This study aimed to determine the mutational spectrum of familial Parkinson’s disease and sporadic early-onset Parkinson’s disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson’s disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson’s disease, 242 probands from families with autosomal-dominant Parkinson’s disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson’s disease-associated genes occurred more frequently in the autosomal-recessive Parkinson’s disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson’s disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson’s disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson’s disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson’s disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson’s disease-associated genes. Our data highlight the importance of genetic testing in Parkinson’s disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

The metabolomic profile of aging is complex. Here, we analyse 325 nuclear magnetic resonance (NMR) biomarkers from 250,341 UK Biobank participants, identifying 54 representative aging-related biomarkers associated with all-cause mortality. We conduct genome-wide association studies (GWAS) for these 325 biomarkers using whole-genome sequencing (WGS) data from 95,372 individuals and perform multivariable Mendelian randomization (MVMR) analyses, discovering 439 candidate “biomarker - disease” causal pairs at the nominal significance level. We develop a metabolomic aging score that outperforms other aging metrics in predicting short-term mortality risk and exhibits strong potential for discriminating aging-accelerated populations and improving disease risk prediction. A longitudinal analysis of 13,263 individuals enables us to calculate a metabolomic aging rate which provides more refined aging assessments and to identify candidate anti-aging and pro-aging NMR biomarkers. Taken together, our study has presented a comprehensive aging-related metabolomic profile and highlighted its potential for personalized aging monitoring and early disease intervention.

De novo mutations (DNMs) significantly contribute to sporadic diseases, particularly in neuropsychiatric disorders. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) provide effective methods for detecting DNMs and prioritizing candidate genes. However, it remains a challenge for scientists, clinicians, and biologists to conveniently access and analyse data regarding DNMs and candidate genes from scattered publications. To fill the unmet need, we integrated 580 799 DNMs, including 30 060 coding DNMs detected by WES/WGS from 23 951 individuals across 24 phenotypes and prioritized a list of candidate genes with different degrees of statistical evidence, including 346 genes with false discovery rates <0.05. We then developed a database called Gene4Denovo (http://www.genemed.tech/gene4denovo/), which allowed these genetic data to be conveniently catalogued, searched, browsed, and analysed. In addition, Gene4Denovo integrated data from >60 genomic sources to provide comprehensive variant-level and gene-level annotation and information regarding the DNMs and candidate genes. Furthermore, Gene4Denovo provides end-users with limited bioinformatics skills to analyse their own genetic data, perform comprehensive annotation, and prioritize candidate genes using custom parameters. In conclusion, Gene4Denovo conveniently allows for the accelerated interpretation of DNM pathogenicity and the clinical implication of DNMs in humans.

Objectives: Blood lipid profiles have been ambiguously reported as biomarkers of AD in recent years. This study was conducted to evaluate the correlation between blood lipid levels and AD in later-life and to explore the effectiveness and reliability of blood lipid profiles as biomarkers of AD. Methods: Database searching was conducted using PubMed, the Cochrane Library, EMBASE, and Medline. This study was designed following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) criteria. Review Manager 5.3 (RevMan 5.3) software was adopted to perform meta-analysis evaluating the standard mean difference (SMD) with its 95% confidence intervals (CI). Results: A total of 5,286 participants were enrolled from 27 case–control studies in this meta-analysis. The pooled results demonstrated that total cholesterol (TC) level was significantly associated with AD in late-life (SMD = 0.17, 95% CI: [0.01, 0.32], P = 0.03), especially in the subgroup under 70 years old (SMD: 0.45, 95% CI: [0.11, 0.79], P = 0.01) and the subgroup of Western population (SMD: 0.29, 95% CI: [0.04, 0.53], P = 0.02). In the subgroup under 70 years old, the high-density lipoprotein cholesterol (HDL-C) level (SMD = −0.50, 95% CI: [−0.76, −0.25], P = 0.0001) and the low-density lipoprotein cholesterol (LDL-C) level (SMD = 0.59, 95% CI: [0.02, 1.16], P = 0.04) in the AD group were significantly lower and higher than in the control group, respectively. In the subgroup with a sample size larger than 100 subjects, the LDL-C level was significantly higher in AD patients than in the control elderly group (SMD = 0.31, 95% CI: [0.05, 0.56], P = 0.02). There was no significant association between triglyceride (TG) levels and AD in later-life (SMD = −0.00, 95% CI: [−0.12, 0.12], P = 1.00). Conclusion: TC can be a new predictive biomarker of AD or cognitive decline in later-life. Increased TC levels are found to be associated with an elevated risk of AD. Decreased HDL-C levels and increased LDL-C levels may relate to an elevated risk of AD in subjects aged 60–70. Further comprehensive researches will be necessary in the future.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. It is caused by the expansion of the CAG trinucleotide repeat sequence in the HTT gene. HD mainly manifests as involuntary dance-like movements and severe mental disorders. As it progresses, patients lose the ability to speak, think, and even swallow. Although the pathogenesis is unclear, studies have found that mitochondrial dysfunctions occupy an important position in the pathogenesis of HD. Based on the latest research advances, this review sorts out and discusses the role of mitochondrial dysfunction on HD in terms of bioenergetics, abnormal autophagy, and abnormal mitochondrial membranes. This review provides researchers with a more complete perspective on the mechanisms underlying the relationship between mitochondrial dysregulation and HD.

This study investigated the benefits of resistance training on cognition in patients with mild cognitive impairment. We searched the PubMed, Embase and Cochrane Library databases, and seven randomized controlled trials were reviewed. We evaluated the risk of bias using the Cochrane Collaboration’s bias assessment tool. Standard mean differences with 95% confidence intervals were calculated for statistical analysis. This meta-analysis assessed three variables: general cognitive function, executive function and working memory. The results indicate that general cognitive function improved significantly (standardized mean difference: 0.53, P=0.04), and further subgroup analyses on frequency and duration per session showed that the subgroups ‘twice a week’ (P=0.01) and ‘duration per session >60 min’ (P=0.0006) exhibited better performance than the subgroups ‘three time a week’ (P=0.47) and ‘duration per session <60 min’ (P=0.53). Additionally, a moderate effect size was found in executive function (standardized mean difference: 0.50, P=0.0003), and there was non-significant effect in working memory (P=0.14). In summary, resistance training may mitigate mild cognitive impairment by improving cognition. Larger-scale studies are recommended to demonstrate the relationship between resistance training and cognition in mild cognitive impairment.