Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS. METHODS: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis. RESULTS: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128). CONCLUSION: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.

Genetic Modifiers of Age at Onset for Amyotrophic Lateral Sclerosis: A Genome-Wide Association Study.

OBJECTIVE: Age at onset (AAO) is an essential clinical feature associated with disease progression and mortality in amyotrophic lateral sclerosis (ALS). Identification of genetic variants and environmental risk factors influencing AAO of ALS could help better understand the disease's biological mechanism and provide clinical guidance. However, most genetic studies focused on the risk of ALS, while the genetic background of AAO is less explored. This study aimed to identify genetic and environmental determinants for AAO of ALS. METHODS: We performed a genome-wide association analysis using a Cox proportional hazards model on AAO of ALS in 10,068 patients. We further conducted colocalization analysis and in-vitro functional exploration for the target variants, as well as Mendelian randomization analysis to identify risk factors influencing AAO of ALS. RESULTS: The total heritability of AAO of ALS was ~0.16 (standard error [SE] = 0.03). One novel locus rs2046243 (CTIF) was significantly associated with earlier AAO by ~1.29 years (p = 1.68E-08, beta = 0.10, SE = 0.02). Functional exploration suggested this variant was associated with increased expression of CTIF in multiple tissues including the brain. Colocalization analysis detected a colocalization signal at the locus between AAO of ALS and expression of CTIF. Causal inference indicated higher education level was associated with later AAO. INTERPRETATION: These findings improve the current knowledge of the genetic and environmental etiology of AAO of ALS, and provide a novel target CTIF for further research on ALS pathogenesis and potential therapeutic options to delay the disease onset. ANN NEUROL 2023;94:933-941.

Mutation screening of SPTLC1 and SPTLC2 in amyotrophic lateral sclerosis.

BACKGROUND: Recently, several rare variants of SPTLC1 were identified as disease cause for juvenile amyotrophic lateral sclerosis (ALS) by disrupting the normal homeostatic regulation of serine palmitoyltransferase (SPT). However, further exploration of the rare variants in large cohorts was still necessary. Meanwhile, SPTLC2 plays a similar role as SPTLC1 in the SPT function. METHODS: To explore the genetic role of SPTLC1 and SPTLC2 in ALS, we analyzed the rare protein-coding variants in 2011 patients with ALS and 3298 controls from the Chinese population with whole exome sequencing. Fisher's exact test was performed between each variant and disease risk, while at gene level over-representation of rare variants in patients was examined with optimized sequence kernel association test (SKAT-O). RESULTS: Totally 33 rare variants with minor allele frequency < 0.01 were identified, including 17 in SPTLC1 and 16 in SPTLC2. One adult-onset patient carried the variant p.E406K (SPTLC1) which was reported in previous study. Additionally, three adult-onset patients carried variants in the same amino acids as the variants identified in previous studies (p.Y509C, p.S331T, and p.R239Q in SPTLC1). At gene level, rare variants of SPTLC1 and STPLC2 were not enriched in patients. CONCLUSION: These results broadened the variant spectrum of SPTLC1 and SPTLC2 in ALS, and paved the way for future research. Further replication was still needed to explore the genetic role of SPTLC1 in ALS.

Systemic inflammation and risk of Parkinson's disease: A prospective cohort study and genetic analysis.

BACKGROUND: Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. METHODS: Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. RESULTS: A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. CONCLUSIONS: Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

Motor progression marker for newly diagnosed drug-naïve patients with Parkinson's disease: A resting-state functional MRI study.

The effective early prediction of clinical outcomes of Parkinson's disease (PD) is of great significance in the implementation of appropriate interventions. We aimed to propose a method based on the use of baseline resting-state functional characteristics (i.e., fractional amplitude of low-frequency fluctuations, fALFF) to predict motor progression in PD patients. Resting-state functional magnetic resonance imaging was performed on 48 newly-diagnosed drug-naïve PD patients and 27 age- and sex- matched healthy controls (HCs). Two PD subgroups were defined with different annual increase of Unified PD Rating Scale Part III motor scores. Least absolute shrinkage and selection operator regression analysis was performed to explore the baseline region-functional indicators for PD discrimination as well as the predictors for future motor deficits. Two significant models composed of baseline fALFF values from cerebral subregions were proposed. The classification model that distinguished PD patients from HCs (area under the curve [AUC] = 0.897) showed the most significant imaging characteristics in the putamen and precentral gyrus. The other prediction model that evaluated the degree of future deterioration of motor symptoms in PD patients (AUC = 0.916) showed the most significant imaging characteristics in the superior occipital gyrus and caudate nucleus. Furthermore, the increased regional function in bilateral caudate nuclei was correlated with the lower annual increase in motor deficits in all PD patients. The caudate nucleus might be the core region responsible for future motor deficits in newly-diagnosed PD patients, which may aid the development of disease progression preventive strategies in clinical practice.

Longitudinal evolution of sleep disturbances in early multiple system atrophy: a 2-year prospective cohort study.

BACKGROUND: The progression of sleep disturbances remains unclear in patients with early multiple system atrophy (MSA). We aimed to explore the frequency, severity, and coexistence of 2-year longitudinal changes of sleep disturbances including REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and Parkinson's disease-related sleep problems (PD-SP) in early MSA. METHODS: MSA patients with a disease duration < 3 years were enrolled to complete a 2-year follow-up visit. Sleep disturbances including RBD, EDS, and PD-SP were assessed using the RBD Screening Questionnaire, Epworth sleepiness scale, and PD sleep scale-2, respectively. RESULTS: A total of 220 patients with MSA enrolled in the study and 90 patients completed the 2-year follow-up visit. The score of all three sleep disturbances significantly increased over the 2-year follow-up in MSA and MSA with the predominant parkinsonism group (all p < 0.05). The frequency of PD-SP (from 14.5 to 26.7%) and EDS (from 17.7 to 37.8%) was progressively increased (all p < 0.05) except for RBD (from 51.8 to 65.6%, p = 0.152) over the 2-year follow-up in MSA. The frequency of coexistence of two or three sleep disturbances also increased over time. The most common sleep disturbance was RBD, followed by EDS and PD-SP over the 2-year follow-up. CONCLUSIONS: The present study demonstrated that the frequency of different types of sleep disturbances progressively increased except for RBD and the coexistence of two or three sleep disturbances became more common over time in early MSA. Our study suggested that the assessment and management of sleep disturbances should begin early in MSA.

Plasma glial fibrillary acidic protein as a biomarker of disease progression in Parkinson's disease: a prospective cohort study.

BACKGROUND: Reactive astrogliosis has been demonstrated to have a role in Parkinson's disease (PD); however, astrocyte-specific plasma glial fibrillary acidic protein (GFAP)'s correlation with PD progression remains unknown. We aimed to determine whether plasma GFAP can monitor and predict PD progression. METHODS: A total of 184 patients with PD and 95 healthy controls (HCs) were included in this prospective cohort study and followed-up for 5 years. Plasma GFAP, amyloid-beta (Aß), p-tau181, and neurofilament light chain (NfL) were measured at baseline and at 1- and 2-year follow-ups. Motor and non-motor symptoms, activities of daily living, global cognitive function, executive function, and disease stage were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) part III, UPDRS-I, UPDRS-II, Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), and Hoehn and Yahr (H&Y) scales at each visit, respectively. RESULTS: Plasma GFAP levels were higher in patients with PD (mean [SD]: 69.80 [36.18], pg/mL) compared to HCs (mean [SD]: 57.89 [23.54], pg/mL). Higher levels of GFAP were observed in female and older PD patients. The adjusted linear mixed-effects models showed that plasma GFAP levels were significantly associated with UPDRS-I scores (ß: 0.006, 95% CI [0.001-0.011], p = 0.027). Higher baseline plasma GFAP correlated with faster increase in UPDRS-I (ß: 0.237, 95% CI [0.055-0.419], p = 0.011) and UPDRS-III (ß: 0.676, 95% CI [0.023-1.330], p = 0.043) scores and H&Y stage (ß: 0.098, 95% CI [0.047-0.149], p < 0.001) and faster decrease in MoCA (ß: - 0.501, 95% CI [- 0.768 to - 0.234], p < 0.001) and FAB scores (ß: - 0.358, 95% CI [- 0.587 to - 0.129], p = 0.002). Higher baseline plasma GFAP predicted a more rapid progression to postural instability (hazard ratio: 1.009, 95% CI [1.001-1.017], p = 0.033). CONCLUSIONS: Plasma GFAP might be a potential biomarker for monitoring and predicting disease progression in PD.

Cross-Ethnic Variant Screening and Burden Analysis of PTPA in Parkinson's Disease.

BACKGROUND: Recently, homozygous variants in PTPA were identified as the disease cause for two pedigrees with early-onset parkinsonism and intellectual disability. Although the initial link between PTPA and parkinsonism has been established, further replication was still necessary. OBJECTIVES: To evaluate the genetic role of PTPA in Parkinson's disease (PD). METHODS: We analyzed rare variants of PTPA in cohorts of Asian and European ancestries (Ncase = 2743, Ncontrol = 8177) with whole-exome sequencing, and further explored the functional effect of the target variant. RESULTS: One patient with early-onset PD from a consanguineous family carried the homozygous variant p.Met329Val, while her parents and elder sister with heterozygous p.Met329Val were healthy. This patient developed minor cognitive decline within 1 year, with a Montreal Cognitive Assessment (MoCA) score dropping from 28 to 25. Functional exploration with overexpression studies suggested that this variant was associated with decreased protein phosphatase 2A (PTPA) protein level by affecting protein stability, but not mRNA expression. CONCLUSIONS: These results have broadened the mutation spectrum of PTPA, and paved the way for further research into the role of PTPA in PD. © 2023 International Parkinson and Movement Disorder Society.

Lack of association of TP73 rare variants with amyotrophic lateral sclerosis in a Chinese cohort.

BACKGROUND: Recently, several rare variants of TP73 were identified as potential disease cause for amyotrophic lateral sclerosis (ALS) in the European population. However, further replication was still necessary, especially in cohorts with different ethnic backgrounds. METHODS: To explore the genetic role of TP73 in ALS in the Asian population, we analyzed the rare protein-coding variants in 2011 patients with ALS and 3298 controls with whole-exome sequencing. Fisher's exact test was performed between each variant and disease risk, while at gene level over-representation of rare variants in patients was examined with optimized sequence kernel association test. RESULTS: Totally 24 rare variants with minor allele frequency < 0.01 were identified, among which nine were absent in controls. One variant p.P335T was previously reported, and another three variants were in the same amino acids as the variants reported in previous studies (p.R36Q, p.R414Q, p.R78C). At gene level, rare variants of TP73 were not enriched in patients. CONCLUSIONS: Our findings did not support the genetic role of TP73 in ALS in the Chinese population. Replication of specific variants identified in patients from different cohorts might provide additional insight. The current results also broadened the mutation spectrum of TP73 and paved the way for further research.

TBK1 variants in Chinese patients with amyotrophic lateral sclerosis: Genetic analysis and clinical features.

BACKGROUND AND PURPOSE: Haploinsufficiency of TANK-binding kinase 1 (TBK1) loss-of-function (LoF) variants has been shown to be pathogenic in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the genetic spectrum of TBK1 and clinical features of ALS patients with TBK1 variants remain largely unknown in Asians. METHODS: Genetic analysis was performed on 2011 Chinese ALS patients. Software was used to predict the deleteriousness of missense variants in TBK1. In addition, PubMed, Embase and Web of Science were searched for related literature. RESULTS: Twenty-six TBK1 variants were identified in 33 of 2011 ALS patients, including six novel LoF variants (0.3%) and 20 rare missense variants, 12 of which were predicted to be deleterious (0.6%). In addition to TBK1 variants, 11 patients had other ALS-related gene variants. Forty-two previous studies found that the frequency of TBK1 variants was 1.81% in ALS/FTD patients. The frequency of TBK1 LoF variants in ALS was 0.5% (Asians 0.4%; Caucasian 0.6%) and that of missense variants was 0.8% (Asians 1.0%; Caucasian 0.8%). ALS patients with TBK1 LoF variants affecting the kinase domain had a significantly younger age of onset than patients carrying LoF variants affecting the coiled coil domains CCD1 and CCD2. FTD has a frequency of 10% in Caucasian ALS patients with TBK1 LoF variants, which was not found in our cohort. CONCLUSION: Our study expanded the genotypic spectrum of ALS patients with TBK1 variants and found that the clinical manifestations of TBK1 carriers are diverse.

Disrupted topological organization of resting-state functional brain networks in Parkinson's disease patients with glucocerebrosidase gene mutations.

PURPOSE: The mutations of the glucocerebrosidase (GBA) gene are the greatest genetic risk factor for Parkinson's disease (PD). The mechanism underlying the association between GBA mutations and PD has not been fully elucidated. METHODS: Using resting-state functional magnetic resonance imaging and graph theory analysis to investigate the disrupted topological organization in PD patients with GBA mutation (GBA-PD). Eleven GBA-PD patients, 11 noncarriers with PD, and 18 healthy controls (HCs) with a similar age and sex distribution were recruited. Individual whole-brain functional connectome was constructed, and the global and nodal topological disruptions were calculated among groups. Partial correlation analyses between the clinical features of patients with PD and topological alterations were performed. RESULTS: The GBA-PD group showed prominently decreased characteristic path length (Lp) and increased global efficiency (Eg) compared to HCs at the global level; a significantly increased nodal betweenness centrality in the medial prefrontal cortex (mPFC) and precuneus within the default mode network, and precentral gyrus within the sensorimotor network, while a significantly decreased betweenness centrality in nodes within the cingulo-opercular network compared to the noncarrier group at the regional level. The altered nodal betweenness centrality of mPFC was positively correlated with fatigue severity scale scores in all patients with PD. CONCLUSION: The preliminary pilot study found that GBA-PD patients had a higher functional integration at the global level. The nodal result of the mPFC is congruent with the potential fatigue pathology in PD and is suggestive of a profound effect of GBA mutations on the clinical fatigue in patients with PD.

Histone deacetylase inhibitor panobinostat in combination with rapamycin confers enhanced efficacy against triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for about 15% of diagnosed breast cancer patients, which has a poor survival outcome owing to a lack of effective therapies. This study aimed to explore the in vitro and in vivo efficiency of histone deacetylase (HDAC) inhibitor panobinostat (PANO) in combination with mTOR inhibitor rapamycin (RAPA) against TNBC. TNBC cells were treated with PANO, RAPA alone or the combination of drugs, then cell growth and apoptosis were evaluated by CCK-8, colony formation and flow cytometry. Cell migration and invasion were detected by wound healing assay and transwell assay, respectively. ROS production was detected by DCFH-DA staining. Western blotting was performed to detect protein levels. In vivo tumor growth was assessed in nude mice. The expression of cleaved caspase-3 and Ki-67 in tumor tissues was detected by immunofluorescence staining. H&E staining was conducted to observe the pathological changes in heart, liver, and kidney tissues. The combination of PANO and RAPA exerted a stronger role in repressing growth, migration, invasion, and inducing apoptosis of TNBC cells compared with monotherapy. Furthermore, this combination presented a more effective anti-cancer efficacy than a single treatment in the xenograft model without apparent toxic side effects. Importantly, mechanistic studies indicated that PANO and RAPA combination led to ROS overproduction, which subsequently activated endoplasmic reticulum stress. Conclusion: PANO in combination with RAPA exhibits enhanced efficacy against TNBC, which may be considered a promising therapeutic candidate.

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

A Multitask Network for People Counting, Motion Recognition, and Localization Using Through-Wall Radar.

Due to the outstanding penetrating detection performance of low-frequency electromagnetic waves, through-wall radar (TWR) has gained widespread applications in various fields, including public safety, counterterrorism operations, and disaster rescue. TWR is required to accomplish various tasks, such as people detection, people counting, and positioning in practical applications. However, most current research primarily focuses on one or two tasks. In this paper, we propose a multitask network that can simultaneously realize people counting, action recognition, and localization. We take the range-time-Doppler (RTD) spectra obtained from one-dimensional (1D) radar signals as datasets and convert the information related to the number, motion, and location of people into confidence matrices as labels. The convolutional layers and novel attention modules automatically extract deep features from the data and output the number, motion category, and localization results of people. We define the total loss function as the sum of individual task loss functions. Through the loss function, we transform the positioning problem into a multilabel classification problem, where a certain position in the distance confidence matrix represents a certain label. On the test set consisting of 10,032 samples from through-wall scenarios with a 24 cm thick brick wall, the accuracy of people counting can reach 96.94%, and the accuracy of motion recognition is 96.03%, with an average distance error of 0.12 m.

Genetic analysis of and clinical characteristics associated with ANXA11 variants in a Chinese cohort with amyotrophic lateral sclerosis.

BACKGROUND: Variants in the annexin A11 gene (ANXA11) have been reported to be associated with amyotrophic lateral sclerosis (ALS). These variants may be involved in the pathogenesis of ALS by causing defects in intracellular protein trafficking. However, the genetic spectrum and clinical characteristics of ALS patients with ANXA11 variants are largely unknown. METHODS: Genetic analysis was performed on 1587 Chinese patients with ALS. Eight software packages were used to predict the deleteriousness of missense variants. In addition, we searched PubMed, Embase, and Web of Science for relevant literature and meta-analysed variant frequencies. RESULTS: In our ALS cohort, we identified 20 non-synonymous variants in 29 ALS patients, including one stop-gain, one frameshift, and 18 rare missense variants with seven predicted pathogenic variants. In a literature review of 11 reported studies that included 69 patients, 37 ANXA11 variants were reported, with a frequency of 1.7%, which was similar to that in our cohort (1.8%). Both our cohort and previous reports showed that ANXA11 carriers were more commonly males than females (12/17 vs. 19/31). Patients carrying ANXA11 variants affecting the C-terminal of the protein had earlier disease onset and shorter survival times than those carrying variants affecting the N-terminal. We found a relatively longer median survival time than that previously reported (53.6 months vs. 46.0 months). Additionally, Caucasian ANXA11 carriers were more likely to have cognitive impairment, typically frontotemporal dementia (FTD) than their Asian counterparts (20.0% vs. 14.3%). While more than half of the patients in our cohort had cognitive impairment, none had FTD. CONCLUSION: In our and previously published cases, ALS-associated ANXA11 variants predominantly affected the N- and C-terminal conserved domains. ANXA11 variant carriers are typically male and cognitively impaired. Our study extends the genotypic and phenotypic spectra of ALS patients with ANXA11 variants. Further expansion of the sample size is needed to analyse the clinical and non-motor symptom characteristics of patients and to deepen the understanding of the pathogenesis of ANXA11-associated ALS.

Shared genetic links between frontotemporal dementia and psychiatric disorders.

BACKGROUND: Epidemiological and clinical studies have suggested comorbidity between frontotemporal dementia (FTD) and psychiatric disorders. FTD patients carrying specific mutations were at higher risk for some psychiatric disorders, and vice versa, implying potential shared genetic etiology, which is still less explored. METHODS: We examined the genetic correlation using summary statistics from genome-wide association studies and analyzed their genetic enrichment leveraging the conditional false discovery rate method. Furthermore, we explored the causal association between FTD and psychiatric disorders with Mendelian randomization (MR) analysis. RESULTS: We identified a significant genetic correlation between FTD and schizophrenia at both genetic and transcriptomic levels. Meanwhile, robust genetic enrichment was observed between FTD and schizophrenia and alcohol use disorder. Seven shared genetic loci were identified, which were mainly involved in interleukin-induced signaling, synaptic vesicle, and brain-derived neurotrophic factor signaling pathways. By integrating cis-expression quantitative trait loci analysis, we identified MAPT and CADM2 as shared risk genes. MR analysis showed mutual causation between FTD and schizophrenia with nominal association. CONCLUSIONS: Our findings provide evidence of shared etiology between FTD and schizophrenia and indicate potential common molecular mechanisms contributing to the overlapping pathophysiological and clinical characteristics. Our results also demonstrate the essential role of autoimmunity in these diseases. These findings provide a better understanding of the pleiotropy between FTD and psychiatric disorders and have implications for therapeutic trials.

Longitudinal evolution of motor and non-motor symptoms in early-stage multiple system atrophy: a 2-year prospective cohort study.

BACKGROUND: The progression of motor and non-motor symptoms (NMS) and the sensitivity of each item of the Unified Multiple System Atrophy Rating Scale (UMSARS) to change remain unclear in Chinese patients with early-stage multiple system atrophy (MSA). We investigated the evolution of motor symptoms and NMS in early-stage MSA and the sensitivity of each item included in the UMSARS to change over a 2-year follow-up. METHODS: Motor symptoms and NMS were recorded at baseline and at 1- and 2-year follow-ups based on the UMSARS and the NMS scale. Generalized estimating equation models were used. The sensitivity of an item included in the UMSARS to change was assessed by calculating a standardized effect using the mean annual change divided by the standard deviation of the change. RESULTS: We enrolled 246 consecutive patients with MSA and 97 MSA completed the 2-year follow-up. The mean total UMSARS score increased by 11.90 and 22.54 points at the 1- and 2-year follow-ups, respectively. UMSARS-I items associated with motor functions were more sensitive to change and those associated with autonomic dysfunction showed less sensitivity to change. Items 4 (tremor at rest), 5 (action tremor), and 3 (ocular motor dysfunction) of the UMSARS-II were less sensitive to change. The prevalence and severity of NMS significantly increased over the 2-year follow-up. CONCLUSIONS: We observed significant progression in motor symptoms and NMS in patients with early-stage MSA. Our results provide useful information to support the revision of the UMSARS.

Seconds-Scale Coherence on Nuclear Spin Transitions of Ultracold Polar Molecules in 3D Optical Lattices.

Ultracold polar molecules (UPMs) are emerging as a novel and powerful platform for fundamental applications in quantum science. Here, we report characterization of the coherence between nuclear spin levels of ultracold ground-state sodium-rubidium molecules loaded into a 3D optical lattice with a nearly photon scattering limited trapping lifetime of 9(1) seconds. After identifying and compensating the main sources of decoherence, we achieve a maximum nuclear spin coherence time of T_{2}^{*}=3.3(6) s with two-photon Ramsey spectroscopy. Furthermore, based on the understanding of the main factor limiting the coherence of the two-photon Rabi transition, we obtain a Rabi line shape with linewidth below 0.8 Hz. The simultaneous realization of long lifetime and coherence time, and ultrahigh spectroscopic resolution in our system unveils the great potentials of Ultracold polar molecules in quantum simulation, computation, and metrology.

Genetic Determinants of Survival in Parkinson's Disease in the Asian Population.

BACKGROUND: Patients with Parkinson's disease (PD) have reduced life expectancy compared to the general population. Genetic variation was shown to play a role in the heterogeneity of survival for patients with PD, although the underlying genetic background remains poorly studied. OBJECTIVE: The aim was to explore the genetic determinants influencing the survival of PD. METHODS: We performed a genome-wide association analysis using a Cox proportional hazards model in a longitudinal cohort of 1080 Chinese patients with PD. Furthermore, we built a clinical-genetic model to predict the survival of patients using clinical variables combined with polygenic risk score (PRS) of survival of PD. RESULTS: The cohort was followed up for an average of 7.13 years, with 85 incidents of death. One locus rs12628329 (RPL3) was significantly associated with reduced survival time by ~10.8 months (P = 2.72E-08, ß = 1.79, standard error = 0.32). Functional exploration suggested this variant could upregulate the expression of RPL3 and induce apoptosis and cell death. In addition, adding PRS of survival in the prediction model substantially improved survival predictability (concordance index [Cindex]: 0.936) compared with the clinical model (Cindex: 0.860). CONCLUSIONS: These findings improve the current understanding of the genetic cause of survival of PD and provide a novel target RPL3 for further research on PD pathogenesis and potential therapeutic options. Our results also demonstrate the potential utility of PRS of survival in identifying patients with shorter survival and providing personalized clinical monitoring and treatment. © 2022 International Parkinson and Movement Disorder Society.

Mutation Screening of TFG in α-Synucleinopathy and Amyotrophic Lateral Sclerosis.

BACKGROUND: Recently, p.R383H in TFG was identified as the disease cause in a family with α-synucleinopathy and amyotrophic lateral sclerosis (ALS). However, no further replication has been conducted in larger cohorts. OBJECTIVE: The aim was to explore the genetic role of TFG in α-synucleinopathy and ALS. METHODS: We analyzed the rare protein-coding variants in patients with Parkinson's disease (PD), ALS, multiple system atrophy (MSA), spastic paraplegia (N = 2709), and 7536 controls with whole-exome sequencing. RESULTS: Nine rare variants were identified in PD and two in MSA. One PD patient carried the same variant p.R383H. Similarly, this patient developed early-onset PD with bradykinesia and rigidity on the left side as the initial symptoms. However, at the gene level, rare variants of TFG were not enriched in patients. CONCLUSIONS: Rare variants of TFG were not enriched in α-synucleinopathy and ALS. However, we could not deny the potential pathogenicity of specific variants such as p.R383H. Further exploration is still necessary. © 2022 International Parkinson and Movement Disorder Society.