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Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease.

TDP‐43 aggregates (skeins and round inclusions [RIs]) are frequent histopathological features of amyotrophic lateral sclerosis (ALS). We have shown that diffuse punctate cytoplasmic staining (DPCS) is the earliest pathologic manifestation of TDP‐43 in ALS, corresponding to nonfibrillar TDP‐43 located in the rough endoplasmic reticulum. Previous in vitro studies have suggested that TDP‐43 inclusions may be derived from stress granules (SGs). Therefore, we investigated the involvement of SGs in the formation of TDP‐43 inclusions. Formalin‐fixed spinal cords of six ALS patients with a disease duration of less than 1 year (short duration), eight patients with a disease duration of 2–5 years (standard duration), and five normal controls were subjected to histopathological examination using antibodies against an SG marker, HuR. In normal controls, the cytoplasm of anterior horn cells was diffusely HuR‐positive. In short‐duration and standard‐duration ALS, the number of HuR‐positive anterior horn cells was significantly decreased relative to the controls. DPCS and RIs were more frequent in short‐duration ALS than in standard‐duration ALS. The majority of DPCS areas and a small proportion of RIs, but not skeins, were positive for HuR. Immunoelectron microscopy showed that ribosome‐like granular structures in DPCS areas and RIs were labeled with anti‐HuR, whereas skeins were not. These findings suggest that colocalization of TDP‐43 and SGs occurs at the early stage of TDP‐43 aggregation. Immunostaining of three serial sections of a spinal anterior horn cell containing a round inclusion (RI) (arrows). The RI is immunopositive for HuR (G), nTDP‐43 (H) and pTDP‐43 (I). In particular, the RI is encapsulated by HuR (G). Bar = 10 μm.

IntroductionAccumulating evidence suggests that glucagon-like peptide-1 (GLP-1) receptor agonists may have therapeutic effects against Parkinson’s disease (PD); however, clinical evidence has not yet been established and remains controversial. This clinical study aims to assess the efficacy, disease-modifying effects, safety and optimal dose of oral semaglutide tablets, a GLP-1 receptor agonist, in idiopathic patients with PD.Methods and analysisThe MOST-ABLE study is a phase 2, multicentre, double-blind, randomised, placebo-controlled trial of oral semaglutide tablets in 99 participants with PD. Patients with PD (Hoehn & Yahr stages 1–2.5) at eight sites in Japan will be randomly assigned in a 1:1:1 ratio to one of three groups: oral semaglutide tablets (7 mg or 14 mg) or placebo. The study drugs will be administered once daily as an add-on to conventional medical treatment for PD. After 36 weeks of treatment, the participants will be treated without the study drugs for 12 weeks. The efficacy outcomes include Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Parkinson’s Disease Questionnaire-39, cognitive tests and dopamine transporter imaging. The primary endpoint is the change in the MDS-UPDRS part 3 score in the practically defined off-medication state from baseline at 48 weeks between the treatment allocation groups. The safety and tolerability will also be evaluated.Ethics and disseminationThe study protocol was approved by the Pharmaceuticals and Medical Devices Agency of Japan and the study was approved by the institutional review boards at the University of Osaka Hospital and each study site. All participants are required to provide informed consent. The results will be disseminated in peer-reviewed journals, presented at scientific meetings and presented to patients in a lay summary format.Trial registration numberjRCT2051230090 (https://jrct.mhlw.go.jp/latest-detail/jRCT2051230090), universal trial number U1111-1271-3794.

ObjectivesNon-motor symptoms (NMSs) negatively impact the health-related quality of life (HrQOL) of patients with Parkinson’s disease (PD). The Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is a comprehensive scale for evaluating PD. It remains unclear whether the NMSs evaluated with MDS-UPDRS are predictive of HrQOL. This study aimed to investigate whether NMSs, as evaluated with the MDS-UPDRS, could predict the HrQOL of patients with PD.Materials and methodsWe conducted a 2-year retrospective observational cohort study assessing 108 patients with PD who were recruited from a single tertiary center between January 2015 and December 2017. MDS-UPDRS was used to assess NMSs and motor symptoms and Parkinson’s Disease Questionnaire-39 (PDQ-39) to measure patients’ HrQOL.ResultsThe median age of patients was 69 years, and 65.7% were female. The median MDS-UPDRS part I, part II, part III, and PDQ-39-summary index scores were 8, 10, 22, and 25, respectively. The final stepwise multiple linear regression model showed that female sex (standard partial regression coefficient β = 0.131, P < 0.05) and baseline MDS-UPDRS part I (β = 0.272, P < 0.01) and part II (β = 0.571, P < 0.01) scores significantly predicted the PDQ-39-SI scores at the 2-year follow-up.ConclusionsIn addition to motor symptoms, NMSs at the 2-year follow-up may be useful for predicting the HrQOL of patients with PD. In clinical practice, MDS-UPDRS-guided assessment and treatment of motor symptoms and NMSs may contribute to improving HrQOL in patients with PD.

Rare autosomal recessive variants in DJ-1 , a causative gene for early-onset Parkinson’s disease, have been associated with a variety of clinical syndromes in a limited number of patients. Here, we report a case of a novel DJ-1 variant in a 39-year-old man with a 4-year history of parkinsonism, cognitive dysfunction, and lower limb spasticity. He was diagnosed with Parkinson’s disease. Genetic testing of the patient revealed compound heterozygous variants in the DJ-1 gene (exon 6 deletion + c.242dup), of which exon 6 deletion was a novel variant. We conclude that variants in DJ-1 should be considered possible causes of early-onset parkinsonism with spasticity and cognitive impairment, as in this case.

Atypical antipsychotics are considered to be better tolerated than typical antipsychotics; however, the risk of drug-induced movement disorders needs to be considered. Aripiprazole, a dopamine partial agonist, is one of the most frequently used atypical antipsychotics in children. In this report, we describe withdrawal dyskinesia after aripiprazole discontinuation in a child with autism spectrum disorder. The patient presented with oral dyskinesia after discontinuation of aripiprazole when he was 13 years old. Dyskinetic movements disappeared after reinitiation of aripiprazole. He developed oral dyskinesia again after a reduction of the aripiprazole dose when he was 14 years old. Dyskinesia gradually disappeared within a few months. Withdrawal dyskinesia associated with aripiprazole has been rarely reported in children. Moreover, there is no large study on the prevalence of dyskinesia associated with aripiprazole discontinuation either in adults or in children. However, relevant cases might be unreported, pretermitted, or regarded as akathisia or symptoms of attention-deficit hyperactivity disorder. The prevalence of withdrawal dyskinesia associated with aripiprazole, especially in children, may be more frequent than thought. Withdrawal dyskinesia is self-limited; however, such dyskinetic movements in children potentially result in irreversible effects that damage the quality of life. As such, physicians should be mindful when changing, reducing, or discontinuing antipsychotics in children.

Abstract Transactivation response DNA-binding protein 43 (TDP-43)-immunoreactive neuronal cytoplasmic inclusions (NCIs) are the histopathological hallmarks of amyotrophic lateral sclerosis (ALS). They are classified as skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining (DPCS). We hypothesized that TDP-43-immunoreactive DPCS may form the early-stage pathology of ALS. Hence, we investigated phosphorylated TDP-43 pathology in the upper and lower motor neurons of patients with ALS and control participants. We designated patients whose disease duration was ≤1 year as short-duration ALS (n = 7) and those whose duration equaled 3–5 years as standard-duration ALS (n = 6). DPCS and skein-like inclusions were the most common NCIs in short-duration and standard-duration ALS, respectively. The density of DPCS was significantly higher in short-duration ALS than that in standard-duration ALS and was inversely correlated with disease duration. DPCS was not ubiquitinated and disappeared after proteinase K treatment, suggesting that it was not aggregated. Immunoelectron microscopy revealed that DPCS corresponded to nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum (ER). These findings suggest that nonfibrillar TDP-43 accumulation in the rough ER is the earliest TDP-43 pathology in ALS, which may be helpful in developing future TDP-43 breakdown strategies for ALS.

Although altered networks inside the hippocampus (hippocampal intra-networks) have been observed in dementia, the evaluation of hippocampal intra-networks using magnetic resonance imaging (MRI) is challenging. We employed conventional structural imaging and incident component analysis (ICA) to investigate the structural covariance of the hippocampal intra-networks. We aimed to assess altered hippocampal intra-networks in patients with mild cognitive impairment (MCI). A cross-sectional study of 2122 participants with 3T MRI (median age 69 years, 60.9% female) were divided into 218 patients with MCI and 1904 cognitively normal older adults (CNOA). By employing 3D T1-weighted imaging, voxels within the hippocampus were entered into the ICA analysis to extract the structural covariance intra-networks within the hippocampus. The ICA extracted 16 intra-networks from the hippocampal structural images, which were divided into two bilateral networks and 14 ipsilateral networks. Of the 16 intra-networks, two (one bilateral network and one ipsilateral networks) were significant predictors of MCI from the CNOA after adjusting for age, sex, education, disease history, and hippocampal volume/total intracranial volume ratio. In conclusion, we found that the relationship between hippocampal intra-networks and MCI was independent from the hippocampal volume. Our results suggest that altered hippocampal intra-networks may reflect a different pathology in MCI from that of brain atrophy.