Nonmotor Symptoms in Patients with PARK2 Mutations

Decreased 123I-meta-iodobenzylguanidine (MIBG) uptake in MIBG myocardial scintigraphy, olfactory dysfunction, and rapid eye movement (REM) sleep behavior disorder (RBD) are considered useful early indicators of Parkinson disease. We investigated whether patients with PARK2 mutations exhibited myocardial sympathetic abnormalities using MIBG scintigraphy, olfactory dysfunction using the Sniffin' Sticks olfactory test, and RBD using polysomnography. None of the examined patients had RBD, and all except 1 patient exhibited an increase in the olfactory threshold. Moreover, one of the oldest patients exhibited impairment in identification and discrimination. Of 12 patients with PARK2 mutations, 4 patients, who were older than patients without abnormal uptake, exhibited decreased MIBG uptake. The results obtained in this study suggest that some patients with PARK2 mutations have increased thresholds of olfactory function and myocardial sympathetic dysfunction as nonmotor symptoms

Case report: Young-onset large vessel ischemic stroke due to hyperhomocysteinemia associated with the C677T polymorphism on 5,10-methylenetetrahydrofolate reductase and multi-vitamin deficiency

Hyperhomocysteinemia is an important risk factor for cerebral infarction. Herein, we report on a 30-year-old man previously diagnosed with epilepsy who presented with right hemiplegia and total aphasia. Magnetic resonance imaging showed a fronto-temporal ischemic lesion due to occlusion of the left middle cerebral artery. Clinical testing and imaging demonstrated that he had hyperhomocysteinemia induced by multiple factors including the C677T polymorphism on 5.10-methylenetetrahydrofolate reductase (MTHFR), and multiple vitamin deficiencies. The C677T polymorphism on MTHFR is closely related to hyperhomocysteinemia and folate deficiency in epileptic patients who are taking multiple anti-convulsants. Given hyperhomocysteinemia can independently cause stroke at a young age, physicians should periodically examine plasma homocysteine and serum folic acid levels in epileptic patients who are on long-term regimens of multiple anti-epileptic drugs

Influence of istradefylline on non-motor symptoms of Parkinson\u27s disease: A subanalysis of a 1-year observational study in Japan (J-FIRST)

IntroductionThe non-motor symptoms (NMSs) of Parkinson\u27s disease (PD) significantly impact the patient\u27s health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A2A receptor antagonist, on NMSs in istradefylline-naïve Japanese patients with PD.MethodsPatients with PD and ≥1 NMS and ‘wearing-off’ with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson\u27s Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model.ResultsOverall, 732 patients were istradefylline-naïve prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score.ConclusionNMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs

Subthalamic deep brain stimulation in Parkinson's disease with SNCA mutations: Based on the follow-up to 10 years

Backgrounds: Although the short-term efficacy of bilateral subthalamic deep brain stimulation (DBS) has been reported in a limited number of Parkinson's disease (PD) patients with SNCA mutations, there are no data for long-term outcome. Methods: This multicenter retrospective study investigated previously reported PD patients with SNCA mutations, implanted with bilateral subthalamic DBS. We compared demographic and clinical data at baseline and last follow-up. Clinical data of motor and nonmotor symptoms and motor fluctuation were collected up to 10 years from DBS surgery. Results: Among four subjects, three had SNCA duplication and one had c.158C.A (p.A53E) mutation. The mean post-implantation follow-up duration was 5.4 +/- 3.7 years. All patients with SNCA duplication showed favorable outcome, although one died from breast cancer 1.5 years after DBS. The patient with the missense mutation became wheelchair-bound due to progressed axial, cognitive and psychiatric symptoms after 3.5 years from DBS despite the benefit on motor fluctuation. Conclusion: Based on findings in our small cohort, subthalamic DBS could be beneficial for motor fluctuation in PD patients with SNCA mutations, especially those with SNCA duplication, and cognitive and psychiatric symptoms are important for the long-term outcome of subthalamic DBS.</p

Effect of SARS-CoV-2 BNT162b2 mRNA vaccine on thyroid autoimmunity: A twelve-month follow-up study

ObjectivesGraves’ disease (GD) has been highlighted as a possible adverse effect of the respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. However, it is unknown if the SARS-CoV-2 vaccine disrupts thyroid autoimmunity. We aimed to present long-term follow-up of thyroid autoimmunity after the SARS-CoV-2 BNT162b2 mRNA vaccine.MethodsSerum samples collected from seventy Japanese healthcare workers at baseline, 32 weeks after the second dose (pre-third dose), and 4 weeks after the third dose of the vaccine were analyzed. The time courses of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibody, thyroid-stimulating hormone receptor antibody (TRAb), and thyroid function were evaluated. Anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were additionally evaluated in thirty-three participants.ResultsThe median age was 50 (IQR, 38-54) years and 69% were female. The median anti-spike IgG antibody titer was 17627 (IQR, 10898-24175) U/mL 4 weeks after the third dose. The mean TRAb was significantly increased from 0.81 (SD, 0.05) IU/L at baseline to 0.97 (SD, 0.30) IU/L 4 weeks after the third dose without functional changes. An increase in TRAb was positively associated with female sex (β = 0.32, P = 0.008) and low basal FT4 (β = -0.29, P = 0.02) and FT3 (β = -0.33, P = 0.004). TgAb was increased by the third dose. Increase in TgAb was associated with history of the thyroid diseases (β = 0.55, P &lt;0.001).ConclusionsSARS-CoV-2 BNT162b2 mRNA vaccine can disrupt thyroid autoimmunity. Clinicians should consider the possibility that the SARS-CoV-2 vaccine may disrupt thyroid autoimmunity

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Motor/Nonmotor Symptoms and Progression in Patients with Parkinson’s Disease: Prevalence and Risks in a Longitudinal Study

We previously assessed the prevalence and risks of motor/nonmotor symptoms in a large sample of Japanese patients with Parkinson’s disease. In the present study, we longitudinally assessed the prevalence and risk of motor/nonmotor symptoms, changes in treatment, disease progression, and death in patients with Parkinson’s disease. We enrolled 1,227 patients diagnosed and treated at our hospital in Tokyo at first evaluation. We were able to follow-up 445 patients until the second evaluation, 7.4 years later. Using Kaplan–Meier survival curves and the Cox proportional-hazards model in 1,227 patients, motor/nonmotor symptoms were analyzed in association with the following events: pain, wearing-off, camptocormia, psychosis, orthostatic hypotension, pneumonia, tube feeding, modified Hoehn and Yahr stages (H–Y) 3 and 4 of the on state, and death. The mean age (standard deviation) at the first evaluation was 67.2 (9.9) years, while the mean ages at onset and disease duration were 57.8 (11.7) years and 9.3 (6.6) years, respectively. The mean H–Y of the on state was 2.7 (1.1) at the first evaluation. Age at onset and duration of levodopa use decreased the hazard ratios (HRs) (0.968 and 0.910, respectively) for wearing-off. Female sex increased the HRs (1.414) for wearing-off and decreased the HRs for orthostatic hypotension (0.540) and pneumonia (0.510). Older age at onset increased the HR for psychosis (1.035), orthostatic hypotension (1.033), H–Y 3 (1.048) and 4 (1.071), pneumonia (1.123), tube feeding (1.140), and death (1.095). Early onset of orthostatic hypotension itself increased the HR for numerous events, especially for death (0.893). Our results indicated that age, sex, and some nonmotor symptoms may predict many Parkinson’s disease-related events. In addition, these data may provide a useful reference for the clinical course of Parkinson’s disease