Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

ANALYSIS OF NEURODEVELOPMENTAL DEFECTS IN HUMAN MIDBRAIN ORGANOIDS FROM GBA-N370S PARKINSON'S DISEASE PATIENTS

With increasing prevalence, Parkinson’s disease presents a major challenge for medical research and public health. Despite years of investigation, significant knowledge gaps exist and Parkinson’s disease (PD) etiology remains unclear. A recent concept in the field is that neurodevelopmental aspects might contribute to the pathogenesis of neurodegenerative diseases such as PD. Our hypothesis is that mutations in PD-linked genes have an impact on the cells’ homeostasis at the neural precursor state, giving rise to vulnerable dopaminergic (DA) neurons, thereby increasing the degree of susceptibility for neurodegeneration with aging. In order to investigate this, we used a human midbrain organoid (hMO) model generated from iPSC-derived neural precursor cells. As part of the optimization of the model, we treated the organoids with the neurotoxin 6-OHDA to develop a neurotoxin-induced PD model and set up a high-content imaging pipeline coupled with machine learning classification to predict neurotoxicity. We then used these tools to derive PD patient-derived hMOs in order to investigate our main hypothesis. First, we focused on PD patients carrying a heterozygous mutation in the GBA gene. We developed a genome-scale metabolic model that predicted significant differences in lipid metabolism between patients and controls. Then, we validated the observations by performing a comprehensive lipidomics analysis confirming a dysregulated lipidome in mutant hMOs. Moreover, GBA-PD hMOs displayed PD-relevant phenotypes, impaired DA differentiation and an increased population of neural progenitor cells (NPCs) in cell cycle arrest, confirming the presence of neurodevelopmental defects. To further investigate the neurodevelopmental component of PD, we used patient-derived cell lines carrying PINK1 mutations. PINK1-PD neural precursors presented differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and an impaired differentiation efficiency to DA neurons compared to controls. Correction of the PINK1 point mutation was able to improve the metabolic properties and neuronal firing rates as well as rescuing the differentiation phenotype. We performed a drug screen using repurposed drugs as well as novel compounds to evaluate their potential to rescue the observed developmental phenotype. Treatment with 2-hydroxypropyl-β- cyclodextrin increased the autophagy and mitophagy capacity of neurons which was accompanied by improved dopaminergic differentiation of patient-specific neurons in midbrain organoids and showed neuroprotective effects in an MPTP-treated mice PD model. In conlusion, PD has a neurodevelopmental component that increases susceptibility to the pathology. Thus, our findings suggest that the use of hMOs are suitable to reveal early PD pathomechanisms, as well as constituting a powerful tool for advanced therapy development

Usefulness of aerobic exercise in managing the proinflammatory status in adults with metabolic syndrome

El presente estudio se diseñó con el objetivo de reducir los niveles plasmáticos de citokinas proiflamatorias en adultos jóvenes con síndrome metabólico a través de un programa de ejercicio físico de 12 semanas. Participaron voluntariamente 60 adultos varones con síndrome metabólico de acuerdo a los criterios establecidos por National Cholesterol Education Program Adult Treatment Panel III (NCEP-AT P-III). Se distribuyeron aleatoriamente en un grupo experimental (n=45) que desarrolló un programa de ejercicio de tipo aeróbico de 12 semanas, 3 sesiones/semana y una intensidad del 60-75% de su frecuencia cardiaca máxima. El grupo control (n=15) estaba ajustado en sexo, edad e índice de masa corporal aunque no desarrolló el programa de entrenamiento. Los niveles plasmáticos de factornecrosis- tumoral-α (TNF-α), Interleukina-1 (IL-1β) e Interleukina-6 (IL-6) se determinaron mediante ELISA. El porcentaje de masa grasa se determinó mediante bioimpedanciometría eléctrica. Ambos parámetros se valoraron 72-h antes de iniciar el programa de entrenamiento (pre-test) y 72-h después de su finalización (post-test). Éste protocolo fue aprobado por un Comité de Ética institucional. Cuando se comparan con valores basales, los niveles plasmáticos de TNF-α (7.2±1.2vs5.6±1.1 pg/ml; p<0.05), IL-1(7.2±1.2vs5.6±1.1 pg/ ml; p<0.05) e IL-6 (7.2±1.2 vs 5.6±1.1 pg/ml; p<0.05) se redujeron significativamente. Por el contrario no se observaron cambios significativos en el grupo control. Un programa de 12 semanas de ejercicio de tipo aeróbico reduce significativamente los niveles plasmáticos de citokinas proinflamatorias en adultos con síndrome metabólico.The present study was designed to determine the influence of regular exercise on proinflammatory biomarkers in young adults with metabolic syndrome. To get this goal, sixty young adult men with metabolic syndrome according to the criteria reported by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) volunteered for this study. Fourty-five were randomly included in experimental group to perform a 12-week aerobic training program, 3 days/week, consisting of warm up (10 min), main part (20-35 min [increasing 5 minutes each three weeks]) at a work intensity of 60-75% of peak heart rate (increasing 5% each three weeks) and cool-down (10 min). Control group included 15 age, sex and BMI-matched men with metabolic syndrome that will not perform any training program. Our protocol was approved by an institutional ethic committee. Plasmatic cytokine levels (TumorNecrosis-Factor [TNF-α]; Interleukin-1 [IL-1β]; Interleukin-6 [IL-6]) were determined by ELISA twice: firstly 72-h before starting the program (pre-test) and finally 72-h after its ending (post-test). Fat mass percentage was determined by bioelectric-impendance method. When compared to baseline plasmatic cytokine levels were decreased significantly after being exercised. On the contrary no changes were reported in controls. We concluded a 12-week training program reduced proinflammatory biomarkers in male adults with metabolic syndrome.Sin financiaciónNo data (2008)UE

Impaired neuron differentiation in GBA-associated Parkinson’s disease is linked to cell cycle defects in organoids

Abstract The mechanisms underlying Parkinson’s disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment, and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population showing signs of oxidative stress-induced damage and premature cellular senescence. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology

Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome

peer reviewedBackground: With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI. Objectives: We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition. Design: Cross-sectional study. Setting: Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany). Participants: Control participants of the Luxembourg Parkinson’s Study. Measurements: Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0–10, 11–16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators. Results: After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15–0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education. Conclusions: Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.MCI-BIOME_20193. Good health and well-bein