渡辺 宏久

Studies have demonstrated loss of serotonergic neurons in the brainstems of patients with multiple-system atrophy (MSA). This study aimed to semiquantitatively investigate the status of serotonin transporter (SERT) distribution in the brainstem of individuals with MSA-parkinsonian type (MSA-P) via 123I-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) SPECT and compare it with pathologic findings in some cases. Methods: We administered 123I-FP-CIT intravenously to 19 patients with MSA-P and 17 healthy controls (HCs) and performed SPECT and MRI scans. Specific binding ratio (SBR) images were generated, and summed voxel-based SBRs for the midbrain, pons, and entire brainstem were quantified. The Mann-Whitney U test was used to compare the MSA-P and HC groups, and receiver operating characteristic curves were used to analyze the midbrain-to-pons ratio of the summed voxel-based SBR. Further, we assessed postmortem SERT immunohistochemistry pathology in the brainstems of representative MSA-P cases and HCs to compare the distribution and density of SERT with SPECT findings. Results: 123I-FP-CIT SPECT results revealed a significant summed voxel-based SBR decrease in the midbrain and an increase in the pons in the MSA-P group, although the brainstem summed voxel-based SBRs did not differ significantly (P < 0.05). The use of the midbrain-to-pons ratio for differentiation generated an area under the curve of 0.93. SERT immunostaining pathology, consistent with the 123I-FP-CIT SPECT findings, demonstrated a significant decrease in SERT expression in the substantia nigra and a significant increase in the pontine raphe nucleus in patients with MSA-P. Conclusion: Our results indicate differences in SERT distribution in the brainstems of patients with MSA-P and HCs.

Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10^-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10^-9). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.

<jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title>Objective</jats:title> <jats:p>Cerebrospinal fluid (CSF) cell‐free mitochondrial DNA (cf‐mtDNA) is a potential biomarker for Parkinson's disease (PD), but its clinical relevance remains unclear. We investigated associations between CSF cf‐mtDNA levels, body composition, nutritional status, and metabolic biomarkers in PD.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>CSF cf‐mtDNA levels, defined as the copy numbers of two regions of the mtDNA circular molecule (mt64‐ND1 and mt96‐ND5), were quantified in 44 PD patients and 43 controls using multiplex digital PCR. The mt96‐ND5/mt64‐ND1 ratio was calculated to estimate mtDNA deletion burden. Associations with clinical features, body composition, serum nutritional markers, and plasma energy metabolism‐related organic acids were examined. Generalized linear models (GLMs) were performed to adjust for confounders.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> CSF mt64‐ND1 and mt96‐ND5 levels were lower in PD patients than controls ( <jats:italic>p</jats:italic>  = 0.002, <jats:italic>p</jats:italic>  = 0.001), while the mt96‐ND5/mt64‐ND1 ratio showed no group difference. GLM analysis identified body composition indices and serum albumin as key determinants of cf‐mtDNA levels. Subgroup analysis showed lower cf‐mtDNA levels in PD patients with preserved body composition and nutritional status. The mt96‐ND5/mt64‐ND1 ratio displayed a biphasic association with body composition and an inverse correlation with plasma 2‐ketoglutaric acid, suggesting a link to energy metabolism. </jats:p> </jats:sec> <jats:sec> <jats:title>Interpretation</jats:title> <jats:p>CSF cf‐mtDNA levels are reduced in PD and influenced by body composition and nutritional status, supporting their role as a metabolic biomarker. While the cf‐mtDNA deletion ratio remained unchanged, its association with body composition suggests a complex interplay between mitochondrial integrity and metabolism. These findings highlight the relevance of cf‐mtDNA in PD pathophysiology and the need for further study.</jats:p> </jats:sec>

<jats:sec> <jats:title>Background</jats:title> <jats:p>Weight loss is a substantial non-motor feature of Parkinson’s disease (PD) associated with worse clinical outcomes, but the underlying mechanisms remain poorly understood. Thus, we investigated the mechanisms of PD-related weight loss by examining the correlation between body composition and various plasma metabolites.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We enrolled 91 patients with PD and 47 healthy controls between July 2021 and October 2023. Body composition was evaluated using bioelectrical impedance analysis. Plasma metabolite profiling was conducted via mass spectrometry, including short-chain and medium-chain fatty acids, Krebs cycle intermediates, ketone bodies and phospholipids. Subsequently, alterations in body composition in PD and their association with plasma metabolites were assessed.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Patients with PD had lower body weight (p=0.003), body mass index (BMI; p=0.001) and body fat mass (p&lt;0.001) compared with controls. Metabolomic analyses revealed that, in patients with PD, glycolysis and Krebs cycle markers (lactic acid and succinic acid) were reduced, while ketone bodies (acetoacetic acid and 3-hydroxybutyric acid), amino acid catabolism-related markers (2-hydroxybutyric acid and 2-oxobutyric acid) and acetic acid were elevated. Notably, in patients with PD, acetoacetic acid and 3-hydroxybutyric acid negatively correlated with BMI. Phosphatidylcholine (40:2) was also elevated in PD and showed higher levels in individuals at more advanced Hoehn and Yahr stages.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>PD-related fat loss was accompanied by a pattern of lower glycolytic activity and higher levels of lipid and amino acid metabolism-related metabolites, consistent with a potential shift in energy utilisation. These findings highlight metabolic pathways as potential targets for interventions to mitigate weight loss in PD.</jats:p> </jats:sec>

<h4>Objective</h4>The development of non-invasive clinical diagnostics is paramount for the early detection of Alzheimer's disease (AD). Neurofibrillary tangles in AD originate from the entorhinal cortex, a cortical memory area that mediates navigation via path integration (PI). Here, we studied correlations between PI errors and levels of a range of AD biomarkers using a 3D virtual reality navigation system to explore PI as a non-invasive surrogate marker for early detection.<h4>Methods</h4>We examined 111 healthy adults for PI using a head-mounted 3D VR system, AD-related plasma biomarkers (GFAP, NfL, Aβ40, Aβ42, and p-tau181), Apolipoprotein E (ApoE) genotype, and demographic and cognitive assessments. Covariance of PI and AD biomarkers was assessed statistically, including tests for multivariate linear regression, logistic regression, and predictor importance ranking using machine learning, to identify predictive relationships for PI errors.<h4>Results</h4>We found significant positive correlations between PI errors with age and plasma GFAP, p-tau181, and NfL levels. Multivariate analysis identified significant correlations of plasma GFAP (t-value = 2.16, p = 0.0332) and p-tau181 (t-value = 2.53, p = 0.0128) with PI errors. Predictor importance ranking using machine learning and receiver operating characteristic curves identified plasma p-tau181 as the most significant predictor of PI. ApoE genotype and plasma p-tau181 showed positive and negative PI associations (ApoE: coefficient = 0.650, p = 0.037; p-tau181: coefficient = -0.899, p = 0.041). EC thickness exhibited negative correlations with age, mean PI errors, and GFAP, NfL, and p-tau181; however, none of these associations remained significant after adjusting for age in linear regression analyses.<h4>Conclusion</h4>These findings suggest that PI quantified by 3D VR navigation systems may be useful as a surrogate diagnostic tool for the detection of early AD pathophysiology. The hierarchical application of 3D VR PI and plasma p-tau181, in particular, may be an effective combinatorial biomarker for early AD neurodegeneration. These findings advance the application of non-invasive diagnostic tools for early testing and monitoring of AD, paving the way for timely therapeutic interventions and improved epidemiological patient outcomes.

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Sialorrhea, caused by various neurological diseases, impairs patient health and quality of life. After the results of a randomized controlled trial, incobotulinumtoxinA was approved for the treatment of chronic sialorrhea in the United States and Europe; however, no pharmacotherapy has been approved in Japan.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective</jats:title> <jats:p>The aim was to evaluate the efficacy and safety of incobotulinumtoxinA treatment for chronic sialorrhea in a single‐arm phase 3 study in Japan.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Patients with chronic sialorrhea caused by neurological diseases (Parkinson's disease, atypical parkinsonism, and stroke, group A) and broader diseases (eg, muscular dystrophy and amyotrophic lateral sclerosis, group B) were enrolled. IncobotulinumtoxinA 100 U was injected into the salivary glands once every 16 weeks for 48 weeks. A primary endpoint was assessed in group A, whereas secondary endpoints and safety were assessed in both groups.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>From November 2021 to August 2023, 92 patients (58 and 34 in groups A and B, respectively) received incobotulinumtoxinA at 28 institutions. The primary endpoint, the least square mean (standard error) of change in unstimulated salivary flow rate from baseline to 4 weeks, was −0.08 (0.009, 95% confidence interval [CI]: −0.10, −0.06) g/min, achieving the prespecified efficacy criteria (upper limit of the 95% CI &lt;−0.04). The secondary endpoints were consistent across efficacy measures, indicating that reduced salivary secretion and improved drooling symptoms persisted for 48 weeks. The most common adverse events were dry mouth and dysphagia.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The first study in Japan confirmed the efficacy of incobotulinumtoxinA treatment for chronic sialorrhea with good patient tolerability and no new safety concerns.</jats:p> </jats:sec>

<jats:title>Abstract</jats:title> <jats:p>Treatment with levodopa, a precursor of dopamine (DA), to compensate for the loss of endogenous DA in Parkinson’s disease (PD), has been a success story for over 50 years. However, in late stages of PD, the progressive degeneration of dopaminergic neurons and the ongoing reduction in endogenous DA concentrations make it increasingly difficult to maintain normal-like DA function. Typically, in late PD, higher doses of levodopa are required, and the fluctuations in striatal DA concentrations—reflecting the timing pattern of levodopa administrations—become more pronounced. These DA fluctuations can include highs that induce involuntary movements (levodopa-induced dyskinesia, LID) or lows that result in insufficient suppression of PD symptoms (“OFF” phases). The enhanced fluctuations primarily arise from the loss of DA buffering capacity, resulting from the degeneration of DA neurons, and an increased reliance on levodopa-derived DA release as a “false neurotransmitter” by serotonergic neurons. In many patients, the LID and OFF-phases can be alleviated by modifying the levodopa therapy to provide a more continuous delivery or by using additional medications, such as monoamine oxidase-B (MAO-B) inhibitors, amantadine, or dopaminergic receptor agonists. Understanding the challenges faced by levodopa therapy also requires considering that the PD striatum is characterized not only by the loss of DA neurons but also by neuroplastic adaptations and PD-induced degenerations of other neural populations. This review provides a broad overview on the use of levodopa in treating PD, with a focus on the underlying science of the challenges encountered in late stages of the disease.</jats:p>

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>To investigate trajectories of regional brain volume changes in multiple system atrophy (MSA) and their potential utility as surrogate markers of disease progression in the cerebellar subtype (MSA‐C).</jats:p></jats:sec><jats:sec><jats:title>Background</jats:title><jats:p>Reliable biomarkers for tracking disease progression in MSA are urgently needed. Although several studies have explored neuroimaging markers, imaging measures that are reliable and reproducible at the individual‐level are lacking.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Longitudinal three‐dimensional (3D)‐T1 images from multiple cohorts of 21 subjects with probable MSA‐C, 19 with probable MSA‐parkinsonian subtype (MSA‐P), 113 with Parkinson's disease, and 227 healthy controls were processed using the FreeSurfer longitudinal pipeline. Extracted volumes were assessed for individual longitudinal trajectories, intra‐individual variability, and pontine regional volume decline.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Pontine volumes showed lower intra‐individual variability in measurements compared with other infratentorial brain regions. All probable MSA‐C patients exhibited a decline in pontine volume, ranging from −3.6% to −16.8% per year (mean: −9.1%), falling more than two standard deviations below the mean of healthy controls. In MSA‐C, the temporal dynamics of pontine volumes exhibited nonlinear changes, characterized by progressive atrophy in the earlier period of the disease, followed by a pre‐plateau phase associated with advanced disability in the later period. Predictive modeling suggests that pontine atrophy may begin before symptom onset of MSA‐C.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Pontine volume is a sensitive marker of disease progression, exhibiting a nonlinear decline with low intra‐individual variability in measurements and greater volume loss in the earlier stages, reaching a pre‐plateau phase in the later stages with advanced disability. © 2025 The Author(s). <jats:italic>Movement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</jats:p></jats:sec>

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Dysphagia significantly impacts prognosis in individuals with multiple system atrophy (MSA). While video‐based assessments are practical, their limited availability highlights the need for a simple tool such as the Dysphagia Severity Scale (DSS) in clinical practice.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>To evaluate the utility of the DSS in assessing dysphagia in MSA patients and its correlations with clinical indices.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We examined 43 MSA patients using the DSS and other clinical measures, including the Unified MSA Rating Scale (UMSARS) and cerebrospinal fluid 5‐hydroxyindoleacetic acid levels. As a follow‐up, 11 of 43 patients underwent a secondary DSS evaluation. Spearman's correlation and linear mixed models were used to analyze cross‐sectional and longitudinal relationships.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>DSS scores were significantly correlated with UMSARS Parts 1, 2, and 4, as well as disease duration and blood pressure changes. This indicates that the DSS is sensitive to MSA‐related motor and autonomic dysfunctions, and that the DSS could provide a more detailed assessment of swallowing function compared with the UMSARS Part 1 swallowing subscore. Additionally, DSS score was correlated with cerebrospinal fluid 5‐hydroxyindoleacetic acid levels. Our longitudinal analysis further supported the role of DSS score as a reliable marker of dysphagia progression over time.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The DSS is a sensitive and practical tool for evaluating dysphagia. Thus, combining the DSS and UMSARS could improve dysphagia monitoring in individuals with MSA. Our data support the use of the DSS as a valuable clinical and research tool in MSA management.</jats:p></jats:sec>

INTRODUCTION: Progressive supranuclear palsy (PSP) involves midbrain structures, including the red nucleus (RN), an iron-rich region that appears as a high-contrast area on quantitative susceptibility mapping (QSM). RN may serve as a promising biomarker for differentiating parkinsonism. However, RN deformation in PSP remains elusive. This study aimed to evaluate RN deformation in PSP using coronal QSM images and compare them with those of Parkinson's disease (PD) and healthy controls (HC). METHODS: We evaluated the QSM images of 22 patients with PSP, 37 patients with PD, and 43 HC. We developed a grading system to assess RN deformation on coronal QSM images and classified them into three grades. The midbrain and RN volumes were extracted using distinct approaches, and their relationship with grading was investigated. For validation, coronal QSM images of 16 PSP patients from a different institution were assessed. RESULTS: In PSP, 59 % of the patients displayed a flattened RN of grade 3, which we termed a Rice-Grain Appearance. The volume reductions in midbrain and RN were associated with deformation. Differentiation based on the presence of this appearance yielded a specificity of 1.000 (CI: 1.000-1.000) and sensitivity of 0.591 (0.385-0.796) for distinguishing PSP from others. Secondary dataset also showed that 56 % of patients with PSP were classified as grade 3. CONCLUSION: In coronal QSM images, the flattened RN shape appears to be specific to PSP compared to PD and HC and may serve as a marker to help differentiate PSP in future clinical settings.

OBJECTIVES: Sudden death in multiple system atrophy (MSA) is caused by decreased serotonergic innervation, but there is no routine test method for this decrease. In addition to dopamine transporters, iodine-123-labelled N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) binds serotonin transporters (SERTs). We noted a binding potential to quantify the total quantity of 123I-FP-CIT binding to its receptors.Following Mintun's binding-potential concept, this study aimed to evaluate the relationship between the specific binding ratio (SBR) and total SERT tissue amount, but not SERT binding, and to develop an SBR imaging method to measure brain-stem SERT. We sought to establish a binding-potential imaging procedure using SBR images to examine differences in the brain-stem SERT distribution between healthy subjects and MSA patients. METHODS: Single-photon emission computed tomography (SPECT) and T1-weighted magnetic resonance (MR) images were aligned. The MR (T1) images were used to set a reference site for the occipital-lobe SBR in each subject, and measurements were made from the SPECT image at the same position. The pixel values and accumulation ratios compared with the occipital lobe were calculated, and a regional SBR distribution image was created. We identified areas with SERT accumulation above a certain level. RESULTS: The SERT accumulation site was visualised as an SBR value on MR images. The accumulation distribution (SERT distribution) on the SBR images significantly differed between the healthy subjects and patients with MSA. CONCLUSION: SERT accumulation was noted in the brain-stem region, indicating that SBR imaging was useful for viewing and quantifying SERT accumulation.

<jats:sec><jats:title>Background</jats:title><jats:p> Recent evidence suggests a link between glycoprotein non-metastatic melanoma protein B (GPNMB) and Parkinson's disease (PD) pathogenesis. Although elevated plasma GPNMB levels associated with disease severity have been reported in PD, cerebrospinal fluid (CSF) alterations remain elusive. </jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p> To explore CSF GPNMB alterations and its clinical significance in PD. </jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p> This study enrolled 118 sporadic PD patients and 40 controls. We examined the potential associations between CSF GPNMB levels and the clinical characteristics or biomarkers of neurodegenerative pathogenesis. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> PD patients had higher CSF GPNMB levels than controls ( p = 0.0159). In the PD group, CSF GPNMB levels correlated with age (age at examination: r<jats:sub>s </jats:sub>= 0.2511, p = 0.0061; age at onset: r<jats:sub>s </jats:sub>= 0.2800, p = 0.0021) and the severity of motor and cognitive dysfunction (MDS-UPDRS III score: r<jats:sub>s </jats:sub>= 0.1998, p = 0.0347; Mini-Mental State Examination score: r<jats:sub>s </jats:sub>= −0.1922, p = 0.0370). After correcting for multiple comparisons, the correlation with age at onset remained significant. CSF GPNMB levels were also positively correlated with CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in both the PD ( r<jats:sub>s </jats:sub>= 0.3582, p &lt; 0.0001) and control ( r<jats:sub>s </jats:sub>= 0.4743, p = 0.0023) groups. Furthermore, multiple regression analysis revealed CSF sTREM2 level as the strongest determinant of CSF GPNMB levels in the PD group (t-value = 3.49, p = 0.0007). </jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p> Elevated CSF GPNMB levels, linked with age and microglial activation, may be a valuable marker for understanding the interplay between aging, neuroinflammation, and PD pathology. </jats:p></jats:sec>