechanisms suggesting astrocytic pathologies related to cognitive decline in PD., (© 2023. The Author(s).)

Objective: Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD., Methods: The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (K m ) and maximal velocity (V max ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level., Results: Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent V max (P = 0.0131), but no change in the apparent K m value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery., Interpretation: This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Dyskinesia frequently occurs during long-term treatment with levodopa in patients with Parkinson's disease (PD) and impacts quality of life. Few studies have examined risk factors for developing dyskinesia in PD patients exhibiting wearing-off. Therefore, we investigated the risk factors and impact of dyskinesia in PD patients exhibiting wearing-off., Methods: We investigated the risk factors and impact of dyskinesia in a 1-year observational study of Japanese PD patients exhibiting wearing-off (J-FIRST). Risk factors were assessed by logistic regression analyses in patients without dyskinesia at study entry. Mixed-effect models were used to evaluate the impact of dyskinesia on changes in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Part I and PD Questionnaire (PDQ)-8 scores from one timepoint before dyskinesia was observed., Results: Of 996 patients analyzed, 450 had dyskinesia at baseline, 133 developed dyskinesia within 1 year, and 413 did not develop dyskinesia. Female sex (odds ratio [95% confidence interval]: 2.636 [1.645-4.223]) and administration of a dopamine agonist (1.840 [1.083-3.126]), a catechol-O-methyltransferase inhibitor (2.044 [1.285-3.250]), or zonisamide (1.869 [1.184-2.950]) were independent risk factors for dyskinesia onset. MDS-UPDRS Part I and PDQ-8 scores increased significantly after the onset of dyskinesia (least-squares mean change [standard error] at 52 weeks: 1.11 [0.52], P = 0.0336; 1.53 [0.48], P = 0.0014; respectively)., Conclusion: Female sex and administration of a dopamine agonist, a catechol-O-methyltransferase inhibitor, or zonisamide were risk factors for dyskinesia onset within 1 year in PD patients exhibiting wearing-off. Nonmotor symptoms and quality of life deteriorated after dyskinesia onset., Competing Interests: Declaration of Competing Interest T. Mishima reports research funds from Kyowa Kirin in relation to this work. S.-W.C. reports research funds from Kyowa Kirin in relation to this work. H.S. reports research funds from Kyowa Kirin in relation to this work; research grants from Otsuka Pharmaceutical and Eisai; and honoraria from Kyowa Kirin, Eisai, Takeda Pharmaceutical, Dainippon Sumitomo Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Novartis, Boston Scientific Japan, AbbVie, Medtronic Japan, and Teijin Pharma. T.Y. reports payments made to the institution from Kyowa Kirin in relation to this work; research grants from AC Medical, A2 Healthcare Corporation, EP Croit, ClinChoice, Japan Tobacco, Japan Media Corporation, Medidata Solutions, Ono Pharmaceutical, Asahi Intecc, 3H Clinical Trial, Medrio, Nipro Corporation, Intellim Corporation, Welby, 3H Medi Solution, Baseconnect, Nobori, Puravida Technologies, and Hemp Kitchen; research grants/payments to the institution from Kyowa Kirin, Tsumura & Co, Daiichi Sankyo, Otsuka Pharmaceutical, and Eisai; consulting fees from EP Croit, Japan Tobacco, Medidata Solutions, Ono Pharmaceutical, Kowa Company, Chugai Pharmaceutical, Tsumura & Co., Daiichi Sankyo, Eisai, Asahi Intecc, Asahi Kasei Pharma Corporation, 3H Clinical Trial, Intellim Corporation, Takeda, AstraZeneca, Sonire Therapeutics, and Seikagaku Corporation; payments or honoraria from Nipro Corporation; and participation on a data safety monitoring board or advisory board for Incyte Biosciences Japan. Y.S. reports research funds from Kyowa Kirin in relation to this work. T. Maeda reports research funds from Kyowa Kirin in relation to this work; lecture fees and scholarship donations from Daiichi Sankyo; lecture fees from Nihon Mediphysics, Biogen, Chugai Pharmaceutical, Kyowa Kirin, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Ono Pharmaceutical, Eisai, and Japan Medtronic; scholarship donations from Bayer Yakuhin, Teijin, and CSL Behring; and consulting fees from Kyowa Kirin and Ono Pharmaceutical. H.W. reports research funds from Kyowa Kirin in relation to this work; and honoraria from Takeda Pharmaceutical, AbbVie, Kyowa Kirin, Sumitomo Dainippon Pharma, Novartis, Otsuka Pharmaceutical, and FP Corporation. K.K. reports research funds from Kyowa Kirin in relation to this work; lecture fees and consulting fees from Kyowa Kirin; and lecture fees from Takeda Pharmaceutical and Ono Pharmaceutical. M.N. reports research funds from Kyowa Kirin in relation to this work; research funds from Kyowa Kirin, Kissei Pharmaceutical, and Hisamitsu Pharmaceutical; and lecture fees from Ehime University School of Medicine, Eisai, and Kyowa Kirin. N.H. reports grants to the Collaborative Research Department of Drug Discovery Research for Synucleopathies, lecture fees, and support for attending advisory boards from Kyowa Kirin in relation to this work; research contracts with Dainippon Sumitomo Pharma, Biogen Japan, and CellSource; consultancy fees from Hisamitsu Pharma and PARKINSON Laboratories; honoraria from Dainippon Sumitomo Pharma, Takeda Pharmaceutical, AbbVie, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, Novartis, Bristol-Myers Squibb, Ono Pharmaceutical, FP Pharmaceutical, Eisai, Kissei Pharmaceutical, Nihon Mediphysics, and Daiichi Sankyo; support for attending advisory boards from Dainippon Sumitomo Pharma, Takeda Pharmaceutical, Teijin Pharma, Novartis, Ono Pharmaceutical, Biogen Idec Japan, Kissei Pharmaceutical, and Mitsubishi Tanabe Pharma; Japanese (2021–0001888; Differential Diagnosis of Parkinson's Disease and Multiple System Atrophy, Patent Applicants: Juntendo University, Nagasaki University, January 4, 2021) and international (International filing date: 2021/09/22; priority date: 2020/10/29; applicant name: Juntendo Educational Foundation) patents; honoraria for team leader role at RIKEN: Center for Brain Science; and holds stock in PARKINSON Laboratories. Y.T. reports research funds from Kyowa Kirin; lecture fees from Sumitomo Dainippon Pharma, Takeda Pharmaceutical Company, Novartis, AbbVie, Otsuka Pharmaceutical, Ono Pharmaceutical, and Eisai; and contributes to courses run by Sunwels and Nipro Corporation., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The dark pigment neuromelanin (NM) is abundant in cell bodies of dopamine (DA) neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) in the human brain. During the progression of Parkinson's disease (PD), together with the degeneration of the respective catecholamine (CA) neurons, the NM levels in the SN and LC markedly decrease. However, questions remain among others on how NM is associated with PD and how it is synthesized. The biosynthesis pathway of NM in the human brain has been controversial because the presence of tyrosinase in CA neurons in the SN and LC has been elusive. We propose the following NM synthesis pathway in these CA neurons: (1) Tyrosine is converted by tyrosine hydroxylase (TH) to L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted by aromatic L-amino acid decarboxylase to DA, which in LC neurons is converted by dopamine β-hydroxylase to NE; (2) DA or NE is autoxidized to dopamine quinone (DAQ) or norepinephrine quinone (NEQ); and (3) DAQ or NEQ is converted to eumelanic NM (euNM) and pheomelanic NM (pheoNM) in the absence and presence of cysteine, respectively. This process involves proteins as cysteine source and iron. We also discuss whether the NM amounts per neuromelanin-positive (NM + ) CA neuron are higher in PD brain, whether NM quantitatively correlates with neurodegeneration, and whether an active lifestyle may reduce NM formation., (© 2023. The Author(s).)

Introduction: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123 I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy., Methods: This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG., Results: Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score., Conclusion: Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores., Competing Interests: Declaration of competing interest Funding sources: This study was supported by a grant from the AMED under grant numbers JP18dm0207022 and JP19dm0207070, Japan Science and Technology Agency Moonshot Research and Development Program (JPMJMS2024-5), FUJIFILM Toyama Chemical Co., Ltd., and Nihon Medi-Physics Co., Ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is an aging-related disease and the second most common neurodegenerative disease after Alzheimer's disease. The main symptoms of PD are movement disorders accompanied with deficiency of neurotransmitter dopamine (DA) in the striatum due to cell death of the nigrostriatal DA neurons. Two main histopathological hallmarks exist in PD: cytosolic inclusion bodies termed Lewy bodies that mainly consist of α-synuclein protein, the oligomers of which produced by misfolding are regarded to be neurotoxic, causing DA cell death; and black pigments termed neuromelanin (NM) that are contained in DA neurons and markedly decrease in PD. The synthesis of human NM is regarded to be similar to that of melanin in melanocytes; melanin synthesis in skin is via DOPAquinone (DQ) by tyrosinase, whereas NM synthesis in DA neurons is via DAquinone (DAQ) by tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). DA in cytoplasm is highly reactive and is assumed to be oxidized spontaneously or by an unidentified tyrosinase to DAQ and then, synthesized to NM. Intracellular NM accumulation above a specific threshold has been reported to be associated with DA neuron death and PD phenotypes. This review reports recent progress in the biosynthesis and pathophysiology of NM in PD.

Introduction: The impact of deep brain stimulation (DBS) on speech rhythm and its mechanism remains unclear. We investigated speech rhythm characteristics of patients with Parkinson's disease (PD) treated with subthalamic nucleus (STN) DBS to understand the underlying pathophysiology better., Methods: We enrolled a total of 105 participants and evaluated speech rhythm performances among patients with PD who had undergone STN-DBS (the PD-DBS group), patients with PD treated only with medication (the PD-Med group), patients with cerebellar ataxia (the CA group), and healthy controls (the HC group). Each participant was asked to repeat the syllable/pa/at a comfortable self-chosen steady pace. A widely-used software (the Motor Speech Profile) program performed an acoustic analysis., Results: Compared to the PD-Med and HC groups, speech rate instability (DDKjit) was significantly higher in the PD-DBS and CA groups (p < 0.01). However, after DBS was turned off, the DDKjit of the PD-DBS group improved to a level comparable to that of the PD-Med and HC groups. In contrast to the significantly higher variability of speech volume (DDKcvi) in the CA group, the PD-DBS group showed similar DDKcvi to the PD-Med and HC groups., Conclusions: STN-DBS affects the speech rate stability of patients with PD. Speech rhythm disorders caused by STN-DBS were phenotypically similar to that in CA in terms of interval variability but different regarding amplitude variability. Further studies are warranted to elucidate the underlying pathophysiology of speech rhythm disorders in PD patients treated with DBS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The non-motor symptoms (NMSs) of Parkinson's disease (PD) significantly impact the patient's health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A 2A receptor antagonist, on NMSs in istradefylline-naïve Japanese patients with PD., Methods: Patients with PD and ≥1 NMS and 'wearing-off' with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model., Results: Overall, 732 patients were istradefylline-naïve prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score., Conclusion: NMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: This study aimed to evaluate whether novel individual voxel-based morphometry adjusting covariates (iVAC), such as age, sex, and total intracranial volume, could increase the accuracy of a diagnosis of multiple system atrophy (MSA) and enable the differentiation of MSA from Parkinson's disease (PD)., Methods: We included 53 MSA patients (MSA-C: 33, MSA-P: 20), 53 PD patients, and 189 healthy controls in this study. All participants underwent high-resolution T1-weighted imaging (WI) and T2-WI with a 3.0-T MRI scanner. We evaluated the occurrence of significant atrophic findings in the pons/middle cerebellar peduncle (MCP) and putamen on iVAC and compared these findings with characteristic changes on T2-WI., Results: On iVAC, abnormal findings were observed in the pons/MCP of 96.2% of MSA patients and in the putamen of 80% of MSA patients; however, on T2-WI, they were both observed at a frequency of 60.4% in MSA patients. On iVAC, all but one MSA-P patient (98.1%) showed significant atrophic changes in the pons/MCP or putamen. By contrast, 69.8% of patients with MSA showed abnormal signal changes in the pons/MCP or putamen on T2-WI. iVAC yielded 95.0% sensitivity and 96.2% specificity for differentiating MSA-P from PD., Conclusion: iVAC enabled us to recognize the morphological characteristics of MSA visually and with high accuracy compared to T2-WI, indicating that iVAC is a potential diagnostic screening tool for MSA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson's disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD., Objective: We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD., Methods: We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n = 8) were also measured., Results: C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD., Conclusion: Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.

The present report documents a patient harboring an alpha-synuclein p.A53T variant from a family presenting with autosomal dominant inheritance, including four patients clinically diagnosed with Parkinson's disease (PD) and two with dementia. The alpha-synuclein p.A53T variant is linked to young- or middle-aged onset parkinsonism and cognitive decline. Our patient had a different haplotype from that of a patient with a p.A53T variant from an Italian family. The proband presented at 42 years of age with progressive parkinsonism and good response to levodopa in the early stages of the disease. At 46 years of age, he developed delusions and cognitive decline. Brain magnetic resonance imaging showed bilateral atrophic changes in the hippocampus and temporal lobes. He died of pneumonia at the age of 52 years. Neuropathological examination revealed severe neuronal loss in the substantia nigra, locus coeruleus, and dorsal nucleus of the vagus nerve, as well as widespread Lewy pathology including Lewy bodies and neurites, corresponding to Braak stage 6, and diffuse neocortical-type PD. There was mild appearance of tau pathology and glial cytoplasmic inclusion, in the absence of TDP-43 pathology. Alpha-synuclein p.A53T characteristically cause the Lewy body pathology and the symptoms, that resembled those of the reported patients with p.A53T., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific.

Introduction: The role of the cerebellum in Parkinson's disease (PD) has attracted increasing attention; however, the role of functional connectivity (FC) between the basal ganglia and particular cerebellar subregions remains to be elucidated. We aimed to clarify the FC and its contribution to motor and cognitive performances in patients with PD., Methods: We included 99 patients with PD and 99 age- and sex-matched healthy controls in this study. We created a cerebellar functional parcellation by performing cerebellum-only independent component analysis. Using the functional parcellation map, we performed seed-based connectivity analysis using each region as a seed and extracted the mean correlation coefficients within the thalamus and basal ganglia, including the caudate, pallidum, putamen and subthalamic nucleus. We examined the group differences and correlations with the motor and general cognitive scores. In addition, we conducted a mediation analysis to clarify the relationship among FC, motor severity, and cognition., Results: The PD group showed decreased FC between a wide range of cerebellar subregions and the basal ganglia. Motor severity was correlated with FC between the subthalamic nucleus and posterior Crus I/II, and general cognitive performance scores correlated with FC between the caudate nucleus and medial-posterior part of the Crus I/II (p < 0.05, corrected for multiple comparisons). The cerebello-caudate network had a direct effect on cognitive performance (p = 9.0 × 10 -3 ), although partially mediated by motor performance (p = 8.2 × 10 -3 )., Conclusion: FC between cerebellar Crus I/II and divergent basal ganglia related to motor and cognitive performance in PD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cognitive deficits in Parkinson's disease (PD) are heterogeneous entities, and the cognitive status fluctuates over time. However, individual changes in longitudinal cognitive performance in PD are not fully understood. We evaluated three visual indices (visuoperception, visuoconstruction, and visuospatial ability) and four cognitive domains (attention/working memory, executive function, memory, and language) at baseline (Time1) and at 1-year follow-up (Time2) in 36 patients with PD and 32 healthy controls (HCs). To explore the magnitude and frequency of cognitive changes, we analyzed data using the simple difference method and the standardized regression-based method. We also explored the correlations between changes in test scores and several clinical predictors, using logistic regression analysis. At 1 year, patients with PD showed higher rates of change in scores on several cognitive tests, especially the Incomplete Letters test of visuoperception, compared to HCs. After adjusting for demographic variables, the visuoperceptual change was 61.1% overall, with the largest effect size. The changes in scores of visuoperception correlated with those of memory (r = 0.672, p < 0.001), language (r = 0.389, p < 0.05), and visuospatial ability (r = 0.379, p < 0.05). The severity of olfactory disturbance, the MDS-UPDRS Part I score, and younger PD onset predicted the significant changes observed in the Incomplete Letters test scores. Visuoperception changed more in non-demented PD patients than in HCs at 1-year follow-up. The changes in visuoperception could relate to involvement of the ventral occipitotemporal pathway, the more widespread temporal lobe, and brain reserve in PD.

Background: Cellular energetics play an important role in Parkinsons disease etiology, but no treatments directly address this deficiency. Our past research showed that treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 3 Parkinson's disease patients suggested some symptomatic improvements with no adverse effects., Methods: To examine the efficacy on symptoms and safety in a larger group of Parkinsons disease patients, we conducted a single-arm, open-label trial at 5 Japanese neurology clinics and enrolled thirty patients (nmales = 11; nfemales = 19); 26 patients completed the study (nmales = 10; nfemales = 16). Each patient was administered febuxostat 20 mg and inosine 500 mg twice-per-day (after breakfast and dinner) for 8 weeks. The primary endpoint was the difference of MDS-UPDRS Part III score immediately before and after 57 days of treatment., Results: Serum hypoxanthine concentrations were raised significantly after treatment (Pre = 11.4 μM; Post = 38.1 μM; P < .0001). MDS-UPDRS Part III score was significantly lower after treatment (Pre = 28.1 ± 9.3; Post = 24.7 ± 10.8; mean ± SD; P = .0146). Sixteen adverse events occurred in 13/29 (44.8%) patients, including 1 serious adverse event (fracture of the second lumbar vertebra) that was considered not related to the treatment., Conclusions: The results of this study suggest that co-administration of febuxostat and inosine is relatively safe and effective for improving symptoms of Parkinsons disease patients. Further controlled trials need to be performed to confirm the symptomatic improvement and to examine the disease-modifying effect in long-term trials.

Introduction: The present study aimed to survey the prevalence of prodromal symptoms of Parkinson's disease (PD) in Japanese health checkup examinees, for identifying at-risk subjects., Methods: We conducted a questionnaire survey of annual health checkup examinees without neurological symptoms using the following self-reported questionnaires: Japanese version of the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT); Self-administered Odor Question (SAOQ); REM Sleep Behavior Disorder Screening Scale (RBDSQ); Beck Depression Inventory-Second Edition (BDI-II); Epworth Sleepiness Scale (ESS); and Physical Activity Scale for the Elderly (PASE). The presence of prodromal symptoms was determined using the 90th percentile threshold of each questionnaire. Subjects ≥ 50 years of age with ≥ 2 core prodromal symptoms (dysautonomia, hyposmia, and RBD), were classified as at risk., Results: Between March 2017 and March 2018, 4,953 participants sufficiently answered the questionnaires. Among 2,726 subjects ≥ 50 years of age, 155 were classified as at risk. These subjects had worse values of BDI-II (12.0 ± 8.3 vs. 4.4 ± 3.8, p < 0.001) and ESS (9.6 ± 5.0 vs. 6.3 ± 3.2, p < 0.001), in addition to SCOPA-AUT, SAOQ, and RBDSQ. Male at-risk subjects showed lower values of hemoglobin (14.8 ± 1.3 vs. 15.0 ± 1.1, p = 0.032) and low density lipoprotein cholesterol (114.5 ± 30.3 vs. 123.0 ± 28.9, p = 0.004) than the examinees reporting no prodromal symptoms., Conclusion: Approximately 6% of the population aged 50 years or older was at risk for PD. Male at-risk subjects had mild hematological and metabolic changes relevant to PD.

Background: Speech disorders are among the most common adverse effects after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients. However, longitudinal speech changes after STN-DBS are not fully understood., Objective: We performed a two-year prospective study on PD patients who underwent STN-DBS and analyzed changes in speech function to clarify factors predicting for speech deterioration., Methods: Twenty-five PD patients were assessed before and up to two years after STN implantation. Speech function was evaluated in the on-stimulation condition and 30 min after stimulation cessation using auditory-perceptual assessment. Patients who experienced overall worsening in speech intelligibility or naturalness ≥1 point during follow-up were classified into a deteriorated group (n = 16), with the remaining subjects being classified into a stable group (n = 9). Cognitive and motor functions were also assessed., Results: The stable group had significantly better values of low volume, monoloudness, and asthenic voice subscores of the auditory-perceptual assessment in the on-stimulation condition compared with the off-stimulation condition. Imprecise consonants, excess loudness variation, and strained voice subscores were improved via cessation of stimulation in both groups. Before surgery, the deteriorated group had significantly lower scores in the Stroop Color-Word Test and Digit Span compared to the stable group., Conclusions: During follow-up, some subscores showed significant worsening in the on-stimulation condition in both groups. However, beneficial effects of STN-DBS on speech appeared to counterbalance negative effects of STN-DBS on speech function only in the stable group. Worse cognitive function may be a potential predictor for speech deterioration after STN-DBS in PD patients.

Objectives: This study aimed to explore clinical correlates of repetitive speech disorders in patients with Parkinson's disease (PD)., Methods: This study investigated speech function (Assessment of Motor Speech for Dysarthria and Stuttering Severity Instrument-3), motor function (Unified Parkinson's Disease Rating Scale III [UPDRS-III] and UPDRS-IV), cognitive function (Mini-Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA], Stroop color-word test, verbal fluency, digit span tests, and line orientation), and activities of daily living of 113 PD patients. Comparison between groups (independent t-tests, Mann-Whitney U tests, or χ 2 test) and linear regression analyses were performed to determine clinical correlates of repetitive speech disorders., Results: Totally, 65 patients (57.5%) had repetitive speech disorders. Patients with repetitive speech disorders had significantly worse UPDRS-III (P = .049), MoCA (P = .030), and speech function and higher levodopa equivalent daily dose (LEDD; P = .031) than those without repetitive speech disorders. Males were significantly predominant in patients with repetitive speech disorders (64.6%) compared to those without repetitive speech disorders (18.7%; P < .001). The univariate and subsequent multiple linear regression analyses revealed that the severity of repetitive speech disorders significantly correlated with gender (P < .001), MoCA (P = .006), and speech variables (abnormal rate, P = .007; imprecise consonants, P = .043), independent from disease duration, UPDRS III, and LEDD., Conclusions: PD patients with repetitive speech disorders had worse motor, cognitive, and speech functions than those without repetitive speech disorders. The most influential factor for repetitive speech disorders might be male gender., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cognitive deficits in Parkinson's disease (PD) are heterogeneous entities, but a relationship between the heterogeneity of cognitive deficits and resting-state network (RSN) changes remains elusive. In this study, we examined five sub-domain scores according to Addenbrooke's Cognitive Examination-Revised (ACE-R) for the cognitive evaluation and classification of 72 non-demented patients with PD. Twenty-eight patients were classified as PD with normal cognition (PD-NC). The remaining 44 were subdivided into the following 2 groups using a hierarchical cluster analysis: 20 with a predominant decrease in memory (PD with amnestic cognitive deficits: PD-A) and 24 with good memory who exhibited a decrease in other sub-domains (PD with non-amnestic cognitive deficits: PD-NA). We used an independent component analysis of RS-fMRI data to investigate the inter-group differences of RSN. Compared to the controls, the PD-A showed lower FC within the ventral default mode network (vDMN) and the visuospatial network. On the other hand, the PD-NA showed lower FC within the visual networks and the cerebellum-brainstem network. Significant differences in the FC within the vDMN and cerebellum-brainstem network were observed between the PD-A and PD-NA, which provided a good discrimination between PD-A and PD-NA using a support vector machine. Distinct patterns of cognitive deficits correspond to different RSN changes.

The International Parkinson and Movement Disorder Society offered standard diagnostic criteria for Parkinson's disease (PD) in 2015. These diagnostic criteria provided systematization of the diagnostic process and detailed explanations of parkinsonism, absolute exclusion criteria, red flags, and supportive criteria. The presence of parkinsonism was a core feature of the criteria. Clear instructions for defining the motor features were described. With regard to the novel aspects, non-motor manifestations (hyposmia, autonomic dysfunction, psychiatric dysfunction, and sleep dysfunction) and ancillary diagnostic tests (olfactory test, cardiac MIBG scintigraphy, and presynaptic dopaminergic imaging) were incorporated. Absolute exclusion criteria comprised 9 features that have the potential to exclude PD with greater than 97% sensitivity. The presence of dementia during the early stage of the illness was not classified as an exclusion criterion. The 10 red flags that indicate another cause of parkinsonism but can also be observed in pathologically proven PD were listed. Red flags were counterbalanced by supportive criteria to allow diagnosis of PD. These 4 supportive criteria were highly specific for a diagnosis of PD. With regard to the level of certainty, clinically established PD and clinically probable PD were described. In this review, we summarize the main points of the MDS-PD criteria and discuss the utility and limitations.

Objective: Severe hyposmia is a risk factor of dementia in Parkinson's disease (PD), while the underlying functional connectivity (FC) and brain volume alterations in PD patients with severe hyposmia (PD-SH) are unclear., Methods: We examined voxel-based morphometric and resting state functional magnetic resonance imaging findings in 15 cognitively normal PD-SH, 15 cognitively normal patients with PD with no/mild hyposmia (PD-N/MH), and 15 healthy controls (HCs)., Results: Decreased gray matter volume (GMV) was observed in the bilateral cuneus, right associative visual area, precuneus, and some areas in anterior temporal lobes in PD-SH group compared to HCs. Both the PD-SH and PD-N/MH groups showed increased GMV in the bilateral posterior insula and its surrounding regions. A widespread significant decrease in amygdala FC beyond the decreased GMV areas and olfactory cortices were found in the PD-SH group compared with the HCs. Above all, decreased amygdala FC with the inferior parietal lobule, lingual gyrus, and fusiform gyrus was significantly correlated with both reduction of Addenbrooke's Cognitive Examination-Revised scores and severity of hyposmia in all participants. Canonical resting state networks exhibited decreased FC in the precuneus and left executive control networks but increased FC in the primary and high visual networks of patients with PD compared with HCs. Canonical network FC to other brain regions was enhanced in the executive control, salience, primary visual, and visuospatial networks of the PD-SH., Conclusion: PD-SH showed extensive decreased amygdala FC. Particularly, decreased FC between the amygdala and inferior parietal lobule, lingual gyrus, and fusiform gyrus were associated with the severity of hyposmia and cognitive performance. In contrast, relatively preserved canonical networks in combination with increased FC to brain regions outside of canonical networks may be related to compensatory mechanisms, and preservation of brain function.

We previously reported that Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) had distinct phenotypes of speech and voice disorders: hypokinetic dysarthria, stuttering, breathy voice, strained voice, and spastic dysarthria. However, changes over time remain unclear. In the present study, 32 consecutive PD patients were assessed before and up to 1 year after surgery (PD-DBS). Eleven medically treated PD patients were also assessed (PD-Med). Speech, voice, motor, and cognitive functions were evaluated. At baseline, the incidence of hypokinetic dysarthria (63% of PD-DBS vs. 82% of PD-Med), stuttering (50% vs. 45%), breathy voice (66% vs. 73%), and strained voice (3% vs. 9%) was similar between groups. At 1 year, a slight but significant deterioration in speech intelligibility (p < 0.001) and grade of dysphonia (p = 0.001) were observed only in PD-DBS group compared with baseline. During the follow-up, stuttering (9% vs. 18%) and breathy voice (13% vs. 9%) emerged in PD-DBS and PD-Med, but strained voice (28%) and spastic dysarthria (44%) emerged only in PD-DBS. After the stimulation was stopped, strained voice and spastic dysarthria improved in most patients, while stuttering and breathy voice improved in a minority of patients. These findings indicate that the most common DBS-induced speech and voice disorders are strained voice and spastic dysarthria and that STN-DBS potentially aggravates stuttering and breathy voice. An improved understanding of these types of disorders may help detect speech and voice deteriorations during the early phase and lead to appropriate treatments.

Introduction: We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify factors affecting NMSs and the health-related quality of life of Japanese patients with Parkinson's disease (PD)., Methods: A total of 1021 patients with PD who had one or more NMS and showed wearing-off under anti-parkinsonian treatment were enrolled from 35 medical centers in Japan for this observational study. The primary measurements were the Movement Disorder Society unified Parkinson's disease rating scale (MDS-UPDRS) part I and the Parkinson's Disease Questionnaire (PDQ-8). The relationships of MDS-UPDRS and PDQ-8 with the patient's clinical background and undertaken medical interventions were determined. Here, we report baseline data of our 52-week ongoing study., Results: The mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively. The most common NMSs were constipation problems (85.4%), sleep problems (73.7%), pain and other sensations (72.7%) and daytime sleepiness (72.0%). Fatigue was an NMS that affected 79.6% of females but only 72.6% of males, whereas features of dopamine dysregulation syndrome affected only 5.6% of females and 10.8% of males. Positive correlations were found between the MDS-UPDRS part I and the PDQ-8 (p < 0.0001, r = 0.56) and between the number of NMSs and the PDQ-8 score (p < 0.0001, r = 0.47)., Conclusions: This study revealed distinctive patterns of NMSs in Japanese patients with PD and suggested that the prevalence and severity of NMSs vary between sexes, and that the NMSs are important factors affecting the long-term quality of life of PD patients., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Visual dysfunction can be caused by several abnormalities, including dysfunctions in the visual cortex and retina. Our aim was to investigate changes in visual evoked brain responses in the primary visual cortex associated with Parkinson's disease (PD). Sixteen healthy control subjects and ten patients with PD participated in this study. We assessed the visual evoked magnetic field (VEF) using magnetoencephalography (MEG). Checkerboard pattern reversal (CPR) and monotonous grating pattern (MGP) stimulations were used. Magnetic resonance imaging (MRI) was performed to analyze brain volume and generate a tractogram. Cognitive and olfactory function, and Unified Parkinson's Disease Rating Scale (UPDRS) scores were evaluated in patients with PD. Four components of the VEF (1M, 2M, 3M, 4M) were observed following stimulation. For both stimuli, results from the 1M and 2M components were significantly greater and the latency of the 1M component was increased markedly in the PD group compared with the healthy control group. In the PD group, 1M latency correlated with the UPDRS score of 1 for both stimuli, and a correlation was observed between olfactory function and the UPDRS score of 3 for the CPR stimulation alone. We suggest that the conduction delay observed following visual stimulation occurs peripherally rather than in the primary visual cortex. Degeneration of selective elements of the visual system in the retina, possibly midget cells, may be involved.

Anhedonia is one of the non-motor symptoms observed in the Parkinson's disease (PD). However, there is no clear relationship between anhedonia and its correlation with other symptoms of PD. The aim of this study is to evaluate the characteristics of anhedonia and its correlation with clinical aspects of PD in a relatively large cohort. We enrolled 318 patients with PD and 62 control subjects for this study. Patients and subjects were tested using the Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition for the assessment of anhedonia and depression. We also investigated the correlation among clinical aspects of PD, anhedonia, and depression in patients with PD. The Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition scores were significantly higher in patients with PD than in control subjects (p=0.03 and p=0.0006, respectively). All PD patients with anhedonia had a significantly higher score on the unified Parkinson's disease rating scale (UPDRS) parts I and II compared to PD patients without anhedonia. Additionally, all PD patients with depression scored significantly higher on UPDRS part I-IV than PD patients without depression. The patients with anhedonia and without depression had mild motor severity and their treatment was relatively low dosage. These results suggest that anhedonia and depression are slightly linked, but not the same. PD patients with only anhedonia may be closely linked apathy found in untreated early stages of PD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Voice and speech disorders are one of the most important issues after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients. However, articulation features in this patient population remain unclear., Objective: We studied the articulation features of PD patients with STN-DBS., Methods: Participants were 56 PD patients treated with STN-DBS (STN-DBS group) and 41 patients treated only with medical therapy (medical-therapy-alone group). Articulation function was evaluated with acoustic and auditory-perceptual analyses. The vowel space area (VSA) was calculated using the formant frequency data of three vowels (/a/, /i/, and /u/) from sustained phonation task. The VSA reportedly reflects the distance of mouth/jaw and tongue movements during speech and phonation. Correlations between acoustic and auditory-perceptual measurements were also assessed., Results: The VSA did not significantly differ between the medical-therapy-alone group and the STN-DBS group in the off-stimulation condition. In the STN-DBS group, the VSA was larger in the on-stimulation condition than in the off-stimulation condition. However, individual analysis showed the VSA changes after stopping stimulation were heterogeneous. In total, 89.8% of the STN-DBS group showed a large VSA size in the on- than in the off-stimulation condition. In contrast, the VSA of the remaining patients in that group was smaller in the on- than the off-stimulation condition., Conclusions: STN-DBS may resolve hypokinesia of the articulation structures, including the mouth/jaw and tongue, and improve maximal vowel articulation. However, in the on-stimulation condition, the VSA was not significantly correlated with speech intelligibility. This may be because STN-DBS potentially affects other speech processes such as voice and/or respiratory process.

Background: Pain is a frequent, troublesome symptom of PD but is under-recognized and poorly understood., Aim: We characterized pain prevalence, severity, and location in PD, to better understand its pathophysiology and improve diagnosis and treatment., Subjects and Methods: A cross-sectional controlled study was conducted at 19 centers across Japan. A total of 632 subjects with Mini-Mental State Examination scores ≥24 were enrolled, including 324 PD patients and 308 controls. Sex and mean age did not differ between the two groups. Demographic and clinical data were collected. Pain was assessed using questionnaires, the SF-36v2 bodily pain scale, and a body illustration for patients to indicate the location of pain in 45 anatomical areas., Results: Pain prevalence in the PD group was 78.6%, significantly higher than in controls (49.0%), as was its severity. There was no correlation between SF-36v2 score and motor scores, such as Unified Parkinson's Disease Rating Scale III or Hoehn & Yahr scores. Pain distribution was similar between groups, predominantly in the lower back, followed by the gluteal region, lower legs, thighs, posterior neck, and shoulders., Conclusion: Pain is a significant problem in the Japanese PD population and we discuss its pathophysiology., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial., Methods: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized., Discussion: This study will confirm whether H2 water can improve PD symptoms., Trial Registration: UMIN000010014 (February, 13, 2013).

Speech and voice disorders are one of the most common adverse effects in Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). However, the pathophysiology of voice and laryngeal dysfunction after STN-DBS remains unclear. We assessed 47 PD patients (22 treated with bilateral STN-DBS (PD-DBS) and 25 treated medically (PD-Med); all patients in both groups matched by age, sex, disease duration, and motor and cognitive function) using the objective and subjective voice assessment batteries (GRBAS scale and Voice Handicap Index), and laryngoscopy. Laryngoscopic examinations revealed that PD-DBS patients showed a significantly higher incidence of incomplete glottal closure (77 vs 48 %; p = 0.039), hyperadduction of the false vocal folds (73 vs 44 %; p = 0.047), anteroposterior hypercompression (50 vs 20 %; p = 0.030) and asymmetrical glottal movement (50 vs 16 %; p = 0.002) than PD-Med patients. On- and off-stimulation assessment revealed that STN-DBS could induce or aggravate incomplete glottal closure, hyperadduction of the false vocal folds, anteroposterior hypercompression, and asymmetrical glottal movement. Incomplete glottal closure and hyperadduction of the false vocal folds significantly correlated with breathiness and strained voice, respectively (r = 0.590 and 0.539). We should adjust patients' DBS settings in consideration of voice and laryngeal functions as well as motor function.

Objectives: To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinson's disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS)., Methods: We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients., Results: Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres., Conclusions: Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Voice and speech disorders are one of the most important issues after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease patients; however, their characteristics remain unclear. We performed a comprehensive voice evaluation including the multi-dimensional voice program for acoustic analysis, the GRBAS scale for perceptual analysis, and the evaluation of the voice handicap index (VHI) for psychosocial analysis. In total, 68 patients who had undergone STN-DBS (37 assessed in the on- and off-stimulation conditions) and 40 who had been treated with medical therapy alone were evaluated. Further, we performed laryngoscopic examinations in 13 STN-DBS and 19 medical-therapy-alone patients. The STN-DBS group, especially females, showed widespread impairment of voice parameters and significantly poorer VHI scores than the medical-therapy-alone group. The degree of voiceless (DUV) and strained voice were the most impaired factors in the STN-DBS group; and DUV significantly improved after stopping stimulation. Furthermore strained voice, breathiness, and asthenia improved after stopping stimulation. Laryngoscopic examination showed that abnormal laryngeal muscle contraction and incomplete glottal closure were more prominent in the STN-DBS group than in the medical-therapy-alone group. We demonstrated that (1) more widespread voice impairment in females, (2) poorer voice-related QOL, (3) worse DUV and strained voice, and (4) abnormal laryngeal muscle contraction were the characteristic voice and laryngeal findings in the STN-DBS group compared with those in the medical-therapy-alone group.

Recent reports suggest that rhinorrhea, defined as the presence of a runny nose unrelated to respiratory infections, allergies, or sinus problems, occurs more frequently among patients with Parkinson's disease (PD) than among healthy controls. We conducted a questionnaire survey in a multicenter study throughout Japan and compared the frequency of rhinorrhea between 231 PD and 187 normal control (NC) subjects. After excluding patients with rhinitis or paranasal sinusitis, a total of 159 PD and 59 NC subjects were included in our analysis. Rhinorrhea occurred more frequently in PD patients than NC subjects (33.3% vs. 11.9%; P=0.01). Among PD patients, rhinorrhea was more common in men than women (P=0.005). Rhinorrhea was not correlated with disease duration, modified Hoehn and Yahr score, disease type (akinesia rigidity vs. tremor dominant), or cardiac sympathetic function (evaluated by (123)I-metaiodobenzylguanidine uptake). To our knowledge, this is the first multicenter study on the frequency of PD-related rhinorrhea in Asian countries., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Olfactory dysfunction is considered to precede motor symptoms and early markers of Parkinson's disease (PD), while the relative time at which cardiovascular dysautonomia appears in PD is not well understood. To assess the appearance of cardiovascular dysautonomia in PD, we evaluated its relation to olfactory dysfunction in early-stage PD patients., Methods: Twenty-three non-demented PD patients within 2 years from the onset of motor symptoms were enrolled. We evaluated olfactory dysfunction by the Odor Stick Identification Test for Japanese (OSIT-J) and analyzed its relationship to the results of other cardiovascular autonomic tests and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy., Results: There was a correlation between olfactory scores and increased blood pressure in both the norepinephrine (r = 0.75, p < 0.0001, n = 21) and dobutamine (r = 0.57, p = 0.0087, n = 20) infusion tests and cardiac MIBG uptake (r = 0.42, p = 0.049, n = 23). The fall in orthostatic blood pressure during the head-up tilt test was not correlated with the olfactory scores, but the Valsalva maneuver revealed that OSIT-J scores correlated with the pressure recovery time from phase III to the return of blood pressure to baseline (r = 0.54, p = 0.037, n = 15) and with the magnitude of blood pressure overshoot during phase IV (r = 0.67, p = 0.0016, n = 20)., Conclusion: Our results demonstrate that extensive components of the cardiovascular sympathetic system as well as the olfactory system are correlatively impaired in the early stage of PD, suggesting that degeneration of broad aspects of the cardiovascular sympathetic system occurs concurrently with olfactory system degeneration during the premotor phase of PD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Cardiac sympathetic denervation is associated with orthostatic hypotension (OH) in Parkinson's disease (PD); however, the physiological role of cardiac sympathetic nerves has yet to be elucidated. To clarify the role of the heart in orthostatic stress, we evaluated whether cardiac sympathetic nerves can alter cardiac activity and systolic blood pressure (BP) in association with elevations or depressions of total peripheral resistance during the head-up tilt test., Methods: Ninety-five PD patients and 17 normal controls were enrolled. Using impedance cardiography, we measured total peripheral resistance, stroke volume, heart rate, and systolic BP during the head-up tilt test. Cardiac denervation was defined as a heart-to-mediastinum ratio <1.7 for cardiac (123)I-metaiodobenzylguanidine uptake on delayed images., Results: At 60° tilt, total peripheral resistance decreased from the initial value in 49 PD patients. Among these, 36 patients exhibited cardiac denervation with severe reductions in systolic BP but little change in stroke volume; among these patients 22 had OH. The remaining 13 patients without cardiac denervation exhibited significant increases in stroke volume and well-preserved systolic BP with no OH. On the other hand, 46 patients had elevations in total peripheral resistance and reduced stroke volume, but little change in systolic BP, regardless of the presence or absence of cardiac denervation. Only one of these patients experienced OH., Conclusion: Under orthostatic stress, cardiac sympathetic denervation with failure to increase total peripheral resistance leads to large reductions in systolic BP. However, patients without cardiac denervation exhibited a positive inotropic response against vasodilatation, which may prevent OH., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: We assessed the usefulness of differential diagnosis of parkinsonism by evaluating lesions of the decussation of the superior cerebellar peduncle (SCP) in patients with progressive supranuclear palsy (PSP) using a new MRI procedure known as readout segmentation of long variable echo-trains (RESOLVE)., Methods: We evaluated 100 cases, consisting of 20 with PSP, 24 with Parkinson's disease (PD), 13 with multiple system atrophy with predominant parkinsonism (MSA-P), 18 with multiple system atrophy with predominant cerebellar ataxia (MSA-C), and 24 controls. All patients were scored on the Unified Parkinson's Disease Rating Scale Part III and the Scale for the Assessment and Rating Scale of Ataxia, and MRI using RESOLVE was conducted., Results: Images acquired by this MRI procedure clearly showed high intensity areas corresponding to the decussation of the SCP in all controls, PD, and MSA patients. In contrast, ten of the 20 PSP patients exhibited abnormal iso intensities of the decussation of the SCP, while the other 10 showed high intensity signals. Among the PSP patients, there were no differences in clinical features between those with and those without visualization of the decussation of the SCP. Iso intensity signals had a sensitivity of 50% and a specificity of 100% for differentiating PSP from PD, MSA, and controls., Conclusion: This MRI procedure (RESOLVE) shows a potential for detecting the involvement of the decussation of the SCP in PSP, and can be used for discriminating PSP from PD and MSA-P., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to investigate the cortical and subcortical brain structures in Parkinson's disease (PD) with visual hallucination (VH), and to elucidate the association between the proposed hypothesis of VH in PD and regional brain volume changes., Methods: We used 3T magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to investigate the brain structures of PD patients with VH (PD-VH; n = 13) and PD patients without VH (PD-C; n = 13)., Results: The PD-VH patients showed significant cortical atrophy compared to the PD-C patients in the bilateral dorsolateral prefrontal cortex, left rostral region of the prefrontal cortex, left ventral section of the cingulate cortex, bilateral primary visual cortex, and secondary visual cortex including the left inferior occipital gyrus, right lingual cortex, right supramarginal gyrus, and left fusiform gyrus. Significant subcortical atrophic changes were observed in the white matter of the right parahippocampal gyrus, the bilateral posterior part of the cingulate gyrus, the left lingual gyrus, and the right middle occipital gyrus., Conclusions: VH in PD can occur due to distinctive neuroanatomical involvement., (© 2013 Movement Disorder Society.)

We report a 61-year-old Parkinson's disease patient presenting with severe repetitive speech phenomena after deep brain stimulation. On admission, he showed impaired loudness, rough hoarseness, monoloudness and monopitch. It had been difficult for him to converse because of voice repetitive speech phenomena since 57 years of age. Medical control, regulation of contact location and voltage amplitude did not improve these symptoms. Lee Silverman Voice Treatment(®) improved loudness and voice quality, but did not improve repetitive speech phenomena. After speech treatment with a pacing board, his repetitive speech phenomena improved more than before. Treatment with a pacing board may be effective for repetitive speech phenomena in Parkinson's disease after deep brain stimulation.

Background and Purpose: Many non-motor symptoms are associated with Parkinson's disease (PD). Of these, pain and olfactory disturbance tend to be common premotor symptoms. PD has been shown to exhibit abnormal central pain processing, although underlying mechanisms are not yet fully understood. In order to investigate this further, we assessed PD patients by specific Aδ stimulation with intra-epidermal needle electrode and determined olfactory function., Methods: Forty-two patients (18 males and 24 females) with PD and 17 healthy control subjects (8 males and 9 females) were studied. A thin needle electrode was used to stimulate epidermal Aδ fibers, and somatosensory evoked potentials (SEPs) recorded at the vertex. Olfactory function was evaluated using the Odor Stick Identification Test for Japanese (OSIT-J) and its relationship with pain-related SEPs was investigated., Results: There were no significant differences in N1 latencies or P1 latencies although N1/P1 peak-to-peak amplitudes were significantly lower (p < 0.01) in PD patients than in control subjects. In PD patients, there were significant correlations between N1/P1 amplitudes and disease duration (r = -0.35, p < 0.05), Hoehn-Yahr stage (r = -0.38, p < 0.05) and UPDRS part III (r = -0.42, p < 0.01). Furthermore, the OSIT-J scores correlated with SEP amplitude (r = 0.41, p < 0.01)., Conclusion: Pain processing in PD patients was impaired under specific nociceptive stimulation of Aδ fibers and significant correlation with smell dysfunction was detected. We suggest that this mechanism may involve the limbic system during PD pathology., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Anhedonia is one of the main non-motor symptoms in Parkinson's disease (PD); it is assessed using the Snaith-Hamilton pleasure scale (SHAPS). To assess anhedonia in the Japanese population, we prepared a Japanese language version of SHAPS (SHAPS-J), and evaluated its validity and reliability in 8 neurological centers. Seventy subjects (48 patients with PD and 22 healthy subjects) were enrolled in this study., Methods: The validity of the test was assessed by the correlation between SHAPS-J and the apathy scale, based on the fact that anhedonia is considered a symptom of apathy syndrome. Test-retest reliability and internal consistency were assessed by Cohen's kappa and Cronbach's alpha coefficients, respectively., Results: In the evaluation of validity, the total scores obtained on SHAPS-J during the test and retest significantly correlated with scores on Item 4 in Part 1 of the unified Parkinson's disease rating scale (p<0.0008 and p<0.0036, respectively). Cohen's kappa coefficient was >0.3 on all items (p<0.0005 on all items). Cronbach's alpha coefficient was 0.90 at the baseline and 0.88 at the retest., Conclusion: These results indicate that SHAPS-J has good validity, test-retest reliability, and internal consistency, thus establishing an available measure of anhedonia in Japanese.

Patients with Parkinson's disease often complain of fatigue, and although cardiac sympathetic denervation is thought to be associated with fatigue, this link remains unclear. Previously, we detected cardiac sympathetic denervation in patients with Parkinson's disease using dobutamine, a selective beta-1 stimulant. To clarify the involvement of autonomic dysfunction in fatigue in Parkinson's disease, we conducted autonomic function tests on 33 patients with Parkinson's disease (mean age, 66.1 ± 5.6 years; 20 men, 13 women) and evaluated their relationships to fatigue. We divided patients into 2 groups, fatigued (n = 12) and nonfatigued (n = 21), based on an average score ≥ 3.3 on the Parkinson fatigue scale. Autonomic function tests included the coefficient of variation of R-R intervals, head-up tilt test, norepinephrine and dobutamine infusion tests, and cardiac (123) I-metaiodobenzylguanidine scintigraphy. The coefficient of variation of R-R intervals and the systolic blood pressure changes accompanying the head-up tilt test did not show significant differences between the 2 groups; however, the pressor responses in the norepinephrine and dobutamine infusion tests were significantly greater in the fatigued group than in the nonfatigued group. The (123) I-metaiodobenzylguanidine heart-to-mediastinal uptake ratio was lower in the fatigued group than in the nonfatigued group. Partial correlation analyses, using disease duration and Hoehn and Yahr stage as control variables, also demonstrated significant correlations between the Parkinson fatigue scale score and the results of the autonomic function tests and cardiac (123) I-metaiodobenzylguanidine uptake. Our results suggest that autonomic dysfunction, including cardiac sympathetic denervation, is associated with fatigue in patients with Parkinson's disease., (Copyright © 2011 Movement Disorder Society.)

Background: Oxidative stress is causally associated with the pathogenesis of Parkinson's disease (PD). Oxygen generates a large amount of reactive oxygen species (ROS). ROS including hydroxyl radicals and H(2)O(2) react with guanine residues in DNA and produce 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG serves as a biomarker for oxidative stress in various diseases., Method: We investigated urinary 8-OHdG levels in 61 PD patients and 28 normal subjects to evaluate the correlation with various clinical features. We quantified disease severity using the Unified Parkinson's Disease Rating Scale for motor symptoms (UPDRS part 3), the Mini-Mental State Examination (MMSE) for mental function, and the Tottori University Hallucination Rating Scale (TUHARS) for quantifying hallucinations., Results: There were significant correlations between 8-OHdG and all the examined parameters, but the partial correlation coefficients excluding contributions of all the other parameters showed that only TUHARS and UPDRS part 3 are significantly related to 8-OHdG. In particular, TUHARS correlates best with urinary 8-OHdG levels., Conclusion: The significant correlation between urinary 8-OHdG levels and hallucinations but not with dementia suggests that hallucinations are likely to have unique but unidentified mechanisms that lead to excessive production of 8-OHdG., (© 2010 Elsevier Ltd. All rights reserved.)

We examined whether cardiac sympathetic denervation influences the cardiovascular response to exercise in Parkinson's disease (PD). Sixteen patients with PD were divided into two groups, according to their cardiac uptake of (123)I-metaiodobenzylguanidine (denervated group, 10 patients with heart to mediastinum (H/M) ratio < 1.7; innervated group, six patients with H/M ratio > 1.7) and compared changes in blood pressure (BP), heart rate (HR), and cardiac contractility with 13 control subjects during ergometric exercise stress. Velocity index (VI), an indicator of cardiac contractility, was measured using impedance cardiography and recorded every minute. Exercise began at a power output of 20 W for the first 2 min and increased 10 W every 2 min to a maximal intensity of 60 W. All control subjects accomplished the procedure while six patients with PD could not continue after the first minute of 50 W loading. There were no significant differences in BP or HR change between the three groups. However, a significant reduction in VI was observed from the first minute of the 30 W workload in the denervated group compared to the control group. This lowered response continued till 50 W loading and was significantly different to the innervated group at 50 W loading. No significant VI changes were observed between the control and innervated groups throughout the exercise test. Patients with PD with reduced MIBG uptake had a lowered cardiac contractility than innervated subjects during exercise, suggesting that this response represents the impaired exercise capacity of patients with PD with cardiac sympathetic denervation.

This study evaluated pupillary postganglionic autonomic dysfunction and its relationship to visual disturbance in idiopathic Parkinson's disease (PD). Pupillary sensitivity was examined in relation to a parasympathomimetic agent [0.05% pilocarpine hydrochloride (PL)] and to a sympathomimetic agent [0.02% dipivefrine hydrochloride (DPE)] using infrared pupillography in 40 PD patients and 17 age-matched controls. Visual disturbances were evaluated as well, including blurring, photophobia, night blindness and involuntary eyelid closure in response to light. Pupillary supersensitivity to PL and DPE and their relation to visual disturbances were found to be significantly greater in PD patients than in controls (22.3 +/- 15.1 vs. 10.4 +/- 11.4%, P < 0.005, and14.5 +/- 14.5 vs. 4.9 +/- 8.7%, P < 0.01, respectively). In addition, pupillary sympathetic supersensitivity did not correlate with a reduction of 123I-metaiodobenzylguanidine (MIBG) cardiac accumulation. Patients with PD reported more blurred vision (P < 0.001) and involuntary eyelid closure in response to light (P < 0.05) than controls. Patients with supersensitivity to both PL and DPE complained more often of blurred vision than patients without supersensitivity (P < 0.05). Pupillary sensitivity to PL correlated significantly with a summed score for visual disturbance (P < 0.05, r = 0.417), but DPE sensitivity did not. PD patients have both parasympathetic and sympathetic postganglionic impairments affecting the pupil. Our findings demonstrate that parasympathetic dysfunction contributes significantly to visual disturbance in PD.

Objective: Cardiac uptake of [(123)I]metaiodobenzyl guanidine (MIBG) is reduced in patients with Parkinson's disease (PD). However, the cardiac sympathetic abnormality associated with this reduction is unclear. To unmask this abnormality in PD patients we examined the functional consequences of cardiac beta-receptor activation., Methods: Cardiovascular responses to stepwise administration of the beta1-receptor agonist, dobutamine (DOB), were assessed in 25 PD patients and 12 age-matched controls. Changes in blood pressure were compared to determine the optimal dose at which to detect denervation supersensitivity, and cardiac contractility was measured by DOB echocardiography, based on peak aortic flow velocity. The relations of these cardiovascular responses to the ratio of MIBG uptake into the heart vs. that into the mediastinum (H/M ratio) were analyzed., Results: At 4 microg/kg/min DOB, systolic blood pressure increased more in PD patients than in controls (PD, 17.5+/-12.3 mm Hg; control, 7.2+/-6.2 mm Hg, p<0.01), suggesting the presence of denervation supersensitivity. At this DOB dose cardiac contractility also increased more in PD than in controls (PD, 39.0+/-15.7%; control, 23.5+/-5.2%, p<0.005) and this hyperdynamic response was significantly correlated with reduced H/M ratios (early: r=-0.63, p<0.01, delayed: r=-0.66, p<0.01)., Conclusion: Low-dose DOB unmasks cardiac sympathetic denervation in PD patients, and decreased MIBG uptake indicates the presence of denervation supersensitivity within the heart, resulting in hyperdynamic cardiac contractility in response to a beta 1-stress condition.

Objective: To determine whether apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values can detect early pathological involvement in multiple system atrophy (MSA), and be used to differentiate MSA-P (multiple system atrophy if parkinsonian features predominate) from Parkinson's disease (PD)., Methods: We compared ADC and FA values in the pons, cerebellum and putamen of 61 subjects (20 probable MSA patients, 21 age matched PD patients and 20 age matched healthy controls) using a 3.0 T magnetic resonance system., Results: ADC values in the pons, cerebellum and putamen were significantly higher, and FA values lower in MSA than in PD or controls. These differences were prominent in MSA lacking dorsolateral putaminal hyperintensity (DPH) or hot cross bun (HCB) sign. In differentiating MSA-P from PD using FA and ADC values, we obtained equal sensitivity (70%) and higher specificity (100%) in the pons than in the putamen and cerebellum. In addition, all patients that had both significant low FA and high ADC values in each of these three areas were MSA-P cases, and those that had both normal FA and ADC values in the pons were all PD cases. Our diagnostic algorithm based on these results accurately diagnosed 90% of patients with MSA-P., Conclusion: FA and ADC values detected early pathological involvement prior to magnetic resonance signal changes in MSA. In particular, low FA values in the pons showed high specificity in discriminating MSA-P from PD. In addition, combined analysis of both FA and ADC values in all three areas was more useful than only one.

We investigated the usefulness of quetiapine and olanzapine for delusion in nine patients with Parkinson's disease (PD). Two of five patients initially treated with quetiapine showed resolution of delusion on low dose (25 mg and 50 mg/day), whereas three patients had no improvement in spite of increasing the dose to 300 mg/day. Quetiapine non-responders had a tendency to more severe delusion and dementia compared with responders. Not only all four patients initially treated but also two of three quetiapine non-responders showed a remarkable resolution of delusion on olanzapine. In particular, three of seven patients responded to an extremely low dose of 0.625 mg/day. However, severe motor debilitation was observed in one patient treated with 1.25 mg/day. Olanzapine might be useful for delusion of PD in patients not responded to quetiapine, although it should be started at a very low dosage to ameliorate worsening parkinsonism.