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.

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.

The impact of maternal smoking during pregnancy and the age of smoking initiation on incident dementia: A prospective cohort study.

INTRODUCTION: The impact of early-life tobacco exposure on dementia has remained unknown. METHODS: Using the UK Biobank, the associations of maternal smoking during pregnancy (MSDP) and age of smoking initiation (ASI) with the onset time of all-cause dementia were estimated with accelerated failure time models. The effects of MSDP and ASI on brain structure and their genetic correlation to Alzheimer's disease (AD) were analyzed. A Mendelian randomization (MR) analysis was conducted. RESULTS: The time ratios for smokers starting in childhood, adolescence, and adulthood (vs never smokers) were 0.87 (0.76 to 0.99), 0.92 (0.88 to 0.96), and 0.95 (0.89 to 1.01). MSDP and smoking in adolescence altered many brain regions, including the hippocampus. In genetic analysis, MSDP was genetically and causally linked to AD, and a younger ASI was genetically correlated to a higher AD risk. DISCUSSION: Early-life smoking accelerated dementia onset and was genetically correlated to AD. MSDP demonstrated genetic and causal linkage to AD risks. HIGHLIGHTS: Unlike the commonly used Cox proportional hazards model, this article uses a parametric survival analysis method - the accelerated failure model - to explore the relationship between exposure to onset time. It can be used as an alternative method when the proportional hazards assumption is not met. Genetic analyses including genetic correlation study and MR analysis and brain structure analyses were conducted to support our findings and explore the potential mechanisms. The study reveals the relationship between different smoking initiation periods and the onset time of dementia and shows that earlier smoking exposure has a more significant impact on dementia. It emphasizes the importance of preventing early smoking. In the future, more research focusing on the relationship between early exposure and dementia is called for to provide more detailed prevention measures for dementia that cover all age groups.

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.

Association between self-reported oral health and Parkinson's disease: evidence from UK biobank.

Objectives Oral health problem is prevalent in the elderly population which is also at high risk of Parkinson's disease (PD). However, the association between self-reported oral health and PD is still unclear. We aimed to explore the association between baseline self-reported oral health (mouth ulcers, painful gums, bleeding gums, loosen teeth, toothache, dentures) and future incidence of PD. Methods Participants were enrolled in the UK biobank from 2006 to 2010 and those without PD at baseline were included in the current study. We used Cox regression analysis to explore the question and adjusted for age, sex, body mass index, smoking, drinking, ethnicity, education, socioeconomic status, and average total household income before tax. Results We included 421180 participants with a mean age of 56.26 years old and 46.5% of them were male. And 2339 participants were diagnosed with PD in the follow-up. Mouth ulcers, loosen teeth, dentures, toothache, and bleeding gums were not related to the risk of PD. Painful gums were related to a higher risk of PD (HR: 1.39, 95%CI: 1.12-1.72, P = 0.003), and similar results were reached after adjusting for gene risk (HR: 1.39, 95%CI: 1.12-1.73, P = 0.003), or source of diagnosis (HR: 1.39, 95%CI: 1.12-1.72, P = 0.002), and time of diagnosis (HR: 1.29, 95%CI: 1.03-1.63, P = 0.02). Conclusions Our study has demonstrated a substantial correlation between painful gums and elevated susceptibility to PD, underscoring the potential advantages of implementing oral health interventions for decreasing the risk of PD.

Droplet Cas12a Assay Enables DNA Quantification from Unamplified Samples at the Single-Molecule Level.

DNA quantification is important for biomedical research, but the routinely used techniques rely on nucleic acid amplification which have inherent issues like cross-contamination risk and quantification bias. Here, we report a CRISPR-Cas12a-based molecular diagnostic technique for amplification-free and absolute quantification of DNA at the single-molecule level. To achieve this, we first screened out the optimal reaction parameters for high-efficient Cas12a assay, yielding over 50-fold improvement in sensitivity compared with the reported Cas12a assays. We further leveraged the microdroplet-enabled confinement effect to perform an ultralocalized droplet Cas12a assay, obtaining excellent specificity and single-molecule sensitivity. Moreover, we demonstrated its versatility and quantification capability by direct counting of diverse virus's DNAs (African swine fever virus, Epstein-Barr virus, and Hepatitis B virus) from clinical serum samples with a wide range of viral titers. Given the flexible programmability of crRNA, we envision this amplification-free technique as a versatile and quantitative platform for molecular diagnosis.

Improvement of temperature-induced spectrum characterization in a holographic sensor based on N-isopropylacrylamide photopolymer hydrogel: publisher's note.

This publisher's note amends the funding section in Appl. Opt.56, 9006 (2017)APOPAI0003-693510.1364/AO.56.009006.

Improvement of temperature-induced spectrum characterization in a holographic sensor based on N-isopropylacrylamide photopolymer hydrogel.

A novel thermo-sensitive N-isopropylacrylamide photopolymer was developed for improving the temperature and humidity responses of holographic sensors. Diffraction spectra of holographic volume gratings recorded in the materials were characterized to explore the sensing response capacity. A dependence of peak wavelength on the temperature was observed and provided a quantitative strategy for holographic sensing applications. Expansion of the humidity range induced a strong extension of wavelength shift. Finally, the temperature response reversibility was demonstrated experimentally. Our sensing results were completely different from the reported typical acrylamide polymer system. Compared with the former, we obtained a more sensitive temperature response and an evident shift expansion (>200 nm) at a relative humidity of 70% or higher. These results can obviously improve the thermo-sensitivity of a holographic sensor and expand the practical application area of the holographic sensing strategy.

Improvement of holographic sensing response in substrate-free acrylamide photopolymer.

A novel substrate-free acrylamide photopolymer was proposed to improve holographic sensing characterization. The diffraction spectrum response of reflection volume grating recorded in the medium was characterized for exploring the improvement of sensitivity. The compared result indicated that the response rate and sensitivity were evidently improved by absorption of double surface in substrate-free polymer. The thickness of the sample as a significant factor was discussed in detail experimentally. During the sensing process, the inhibition concentration and concentration constant of organic vapor were extracted to evaluate the significance of sample thickness. Simultaneously, optimization of thickness could be considered as an effective approach to improve the response rate of holographic sensing. The reversibility of a novel holographic sensor with double surface was demonstrated by recovery measurement. The swelling ratio indicated that the peak wavelength shift was attributed to the expansion of binder induced by absorption of organic vapor. Theoretically, the sensing physical mechanism and the dynamic swelling process were analyzed and simulated using a diffusional model with nonlocal response. These experimental results provide an effective strategy for improving the response of a holographic sensor and accelerate the development of the holographic optical element based on photopolymer.

Predictors for survival in patients with Alzheimer's disease: a large comprehensive meta-analysis.

The prevalence of Alzheimer's disease (AD) is increasing as the population ages, and patients with AD have a poor prognosis. However, knowledge on factors for predicting the survival of AD remains sparse. Here, we aimed to systematically explore predictors of AD survival. We searched the PubMed, Embase and Cochrane databases for relevant literature from inception to December 2022. Cohort and case-control studies were selected, and multivariable adjusted relative risks (RRs) were pooled by random-effects models. A total of 40,784 reports were identified, among which 64 studies involving 297,279 AD patients were included in the meta-analysis after filtering based on predetermined criteria. Four aspects, including demographic features (n = 7), clinical features or comorbidities (n = 13), rating scales (n = 3) and biomarkers (n = 3), were explored and 26 probable prognostic factors were finally investigated for AD survival. We observed that AD patients who had hyperlipidaemia (RR: 0.69) were at a lower risk of death. In contrast, male sex (RR: 1.53), movement disorders (including extrapyramidal signs) (RR: 1.60) and cancer (RR: 2.07) were detrimental to AD patient survival. However, our results did not support the involvement of education, hypertension, APOE genotype, Aß42 and t-tau in AD survival. Our study comprehensively summarized risk factors affecting survival in patients with AD, provided a better understanding on the role of different factors in the survival of AD from four dimensions, and paved the way for further research.

Sleep characteristics and risk of Alzheimer's disease: a systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Alzheimer's disease (AD) is on the rise in our aging society, making it crucial to identify additional risk factors to mitigate its increasing incidence. This systematic review and meta-analysis aimed to provide updated evidence regarding the association between sleep and AD. METHODS: We conducted a comprehensive search of MEDLINE, EMBASE, and Web of Science databases from inception to July 2023 to identify longitudinal studies. Adjusted relative risks were pooled for each sleep characteristic, and a dose-response analysis was performed specifically for sleep duration. RESULTS: A total of 15,278 records were initially retrieved, and after screening, 35 records were ultimately included in the final analysis. The results showed that insomnia (RR, 1.43; 95%CI, 1.17-1.74), sleep-disordered breathing (RR, 1.22; 95%CI, 1.07-1.39), as well as other sleep problems, including sleep fragmentation and sleep-related movement disorders, were associated with a higher risk of developing AD, while daytime napping or excessive daytime sleepiness (RR, 1.18; 95%CI, 1.00-1.40) only exhibited a trend toward a higher risk of AD development. Furthermore, our analysis revealed a significant association between self-reported sleep problems (RR, 1.34; 95%CI, 1.26-1.42) and the incidence of AD, whereas this association was not observed with sleep problems detected by objective measurements (RR, 1.14; 95%CI, 0.99-1.31). Moreover, both quite short sleep duration (< 4 h) and long duration (> 8 h) were identified as potential risk factors for AD. CONCLUSIONS: Our study found the association between various types of sleep problems and an increased risk of AD development. However, these findings should be further validated through additional objective device-based assessments. Additional investigation is required to establish a definitive causal connection between sleep problems and AD.

Rare DNAJC7 Variants May Play a Minor Role in Chinese Patients with ALS.

DnaJ heat shock protein family member C7 gene (DNAJC7) has been identified as a genetic risk factor for amyotrophic lateral sclerosis (ALS). In our study, we aimed to screen for rare variants in DNAJC7 in a large cohort of Chinese ALS patients, and investigate the genotype-phenotype correlation of DNAJC7 in ALS. Four (0.19%) variants of DNAJC7 with minor allele frequency (MAF) < 0.1% among 2124 patients were identified, including 1 protein-truncating variant and 3 missense variants, all of which were predicted to be damaging. The patients carrying variants of DNAJC7 in our cohort tented to have a limb onset and a relatively slow disease progression. However, burden analysis did not show an enrichment of rare damaging variants in ALS patients compared to controls. Further analysis involving diverse regions and larger sample size is necessary to elucidate the role of DNAJC7 in the pathogenicity of ALS.

Rare variant analysis of UQCRC1 in Chinese patients with early-onset Parkinson's disease.

Mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene has been identified as a causative gene for autosomal dominant Parkinson's disease (PD), with the p.Y314S variant potentially associated with polyneuropathy in PD patients. The objectives of our study were to screen for UQCRC1 variants in Chinese patients with early-onset PD (EOPD) and explore the role of UQCRC1 in EOPD. We investigated the rare variants in 913 EOPD patients in our cohort using whole-exome sequencing, assessing their link to PD at both allele and gene levels. A total of 7 rare variants (minor allele frequency < 0.1%) of UQCRC1 were identified. However, no excessive burden of rare UQCRC1 variants was suggested in the EOPD patients. Further analysis with larger sample size and diverse regions is needed to determine the role of UQCRC1 in PD.

Genome-wide DNA methylation analysis related to ALS patient progression and survival.

BACKGROUND: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients. METHODS: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted. RESULTS: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = - 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006). CONCLUSION: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.

Clinical and genetic characteristics of ALS patients with variants in genes regulating DNA methylation.

BACKGROUND: Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS. METHODS: Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival. RESULTS: A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039). CONCLUSIONS: This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS.

Plasma GFAP as a prognostic biomarker of motor subtype in early Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous movement disorder with different motor subtypes including tremor dominant (TD), indeterminate and postural instability, and gait disturbance (PIGD) motor subtypes. Plasma glial fibrillary acidic protein (GFAP) was elevated in PD patients and may be regarded as a biomarker for motor and cognitive progression. Here we explore if there was an association between plasma GFAP and different motor subtypes and whether baseline plasma GFAP level can predict motor subtype conversion. Patients with PD classified as TD, PIGD or indeterminate subtypes underwent neurological evaluation at baseline and 2 years follow-up. Plasma GFAP in PD patients and controls were measured using an ultrasensitive single molecule array. The study enrolled 184 PD patients and 95 control subjects. Plasma GFAP levels were significantly higher in the PIGD group compared to the TD group at 2-year follow-up. Finally, 45% of TD patients at baseline had a subtype shift and 85% of PIGD patients at baseline remained as PIGD subtypes at 2 years follow-up. Baseline plasma GFAP levels were significantly higher in TD patients converted to PIGD than non-converters in the baseline TD group. Higher baseline plasma GFAP levels were significantly associated with the TD motor subtype conversion (OR = 1.283, P = 0.033) and lower baseline plasma GFAP levels in PIGD patients were likely to shift to TD and indeterminate subtype (OR = 0.551, P = 0.021) after adjusting for confounders. Plasma GFAP may serve as a clinical utility biomarker in differentiating motor subtypes and predicting baseline motor subtypes conversion in PD patients.

Restless legs syndrome and cognitive function among adults: a systematic review and meta-analysis.

BACKGROUND: Changes in the cognitive function of patients with restless legs syndrome is a growing area of research. Although several studies have been performed to investigate the association between restless legs syndrome (RLS) and cognitive function, the outcomes are still controversial. The meta-analysis aimed to elucidate the relationship between RLS and cognition, including global cognition and various cognitive domains including memory, attention, executive function, and spatial cognition. METHODS: We searched the MEDLINE, EMBASE, and Web of Science databases from inception to November 2022 to screen eligible records. The means and standard deviations of cognitive test scores were obtained to calculate the standard mean difference and 95% confidence intervals. RESULTS: A total of 1437 records were collected from the initial search and 16 records involving 4635 individuals were ultimately included in the systematic review and meta-analysis. Our data suggest negative associations between RLS and global cognition (SMD, - 0.42; 95% CI - 0.72 to - 0.11; I2 = 76.6%) and attention (SMD, - 0.43; 95% CI - 0.73 to - 0.12; I2 = 85.3%). No significant differences in memory (SMD, - 0.01; 95% CI - 0.31 to 0.28; I2 = 68.0%), executive function (SMD, - 0.10; 95% CI, - 0.30 to 0.11; I2 = 52.1%), or spatial cognition (SMD, - 0.17; 95% CI - 0.38 to 0.03; I2 = 58.5%) were observed between the RLS and control groups. Moreover, the strength of the results was modified by age but not by sex or region. CONCLUSIONS: Our findings suggest that RLS is negatively correlated with cognitive function, particularly global cognition and attention. However, the causal relationship, considering more confounders, is worthy of further exploration.

Physical activity as risk factor in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with rapid progression and high mortality. Physical activity (PA) has been identified as a major risk factor for ALS. However, the results across studies are still controversial. We aimed to explore the association between different types of PA and ALS. METHODS: The PubMed, EMBASE, Cochrane and Web of Science databases were systematically searched for case-control and cohort studies which explored the relationship between PA and ALS from inception to October 2022. The data were analyzed to generate a pooled effect and 95% confidence interval (CI). RESULTS: A total of 16,686 articles were included in the systematic search. After filtering, 28 studies from online database and 6 studies from references of relevant articles remained in the analysis. Individuals with a history of vigorous physical activity (OR 1.26, 95% CI 1.06-1.49), occupational-related activity (OR 1.14, 95% CI 1.04-1.25), leisure time activity (OR 1.08, 95% CI 1.04-1.12), unclassified PA (OR 1.05 95% CI 1.02-1.09) and professional athletes (SMR 5.23, 95% CI 2.67-10.25; SIR 2.54, 95% CI 1.37-4.69) were in higher risk of developing ALS. In contrast, sport-related activity (OR 0.97, 95% CI 0.76-1.26) was not associated with ALS. CONCLUSIONS: Vigorous physical activity, occupational-related activity, leisure time activity, unclassified PA and professional athletes were associated with a higher risk of ALS, while sport-related activity showed no association with ALS. Our findings clarified the relation between different types of PA and ALS and provided some practicable advice for the lifestyle of high-risk populations.