Increased Risk of Parkinson's Disease in Patients With Schizophrenia Spectrum Disorders

Background PD comorbid with schizophrenia has been considered rare because these diseases associate with opposite alterations in the brain dopamine system. The objective of this study was to investigate the risk of PD after a diagnosis of a schizophrenia spectrum disorder. Methods Regionally, this was a retrospective record-based case-control study. The cohort included 3045 PD patients treated 2004-2019 in southwestern Finland. Nationally this was a nested case-control study using registers to examine Finnish patients who received a clinically confirmed PD diagnosis 1996-2015 (n = 22,189). PD patients with previously diagnosed schizophrenia spectrum disorder (separate analysis for schizophrenia) were included. Comparable non-PD control groups were derived from both data sets. All PD diagnoses were based on individual clinical examinations by certified neurologists. Results In PD patients, the prevalence of earlier schizophrenia spectrum disorder was 0.76% in regional data and 1.50% in nationwide data. In age-matched controls, the prevalence in the regional and national data was 0.16% and 1.31%, respectively. The odds ratio for PD after schizophrenia spectrum disorder diagnosis was 4.63 (95% CI, 1.76-12.19; P <0.01) in the regional data and 1.17 (95% CI, 1.04-1.31; P <0.01) in the national data. Conclusions Schizophrenia spectrum disorder increases the risk of PD later in life. This association was observed in both individual patient data and nationwide register data. Therefore, despite the opposite dopaminergic disease mechanisms, schizophrenia spectrum disorder increases rather than decreases the risk of PD. The increased PD risk could be related to risk-altering effects of dopamine receptor antagonists or to the increased vulnerability of the dopamine system induced by illness phase-dependent dopamine dysregulation in schizophrenia/schizophrenia spectrum disorder. (c) 2021 International Parkinson and Movement Disorder SocietyPeer reviewe

Spin and Statistics and First Principles

It was shown in the early Seventies that, in Local Quantum Theory (that is the most general formulation of Quantum Field Theory, if we leave out only the unknown scenario of Quantum Gravity) the notion of Statistics can be grounded solely on the local observable quantities (without assuming neither the commutation relations nor even the existence of unobservable charged field operators); one finds that only the well known (para)statistics of Bose/Fermi type are allowed by the key principle of local commutativity of observables. In this frame it was possible to formulate and prove the Spin and Statistics Theorem purely on the basis of First Principles. In a subsequent stage it has been possible to prove the existence of a unique, canonical algebra of local field operators obeying ordinary Bose/Fermi commutation relations at spacelike separations. In this general guise the Spin - Statistics Theorem applies to Theories (on the four dimensional Minkowski space) where only massive particles with finite mass degeneracy can occur. Here we describe the underlying simple basic ideas, and briefly mention the subsequent generalisations; eventually we comment on the possible validity of the Spin - Statistics Theorem in presence of massless particles, or of violations of locality as expected in Quantum Gravity.Comment: Survey based on a talk given at the Meeting on "Theoretical and experimental aspects of the spin - statistics connection and related symmetries", Trieste, Italy - October 21-25, 200

Increased Risk of Parkinson's Disease in Patients With Schizophrenia Spectrum Disorders

Background PD comorbid with schizophrenia has been considered rare because these diseases associate with opposite alterations in the brain dopamine system. The objective of this study was to investigate the risk of PD after a diagnosis of a schizophrenia spectrum disorder.Methods Regionally, this was a retrospective record-based case-control study. The cohort included 3045 PD patients treated 2004-2019 in southwestern Finland. Nationally this was a nested case-control study using registers to examine Finnish patients who received a clinically confirmed PD diagnosis 1996-2015 (n = 22,189). PD patients with previously diagnosed schizophrenia spectrum disorder (separate analysis for schizophrenia) were included. Comparable non-PD control groups were derived from both data sets. All PD diagnoses were based on individual clinical examinations by certified neurologists.Results In PD patients, the prevalence of earlier schizophrenia spectrum disorder was 0.76% in regional data and 1.50% in nationwide data. In age-matched controls, the prevalence in the regional and national data was 0.16% and 1.31%, respectively. The odds ratio for PD after schizophrenia spectrum disorder diagnosis was 4.63 (95% CI, 1.76-12.19; P < 0.01) in the regional data and 1.17 (95% CI, 1.04-1.31; P < 0.01) in the national data.Conclusions Schizophrenia spectrum disorder increases the risk of PD later in life. This association was observed in both individual patient data and nationwide register data. Therefore, despite the opposite dopaminergic disease mechanisms, schizophrenia spectrum disorder increases rather than decreases the risk of PD. The increased PD risk could be related to risk-altering effects of dopamine receptor antagonists or to the increased vulnerability of the dopamine system induced by illness phase-dependent dopamine dysregulation in schizophrenia/schizophrenia spectrum disorder. (c) 2021 International Parkinson and Movement Disorder Societ

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Causal relationship between obesity and vitamin d status : Bi-directional mendelian randomization analysis of multiple cohorts

Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52610227). The BMI allele score was associated both with BMI (p = 6.30610262) and 25(OH)D (20.06% [95% CI 20.10 to 20.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p#8.07610257 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: 24.2 [95% CI 27.1 to 21.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p$0.57 for both vitamin D scores). Conclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency

Progesterone after previous preterm birth for prevention of neonatal respiratory distress syndrome (PROGRESS): a randomised controlled trial

Background: Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity during infancy and childhood. Survivors of preterm birth continue to remain at considerable risk of both chronic lung disease and long-term neurological handicap. Progesterone is involved in the maintenance of uterine quiescence through modulation of the calcium-calmodulin-myosin-light-chain-kinase system in smooth muscle cells. The withdrawal of progesterone, either actual or functional is thought to be an antecedent to the onset of labour. While there have been recent reports of progesterone supplementation for women at risk of preterm birth which show promise in this intervention, there is currently insufficient data on clinically important outcomes for both women and infants to enable informed clinical decision-making. The aims of this randomised, double blind, placebo controlled trial are to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth will reduce the risk and severity of respiratory distress syndrome, so improving their infant's health, without increasing maternal risks. Methods Design: Multicentred randomised, double blind, placebo-controlled trial. Inclusion Criteria: pregnant women with a live fetus, and a history of prior preterm birth at less than 37 weeks gestation and greater than 20 weeks gestation in the immediately preceding pregnancy, where onset of labour occurred spontaneously, or in association with cervical incompetence, or following preterm prelabour ruptured membranes. Trial Entry & Randomisation: After obtaining written informed consent, eligible women will be randomised between 18 and 23+6 weeks gestation using a central telephone randomisation service. The randomisation schedule prepared by non clinical research staff will use balanced variable blocks, with stratification according to plurality of the pregnancy and centre where planned to give birth. Eligible women will be randomised to either vaginal progesterone or vaginal placebo. Study Medication & Treatment Schedules: Treatment packs will appear identical. Woman, caregivers and research staff will be blinded to treatment allocation. Primary Study Outcome: Neonatal Respiratory Distress Syndrome (defined by incidence and severity). Sample Size: of 984 women to show a 40% reduction in respiratory distress syndrome from 15% to 9% (p = 0.05, 80% power). Discussion: This is a protocol for a randomised trial.Jodie M. Dodd, Caroline A. Crowther, Andrew J. McPhee, Vicki Flenady, and Jeffrey S. Robinso

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease