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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, loose teeth, toothache, dentures) and future incidence of PD. Methods and Participants: 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 421,180 participants with a mean age of 56.26 years old, and 46.5% of them were male. And 2,339 participants were diagnosed with PD in the follow-up. Mouth ulcers, loose 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Several variants of sequestosome 1 ( SQSTM1 ) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear., Methods: We screened variants of SQSTM1 gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants of SQSTM1 gene in patients with ALS from our cohort and published studies., Results: In our cohort, we identified 32 patients with 25 different SQSTM1 variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with SQSTM1 variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency of SQSTM1 variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants in SQSTM1 . Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget's disease of bone and FTD., Conclusion: Our study established the largest cohort of patients with ALS with SQSTM1 variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of SQSTM1 variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The overlapping clinical manifestations in parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson's Disease (PD) can complicate clinical diagnostic accuracy, particularly in the early stage. The study aims to uncover the patterns of brain function in the initial phase of the two conditions., Methods: We recruited 24 MSA-P patients, 34 PD patients and 27 healthy controls (HC). Voxel-wise fractional amplitude of low-frequency fluctuation (fALFF) was compared to characterize regional brain function, followed by seed-based functional connectivity (FC) analysis. Receiver operating characteristic (ROC) analyses were used to examine the diagnostic accuracy of fALFF., Results: Compared to HC, decreased fALFF was observed in the bilateral basal ganglia (BG) of MSA-P patients, while decreased fALFF was identified in the left BG of PD patients. Additionally, elevated fALFF was found in the superior cerebellum for MSA-P patients and the temporo-occipital cortex for PD patients. Furthermore, PD patients exhibited increased FC in the cortico-striatal loop compared to MSA-P patients. The fALFF of the left caudate distinguished MSA-P from HC with an area under the curve (AUC) of 0.838 ( p < 0.001) and from PD with an AUC of 0.772 ( p < 0.001). The fALFF of the left putamen distinguished PD from HC with an AUC of 0.736 ( p = 0.002)., Conclusion: Our findings indicated common and distinct abnormalities in spontaneous brain activity within BG, cerebellum, and cortices in early-stage MSA-P and PD patients. PD patients employed more compensatory mechanisms than MSA-P patients. Furthermore, fALFF may aid in early differentiation between MSA-P and PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Wang, Xiao, Hou, Li, Zhang, Ou, Wei, Lin, Yang, Che, Jiang, Zheng, Liu and Shang.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A number of studies have explored the link between neurodegenerative disorders (NDDs) and albumin, the main protein in human plasma. However, the results have been inconsistent, highlighting the necessity for a detailed systemic analysis., Methods: Utilizing data from the United Kingdom Biobank, we investigated the relationship between baseline levels of serum and urine albumin and the occurrence of common NDDs, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and dementia, employing Cox proportional hazards regression analysis., Results: Our results reveal that elevated baseline serum albumin levels are linked to a decreased risk of developing dementia (beta = -0.024, SE = 0.004, p  < 0.001). Subgroup and interaction analyses highlighted the impact of factors like body mass index (BMI), age, and alcohol consumption on this relationship. Specifically, participants with higher BMI, younger age, or lower alcohol intake exhibited a stronger protective effect. On the other hand, a higher baseline level of urine microalbumin was connected to a slight increase in dementia risk (beta = 0.003, SE = 3.30E-04, p  < 0.001). No significant associations were found between albumin levels and the risk of PD or ALS., Conclusion: Our study underscores the potential role of serum albumin as a biomarker associated with reduced dementia risk. These findings contribute valuable insights into the understanding of albumin's impact on NDDs, suggesting its utility as a biomarker for dementia in clinical settings and informing future therapeutic strategies in clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cui, Li, Ke, Xiao, Wang, Jiang, Zheng, Lin, Huang and Shang.)