Metagenomic next-generation sequencing for diagnosis of fatal Balamuthia amoebic encephalitis.

INTRODUCTION: Balamuthia amoebic encephalitis (BAE), caused by Balamuthia mandrillaris, is a rare and life-threatening infectious disease with no specific and effective treatments available. The diagnosis of BAE at an early stage is difficult because of the non-specific clinical manifestations and neuroimaging. CASE DESCRIPTION: A 52-year-old male patient, who had no previous history of skin lesions, presented to the emergency department with an acute headache, walking difficulties, and disturbance of consciousness. The patient underwent a series of examinations, including regular cerebrospinal fluid (CSF) studies and magnetic resonance imaging, and tuberculous meningoencephalitis was suspected. Despite being treated with anti-TB drugs, no clinical improvement was observed in the patient. Following corticosteroid therapy, the patient developed a rapid deterioration in consciousness with dilated pupils. Metagenomic next-generation sequencing (mNGS) revealed an unexpected central nervous system (CNS) amoebic infection, and the patient died soon after the confirmed diagnosis. CONCLUSION: This study highlights the application of mNGS for the diagnosis of patients with suspected encephalitis or meningitis, especially those caused by rare opportunistic infections.

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration.

BACKGROUND AND PURPOSE: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. METHODS: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. RESULTS: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. CONCLUSIONS: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.

Genetic analysis of transcription factors in dopaminergic neuronal development in Parkinson's disease.

BACKGROUND: Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson's disease (PD) risk factors; however, no comprehensive analyses of these genes in patients with PD have been undertaken. Therefore, we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD. METHODS: Whole-exome sequencing (WES) was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls. Additionally, whole-genome sequencing (WGS) was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls. RESULTS: We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts, respectively. Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD. However, the significance did not pass the Bonferroni correction. Meanwhile, 72 and 1730 common variants were found in the WES and WGS cohorts, respectively. Unfortunately, single-variant logistic association analyses did not identify significant associations between common variants and PD. CONCLUSIONS: Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients. However, we highlight the complexity of PD and the need for extensive research elucidating its etiology.

Estimating the sequence of biomarker changes in Parkinson's disease.

OBJECTIVE: To estimate the sequence of several common biomarker changes in Parkinson's disease (PD) using a novel data-driven method. METHODS: We included 374 PD patients and 169 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI). Biomarkers, including the left putamen striatal binding ratio (SBR), right putamen SBR, left caudate SBR, right caudate SBR, cerebrospinal fluid (CSF) α-synuclein, and serum neurofilament light chain (NfL), were selected in our study. The discriminative event-based model (DEBM) was utilized to model the sequence of biomarker changes and establish the disease progression timeline. The estimated disease stages for each subject were obtained through cross-validation. The associations between the estimated disease stages and the clinical symptoms of PD were explored using Spearman's correlation. RESULTS: The left putamen is the earliest biomarker to become abnormal among the selected biomarkers, followed by the right putamen, CSF α-synuclein, right caudate, left caudate, and serum NfL. The estimated disease stages are significantly different between PD and HC and yield a high accuracy for distinguishing PD from HC, with an area under the curve (AUC) of 0.98 (95% confidence interval 0.97-0.99), a sensitivity of 0.95, and a specificity of 0.92. Moreover, the estimated disease stages correlate with motor experiences of daily living, motor symptoms, autonomic dysfunction, and anxiety in PD patients. CONCLUSION: We determined the sequence of several common biomarker changes in PD using DEBM, providing data-driven evidence of the disease progression of PD.

Mutational spectrum and clinical features of GBA1 variants in a Chinese cohort with Parkinson's disease.

GBA1 variants are important risk factors for Parkinson's disease (PD). Most studies assessing GBA1-related PD risk have been performed in European-derived populations. Although the coding region of the GBA1 gene in the Chinese population has been analyzed, the sample sizes were not adequate. In this study, we aimed to investigate GBA1 variants in a large Chinese cohort of patients with PD and healthy control and explore the associated clinical characteristics. GBA1 variants in 4034 patients and 2931 control participants were investigated using whole-exome and whole-genome sequencing. The clinical features of patients were evaluated using several scales. Regression analysis, chi-square, and Fisher exact tests were used to analyze GBA1 variants and the clinical symptoms of different groups. We identified 104 variants, including 8 novel variants, expanding the spectrum of GBA1 variants. The frequency of GBA1 variants in patients with PD was 7.46%, higher than that in the control (1.81%) (P < 0.001, odds ratio [OR] = 4.38, 95% confidence interval [CI]: 3.26-5.89). Among patients, 176 (4.36%) had severe variants, 34 (0.84%) carried mild variants, three (0.07%) had risk variants, and 88 (2.18%) carried unknown variants. Our study, for the first time, found that p.G241R (P = 0.007, OR = 15.3, 95% CI: 1.25-261.1) and p.S310G (P = 0.005, OR = 4.86, 95% CI: 1.52-28.04) variants increased the risk of PD. Patients with GBA1 variants exhibited an earlier onset age and higher risk of probable rapid-eye-movement sleep behavior disorder, olfactory dysfunction, depression, and autonomic dysfunction than patients without GBA1 variants.

Evaluation of the role of FMR1 CGG repeat allele in Parkinson's disease from the Chinese population.

Objective: There is controversial evidence that FMR1 premutation or "gray zone" (GZ) allele (small CGG expansion, 45-54 repeats) was associated with Parkinson's disease (PD). We aimed to explore further the association between FMR1 CGG repeat expansions and PD in a large sample of Chinese origin. Methods: We included a cohort of 2,362 PD patients and 1,072 controls from the Parkinson's Disease and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) in this study and conducted repeat-primed polymerase chain reaction (RP-PCR) for the size of FMR1 CGG repeat expansions. Results: Two PD patients were detected with FMR1 premutation (61 and 56 repeats), and the other eleven PD patients were detected with the GZ allele of FMR1 CGG repeat expansions. Those thirteen PD patients responded well to levodopa and were diagnosed with clinically established PD. Specifically, one female PD patient with GZ allele was also found with premature ovarian failure. However, compared to healthy controls, we found no significant enrichment of GZ allele carriers in PD patients or other subgroups of PD cases, including the subgroups of female, male, early-onset, and late-onset PD patients. Furthermore, we did not find any correlation between the FMR1 gene CGG repeat sizes and age at onset of PD. Conclusion: It suggested that FMR1 premutation was related to PD, but the GZ allele of FMR1 CGG repeat expansions was not significantly enriched in PD cases of Chinese origin. Further larger multiple ethnic studies are needed to determine further the role of the FMR1 GZ allele in PD.

The risk factors for probable REM sleep behavior disorder: A case-control study.

OBJECTIVE: To investigate the risk factors for REM sleep behavior disorder (RBD) in a case-control study. METHODS: Participants with probable RBD (pRBD) were defined using the RBD Questionnaire-Hong Kong (RBDQ-HK). Controls were collected by matching age and sex. Demographic information, lifestyle, comorbidity, prodromal symptoms of Parkinson's disease (PD), and blood biomarkers were assessed. The associations between these factors and pRBD were investigated by logistic regression. Partial correlation analysis was used to assess the association between the severity of RBD and depression. RESULTS: A total of 278 pRBD participants (age = 58.31 ± 15.82 years) and 556 controls (age = 58.16 ± 15.84 years) were enrolled in this study. Patients with pRBD were more likely to be current alcohol drinkers (OR 1.50, 95% CI 1.0-2.32). Participants with pRBD had a higher Hamilton Depression Rating Scale (HAMD-17) score (OR 1.17, 95% CI 1.11-1.22) than controls and were more likely to report arthritis (OR 1.53, 95% CI 1.08-2.16), constipation (OR 1.93, 95% CI 1.31-2.86), hyposmia (OR 1.71, 95% CI 1.10-2.67), and depression (OR 3.15, 95% CI 2.17-4.58). Higher levels of total cholesterol (OR 1.15, 95% CI 0.99-1.33) and low-density lipoprotein (OR 1.21, 95% CI 0.99-1.47) had borderline associations with pRBD. Additionally, the severity of pRBD was positively related to depression (r = 0.31, P < 0.01). CONCLUSIONS: We determined several risk factors for pRBD in this case-control study. Future studies are needed to understand the mechanism underlying the association between these factors and pRBD.

Genetic analysis of dystonia-related genes in Parkinson's disease.

Objective: Parkinson's disease (PD) and dystonia are two closely related movement disorders with overlaps in clinical phenotype. Variants in several dystonia-related genes were demonstrated to be associated with PD; however, genetic evidence for the involvement of dystonia-related genes in PD has not been fully studied. Here, we comprehensively investigated the association between rare variants in dystonia-related genes and PD in a large Chinese cohort. Methods: We comprehensively analyzed the rare variants of 47 known dystonia-related genes by mining the whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 3,959 PD patients and 2,931 healthy controls. We initially identified potentially pathogenic variants of dystonia-related genes in patients with PD based on different inheritance models. Sequence kernel association tests were conducted in the next step to detect the association between the burden of rare variants and the risk for PD. Results: We found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including COL6A3 and TH. Additionally, we identified 180 deleterious variants in dominant dystonia-related genes based on computational pathogenicity predictions and four of which were considered as potentially pathogenic variants (p.W591X and p.G820S in ANO3, p.R678H in ADCY5, and p.R458Q in SLC2A1). A gene-based burden analysis revealed the increased burden of variant subgroups of TH, SQSTM1, THAP1, and ADCY5 in sporadic early-onset PD, whereas COL6A3 was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction. Conclusion: Our findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of COL6A3 and TH genes in PD is highlighted.

Characteristics of fatigue in Parkinson's disease: A longitudinal cohort study.

Objective: To assess the prevalence, evolution, clinical characteristics, correlates and predictors of fatigue as well as to investigate the influence of comorbid fatigue on the longitudinal changes in motor and non-motor symptoms over a 2-year longitudinal follow-up period in a large cohort of patients with Parkinson's disease (PD). Materials and methods: A total of 2,100 PD patients were enrolled from the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC), and their motor and non-motor symptoms were assessed biennially using comprehensive scales, including the 16-item Parkinson Fatigue Scale (PFS-16). Each PD patient was categorized as PD with or without fatigue on the basis of a cut-off mean PFS-16 score of 3.3. Results: The prevalence of fatigue in our cohort was 36.8%. Compared to PD patients without fatigue, PD patients with fatigue were more likely to be older, have a longer disease duration, and higher baseline levodopa equivalent daily dose (all p < 0.05). Moreover, PD patients with fatigue showed more severe motor and non-motor phenotypes than those without fatigue. Overall, high total Unified Parkinson's Disease Rating Scale (UPDRS) score (odds ratio [OR] = 1.016, 95% confidence interval [CI]: 1.009-1.024), Non-Motor Symptoms Scale score (OR = 1.022, 95% CI: 1.015-1.029), postural instability and gait difficulty (PIGD) subtype (OR = 1.586, 95% CI: 1.211-2.079), presence of excessive daytime sleepiness (EDS; OR = 1.343, 95% CI: 1.083-1.666), and wearing-off (OR = 1.282, 95% CI: 1.023-1.607) were significantly associated with fatigue in PD patients (all p < 0.05). High total UPDRS score at baseline (OR = 1.014, 95% CI: 1.002-1.027, p = 0.028) increased the risk of developing fatigue during follow-up. Although significant, the odds ratios were low and confidence intervals were narrow. Analysis of disease progression showed significant group differences in motor and non-motor symptoms. In comparison with the never-fatigue group, the persistent-fatigue group showed significantly greater progression in motor, autonomic dysfunction, sleep, depression and cognitive symptoms (all p < 0.05). Conclusion: Increased disease severity, presence of the PIGD subtype, EDS, and wearing-off were associated with fatigue in PD patients. Significant subgroup-level differences were observed in the progression of motor and non-motor symptoms across different fatigue subgroups of PD patients.

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population.

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (Pcombined = 1.47 × 10-9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10-8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (rb) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14-0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (rg = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.

Evaluating the Genetic Role of Circadian Clock Genes in Parkinson's Disease.

Increasing evidence suggests that circadian dysfunction is related to Parkinson's disease (PD). However, the role of circadian clock genes in PD is still poorly understood. This study aimed to illustrate the association between genetic variants of circadian clock genes and PD in a large Chinese population cohort. Ten circadian clock genes were included in this study. Whole-exome sequencing (WES) was conducted in 1997 early-onset or familial PD patients and 1652 controls (WES cohort), and whole-genome sequencing (WGS) was conducted in 1962 sporadic late-onset PD patients and 1279 controls (WGS cohort). Analyses were completed using the optimized sequence kernel association test and regression analyses. In the burden analysis of the circadian clock gene set, we found suggestive significant associations between the circadian clock genes and PD in the WES cohort when considering missense, damaging missense (Dmis), and deleterious variants. Moreover, the burden analysis of single genes revealed suggestive significant associations between PD and the loss-of-function variants of the CRY1 gene, missense, Dmis, and deleterious variants of the PER1 gene, and Dmis and deleterious variants of the PER2 gene in the WES cohort. Rare variants in the WGS cohort and all common variants in the WGS and WES cohorts were unrelated to PD. Phenotypic analysis indicated that deleterious variants of the PER1 gene were associated with dyskinesia in the WES cohort. Our study provides evidence of a potential link between circadian clock genes and PD from a genetic perspective.

Subtyping of early-onset Parkinson's disease using cluster analysis: A large cohort study.

Background: Increasing evidence suggests that early-onset Parkinson's disease (EOPD) is heterogeneous in its clinical presentation and progression. Defining subtypes of EOPD is needed to better understand underlying mechanisms, predict disease course, and eventually design more efficient personalized management strategies. Objective: To identify clinical subtypes of EOPD, assess the clinical characteristics of each EOPD subtype, and compare the progression between EOPD subtypes. Materials and methods: A total of 1,217 patients were enrolled from a large EOPD cohort of the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) between January 2017 and September 2021. A comprehensive spectrum of motor and non-motor features were assessed at baseline. Cluster analysis was performed using data on demographics, motor symptoms and signs, and other non-motor manifestations. In 454 out of total patients were reassessed after a mean follow-up time of 1.5 years to compare progression between different subtypes. Results: Three subtypes were defined: mild motor and non-motor dysfunction/slow progression, intermediate and severe motor and non-motor dysfunction/malignant. Compared to patients with mild subtype, patients with the severe subtype were more likely to have rapid eye movement sleep behavior disorder, wearing-off, and dyskinesia, after adjusting for age and disease duration at baseline, and showed a more rapid progression in Unified Parkinson's Disease Rating Scale (UPDRS) total score (P = 0.002), UPDRS part II (P = 0.014), and III (P = 0.001) scores, Hoehn and Yahr stage (P = 0.001), and Parkinson's disease questionnaire-39 item version score (P = 0.012) at prospective follow-up. Conclusion: We identified three different clinical subtypes (mild, intermediate, and severe) using cluster analysis in a large EOPD cohort for the first time, which is important for tailoring therapy to individuals with EOPD.

Sensitivity of Sniffer Dogs for a Diagnosis of Parkinson's Disease: A Diagnostic Accuracy Study.

BACKGROUND: The diagnostic criteria for Parkinson's disease (PD) remain complex, which is especially problematic for nonmovement disorder experts. A test is required to establish a diagnosis of PD with improved accuracy and reproducibility. OBJECTIVE: The study aimed to investigate the sensitivity and specificity of tests using sniffer dogs to diagnose PD. METHODS: A prospective, diagnostic case-control study was conducted in four tertiary medical centers in China to evaluate the accuracy of sniffer dogs to distinguish between 109 clinically established medicated patients with PD, 654 subjects without PD, 37 drug-naïve patients with PD, and 185 non-PD controls. The primary outcomes were sensitivity and specificity of sniffer dog's identification. RESULTS: In the study with patients who were medicated, when two or all three sniffer dogs yielded positive detection results in a sample tested, the index test sensitivity, specificity, and positive and negative likelihood ratios were 91% (95% CI: 84%-96%), 95% (95% CI: 93%-97%), and 19.16 (95% CI: 13.52-27.16) and 0.10 (95% CI: 0.05-0.17), respectively. The corresponding sensitivity, specificity, and positive and negative likelihood ratios in patients who were drug-naïve were 89% (95% CI: 75%-96%), 86% (95% CI: 81%-91%), and 6.6 (95% CI: 4.51-9.66) and 0.13 (95% CI: 0.05-0.32), respectively. CONCLUSIONS: Tests using sniffer dogs may be a useful, noninvasive, fast, and cost-effective method to identify patients with PD in community screening and health prevention checkups as well as in neurological practice. © 2022 International Parkinson and Movement Disorder Society.

Constructing prediction models for excessive daytime sleepiness by nomogram and machine learning: A large Chinese multicenter cohort study.

Objective: Although risk factors for excessive daytime sleepiness (EDS) have been reported, there are still few cohort-based predictive models for EDS in Parkinson's disease (PD). This 1-year longitudinal study aimed to develop a predictive model of EDS in patients with PD using a nomogram and machine learning (ML). Materials and methods: A total of 995 patients with PD without EDS were included, and clinical data during the baseline period were recorded, which included basic information as well as motor and non-motor symptoms. One year later, the presence of EDS in this population was re-evaluated. First, the baseline characteristics of patients with PD with or without EDS were analyzed. Furthermore, a Cox proportional risk regression model and XGBoost ML were used to construct a prediction model of EDS in PD. Results: At the 1-year follow-up, EDS occurred in 260 of 995 patients with PD (26.13%). Baseline features analysis showed that EDS correlated significantly with age, age of onset (AOO), hypertension, freezing of gait (FOG). In the Cox proportional risk regression model, we included high body mass index (BMI), late AOO, low motor score on the 39-item Parkinson's Disease Questionnaire (PDQ-39), low orientation score on the Mini-Mental State Examination (MMSE), and absence of FOG. Kaplan-Meier survival curves showed that the survival prognosis of patients with PD in the high-risk group was significantly worse than that in the low-risk group. XGBoost demonstrated that BMI, AOO, PDQ-39 motor score, MMSE orientation score, and FOG contributed to the model to different degrees, in decreasing order of importance, and the overall accuracy of the model was 71.86% after testing. Conclusion: In this study, we showed that risk factors for EDS in patients with PD include high BMI, late AOO, a low motor score of PDQ-39, low orientation score of MMSE, and lack of FOG, and their importance decreased in turn. Our model can predict EDS in PD with relative effectivity and accuracy.

Association of rare PPARGC1A variants with Parkinson's disease risk.

BACKGROUND: Recent researches on Parkinson's disease (PD) pathogenesis discovered the correlation between PD and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) dysfunction and reduction of PPARGC1A gene expression. Hence, we detected PPARGC1A rare variants to clarify their effect on PD risk in a large population of PD patients in mainland China. METHODS: We applied whole-exome sequencing (WES) to 1917 patients with early-onset or familial PD and 1652 controls (WES cohort), and whole-genome sequencing (WGS) to 1962 patients with sporadic late-onset PD and 1279 controls (WGS cohort). To identify PPARGC1A rare variants, we used burden analysis to assess the relationship between PPARGC1A rare variants and PD susceptibility. RESULTS: 30 rare missense variants in the cohort WES and 21 missense variants in the cohort WGS have been detected in the study and PPARGC1A missense variants are significantly associated with early-onset and familial PD susceptibility in our study (P = 0.012), which supports evidence that PPARGC1A rare variants are involved in the onset of early-onset and familial PD. CONCLUSIONS: The study suggested that PPARGC1A rare variants may contribute to the risk of early-onset and familial PD.

Genetic Analysis of Six Transmembrane Protein Family Genes in Parkinson's Disease in a Large Chinese Cohort.

Objectives: Parkinson's disease (PD) is a neurodegenerative disorder with the manifestation of motor symptoms and non-motor symptoms. Previous studies have indicated the role of several transmembrane (TMEM) protein family genes in PD pathogenesis. Materials and Methods: In order to better investigate the genetic role of PD-related TMEM protein family genes in PD, including TMEM230, TMEM59, TMEM108, TMEM163, TMEM175, and TMEM229B, 1,917 sporadic early onset PD (sEOPD) or familial PD (FPD) patients and 1,652 healthy controls were analyzed by whole-exome sequencing (WES) while 1,962 sporadic late-onset PD (sLOPD) and 1,279 healthy controls were analyzed by whole-genome sequencing (WGS). Rare and common variants for each gene were included in the analysis. Results: One hundred rare damaging or loss of function variants of six genes were found at the threshold of MAF < 0.1%. Three rare Dmis variants of TMEM230 were specifically identified in PD. Rare missense variants of TMEM59 were statistically significantly associated with PD in the WES cohort, indicating the role of TMEM59 in FPD and sEOPD. Rare missense variants of TMEM108 were suggestively associated with PD in the WGS cohort, indicating the potential role of TMEM108 in sLOPD. The rare variant of the other three genes and common variants of six genes were not significantly associated with PD. Conclusion: We performed a large case-control study to systematically investigate the role of several PD-related TMEM protein family genes in PD. We identified three PD-specific variants in TMEM230, the significant association of TMEM59 with FPD, and sEOPD and the suggestive association of TMEM108 with sLOPD.

Genetic Analysis of HSP40/DNAJ Family Genes in Parkinson's Disease: a Large Case-Control Study.

Molecular chaperones were reported to play an important role in PD pathogenesis. Recent studies revealed the association of several HSP40/DNAJ family genes with PD, but no genetic analysis of all the DNAJ family genes in PD has been conducted. To systematically analyze the genetic impact of all the DNAJ family genes in PD, we performed genetic analysis for these genes in a large case-control study. We analyzed the rare variants in 49 DNAJ family genes from 3879 PD patients and 2931 healthy controls by whole-exome sequencing and whole-genome sequencing. All rare missense variants and the subgroups of rare damaging missense (Dmis) and loss-of-function (LoF) variants were gathered to test the accumulated association of these variants in each gene with PD. In total, 1617 rare nonsynonymous variants of DNAJ family genes with minor allele frequency less than 1% were identified in our cohort. We identified 82 rare missense variants for DNAJC26 in sporadic early-onset PD (sEOPD) or familial PD (FPD), and 17 Dmis and one LoF variant were detected among them. Gene-based burden analysis showed that the rare Dmis variants alone or Dmis plus LoF variants together of DNAJC26 were significantly enriched in PD patients. We also found suggestive associations of DNAJB2 and DNAJC18 with PD in sEOPD or FPD and DNAJC2, DNAJC10, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 with PD in sporadic late-onset PD. In conclusion, rare missense variants of DNAJC26 were significantly enriched in FPD or sEOPD. Moreover, DNAJB2, DNAJC2, DNAJC10, DNAJC18, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 were suggestively associated with PD.

The Chinese Parkinson's Disease Registry (CPDR): Study Design and Baseline Patient Characteristics.

BACKGROUND: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. OBJECTIVES: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross-sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. METHODS: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face-to-face interviews biennially. RESULTS: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD-MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early-onset PD (EOPD, age at onset ≤50 years) and late-onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa-induced dyskinesias in women. CONCLUSIONS: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society.

Characteristics of Autonomic Dysfunction in Parkinson's Disease: A Large Chinese Multicenter Cohort Study.

Autonomic dysfunction (AutD) is one of the non-motor symptoms (NMSs) in Parkinson's disease (PD). To investigate the prevalence and clinical features of AutD in Chinese patients with PD, a large multicenter cohort of 2,556 individuals with PD were consecutively involved in the Parkinson's Disease and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) between January 1, 2017, and December 31, 2019. The assessment of AutD was performed using the Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT). The evaluation of motor symptoms and other NMSs were performed using well-established scales recommended by the Movement Disorder Society. We found that out of 2,556 patients with PD, 2,333 patients with PD (91.28%) had AutD. Compared with the group of patients with PD without AutD, the group of patients with PD with AutD had older age, older age of onset, longer disease duration, more severe motor symptoms, motor complications, and more frequent NMSs. As for partial correlation analysis, the total SCOPA-AUT score was significantly and positively associated with motor severity scales [Unified Parkinson's Disease Rating Scale (UPDRS) total score] and some of the NMSs [Rapid Eye Movement Sleep Behavior Disorder Questionnaire (RBD), Epworth Sleepiness Scale, Hamilton Depression Scale], Fatigue Severity Scale, and Parkinson's disease questionnaire. PD Sleep Scale was significantly and negatively correlated with AutD. With logistic regression analysis for potentially related factors, age, UPDRS total score, RBD, hyposmia, depression, and fatigue may be associated with PD with AutD. In conclusion, our multicenter cohort study reported the high prevalence of AutD in Chinese PD and revealed the associated factors of PD with AutD.

Study on the Clinical Features of Parkinson's Disease With Probable Rapid Eye Movement Sleep Behavior Disorder.

Objective: To investigate the clinical features and factors associated with Parkinson's disease (PD) patients with probable rapid eye movement sleep behavior disorder (PD-pRBD). Methods: A total of 2,440 patients with clinically established or clinically probable PD were divided into two groups: PD-pRBD and PD without pRBD (PD-NRBD), according to the RBD questionnaire-Hong Kong. Data collection included demographic data, basic clinical history, and motor and non-motor symptoms. Based on the onset time of pRBD and the motor symptoms in PD, PD-pRBD patients were further divided into the pRBD prior to PD (PD-prRBD) group and the pRBD posterior to PD (PD-poRBD) group. Clinical features were compared between the PD-pRBD and PD-NRBD groups, as well as the PD-prRBD and PD-poRBD groups. The associated factors of pRBD were also explored. Results: The prevalence of pRBD was 41.4% (1,010 out of the total of 2,440) in our PD cohort. Further, compared with the PD-NRBD group, the PD-pRBD group had longer disease duration and more severe motor symptoms. Moreover, the PD-pRBD group had significantly higher levodopa equivalent daily dose and a higher ratio of dyskinesia, wearing-off, and offset of the Hoehn-Yahr stage. The scores on the non-motor symptom rating scale (NMSS), cognitive impairment, Parkinson's disease sleep scale (PDSS), excessive daytime sleepiness, constipation, hyposmia, depression, and the 39-item Parkinson's disease questionnaire also appeared worse in the PD-pRBD group. Significant differences in the educational level, disease duration, disease progression, Unified Parkinson's Disease Rating Scale (UPDRS)-II, UPDRS-III, tremor, rigidity, bradykinesia, posture gait, frozen gait, levodopa equivalent daily dose, dyskinesia, wearing-off, Hoehn-Yahr stage, NMSS-6, PDSS, and communication score widely existed between the PD-prRBD and PD-poRBD groups. Late-onset PD, long disease duration, high UPDRS-I score, high NMSS-4 score, low PDSS score, constipation, and hyposmia were all identified as the risk factors for PD-pRBD. Conclusions: Compared with the PD-NRBD group, the PD-pRBD group may have more severe motor symptoms, motor complications, and non-motor symptoms as well as a substandard quality of life. Further, late-onset PD, long disease duration, high UPDRS-I score, high NMSS-4 score, low PDSS score, constipation, and hyposmia can be risk factors for RBD in PD. Differences also occurred between the PD-prRBD and PD-poRBD groups.