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This study aimed to discriminate between neuroinflammation and neuronal degeneration in the white matter (WM) and gray matter (GM) of patients with Parkinson's disease (PD) using free-water (FW) imaging. Analysis using tract-based spatial statistics (TBSS) of 20 patients with PD and 20 healthy individuals revealed changes in FW imaging indices (i.e., reduced FW-corrected fractional anisotropy (FAT), increased FW-corrected mean, axial, and radial diffusivities (MDT, ADT, and RDT, respectively) and fractional volume of FW (FW) in somewhat more specific WM areas compared with the changes of DTI indices. The region-of-interest (ROI) analysis further supported these findings, whereby those with PD showed significantly lower FAT and higher MDT, ADT, and RDT (indices of neuronal degeneration) in anterior WM areas as well as higher FW (index of neuroinflammation) in posterior WM areas compared with the controls. Results of GM-based spatial statistics (GBSS) analysis revealed that patients with PD had significantly higher MDT, ADT, and FW than the controls, whereas ROI analysis showed significantly increased MDT and FW and a trend toward increased ADT in GM areas, corresponding to Braak stage IV. These findings support the hypothesis that neuroinflammation precedes neuronal degeneration in PD, whereas WM microstructural alterations precede changes in GM. [ABSTRACT FROM AUTHOR]

Although many experimental studies have shown the favorable effects of zonisamide on mitochondria using models of Parkinson's disease (PD), the influence of zonisamide on metabolism in PD patients remains unclear. To assess metabolic status under zonisamide treatment in PD, we performed a pilot study using a comprehensive metabolome analysis. Plasma samples were collected for at least one year from 30 patients with PD: 10 without zonisamide medication and 20 with zonisamide medication. We performed comprehensive metabolome analyses of plasma with capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. We also measured disease severity using Hoehn and Yahr (H&Y) staging and the Unified Parkinson's Disease Rating Scale (UPDRS) motor section, and analyzed blood chemistry. In PD with zonisamide treatment, 15 long-chain acylcarnitines (LCACs) tended to be increased, of which four (AC(12:0), AC(12:1)-1, AC(16:1), and AC(16:2)) showed statistical significance. Of these, two LCACs (AC(16:1) and AC(16:2)) were also identified by partial least squares analysis. There was no association of any LCAC with age, disease severity, levodopa daily dose, or levodopa equivalent dose. Because an upregulation of LCACs implies improvement of mitochondrial β-oxidation, zonisamide might be beneficial for mitochondrial β-oxidation, which is suppressed in PD. [ABSTRACT FROM AUTHOR]

Background: Parkin RBR E3 ubiquitin‐protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants. Objectives: To identify complex structural variants in PRKN using long‐read sequencing. Methods: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia‐parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long‐read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole‐genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP‐PD) and United Kingdom (UK)‐Biobank datasets. Results: Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long‐read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK‐Biobank and 4941 participants of the AMP‐PD datasets. Nine inversions in the UK‐Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression. Conclusions: This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long‐read sequencing for structural variant analysis in unresolved young‐onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Highlights • We studied how deep brain stimulation (DBS) affects eye movements made during visual scanning. • DBS increased the amplitude of voluntary saccades, but not reflexive saccades. • DBS mainly affects voluntary saccades mediated by the basal ganglia. Abstract Objective Deep brain stimulation (DBS) can provide insights into the workings of the basal ganglia (BG) by interfering with their function. In patients with Parkinson's disease (PD) treated with DBS of the subthalamic nucleus, we studied the effect of DBS on scanning eye movements. Methods In the visual memory task, subjects viewed images of various complexities for later recall. In visual search tasks, subjects looked for and fixated one odd target ring, embedded among 48 Landolt rings, which either stood out or not from the distractors. We compared the parameters of scanning saccades when DBS was on and off. Results In the visual memory task, DBS increased the amplitude of saccades scanning simple but not complex drawings. In the visual search tasks, DBS showed no effect on saccade amplitude or frequency. Conclusions Saccades when viewing simple images were affected by DBS since they are internally guided saccades, for which the involvement of BG is large. In contrast, saccades when viewing complex images or during visual search, made with the help of visual cues in the images (externally guided saccades) and less dependent on BG, were resistant to the effect of DBS. Significance DBS affects saccades differentially depending on the task. [ABSTRACT FROM AUTHOR]

Background. The effects of subthalamic nuclear deep brain stimulation therapy (STN-DBS) and combined postoperative rehabilitation for patients with Parkinson's disease with postural instability have yet to be well reported. This study investigated the effects of short-term postoperative rehabilitation with STN-DBS on physical function in patients with Parkinson's disease. Methods. Patients diagnosed with Parkinson's disease who were admitted to our hospital for STN-DBS surgery were included in this study. Data were prospectively collected and retrospectively analyzed. Postoperative rehabilitation consisted of muscle-strengthening exercises, stretching, and balance exercises for 40–60 minutes per day for approximately 14 days. The Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go test (TUG) seconds and steps, Trunk Impairment Scale (TIS), seconds for 10 times toe-tapping, lower limb extension torque using StrengthErgo240, and center of pressure sway in the quiet standing posture were evaluated preoperatively, postoperatively, and at discharge. Mini-BESTest changes were also evaluated in the two groups classified by the presence or absence of postural instability. One-way and two-way repeated measures analyses of variance were performed for each of the three periods of change, and paired t-tests with the Bonferroni method were performed as multiple comparison tests. A stepwise multiple regression model was used to identify factors associated with balance improvement. Results. A total of 60 patients with Parkinson's disease were included, and there were significant increases in Mini-BESTest, TIS, StrengthErgo240, and postural sway during closed-eye standing compared to pre- and postoperative conditions at discharge (p < 0.05), and they decreased significantly compared to the postoperative period (p < 0.05). On stepwise multiple regression analysis, decreased steps of TUG and improvement of TIS scores were related to improvement of the Mini-BESTest (p < 0.05). In addition, Mini-BESTest scores in both groups with and without postural instability were significantly increased at discharge compared to preoperative and postoperative conditions (p < 0.01). Conclusion. Postoperative rehabilitation combined with STN-DBS may provide short-term improvements in physical function compared with the preoperative medicated status. The improvements in gait step length and trunk function may be important factors for obtaining improvement of postoperative postural stability. [ABSTRACT FROM AUTHOR]

To investigate the prevalence and genotype-phenotype correlations of parkin RBR E3 ubiquitin protein ligase (PRKN) variants in Parkinson's disease (PD), we first included 2,527 patients with PD. Through the defined selection, we enrolled 2,322 patients, including 1,204 with familial and 1,118 with sporadic PD. We identified 242 patients harboring PRKN variants, which were thought to be susceptibility factors, comprising 137 patients with familial and 105 with sporadic PD; among the 26 identified variants, 13 were novel. We divided our cohort into 2 groups: heterozygote (hereafter called one-allele) and homozygote or compound heterozygote (hereafter called two-allele). The patients with two-allele were significantly younger at onset than those with one-allele. Six families harbored the complex forms of one- and two-allele in different individuals of the same family. The presence of two-allele reflected more frequent normal values of [123I] metaiodobenzylguanidine myocardial scintigraphy. The log-rank test revealed an exacerbation associated with two-allele over 15 years of the disease course. The patients with PRKN variants showed specific symptoms dependent on the number of mutated alleles. • To investigate the prevalence and genotype-phenotype correlations of PRKN variants. • We identified 242 patients with PRKN variants among enrolled 2322 patients. • Two-allele were significantly younger at onset than one-allele. • Two-allele reflected more frequent normal values of MIBG myocardial scintigraphy. • The severities of the patients dependent on the number of mutated alleles. [ABSTRACT FROM AUTHOR]

Introduction: Levodopa-induced dyskinesia is a complication of levodopa therapy and negatively impacts the quality of life of patients. We aimed to elucidate white matter alterations in Parkinson's disease with levodopa-induced dyskinesia using advanced diffusion magnetic resonance imaging techniques.Methods: The enrolled subjects included 26 clinically confirmed Parkinson's disease patients without levodopa-induced dyskinesia, 25 Parkinson's disease patients with levodopa-induced dyskinesia, and 23 healthy controls. Subjects were imaged using a 3-T magnetic resonance scanner. Diffusion tensor imaging, diffusion kurtosis imaging, and neurite orientation dispersion and density imaging findings were compared between groups with a group-wise whole brain approach and a region-of-interest analysis for each white matter tract. Additionally, logistic regression analysis was used to calculate odds ratios for levodopa-induced dyskinesia.Results: Group-wise tract-based spatial statistical analysis revealed significant white matter differences in isotropic diffusion, complexity, or heterogeneity, and neurite density between healthy controls and Parkinson's disease patients without levodopa-induced dyskinesia and between patients with and without levodopa-induced dyskinesia. Region-of-interest analysis revealed similar alterations using a group-wise whole-brain approach in the external capsule, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus. These tracts had an odds ratio of approximately 2.3 for the presence of levodopa-induced dyskinesia.Conclusions: Our findings suggest that Parkinson's disease with levodopa-induced dyskinesia produces less white matter microstructural disruption, especially in temporal lobe fibers, than Parkinson's disease without levodopa-induced dyskinesia. These fibers has a more than 2-fold odds ratio for the presence of levodopa-induced dyskinesia and might be associated with the pathogenesis of the sequela. [ABSTRACT FROM AUTHOR]

Purpose: Micro fractional anisotropy (μFA) is more accurate than conventional fractional anisotropy (FA) for assessing microscopic tissue properties and can overcome limitations related to crossing white matter fibres. We compared μFA and FA for evaluating white matter changes in patients with Parkinson's disease (PD). Methods: We compared FA and μFA measures between 25 patients with PD and 25 age- and gender-matched healthy controls using tract-based spatial statistics (TBSS) analysis. We also examined potential correlations between changes, revealed by conventional FA or μFA, and disease duration or Unified Parkinson's Disease Rating Scale (UPDRS)-III scores. Results: Compared with healthy controls, patients with PD had significantly reduced μFA values, mainly in the anterior corona radiata (ACR). In the PD group, μFA values (primarily those from the ACR) were significantly negatively correlated with UPDRS-III motor scores. No significant changes or correlations with disease duration or UPDRS-III scores with tissue properties were detected using conventional FA. Conclusion: μFA can evaluate microstructural changes that occur during white matter degeneration in patients with PD and may overcome a key limitation of FA. [ABSTRACT FROM AUTHOR]

Monoamine oxidase type B inhibitors, including selegiline, are established as anti-Parkinsonian Drugs. Inhibition of monoamine oxidase type B enzymes might suppress the inflammation because of inhibition to generate reactive oxygen species. However, its effect on brain microstructure remains unclear. The aim of this study is to elucidate white matter and substantia nigra (SN) microstructural differences between Patients with Parkinson's disease with and without selegiline treatment by two independently recruited cohorts. Diffusion tensor imaging and free water imaging indices of WM and SN were compared among 22/15 Patients with Parkinson's disease with selegiline (PDselegiline(+)), 33/23 Patients with Parkinson's disease without selegiline (PDselegiline(−)), and 25/20 controls, in the first/second cohorts. Two cohorts were analyzed with different MRI protocols. Diffusion tensor imaging and free-water indices of major white matter tracts were significantly differed between the PDselegiline(−) and controls in both cohorts, although not between the PDselegiline(+) and controls except for restricted areas. Compared with the PDselegiline(+), free-water was significantly higher in the PDselegiline(−) in the inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and superior and posterior corona radiata (first cohort) and the forceps major and splenium of the corpus callosum (second cohort). There were no significant differences in free-water of anterior or posterior substantia nigra between PDselegiline(+) and PDselegiline(−). Selegiline treatment might reduce the white matter microstructural abnormalities detected by free-water imaging in Parkinson's disease. • Neuroinflammation may play a role in the pathomechanism of Parkinson's disease (PD) • Free water (FW) MRI captures PD's white matter (WM) microstructural alteration. • Less FW elevation was seen in WM of PD treated with selegiline than those without. • Some affected areas are associated with the effects of selegiline against PD symptoms. • Selegiline might ameliorate PD's WM inflammation. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the accuracy and diagnostic test performance of the U-net-based segmentation method in neuromelanin magnetic resonance imaging (NM-MRI) compared to the established manual segmentation method for Parkinson's disease (PD) diagnosis. Methods: NM-MRI datasets from two different 3T-scanners were used: a "principal dataset" with 122 participants and an "external validation dataset" with 24 participants, including 62 and 12 PD patients, respectively. Two radiologists performed SNpc manual segmentation. Inter-reader precision was determined using Dice coefficients. The U-net was trained with manual segmentation as ground truth and Dice coefficients used to measure accuracy. Training and validation steps were performed on the principal dataset using a 4-fold cross-validation method. We tested the U-net on the external validation dataset. SNpc hyperintense areas were estimated from U-net and manual segmentation masks, replicating a previously validated thresholding method, and their diagnostic test performances for PD determined. Results: For SNpc segmentation, U-net accuracy was comparable to inter-reader precision in the principal dataset (Dice coefficient: U-net, 0.83 ± 0.04; inter-reader, 0.83 ± 0.04), but lower in external validation dataset (Dice coefficient: U-net, 079 ± 0.04; inter-reader, 0.85 ± 0.03). Diagnostic test performances for PD were comparable between U-net and manual segmentation methods in both principal (area under the receiver operating characteristic curve: U-net, 0.950; manual, 0.948) and external (U-net, 0.944; manual, 0.931) datasets. Conclusion: U-net segmentation provided relatively high accuracy in the evaluation of the SNpc in NM-MRI and yielded diagnostic performance comparable to that of the established manual method. [ABSTRACT FROM AUTHOR]

Abstract Background Cerebral microbleeds (CMBs) are often observed in Parkinson's disease (PD); however, their association with cognitive decline has been unclear. We performed a retrospective analysis of 124 cases of clinically diagnosed PD to determine the association between the presence of CMBs and cognitive decline. Results Of the 124 participants, 21 (16.9%) was diagnosed as PDD in this cohort. CMBs were observed significantly more frequently in the PDD than in the PD (47.6% vs 7.8%, P <.001). The presence of both deep/infratentorial (40% vs 14.9%, P <.05) and strictly lobar (75% vs 12.9%, P <.001) CMBs were associated with PDD. The values of cognitive scales such as Mini-Mental State Examination and the Hasegawa Dementia Scale-revised, were also significantly lower in the presence of each type of CMB. A multivariable logistic regression analysis showed the presence of strictly lobar CMBs as well as a male gender, orthostatic hypotension, periventricular hyperintensity on magnetic resonance imaging were significantly associated with PDD in this cohort. Conclusions This study showed the presence of CMBs, especially strictly lobar type, was strongly associated with PDD. We suspect that the burden of small vessel disease and cerebral amyloid angiopathy may be related to the development of cognitive decline in PD, and a prospective study enrolling more cases is warranted. Highlights • Cerebral microbleeds (CMBs) are often observed in Parkinson's disease (PD). • CMBs is significantly highly found in PD with dementia than without. • Both deep/infratentorial and strictly lobar CMBs are associated with dementia in PD. • Strictly lobar CMBs is independent risk for cognitive impairment in PD. [ABSTRACT FROM AUTHOR]

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson’s disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms. [ABSTRACT FROM AUTHOR]

Imaging studies are necessary prior to subthalamic deep brain stimulation (STN-DBS). Dopamine transporter (DAT) imaging is a powerful tool for visualizing dopamine terminals in the striatum, but its usefulness in STN-DBS is unclear. Here, we retrospectively investigated the relationship between motor symptoms and the specific binding ratio (SBR) on DAT imaging in patients with Parkinson's disease (PD). We included 23 consecutive patients (9 female; 14 male) who were evaluated for DBS eligibility between October 2013 and October 2014 and subsequently received bilateral STN-DBS. Correlation and simple regression analyses were performed on SBR values and clinical parameters before and after surgery. SBR value was negatively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the “ON” state before surgery (r s = − 0.637, p = 0.001) and positively correlated with the reduction of the levodopa equivalent daily dose by surgery (r = 0.422, p = 0.045). A simple regression analysis revealed that SBR value was positively correlated with UPDRS motor score improvement after levodopa challenge before surgery (p = 0.001, R 2 = 0.423). DAT imaging may be useful in STN-DBS candidate selection and the identification of the therapeutic mechanism of STN-DBS in patients with advanced PD and motor symptom fluctuations. [ABSTRACT FROM AUTHOR]

Background: Circadian blood pressure alterations are frequently observed in Parkinson's disease, but the association between these changes and dementia in the condition remains unclear. Here, we assess the relationship between abnormal nocturnal blood pressure profiles and dementia in Parkinson's disease.Methods: We enrolled 137 patients with Parkinson's disease, who underwent 24 h ambulatory blood pressure monitoring, following cognitive and clinical assessment.Results: Twenty-seven patients (19.7%) were diagnosed with dementia in this cohort. We observed significant associations of dementia with age, male gender, Hoehn-Yahr (H-Y) stage, diabetes mellitus, history of stroke, presence of cerebrovascular lesions on MRI, and orthostatic hypotension. Univariate logistic regression analysis showed that among the patterns of nocturnal blood pressure profiles, the riser pattern was significantly associated with dementia (OR 11.6, 95%CI: 2.14-215.0, P < 0.01), and this trend was observed after adjusting for all confounding factors except orthostatic hypotension (OR 19.2, 95%CI: 1.12-1960.3, P = 0.04). However, coexistence of a riser pattern and orthostatic hypotension was related to a higher prevalence of dementia (45.2%) than was a riser pattern alone (9.5%). Furthermore, coexistence of a riser pattern and orthostatic hypotension was significantly more associated with dementia than was a riser pattern alone, even after adjusting for confounders (OR 1625.1, 95%CI: 21.9-1343909.5, P < 0.01).Conclusions: Our results suggest a relationship between a riser pattern coexisting with orthostatic hypotension and dementia in Parkinson's disease. Further prospective studies are warranted to investigate whether abnormal nocturnal blood pressure profiles predict dementia in Parkinson's disease. [ABSTRACT FROM AUTHOR]

While dopamine (DA) may be clearly detected by voltammetric techniques such as fast-scan cyclic voltammetry (FSCV) in the heavily-innervated striatum, the differentiation of DA from other monoamines, including norepinephrine (NE) and serotonin (5-HT), is crucial for further applications outside of the striatum. We show that using normal pulse voltammetry (NPV) with 0.1 V to 0.3 V rectangular pulses can differentiate between NE and DA. While the major electrochemical current of NE and DA is obtained on 0.2 V rectangular pulse of NPV, the relative current on 0.1 V pulse was higher for DA than NE. It was possible to differentiate NE from DA by electrochemical current on three NPV pulses using simple mathematics of sequential equation. Since FSCV obtains a larger current value and less noisy results than NPV, we alternately recorded both. The electrochemical current data of NPV was combined with FSCV for principal component regression (PCR) analysis. The estimated value was evaluated by percent error and correlation coefficient from the true concentration, and the slope of the linear regression line. Estimation by sequential equation using NPV results could differentiate NE from DA, while PCR without NPV current data could not. PCR including NPV current data also could differentiate NE from DA. In this study, we compared the performance of electrochemical recordings with rectangular and triangular waveforms under the same conditions, and the advantages and disadvantages became very clear. Together with our previous finding of significant differentiation of pH changes from monoamines on rectangular pulses of NPV, the combined use of rectangular and triangular pulses would improve the molecular identification of monoamines in the brain using voltammetric recording. [ABSTRACT FROM AUTHOR]

Lewy body diseases, including Parkinson's disease (PD), are characterized by the spread of alpha-synuclein (αSyn) between neurons across synapses, a process crucial for understanding their pathophysiology and developing effective treatments. In this study, we aimed to investigate the role of neuronal activity in releasing αSyn from human induced pluripotent stem cell-derived dopaminergic neurons. We examined human induced pluripotent stem cell-derived dopaminergic neurons, both healthy and those with the αSyn gene mutation associated with PD. We employed pharmacological agents and optogenetic techniques and demonstrated that increased neuronal activity, induced by bicuculline or optogenetic stimulation, significantly enhances αSyn release. However, suppression of neuronal activity with cyanquixaline reduces αSyn secretion. These findings underscore the pivotal role of neuronal activity in αSyn transmission between neurons, showing its potential impact on the spread of Lewy pathology in patients with neurodegenerative diseases like PD. Therefore, this study advances our understanding of PD and opens new avenues for therapeutic strategies to mitigate Lewy body disease progression., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In super-aged societies, dementia has become a critical issue, underscoring the urgent need for tools to assess cognitive status effectively in various sectors, including financial and business settings. Facial and speech features have been tried as cost-effective biomarkers of dementia including Alzheimer's disease (AD). We aimed to establish an easy, automatic, and extensive screening tool for AD using a chatbot and artificial intelligence. Smile images and visual and auditory data of natural conversations with a chatbot from 99 healthy controls (HCs) and 93 individuals with AD or mild cognitive impairment due to AD (PwA) were analyzed using machine learning. A subset of 8 facial and 21 sound features successfully distinguished PwA from HCs, with a high area under the receiver operating characteristic curve of 0.94 ± 0.05. Another subset of 8 facial and 20 sound features predicted the cognitive test scores, with a mean absolute error as low as 5.78 ± 0.08. These results were superior to those obtained from face or auditory data alone or from conventional image depiction tasks. Thus, by combining spontaneous sound and facial data obtained through conversations with a chatbot, the proposed model can be put to practical use in real-life scenarios., (© 2024. The Author(s).)

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, was classically attributed to alpha-synuclein aggregation and consequent loss of dopaminergic neurons in the substantia nigra pars compacta. Recently, emerging evidence suggested a broader spectrum of contributing factors, including exosome-mediated intercellular communication, which can potentially serve as biomarkers and therapeutic targets. However, there is a remarkable lack of comprehensive studies that connect the serum exosome microRNA (miRNA) transcriptome with demographic, clinical, and neuroimaging data in PD patients. Here, we present serum exosome miRNA transcriptome data generated from four cohort studies. Two of these studies include 96 PD patients and 80 age- and gender-matched controls, with anonymised demographic, clinical, and neuroimaging data provided for PD patients. The other two studies involve 96 PD patients who were evaluated both before and after one year of treatment with rasagiline, a widely prescribed anti-parkinsonism drug. Together, the datasets provide a valuable source for understanding pathogenesis and discovering biomarkers and therapeutic targets in PD., (© 2024. The Author(s).)

Introduction: In the advanced stages of Parkinson's disease (PD), motor complications such as wearing-off and dyskinesia are problematic and vary daily. These symptoms need to be monitored precisely to provide adequate care for patients with advanced PD., Methods: This study used wearable devices to explore biomarkers for motor complications by measuring multiple biomarkers in patients with PD residing in facilities and combining them with lifestyle and clinical assessments. Data on the pulse rate and activity index (metabolic equivalents) were collected from 12 patients over 30 days., Results: The pulse rate and activity index during the off- and on- periods and dyskinesia were analyzed for two participants; the pulse rate and activity index did not show any particular trend in each participant; however, the pulse rate/activity index was significantly greater in the off -state compared to that in the dyskinesia and on -states, and this index in the dyskinesia state was significantly greater than that in the on -state in both participants., Conclusion: These results suggest the pulse rate and activity index combination would be a useful indicator of wearing-off and dyskinesia and that biometric information from wearable devices may function as a digital diary. Accumulating more cases and collecting additional data are necessary to verify our findings., Competing Interests: YY and TN are employees of Sunwels. GO reports a relationship with Medtronic, Boston Scientific, Otsuka Pharmaceutical, Sumitomo Pharma, FP Pharmaceutical Corporation, Kyowa Hakko Kirin, Takeda Pharmaceutical Company Ltd, Eisai Co., Ltd, Mylan EPD, and Abbvie that includes: speaking and lecture fees. NH has received speaker honoraria from Sumitomo, Otsuka, Takeda, Kyowa Hakko-Kirin, Boehringer Ingelheim, FP, Eisai, Kissei, Nihon Medi-physics, Novartis, Biogen Idec Japan, AbbVie, Boston Scientific Japan, Sanofi, Alexion, Mylan N. V., and Daiichi Sankyo. NH has received consultancies and subcontracting from Sumitomo, Biogen Idec, Otsuka, Takeda, Kyowa Hakko-Kirin, Meiji Seika, Hisamitsu, Kao, and Ono. Department of Home Medical Care System, based on Information and Communication Technology, Juntendo University Graduate School of Medicine is donated course by Sunwels. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kamo, Oyama, Yamasaki, Nagayama, Nawashiro and Hattori.)

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)., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Deep Brain Stimulation (DBS) is an option to treat advanced Parkinson's Disease (PD), but can cause gait disturbance due to stimulation side efffects. This study aims to evaluate the objective effect of directional current steering by DBS on gait performance in PD, utilizing a three-dimensional gait analysis system., Methods: Eleven patients diagnosed with PD and were implanted with directional lead were recruited. The direction of the pyramidal tract (identified by the directional mode screening) was set as 0°. Patients performed the six-meter-walk test and the time up-and-go (TUG) test while an analysis system recorded gait parameters utilizing a three-dimensional motion capture camera. The gait parameters were measured for the baseline, the directional steering at eight angles (0°, 45°, 90°, 135°, 180°, 225°, 270°, and 315°), and the conventional ring mode with 1, 2, and 3 mA. Pulse width and frequency were fixed. Placebo stimulation (0 mA) was used for a control., Results: Eleven patients completed the study. No significant difference were observed between gait parameters during the directional, baseline, placebo, or ring modes during the six-meter-walk test (p > 0.05). During the TUG test, stride length was significantly different between 0° and other directions (p < 0.001), but no significant differences were observed for the other gait parameters. Stride width was non-significantly narrower in the direction of 0°., Conclusion: Controlling stimulation using directional steering may improve gait in patients with PD, while avoiding pyramidal side effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GO reports a relationship with Medtronic, Boston Scientific, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Novartis Pharma, FP Pharmaceutical Corporation, Kyowa Hakko Kirin, Takeda Pharmaceutical Company Ltd, Eisai Co., Ltd, Mylan EPD, and Abbvie. that includes: speaking and lecture fees. SS, JB, MN, FS, RN, MI have no financial relationship to disclose. NH has received speaker honoraria from Dai-Nippon Sumitomo, Otsuka, Takeda, Kyowa Hakko-Kirin, Boehringer Ingelheim, FP, Eisai, Kissei, Nihon Medi-physics, Novartis, Biogen Idec Japan, AbbVie, Boston Scientific Japan, Sanofi, Alexion, Mylan N. V., and Daiichi Sankyo. NH has received consultancies and subcontracting from Dai-Nippon Sumitomo, Biogen Idec, Otsuka, Takeda, Kyowa Hakko- Kirin, Meiji Seika, Hisamitsu, Kao, and Ono. KB, MT, SK, BT, and TI are employees of Kao Corporation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor functions; it is caused by the loss of midbrain dopaminergic (mDA) neurons. The therapeutic effects of transplanting human-induced pluripotent stem cell (iPSC)-derived mDA neural progenitor cells in animal PD models are known and are being evaluated in an ongoing clinical trial. However, However, improvements in the safety and efficiency of differentiation-inducing methods are crucial for providing a larger scale of cell therapy studies. This study aimed to investigate the usefulness of dopaminergic progenitor cells derived from human iPSCs by our previously reported method, which promotes differentiation and neuronal maturation by treating iPSCs with three inhibitors at the start of induction., Methods: Healthy subject-derived iPS cells were induced into mDA progenitor cells by the CTraS-mediated method we previously reported, and their proprieties and dopaminergic differentiation efficiency were examined in vitro . Then, the induced mDA progenitors were transplanted into 6-hydroxydopamine-lesioned PD model mice, and their efficacy in improving motor function, cell viability, and differentiation ability in vivo was evaluated for 16 weeks., Results: Approximately ≥80% of cells induced by this method without sorting expressed mDA progenitor markers and differentiated primarily into A9 dopaminergic neurons in vitro. After transplantation in 6-hydroxydopamine-lesioned PD model mice, more than 90% of the engrafted cells differentiated into the lineage of mDA neurons, and approximately 15% developed into mature mDA neurons without tumour formation. The grafted PD model mice also demonstrated significantly improved motor functions., Conclusion: This study suggests that the differentiation protocol for the preparation of mDA progenitors is a promising option for cell therapy in patients with PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nakamura, Nonaka, Oyama, Jo, Kamo, Nuermaimaiti, Akamatsu, Ishikawa and Hattori.)

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., (© 2023. The Author(s).)

Sense of time (temporal sense) is believed to be processed by various brain regions in a complex manner, among which the basal ganglia, including the striatum and subthalamic nucleus (STN), play central roles. However, the precise mechanism for processing sense of time has not been clarified. To examine the role of the STN in temporal processing of the sense of time by directly manipulating STN function by switching a deep brain stimulation (DBS) device On/Off in 28 patients with Parkinson's disease undergoing STN-DBS therapy. The test session was performed approximately 20 min after switching the DBS device from On to Off or from Off to On. Temporal sense processing was assessed in three different tasks (time reproduction, time production, and bisection). In the three temporal cognitive tasks, switching STN-DBS to Off caused shorter durations to be produced compared with the switching to the On condition in the time production task. In contrast, no effect of STN-DBS was observed in the time bisection or time reproduction tasks. These findings suggest that the STN is involved in the representation process of time duration and that the role of the STN in the sense of time may be limited to the exteriorization of memories formed by experience., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Honma, Sasaki, Kamo, Nuermaimaiti, Kujirai, Atsumi, Umemura, Iwamuro, Shimo, Oyama, Hattori and Terao.)

The coronavirus disease 2019 pandemic has uncovered several inherent problems in society. While the demand for telemedicine surged worldwide and some countries responded flexibly, in Japan, most telemedicine services were limited to telephone consultations, and full-fledged telemedicine did not become widespread. In addition, the digitalization process in both medicine and wider society lags behind some other nations. It is necessary to accelerate digital transformation in healthcare to build a sustainable society that is resilient to crises, such as new pandemics. In particular, as Japan is facing an issue of super-aged society, a sustainable care model for people with Parkinson's disease, dementia, and intractable neurological diseases should be established. Many neurodegenerative and intractable neurological diseases are progressive; as the disease progresses, patients could become difficult to visit specialists. Although online medical care has many advantages, it does not provide the same quality of information as face-to-face consultations. However, new technology can overcome the limitations of online medical care. As an evolutionary direction for telemedicine, three-dimensional telemedicine technologies are being developed, which enable online medical treatment to be delivered as if the patient was sharing the same space. Telemonitoring can enable the objective and continuous evaluation of patient information at home through the use of motion capture, wearable devices, and other devices. The advancement of digital transformation in medical care should be a game-changer in accumulating big data and analyzing it using artificial intelligence., Competing Interests: GO has received grants from Grant-in-Aid for Scientific Research (Kakenhi) and Novartis Pharma K.K. and honoraria from AbbVie Inc., Boston Scientific Corporation, Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Medtronic Japan Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co. Ltd., and Takeda Pharmaceutical Company Limited. M.O. is an employee of Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. SS declares that there are no conflicts of interest. TH has received grants from: the Japan Agency for Medical Research and Development (grant numbers: 20dm0107156, 21wm0425015, 21ak0101112, and 21dk0207055), the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (grant number: 21K07424), the Setsuro Fujii Memorial Osaka Foundation for Promotion of Fundamental Medical Research, and Daiichi Sankyo TaNeDS; and research funds from: Daiichi Sankyo TaNeDS Funding Program. He has received speaker's honoraria from: Sumitomo Dainippon Pharma Co. Ltd., Takeda Pharmaceutical Company Limited, FP Pharmaceutical Corporation, Kyowa Kirin Co., Ltd., Nihon Medi-Physics Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd, and Otsuka Pharmaceutical Co., Ltd. NH has received consulting fees from GlaxoSmithKline K.K., AbbVie Inc., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co. Ltd., Kyowa Kirin Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., Meiji Seika Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd, and FP Pharmaceutical Corporation; lecture fees from MSD K.K., Eli Lilly Japan K.K., Eisai Co., Ltd., FP Pharmaceutical Corporation, Otsuka Pharmaceutical Co., Ltd., Tsumura & Co., Kyowa Kirin Co., Ltd., GlaxoSmithKline K.K., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Nihon Medi-Physics Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Dainippon Pharma Co. Ltd., and Daiichi Sankyo Company, Limited; honoraria from FP Pharmaceutical Corporation, Novartis Pharma K.K., Kyowa Kirin Co., Ltd., and AbbVie Inc.; research support from Otsuka Pharmaceutical Co., Ltd.; and grants from Astellas Pharma Inc., Eisai Co., Ltd., GlaxoSmithKline K.K., Sumitomo Dainippon Pharma Co. Ltd., Takeda Pharmaceutical Company Limited, Novartis Pharma K.K., Pfizer Japan Inc., Kyowa Kirin Co., Ltd., Medtronic Japan Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co., Ltd, and Otsuka Pharmaceutical Co., Ltd., (© 2023 The Juntendo Medical Society.)

Introduction: The mechanism of Pisa syndrome in Parkinson's disease (PD) is unclear. We aimed to analyze the spatial perception of patients with PD with Pisa syndrome using virtual reality., Methods: In total, 16 patients with Pisa syndrome, 16 age-matched patients without Pisa syndrome, and 16 age-matched controls were included. They viewed the virtual room gradually tilting to different 8 directions randomized across trials. The 75% discrimination threshold angle and the mean tilting discrimination angle for each direction were evaluated. Participants' lateral trunk deviation was measured using Kinect. Neuropsychological status was evaluated, using the Mini-Mental Status Examination (MMSE), the Japanese version of the Montreal-Cognitive Assessment, Frontal Assessment Battery, and the color-word interference task of the Stroop test. Visuospatial abilities were assessed using Benton Judgement of Line Orientation, and vestibular function was evaluated using Subjective Visual Vertical (SVV)., Results: The 75% discrimination threshold in the tilting discrimination angle was larger in all directions for those in the Pisa syndrome group compared to patients in the without Pisa syndrome group and those in the control group. There were significant differences between the three groups for Front-Right, Right, and Back. Patients with Pisa syndrome showed a significantly worse performance in these tests compared with controls and tended to have worse SVV performance compared with patients without Pisa syndrome., Conclusion: The present findings support the hypothesis of visuo-spatial disability and/or attentional impairment in patients with Pisa syndrome., Competing Interests: Declaration of competing interest Department of Neurodegenerative and Demented Disorders is a joint-research course supported by GLORY LTD, Kirin Company LTD, Mitsubishi UFJ Lease & Finance Company LTD. Department of Home Medical Care System based on Information and Communication Technology is a joint-research course supported by Sunwels Co., Ltd. Department of Drug Development for Parkinson's Disease, Juntendo UniversityFaculty of Medicine is a supported course supported by Ohara Pharmaceutical Co.,Ltd. and PARKINSON Laboratories Co., Ltd. Dr. Oyama received speaker honoraria from Medtronic, Boston Scientific, Otsuka Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Company LTD., Kyowa Hakko Kirin Co. Ltd., and AbbVie, Inc. NH received speaker honoraria from AbbVie GK, EA Pharma, Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., OHARA Pharmaceutical Co., Ltd, Kyowa Kirin Co., Ltd., Senju Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Medtronic, Inc., Novartis Pharma K·K., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multiple system atrophy (MSA) is classified into two main types: parkinsonian and cerebellar ataxia with oligodendrogliopathy. We examined microstructural alterations in the white matter and the substantia nigra pars compacta (SNc) of patients with MSA of parkinsonian type (MSA-P) using multishell diffusion magnetic resonance imaging (dMRI) and myelin sensitive imaging techniques. Age- and sex-matched patients with MSA-P (n = 21, n = 10 first and second cohorts, respectively), Parkinson's disease patients (n = 19, 17), and healthy controls (n = 20, 24) were enrolled. Magnetization transfer saturation imaging (MT-sat) and dMRI were obtained using 3-T MRI. Measurements obtained from diffusion tensor imaging (DTI), free-water elimination DTI, neurite orientation dispersion and density imaging (NODDI), and MT-sat were compared between groups. Tract-based spatial statistics analysis revealed differences in diffuse white matter alterations in the free-water fractional volume, myelin volume fraction, and intracellular volume fraction between the patients with MSA-P and healthy controls, whereas free-water and MT-sat differences were limited to the middle cerebellar peduncle in comparison with those with Parkinson's disease. Region-of-interest analysis of white matter and SNc revealed significant differences in the middle and inferior cerebellar peduncle, pontine crossing tract, corticospinal tract, and SNc between the MSA-P and healthy controls and/or Parkinson's disease patients. Our results shed light on alterations to brain microstructure in MSA., (© 2021. The Author(s).)

Dystonia is an abnormal involuntary movement or posture owing to sustained or intermittent muscle contraction. Standard treatment for dystonia includes medications, such as levodopa, anticholinergic and antiepileptic drugs, botulinum toxin, and baclofen pump, and surgeries, such as lesioning surgery and deep-brain stimulation. New treatment modalities aimed toward improving dystonia care in the future are under investigation. There are two main axes to improve dystonia care; one is non-invasive neuromodulation, such as transcranial magnetic stimulation, transcranial electrical stimulation, and transcutaneous electrical nerve stimulation. The other is a quantitative evaluation of dystonia using a wearable device and motion-capturing system, which can be empowered by artificial intelligence. In this article, the current status of these axes will be reviewed.

Introduction: Deep brain stimulation (DBS) is an established treatment for Parkinson's disease (PD). Clinicians face various challenges in adjusting stimulation parameters and configurations in clinical DBS settings owing to inexperience, time constraints, and recent advances in DBS technology that have expanded the number of possible contact configurations. We aimed to assess the efficacy of a closed-loop algorithm (CLA) for the DBS-programming method using external motion sensor-based motor assessments in patients with PD., Methods: In this randomized, double-blind, crossover study, we enrolled 12 patients who underwent eight-ring-contact DBS lead implantations bilaterally in the subthalamic nucleus. The DBS settings of the participants were programmed using a standard of care (SOC) and CLA method. The clinical effects of both programming methods were assessed in a randomized crossover fashion. The outcomes were evaluated using the Unified Parkinson's Disease Scale part III (UPDRS-III) and sensor-based scores for baseline (medication-off/stimulation-off) and both programming methods. The number of programming steps required for each programming method was also recorded., Results: The UPDRS-III scores and sensor-based scores were significantly improved by SOC and CLA settings compared to the baseline. No statistical difference was observed between SOC and CLA. The programming steps were significantly reduced in the CLA settings compared to those in the SOC. No serious adverse events were observed., Conclusion: CLA can optimize DBS settings prospectively with similar therapeutic benefits as that of the SOC and reduce the number of programming steps. Automated optimization of DBS settings would reduce the burden of programming for both clinicians and patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Parkin (encoded by PRKN) is a ubiquitin ligase that plays an important role in cellular mitochondrial quality control. Mutations in PRKN cause selective dopaminergic cell loss in the substantia nigra and are presumed to induce a decrease in mitochondrial function caused by the defective clearance of mitochondria. Several studies have demonstrated that parkin dysfunction causes mitochondrial injury and astrocytic dysfunction. Using immunohistochemical methods, we analyzed astrocytic changes in human brains from individuals with PRKN mutations. Few glial fibrillary acidic protein- and vimentin-positive astrocytes were observed in the substantia nigra in PRKN-mutated subjects compared with subjects with idiopathic Parkinson's disease. We also differentiated patient-specific induced pluripotent stem cells into midbrain organoids and confirmed decreased numbers of glial fibrillary acidic protein-positive astrocytes in PRKN-mutated organoids compared with age- and sex-matched controls. Our study reveals PRKN-mutation-induced astrocytic alteration and suggests the possibility of an astrocyte-related non-autonomous cell death mechanism for dopaminergic neurons in brains of PRKN-mutated patients.

Although non-urgent hospital visits should be avoided during the pandemic, patients with chronic neurological diseases still require a specialist even in such a situation. Telemedicine is a favorable solution to improve patients' access to specialists, and its use has rapidly accelerated worldwide. The need for telemedicine in neurological disorders, the brief history of telemedicine in Japan before and after the pandemic, and how to set up online visits and perform virtual neurological examinations will be discussed in this review.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

Blood pressure abnormalities are frequently observed in patients with Parkinson's disease (PD), and are associated with cerebrovascular diseases such as white matter hyperintensities and carotid atherosclerosis. We assessed the relationship between blood pressure abnormalities and cerebral microbleeds (CMBs), a marker of cerebral small vessel disease, in 128 patients with PD. We examined supine and orthostatic blood pressures and used 24-hour ambulatory blood pressure monitoring to assess the presence or absence of orthostatic hypotension (OH), supine hypertension (SH), nocturnal hypertension (NH), and loss of nocturnal blood pressure dips (non-dipping). CMBs were found in 13 (10.2%) patients, and the median number of CMBs was 1 (range: 1 to 10). Six of these patients had deep or infratentorial CMBs, six had strictly lobar CMBs, and one had mixed CMBs. Linear regression analysis indicated that presence of both OH and SH was independently associated with greater numbers of CMBs in deep or infratentorial regions, independent of age, sex, cardiovascular risk factors, and white matter hyperintensities. NH and non-dipping were not associated with CMBs in deep or infratentorial regions, and there was no association between blood pressure and CMBs in lobar regions. Our results suggest that the presence of both OH and SH may be related to deep or infratentorial CMBs in patients with PD.

Deep brain stimulation (DBS) is a surgical option for advanced Parkinson's disease. Although DBS is used to treat motor fluctuation, DBS may affect non-motor symptoms including mood disorders, cognitive dysfunction, and behavior problems. Impulse control disorders (ICDs) are abnormal behaviors with various manifestations such as pathological gambling, hypersexuality, compulsive shopping, and binge eating, which can affect the quality of life in patients with Parkinson's disease. The effect of DBS on ICD is controversial. Reducing medication by DBS may improve ICDs, however, worsening or even developing new ICDs after DBS can occur. We will review the impact of DBS on ICDs and reveal factors associated with a good response to DBS as well as risk factors for developing ICDs after DBS. We also propose a strategy to manage preexisting ICD and prevent postoperative de novo ICDs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

There is a long history of surgical treatment for Parkinson's disease (PD). After pioneering trials and errors, the current primary surgical treatment for PD is deep brain stimulation (DBS). DBS is a promising treatment option for patients with medically refractory PD. In this review, we summarize accumulated findings concerning patient selection, clinical outcomes, complications, target selection, long-term outcomes, manage- ment of axial symptoms, and timing of surgery in DBS for PD. We also describe new technologies of DBS device.

Background: High frequency stimulation (HFS) of the subthalamic nucleus (STN-DBS) has been shown to have little impact on postural control and gait improvements in Parkinson's disease (PD). There is a lack of consensus and quantitative evidence to suggest that stimulating STN at a lower frequency (LFS) as compared to HFS will be superior in improving symptoms., Objective/hypothesis: To determine if postural control and gait characteristics of persons with PD improve at an LFS (60 Hz) compared to HFS (>100 Hz). We hypothesized that persons with PD would perform better on postural control and gait measures at LFS., Methods: Nineteen participants with bilateral STN-DBS underwent UPDRS, static and dynamic postural control using gait initiation, and gait evaluations in three stimulation conditions (baseline voltage stable across conditions: OFF, LFS of 60 Hz, and HFS of >100 Hz). Additionally 10/19 participants were also stimulated at 30 Hz and 60 Hz and at higher voltages. A one-way ANOVA was performed to compare the conditions., Results: Total UPDRS-III score, step length and velocity during gait initiation, and gait speed significantly improved during 60 Hz and >100 Hz conditions when compared to the OFF condition (P < 0.05). There were no significant differences between 60 Hz and >100 Hz conditions. Using LFS at higher voltage showed no improvement over >100 Hz condition., Conclusions: The positive effects of both LFS and HFS on postural control and gait were similar and clinical changes were relatively small. LFS may not help improve postural control, and gait particularly for persons with PD who do not develop gait-related disorders after HFS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: This study aims to investigate the influence of deep brain stimulation (DBS) on caregiver burden and quality of life in Parkinson's disease., Methods: A cross-sectional retrospective study utilizing the National Parkinson Foundation Quality Improvement Initiative clinical study was conducted. A group of 275 patients who had undergone DBS for Parkinson's disease were extracted from 2916 subjects who were included in this data base. The data were compared to an age, sex, and disease severity matched control group. A secondary analysis was then performed on two more control groups that were matched to account for presence or absence of motor fluctuations. The multidimensional caregiver strain index and Parkinson's disease quality-of-life questionnaire 39 summary index were compared., Results: The multidimensional caregiver strain index did not differ between the DBS group (16.9 ± 11.8) and a matched non-DBS group (16.1 ± 17.6, p = 0.618). The quality-of-life index was, however, significantly better in the DBS group (28.9 ± 15.6) than in the non-DBS group (32.3 ± 17.6, p = 0.034). A secondary analysis revealed that the total caregiver strain score was lower in the no motor fluctuation control group than the other two groups (p < 0.05). Regression analysis revealed significant relationships between the quality-of-life index and caregiver strain index total scores (p < 0.001), between caregiver strain index total score and age at surgery (p = 0.027), and also between the interval since surgery (p = 0.048)., Conclusions: Although there were several limitations to this study, DBS seems to improve quality of life without significantly increasing caregiver burden., (© 2013 International Neuromodulation Society.)

We report a family with autosomal dominant (AD) motor neuron disease. A 41-year-old man developed muscle weakness and fasciculation of the lower extremities. The weakness progressed to the upper extremities and bulbar muscles. The cerebrospinal fluid (CSF) protein level was slightly elevated. A nerve conduction study revealed reduced compound muscle action potentials, but conduction block was not observed. Electromyogram showed acute and chronic neurogenic changes. He was treated with intravenous immunoglobulin (IVIg) and methylprednisolone pulse therapy, but his condition rapidly deteriorated. He developed respiratory failure necessitating artificial ventilation within three months after the onset of the disease. His father developed muscle weakness and atrophy of the upper extremities at age 70, and his cousin developed muscle weakness of the legs at age 41. Their conditions rapidly progressed to quadriplegia. CSF and electrophysiological findings were similar to those of the proband. Treatments by steroid pulse therapy, IVIg, and plasmapheresis were not effective. The father and cousin also required artificial ventilation within 3-4 months from the onset of symptoms, and became locked-in state. Autosomal dominant amyotrophic lateral sclerosis (AD-ALS) was considered, but SOD1 gene mutation was not detected. The present pedigree may have familial ALS caused by a gene mutation other than SOD1.