Ca2+ imaging of self and other in medial prefrontal cortex during social dominance interactions in a tube test.

The study of social dominance interactions between animals offers a window onto the decision-making involved in establishing dominance hierarchies and an opportunity to examine changes in social behavior observed in certain neurogenetic disorders. Competitive social interactions, such as in the widely used tube test, reflect this decision-making. Previous studies have focused on the different patterns of behavior seen in the dominant and submissive animal, neural correlates of effortful behavior believed to mediate the outcome of such encounters, and interbrain correlations of neural activity. Using a rigorous mutual information criterion, we now report that neural responses recorded with endoscopic calcium imaging in the prelimbic zone of the medial prefrontal cortex show unique correlations to specific dominance-related behaviors. Interanimal analyses revealed cell/behavior correlations that are primarily with an animal's own behavior or with the other animal's behavior, or the coincident behavior of both animals (such as pushing by one and resisting by the other). The comparison of unique and coincident cells helps to disentangle cell firing that reflects an animal's own or the other's specific behavior from situations reflecting conjoint action. These correlates point to a more cognitive rather than a solely behavioral dimension of social interactions that needs to be considered in the design of neurobiological studies of social behavior. These could prove useful in studies of disorders affecting social recognition and social engagement, and the treatment of disorders of social interaction.

GBA1 in Parkinson's disease: variant detection and pathogenicity scoring matters.

BACKGROUND: GBA1 variants are the strongest genetic risk factor for Parkinson's disease (PD). However, the pathogenicity of GBA1 variants concerning PD is still not fully understood. Additionally, the frequency of GBA1 variants varies widely across populations. OBJECTIVES: To evaluate Oxford Nanopore sequencing as a strategy, to determine the frequency of GBA1 variants in Norwegian PD patients and controls, and to review the current literature on newly identified variants that add to pathogenicity determination. METHODS: We included 462 Norwegian PD patients and 367 healthy controls. We sequenced the full-length GBA1 gene on the Oxford Nanopore GridION as an 8.9 kb amplicon. Six analysis pipelines were compared using two aligners (NGMLR, Minimap2) and three variant callers (BCFtools, Clair3, Pepper-Margin-Deepvariant). Confirmation of GBA1 variants was performed by Sanger sequencing and the pathogenicity of variants was evaluated. RESULTS: We found 95.8% (115/120) true-positive GBA1 variant calls, while 4.2% (5/120) variant calls were false-positive, with the NGMLR/Minimap2-BCFtools pipeline performing best. In total, 13 rare GBA1 variants were detected: two were predicted to be (likely) pathogenic and eleven were of uncertain significance. The odds of carrying one of the two common GBA1 variants, p.L483P or p.N409S, in PD patients were estimated to be 4.11 times the odds of carrying one of these variants in controls (OR = 4.11 [1.39, 12.12]). CONCLUSIONS: In conclusion, we have demonstrated that Oxford long-read Nanopore sequencing, along with the NGMLR/Minimap2-BCFtools pipeline is an effective tool to investigate GBA1 variants. Further studies on the pathogenicity of GBA1 variants are needed to assess their effect on PD.

Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism.

BACKGROUND: A mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk. OBJECTIVE: To investigate the impact of the MGS and lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic PD (iPD). METHODS: We included N = 486 patients with LRRK2-PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP-PD), Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD-RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO. RESULTS: Our derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10-8 ). We observed that higher MGS was significantly associated with earlier AAO in LRRK2-PD (P = 0.047, ß = -1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, ß = 0.22). There was a correlation between MGS and AAO in LRRK2-PD patients of European descent (P = 0.049, r = -0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = -0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, ß = -5.65) in LRRK2-PD and with tobacco use (P = 0.010, ß = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non-smokers. CONCLUSIONS: The MGS was more strongly associated with earlier AAO in LRRK2-PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - An Update.

In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

How Do I Report Genes in a Paper?

Genetic testing, including whole genome, whole exome, and other next-generation sequencing technologies, has evolved vastly in the past decade. With this, the number of identified genes and genetic variants is constantly increasing. Although a variety of databases and online tools exist that summarize, categorize, and classify genes, a clear guideline of which information is needed when reporting a gene and what to do when identifying a new gene is lacking. This includes the correct nomenclature, descriptive information about genetic loci and genetic variation, aliases, and correlated phenotypes. This tutorial is meant to serve as an introduction to reporting genes in a paper and provides an overview of available databases and tools to obtain all necessary information on the genes of interest.

The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson's disease.

The objective of this study was to investigate the association between a Parkinson's disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. We included data from 4367 patients with idiopathic PD, 159 patients with GBA1-PD, and 3090 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The association between PGS and lifestyle factors on AAO was assessed with linear and Cox proportional hazards models. The PGS showed a negative association with AAO (ß = - 1.07, p = 6 × 10-7) in patients with idiopathic PD. The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p = 0.0001), 44% (p < 2 × 10-16), and 55% (p < 2 × 10-16), compared to no use. An additive effect of aspirin (ß = 7.62, p = 9 × 10-7) and PGS (ß = - 1.58, p = 0.0149) was found for AAO without an interaction (p = 0.9993) in the linear regressions, and similar effects were seen for tobacco. In contrast, no association between aspirin intake and AAO was found in GBA1-PD (p > 0.05). In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect.

Lifestyle factors and clinical severity of Parkinson's disease.

Genetic factors, environmental factors, and gene-environment interactions have been found to modify PD risk, age at onset (AAO), and disease progression. The objective of this study was to explore the association of coffee drinking, aspirin intake, and smoking, with motor and non-motor symptoms in a cohort of 35,959 American patients with PD from the Fox Insight Study using generalized linear models. Coffee drinkers had fewer problems swallowing but dosage and duration of coffee intake were not associated with motor or non-motor symptoms. Aspirin intake correlated with more tremor (p = 0.0026), problems getting up (p = 0.0185), light-headedness (p = 0.0043), and problems remembering (p = 1 × 10-5). Smoking was directly associated with symptoms: smokers had more problems with drooling (p = 0.0106), swallowing (p = 0.0002), and freezing (p < 1 × 10-5). Additionally, smokers had more possibly mood-related symptoms: unexplained pains (p < 1 × 10-5), problems remembering (p = 0.0001), and feeling sad (p < 1 × 10-5). Confirmatory and longitudinal studies are warranted to investigate the clinical correlation over time.

The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson's disease.

Objective: To investigate the association between a Parkinson's disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. Methods: We included data from 4375 patients with idiopathic PD, 167 patients with GBA1-PD, and 3091 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The PGS was calculated based on a previously proposed composition of 1805 variants. The association between PGS and lifestyle factors (i.e., coffee, tobacco, and aspirin) on AAO was assessed with linear and Cox proportional hazards models. Results: The PGS showed a negative association with AAO (ß=-1.07, p=6×10-7). The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p=0.0001), 45% (p<2×10-16), and 55% (p<2×10-16), respectively, compared to no use. An additive effect of aspirin (ß=7.61, p=8×10-7) and PGS (ß=-1.63, p=0.0112) was found for AAO without an interaction (p=0.9789) in the linear regressions, and similar effects were seen for tobacco. Aspirin is shown to be a better predictor of AAO (R2=0.1740) compared to coffee and tobacco use (R2=0.0243, R2=0.0295) or the PGS (R2=0.0141). In contrast, no association between aspirin and AAO was found in GBA1-PD (p>0.05). Interpretation: In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect. External validation of our findings is needed.

Coffee, smoking and aspirin are associated with age at onset in idiopathic Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene-environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann-Whitney U test. Non-parametric Spearman's correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. We found that smoking (p < 0.0001), coffee drinking (p < 0.0001) and aspirin intake (p < 0.0001) show an exploratory association with AAO in PD, that was further supported by multivariate regression models. The association of aspirin with PD AAO was replicated in another cohort (EPIPARK) (n = 237 patients with PD).