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1. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Author

Collaborators, GBD 2016 Neurology, Feigin, Valery L, Nichols, Emma, Alam, Tahiya, Bannick, Marlena S, Beghi, Ettore, Blake, Natacha, Culpepper, William J, Dorsey, E Ray, Elbaz, Alexis, Ellenbogen, Richard G, Fisher, James L, Fitzmaurice, Christina, Giussani, Giorgia, Glennie, Linda, James, Spencer L, Johnson, Catherine Owens, Kassebaum, Nicholas J, Logroscino, Giancarlo, Marin, Benoît, Mountjoy-Venning, W Cliff, Nguyen, Minh, Ofori-Asenso, Richard, Patel, Anoop P, Piccininni, Marco, Roth, Gregory A, Steiner, Timothy J, Stovner, Lars Jacob, Szoeke, Cassandra EI, Theadom, Alice, Vollset, Stein Emil, Wallin, Mitchell Taylor, Wright, Claire, Zunt, Joseph Raymond, Abbasi, Nooshin, Abd-Allah, Foad, Abdelalim, Ahmed, Abdollahpour, Ibrahim, Aboyans, Victor, Abraha, Haftom Niguse, Acharya, Dilaram, Adamu, Abdu A, Adebayo, Oladimeji M, Adeoye, Abiodun Moshood, Adsuar, Jose C, Afarideh, Mohsen, Agrawal, Sutapa, Ahmadi, Alireza, Ahmed, Muktar Beshir, Aichour, Amani Nidhal, Aichour, Ibtihel, Aichour, Miloud Taki Eddine, Akinyemi, Rufus Olusola, Akseer, Nadia, Al-Eyadhy, Ayman, Salman, Rustam Al-Shahi, Alahdab, Fares, Alene, Kefyalew Addis, Aljunid, Syed Mohamed, Altirkawi, Khalid, Alvis-Guzman, Nelson, Anber, Nahla Hamed, Antonio, Carl Abelardo T, Arabloo, Jalal, Aremu, Olatunde, Ärnlöv, Johan, Asayesh, Hamid, Asghar, Rana Jawad, Atalay, Hagos Tasew, Awasthi, Ashish, Quintanilla, Beatriz Paulina Ayala, Ayuk, Tambe B, Badawi, Alaa, Banach, Maciej, Banoub, Joseph Adel Mattar, Barboza, Miguel A, Barker-Collo, Suzanne Lyn, Bärnighausen, Till Winfried, Baune, Bernhard T, Bedi, Neeraj, Behzadifar, Masoud, Behzadifar, Meysam, Béjot, Yannick, Bekele, Bayu Begashaw, Belachew, Abate Bekele, Bennett, Derrick A, Bensenor, Isabela M, Berhane, Adugnaw, Beuran, Mircea, Bhattacharyya, Krittika, Bhutta, Zulfiqar A, Biadgo, Belete, Bijani, Ali, Bililign, Nigus, Bin Sayeed, Muhammad Shahdaat, Blazes, Christopher Kynrint, Brayne, Carol, Butt, Zahid A, Campos-Nonato, Ismael R, and Cantu-Brito, Carlos

Subjects
Neurosciences, Headaches, Pain Research, Aging, Brain Disorders, Prevention, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Adult, Age Factors, Aged, Aged, 80 and over, Cause of Death, Dementia, Disability Evaluation, Female, Global Burden of Disease, Humans, Incidence, Male, Middle Aged, Nervous System Diseases, Prevalence, Quality-Adjusted Life Years, Risk Factors, Sex Factors, Socioeconomic Factors, GBD 2016 Neurology Collaborators, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundNeurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders.MethodsWe estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach.FindingsGlobally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247-308]) and second leading cause of deaths (9·0 million [8·8-9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34-44] and DALYs by 15% [9-21]) whereas their age-standardised rates decreased (deaths by 28% [26-30] and DALYs by 27% [24-31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6-46·1]), migraine (16·3% [11·7-20·8]), Alzheimer's and other dementias (10·4% [9·0-12·1]), and meningitis (7·9% [6·6-10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05-1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5-90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8-35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8-17·5] of DALYs are risk attributable).InterpretationGlobally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies.FundingBill & Melinda Gates Foundation.

Published
2019

2. Smoking and Parkinson disease

Author

Lee, Pei-Chen, Ahmed, Ismaïl, Loriot, Marie-Anne, Mulot, Claire, Paul, Kimberly C, Bronstein, Jeff M, Ritz, Beate, and Elbaz, Alexis

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Tobacco, Brain Disorders, Tobacco Smoke and Health, Parkinson's Disease, Prevention, Genetics, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Bayes Theorem, Case-Control Studies, Female, Gene-Environment Interaction, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Humans, Male, Middle Aged, Parkinson Disease, Polymorphism, Single Nucleotide, Retinoid X Receptor alpha, Smoking, Vesicular Glutamate Transport Protein 2, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo investigate whether cigarette smoking interacts with genes involved in individual susceptibility to xenobiotics for the risk of Parkinson disease (PD).MethodsTwo French population-based case-control studies (513 patients, 1,147 controls) were included as a discovery sample to examine gene-smoking interactions based on 3,179 single nucleotide polymorphisms (SNPs) in 289 genes involved in individual susceptibility to xenobiotics. SNP-by-cigarette smoking interactions were tested in the discovery sample through an empirical Bayes (EB) approach. Nine SNPs were selected for replication in a population-based case-control study from California (410 patients, 845 controls) with standard logistic regression and the EB approach. For SNPs that replicated, we performed pooled analyses including the discovery and replication datasets and computed pooled odds ratios and confidence intervals (CIs) using random-effects meta-analysis.ResultsNine SNPs interacted with smoking in the discovery dataset and were selected for replication. Interactions of smoking with rs4240705 in the RXRA gene and rs1900586 in the SLC17A6 gene were replicated. In pooled analyses (logistic regression), the interactions between smoking and rs4240705-G and rs1900586-G were 1.66 (95% CI 1.28-2.14, p = 1.1 × 10-4, p for heterogeneity = 0.366) and 1.61 (95% CI 1.17-2.21, p = 0.003, p for heterogeneity = 0.616), respectively. For both SNPs, while smoking was significantly less frequent in patients than controls in AA homozygotes, this inverse association disappeared in G allele carriers.ConclusionsWe identified and replicated suggestive gene-by-smoking interactions in PD. The inverse association of smoking with PD was less pronounced in carriers of minor alleles of both RXRA-rs4240705 and SLC17A6-rs1900586. These findings may help identify biological pathways involved in the inverse association between smoking and PD.

Published
2018

3. Mitochondrial haplogroups and cognitive progression in Parkinson's disease

Author

Liu, Ganqiang, Ni, Chunming, Zhan, Jiamin, Li, Weimin, Luo, Junfeng, Liao, Zhixiang, Locascio, Joseph J, Xian, Wenbiao, Chen, Ling, Pei, Zhong, Corvol, Jean-Christophe, Maple-Grødem, Jodi, Campbell, Meghan C, Elbaz, Alexis, Lesage, Suzanne, Brice, Alexis, Hung, Albert Y, Schwarzschild, Michael A, Hayes, Michael T, Wills, Anne-Marie, Ravina, Bernard, Shoulson, Ira, Taba, Pille, Kõks, Sulev, Beach, Thomas G, Cormier-Dequaire, Florence, Alves, Guido, Tysnes, Ole-Bjørn, Perlmutter, Joel S, Heutink, Peter, Van Hilten, Jacobus J, Barker, Roger A, Williams-Gray, Caroline H, Scherzer, Clemens R, International Genetics Of Parkinson Disease Progression (IGPP) Consortium, Liu, Ganqiang [0000-0002-1921-9542], Pei, Zhong [0000-0002-8425-2867], Elbaz, Alexis [0000-0001-9724-5490], Apollo - University of Cambridge Repository, Liu, Ganqiang, Valentino, Rebecca R, Peng, Jiajie, Liao, Zhixiang, Locascio, Joseph J, Corvol, Jean-Christophe, Dong, Xianjun, Maple-Grødem, Jodi, Campbell, Meghan C, Elbaz, Alexis, Lesage, Suzanne, Brice, Alexis, Mangone, Graziella, Growdon, John H, Hung, Albert Y, Schwarzchild, Michael A, Hayes, Michael T, Wills, Anne-Marie, Herrington, Todd M, Ravian, Bernard, Shoulson, Ira, Taba, Pille, Kõks, Sulev, Beach, Thomas G, Cormier-Dequaire, Florence, Alves, Guido, Tysnes, Ole-Bjørn, Perlmutter, Joel S, Heutink, Peter, van Hilten, Jacobus J, Kasten, Meike, Mollenhauer, Brit, Trenkwalder, Claudia, Klein, Christine, Barker, Roger A, Williams-Gray, Caroline H, Marinus, Johan, and Scherzer, Clemens R

Subjects
mitochondrial haplogroups, Parkinson's disease, cognitive progression, Parkinson Disease, genetics [DNA, Mitochondrial], DNA, Mitochondrial, Mitochondria, Cognition, Haplotypes, genetics [Parkinson Disease], Report, Parkinson’s disease, Disease Progression, Humans, Neurology (clinical), ddc:610, epidemiology [Parkinson Disease], genetics [Mitochondria]
Abstract

Liu et al. report that specific mitochondrial haplogroups are associated with the progression of cognitive decline in patients with Parkinson's disease, but not with the progression of motor impairment. Mitochondrial haplotypes may thus be useful for stratifying patients according to their risk of cognitive decline.Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U-# had a 41% lower risk of cognitive progression with P = 2.42 x 10(-6) compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 x 10(-5). Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Published
2023

4. Pooled analysis of iron-related genes in Parkinson's disease: Association with transferrin

Author

Rhodes, Shannon L, Buchanan, Daniel D, Ahmed, Ismaïl, Taylor, Kent D, Loriot, Marie-Anne, Sinsheimer, Janet S, Bronstein, Jeff M, Elbaz, Alexis, Mellick, George D, Rotter, Jerome I, and Ritz, Beate

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Aging, Brain Disorders, Neurosciences, Parkinson's Disease, Neurodegenerative, 2.1 Biological and endogenous factors, Neurological, Adolescent, Adult, Aged, Case-Control Studies, Female, Genetic Association Studies, Humans, Iron, Male, Middle Aged, Parkinson Disease, Polymorphism, Single Nucleotide, Receptors, Transferrin, Transferrin, Young Adult, Epidemiology, Pooled-analysis, Iron homeostasis, Transferrin receptor 2, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of α-synuclein containing Lewy bodies, and iron accumulation in PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case-control studies from the United States, Australia, and France. After screening 90 haplotype tagging single nucleotide polymorphisms (SNPs) within the genes of interest in the US study population, we investigated the five most promising gene regions in two additional independent case-control studies. For the pooled data set (1289 cases, 1391 controls) we observed a protective association (OR=0.83, 95% CI: 0.71-0.96) between PD and a haplotype composed of the A allele at rs1880669 and the T allele at rs1049296 in transferrin (TF; GeneID: 7018). Additionally, we observed a suggestive protective association (OR=0.87, 95% CI: 0.74-1.02) between PD and a haplotype composed of the G allele at rs10247962 and the A allele at rs4434553 in transferrin receptor 2 (TFR2; GeneID: 7036). We observed no associations in our pooled sample for haplotypes in SLC40A1, CYB561, or HFE. Taken together with previous findings in model systems, our results suggest that TF or a TF-TFR2 complex may have a role in the etiology of PD, possibly through iron misregulation or mitochondrial dysfunction within dopaminergic neurons.

Published
2014

5. Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium

Author

Grover, Sandeep, Kumar Sreelatha, Ashwin Ashok, Landoulsi, Zied, May, Patrick, Bobbili, Dheeraj, Edsall, Connor, Bartusch, Felix, Hanussek, Maximilian, Krüger, Jens, Hernandez, Dena G, Blauwendraat, Cornelis, Mellick, George D, Pihlstrom, Lasse, Zimprich, Alexander, Pirker, Walter, Tan, Manuela, Rogaeva, Ekaterina, Lang, Anthony, Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Domenighetti, Cloé, Chartier-Harlin, Marie-Christine, Mutez, Eugenie, Brockmann, Kathrin, Deutschländer, Angela B, Hadjigeorgiou, Georges M, Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Schulte, Claudia, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Burbulla, Lena F, Matsuo, Hirotaka, Sugier, Pierre-Emmanuel, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Pavelka, Lukas, van de Warrenburg, Bart P C, Bloem, Bastiaan R, Singleton, Andrew B, Aasly, Jan, Radivojkov-Blagojevic, Milena, Toft, Mathias, Guedes, Leonor Correia, Ferreira, Joaquim J, Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Lichtner, Peter, Pedersen, Nancy L, Ran, Caroline, Belin, Andrea C, Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E, Morrison, Karen E, Krainc, Dimitri, Farrer, Matt J, Kruger, Rejko, Mohamed, Océane, Elbaz, Alexis, Gasser, Thomas, Sharma, Manu, Genetics, and the Comprehensive Unbiased Risk Factor Assessment for, Disease, Environment in Parkinson's, Portugal, Berta, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FOR2488, INTER/DFG/17/11583046, INTER/DFG/19/14429377, Michael J. Fox Foundation for Parkinson's Research, MJFF, EU Joint Programme – Neurodegenerative Disease Research, JPND: 01ED1406, Multiple System Atrophy Coalition, MSA, European Commission, EC: EP1802749, Deutsche Forschungsgemeinschaft, DFG: DFG/SH 599/6-1, Fonds National de la Recherche Luxembourg, FNR: FNR/P13/6682797, Bundesministerium für Bildung und Forschung, BMBF, Université Paris-Saclay, The COURAGE-PD Consortium is conducted under a partnership agreement between 35 studies. The COURAGE-PD Consortium is supported by the EU Joint Program for Neurodegenerative Disease Research (JPND, neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/ , Grant ID: 01ED1406)., and The Article Processing Charge was funded by the authors.

Subjects
parkinson’s disease, [SDV]Life Sciences [q-bio], burden of disease, Polymorphism, Single Nucleotide, Duration of disease, genetic heritability, duration of disease, genetics [Parkinson Disease], age at onset, Humans, Genetic Predisposition to Disease, ddc:610, Age of Onset, genetics [Genetic Predisposition to Disease], Burden of disease, Age at onset, Parkinson Disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Courage, Parkinson’s disease, Genetic heritability, Female, Neurology (clinical), epidemiology [Parkinson Disease], Genome-Wide Association Study
Abstract

Background and ObjectivesConsiderable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.MethodsA meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC).ResultsThe COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8).DiscussionOur study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

Published
2022

6. Polygenic resilience modulates the penetrance of parkinson disease genetic risk factors

Author

Liu, Hui, Dehestani, Mohammad, Blauwendraat, Cornelis, Makarious, Mary B., Leonard, Hampton, Kim, Jonggeol J., Schulte, Claudia, Noyce, Alastair, Jacobs, Benjamin M., Foote, Isabelle, Sharma, Manu, Koks, Sulev, Mellick, George D., Pirker, Walter, Zimprich, Alexander, Lang, Anthony E., Rogaeva, Ekaterina, Taba, Pille, Brice, Alexis, Chartier-Harlin, Marie Christine, Corvol, Jean Christophe, Domenighetti, Cloé, Elbaz, Alexis, Lesage, Suzanne, Mutez, Eugenie, Sugier, Pierre Emmanuel, Sreelatha, Ashwin Ashok Kumar, Grover, Sandeep, Brockmann, Kathrin, Deutschländer, Angela B., Gasser, Thomas, Krüger, Jens, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Dardiotis, Efthimos, Hadjigeorgiou, Georges M., Simitsi, Athina Maria, Stefanis, Leonidas, Annesi, Grazia, Brighina, Laura, Ferrarese, Carlo, Petrucci, Simona, Pezzoli, Gianni, Quattrone, Andrea, Straniero, Letizia, Gagliardi, Monica, Valente, Enza Maria, Zecchinelli, Anna, and Morrison, Karen E.

Subjects
polygenic risk, Parkinson's disease, Clinical Neurology, Parkinson Disease, Penetrance, Polymorphism, Single Nucleotide, Neurology, Risk Factors, Humans, Genetic Predisposition to Disease, genetics, Neurology (clinical), ddc:610, resilience, Genome-Wide Association Study
Abstract

Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.Results: A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278

Published
2022

7. The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited

Author

Domenighetti, Cloé, Douillard, Venceslas, Sugier, Pierre-Emmanuel, Sreelatha, Ashwin Ashok Kumar, Schulte, Claudia, Grover, Sandeep, May, Patrick, Bobbili, Dheeraj Reddy, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Singleton, Andrew B., Hernandez, Dena G., Edsall, Connor, Gourraud, Pierre-Antoine, Mellick, George D., Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E., Koks, Sulev, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B., Hadjigeorgiou, Georges M., Dardiotis, Efthimos, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Nakayama, Akiyoshi, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, van de Warrenburg, Bart P. C., Bloem, Bastiaan R., Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J., Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L., Ran, Caroline, Belin, Andrea C., Puschmann, Andreas, Ygland Rödström, Emil, Clarke, Carl E., Morrison, Karen E., Tan, Manuela, KraincMD, Dimitri, Burbulla, Lena F., Farrer, Matt J., Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Vince, Nicolas, Elbaz, Alexis, Genetics, Comprehensive Unbiased Risk Factor Assessment For, Consortium, Environment In Parkinson S Disease Courage-P. D., Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center]

Subjects
Neurologie [D14] [Sciences de la santé humaine], genetics [HLA-DRB1 Chains], Neurology [D14] [Human health sciences], Parkinson's disease, Smoking, Parkinson Disease, genetics [Smoking], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Polymorphism, Single Nucleotide, smoking, gene-environment interaction, HLA, Neurology, genetics [Parkinson Disease], genetics [Polymorphism, Single Nucleotide], Humans, Genetic Predisposition to Disease, ddc:610, Genetics & genetic processes [F10] [Life sciences], Neurology (clinical), Génétique & processus génétiques [F10] [Sciences du vivant], HLA-DRB1 Chains
Abstract

Contains fulltext : 282469.pdf (Publisher’s version ) (Open Access) BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P(Interaction) = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022

8. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author

Domenighetti, Cloé, Sugier, Pierre-Emmanuel, Lichtner, Peter, Singleton, Andrew B, Hernandez, Dena Michelle Godwin, Edsall, Connor, Mellick, George D, Zimprich, Alexander, Pirker, Walter, Rogaeva, Ekaterina, Lang, Anthony E, Koks, Sulev, Ashok Kumar Sreelatha, Ashwin, Taba, Pille, Lesage, Suzanne, Brice, Alexis, Corvol, Jean-Christophe, Chartier-Harlin, Marie-Christine, Mutez, Eugénie, Brockmann, Kathrin, Deutschländer, Angela B, Hadjigeorgiou, Georges M, Dardiotis, Efthimos, Schulte, Claudia, Stefanis, Leonidas, Simitsi, Athina Maria, Valente, Enza Maria, Petrucci, Simona, Duga, Stefano, Straniero, Letizia, Zecchinelli, Anna, Pezzoli, Gianni, Brighina, Laura, Ferrarese, Carlo, Grover, Sandeep, Annesi, Grazia, Quattrone, Andrea, Gagliardi, Monica, Matsuo, Hirotaka, Kawamura, Yusuke, Hattori, Nobutaka, Nishioka, Kenya, Chung, Sun Ju, Kim, Yun Joong, Kolber, Pierre, Mohamed, Océane, van de Warrenburg, Bart P C, Bloem, Bastiaan R, Aasly, Jan, Toft, Mathias, Pihlstrøm, Lasse, Correia Guedes, Leonor, Ferreira, Joaquim J, Bardien, Soraya, Carr, Jonathan, Tolosa, Eduardo, Portugal, Berta, Ezquerra, Mario, Pastor, Pau, Diez-Fairen, Monica, Wirdefeldt, Karin, Pedersen, Nancy L, Ran, Caroline, Belin, Andrea C, Puschmann, Andreas, Hellberg, Clara, Clarke, Carl E, May, Patrick, Morrison, Karen E, Tan, Manuela, Krainc, Dimitri, Burbulla, Lena F, Farrer, Matt J, Krüger, Rejko, Gasser, Thomas, Sharma, Manu, Elbaz, Alexis, Genetics, and the Comprehensive Unbiased Risk Factor Assessment for, Bobbili, Dheeraj R, Disease, Environment in Parkinson's, Radivojkov-Blagojevic, Milena, and Repositório da Universidade de Lisboa

Subjects
Male, dairy intake, Parkinson's disease, Mendelian randomization, Parkinson Disease, Dairy intake, Mendelian Randomization Analysis, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Polymorphism, Single Nucleotide, Neurology, genetics [Parkinson Disease], Risk Factors, adverse effects [Dairy Products], genetics [Polymorphism, Single Nucleotide], Humans, Genetic Predisposition to Disease, Female, Dairy Products, Neurology (clinical), ddc:610, epidemiology [Parkinson Disease], genetics [Genetic Predisposition to Disease], Genome-Wide Association Study
Abstract

© 2022 International Parkinson and Movement Disorder Society, Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society., This study used data from the Courage-PD consortium, conducted under a partnership agreement among 35 studies. The Courage-PD consortium is supported by the EU Joint Program for Neurodegenerative Disease research (JPND; https://www.neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/). C.D. is the recipient of a doctoral grant from Université Paris-Saclay, France. P.M. was funded by the Fonds National de Recherche (FNR), Luxembourg, as part of the National Centre of Excellence in Research on Parkinson's Disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377). A.B.S., D.G.H., and C.E. are funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949. E.R. is funded by the Canadian Consortium on Neurodegeneration in Aging. S.K. is funded by MSWA. P.T. is the recipient of an Estonian Research Council Grant PRG957. E.M.V. is funded by the Italian Ministry of Health (Ricerca Corrente 2021). S.B. and J.C. are supported by grants from the National Research Foundation of South Africa (grant number: 106052); the South African Medical Research Council (Self-Initiated Research Grant); and Stellenbosch University, South Africa; they also acknowledge the support of the NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; and Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town. P.P. and M.D.-F. have received funding from the Spanish Ministry of Science and Innovation (SAF2013-47939-R). K.W. and N.L.P. are funded by the Swedish Research Council, grant numbers K2002-27X-14056-02B, 521-2010-2479, 521-2013-2488, and 2017-02175. N.L.P. is funded by the National Institutes of Health, grant numbers ES10758 and AG 08724. C.R. is funded by the Märta Lundkvist Foundation, Swedish Brain Foundation, and Karolinska Institutet Research Fund. A.C.B. is funded by the Swedish Brain Foundation, Swedish Research Council, and Karolinska Institutet Research Funds. M.T. (M. Tan) is funded by the Parkinson's UK. M.S. was supported by grants from the German Research Council (DFG/SH 599/6-1), MSA Coalition, and The Michael J. Fox Foundation (USA Genetic Diversity in PD Program: GAP-India Grant ID: 17473). PG GEN sample collection was funded by the MRC and UK Medical Research Council (C.E.C. and K.E.M.).

Published
2022

9. Blood Metal Levels and Amyotrophic Lateral Sclerosis Risk: A Prospective Cohort

Author

Broberg, Karin E., Kippler, Maria J., Veldink, Jan Herman, Van Den Berg, Leonard H., Middleton, Lefkos T., Travis, Ruth C., Bergmann, Manuela M., Mancini, Francesca Romana, Katzke, Verena Andrea, Agudo, Antonio T., Gómez, Jesús Humberto, Rodríguez-Barranco, Miguel A., Trichopoulou, Antonia D., Vermeulen, Roel C.H., Peters, Susan, Broberg, Karin, Gallo, Valentina, Levi, Michael, Kippler, Maria, Vineis, Paolo, Veldink, Jan, Berg, Leonard, Middleton, Lefkos, Travis, Ruth, Bergmann, Manuela, Palli, Domenico, Grioni, Sara, Tumino, Rosario, Elbaz, Alexis, Vlaar, Tim, Mancini, Francesca, Kühn, Tilman, Katzke, Verena, Agudo, Antonio, Goñi, Fernando, Gómez, Jesús‐humberto, Rodríguez‐barranco, Miguel, Merino, Susana, Barricarte, Aurelio, Trichopoulou, Antonia, Jenab, Mazda, Weiderpass, Elisabete, Vermeulen, Roel, Santé publique France - French National Public Health Agency [Saint-Maurice, France], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), FOOD‐CT‐2005‐513943 Ministry of National Education and Religious Affairs Cancer Research UK, CRUK Wellcome Trust, WT German Cancer Research Center, DKFZ Department of Health, Australian Government Institut National de la Santé et de la Recherche Médicale, Inserm Kræftens Bekæmpelse, DCS Instituto de Salud Carlos III, ISCIII: C03/09 Stichting Diabetes Onderzoek Nederland British Heart Foundation, BHF Norges Forskningsråd QLK4CT199900927 Stroke Association European Commission, EC Deutsche Krebshilfe World Cancer Research Fund, WCRF Kreftforeningen, NCS Medical Research Council, MRC, The EPIC study is funded by a number of grants, however, no funding source had any role in the preparation of this article. The EPIC study was funded by the Europe against Cancer program of the European Commission (SANCO), Italian Association for Research on Cancer, and Italian National Research Council. In addition, the authors thank the following for their financial support: the Environmental Cancer Risk, Nutrition, and Individual Susceptibility Network of Excellence, operating within the European Union Sixth Framework Program, Priority 5: Food Quality and Safety (FOOD‐CT‐2005‐513943), European Community Fifth Framework Program (grant QLK4CT199900927), ISCIII, Red de Centros RCESP (C03/09), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, Danish Cancer Society, Health Research Fund of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra, Cancer Research UK, Medical Research Council, UK, Stroke Association, UK, British Heart Foundation, Department of Health, UK, Food Standards Agency, UK, Wellcome Trust, UK, Greek Ministry of Health, Greek Ministry of Education, Italian Association for Research on Cancer, Italian National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Swedish Cancer, Swedish Scientific Council, Regional Government of Skåne and Västerbotten, Sweden, Norwegian Cancer Society, Research Council of Norway, French League against Cancer, INSERM, Mutuelle Generale l'Education National, and IGR. The EPIC‐Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC‐UU_12015/1) and Cancer Research UK (C864/A14136)., and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
0301 basic medicine, Adult, Male, Risk, medicine.medical_specialty, Clinical Neurology, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, LEAD-EXPOSURE, Internal medicine, medicine, Humans, Prospective Studies, Prospective cohort study, Research Articles, POPULATION, Aged, Retrospective Studies, Science & Technology, Neurology & Neurosurgery, business.industry, Amyotrophic Lateral Sclerosis, Neurosciences, 1103 Clinical Sciences, Retrospective cohort study, Odds ratio, Environmental exposure, Environmental Exposure, Mercury, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, 030104 developmental biology, Neurology, Cohort, Population study, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurosciences & Neurology, Neurology (clinical), SMOKING, 1109 Neurosciences, business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Research Article, Cohort study
Abstract

International audience; Objective: Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. Methods: A nested ALS case–control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma–mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. Results: The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1–15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08–3.87) and lead (OR = 1.89, 95% CI = 0.97–3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27–0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers. Interpretation: This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a–n/a.

Published
2021

10. Testosterone levels and cause-specific mortality in the older French men without metabolic syndrome

Author

Laouali, Nasser, Brailly-Tabard, Sylvie, Helmer, Catherine, Ancelin, Marie-Laure, Tzourio, Christophe, Elbaz, Alexis, Guiochon-Mantel, Anne, and Canonico, Marianne

Subjects
Male, lcsh:R, lcsh:Medicine, cardiovascular diseases mortality, Brief Communication, metabolic syndrome, ageing, Cause of Death, cancer mortality, testosterone, Humans, France, Mortality, Aged, Follow-Up Studies, risk
Abstract

OBJECTIVES Previous studies have reported controversial findings regarding the association of testosterone with mortality in older men. This heterogeneity might be partially explained by comorbidities and the presence of metabolic syndrome, as well as differential associations according to causes of death. METHODS We used data from a random subsample of the Three-City study, in which hormone levels were measured in 338 men ≥65 years without metabolic syndrome who were followed-up for 12 years. Vital status was determined for all participants from different sources. We used inverse-probability-weighted Cox regression to estimate the hazard ratios (HRs) of cause-specific mortality and 95% confidence intervals (CIs). RESULTS Over the follow-up period, 130 men died (30 from cardiovascular disease, 45 from cancer, 55 from other causes). The association of testosterone with mortality showed significant heterogeneity across causes of death (p=0.027 and p=0.022 for total and bioavailable testosterone, respectively). Higher testosterone levels were associated with increased cardiovascular mortality (HR for 1-standard deviation increase, 1.86; 95% CI, 1.28 to 2.71 and 1.50; 95% CI, 1.04 to 2.17 for total and bioavailable testosterone, respectively). By contrast, there were no significant associations of testosterone with mortality from cancer and other causes. CONCLUSIONS Our data suggest that the association of testosterone with mortality in men without metabolic syndrome might be differential according to the cause of death. These findings may partially explain the heterogeneity across studies on the relationship between testosterone levels and mortality.

Published
2020

11. Association between occupational solvent exposure and cognitive performance in the French CONSTANCES study

Author

Letellier, Noémie, Choron, Guillaume, Artaud, Fanny, Descatha, Alexis, Goldberg, Marcel, Zins, Marie, Elbaz, Alexis, Berr, C, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire de Ressources et de Recherche [Grenoble] (CMRR), Centre Hospitalier Universitaire [Grenoble] (CHU), The CONSTANCES cohort study was supported and funded by the ’Caisse nationale d’assurance maladie’ (CNAM). The CONSTANCES cohort study is an ’Infrastructure nationale en Biologie et Santé’ and benefits from a grant from Agence Nationale de la Recherche (ANR-11-INBS-0002). CONSTANCES is also partly funded by MSD, AstraZeneca and Lundbeck. The present analyses were supported by a grant from the French Agency for Food, Environmental and Occupational Health & Safety (ANSES, EST – No. 2016/1/102)., Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR-11-INBS-0002,CONSTANCES,La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance(2011), Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), UMS011 Cohortes épidémiologiques en population (CONSTANCES), Berr, Claudine, and Infrastructures - La cohorte CONSTANCES - Infrastructure épidémiologique ouverte pour la recherche et la surveillance - - CONSTANCES2011 - ANR-11-INBS-0002 - INBS - VALID

Subjects
Male, cognition, [SDV]Life Sciences [q-bio], Neuropsychological Tests, solvent, Surveys and Questionnaires, Humans, Sex Distribution, Workplace, ComputingMilieux_MISCELLANEOUS, Aged, working conditions, occupational exposure, Middle Aged, [SDV] Life Sciences [q-bio], Occupational Diseases, Cross-Sectional Studies, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Solvents, Regression Analysis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, women, Cognition Disorders
Abstract

Objective The objective of this study was to evaluate the association between occupational exposure to solvents and cognitive performance in middle-aged and early-ageing participants, taking into account the working environment. Methods In the French Cohorte des consultants des Centres d'examens de santé (CONSTANCES) cohort, 41 854 participants aged 45–69 years completed a self-reported, lifetime occupational exposure questionnaire. Exposure to solvents (gasoline for hand washing, trichloroethylene, white spirit, cellulosic thinner) was first considered as a binary variable (exposed/not exposed). We computed number of solvent types to which participants were exposed, solvent exposure time and delay since last exposure. Cognitive performance was assessed and analysed in reference to norms of neuropsychological battery previously established in CONSTANCES according to age, sex and education. Multiple linear and modified Poisson regression were used to estimate the associations between solvent exposure and cognitive performance adjusting for individual and environmental characteristics, and working conditions (night shift, repetitive and noisy work). Results Men had a greater risk of global cognitive impairment when they were exposed to gasoline (relative risk (RR)=1.12, 95% CI 1.03 to 1.22), white spirit (RR=1.14, 95% CI 1.05 to 1.25) or cellulosic thinner (RR=1.17, 95% CI 1.06 to 1.31) at the workplace, even after adjusting for confounders. Women exposed to white spirit or exposed for more than 20 years had poorer global cognitive performance. Conclusion These findings strengthen our understanding of the detrimental effect of solvent exposure on cognitive health not only in men but also in women for the first time, in a large general population middle-aged and early-ageing sample from France, taking into account working conditions.

Published
2020

12. Reducing Attentional Bias in Individuals With Alcohol Use Disorders With a Tablet Application: A Randomized Controlled Trial Pilot Study

Author

Pereira, Bruno, Benchetrit, Eve, Socha, Julie, Pineau, Fanny, Elbaz, Alexis, Artaud, Fanny, Mangone, Graziella, You, Hana, Cormier, Florence, Galitstky, Monique, Pomies, Elsa, Derkinderen, Pascal, Weintraub, Daniel, Corvol, Jean Christophe, Chereau-Boudet, Isabelle, Fantini, Maria Livia, Marques, Ana, Derost, Philippe, Boirie, Yves, Girard, Romuald, Obeso, Ignacio, Thobois, Stéphane, Park, Seongmin, Vidal, Tiphaine, Favre, Emilie, Ulla, Miguel, Broussolle, Emmanuel, Krack, Paul, Dreher, Jean-Claude, Corvol, Jean-Christophe, Durif, Franck, Meissner, Wassilios, Azulay, Jean-Philippe, Haddad, Raphaël, Guimarães-Costa, Raquel, Mariani, Louise-Laure, Cormier-Dequaire, Florence, Thalamas, Claire, Galitzky, Monique, Boraud, Thomas, Debilly, Bérengère, Eusebio, Alexandre, Houot, Marion, Dellapina, Estelle, Chaigneau, Véronique, Salis, Alexandrine, Lacomblez, Lucette, Benel, Laurent, Rascol, Olivier, Flaudias, Valentin, Zerhouni, Oulmann, Chakroun-Baggioni, Nadia, Pires, Sylvie, Schmitt, Audrey, De Chazeron, Ingrid, Llorca, Pierre Michel, Brousse, Georges, Service de Psychiatrie de l'Adulte B [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire Parisien de Psychologie Sociale (LAPPS), Université Paris Nanterre (UPN)-Université Paris 8 Vincennes-Saint-Denis (UP8), Laboratoire de Psychologie Sociale et Cognitive (LAPSCO), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), service de Biostatistiques, DRCI, Centre Hospitalier Universitaire de Clermont-Ferrand, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Epidemiology, Departments of Health Sciences Research, Mayo Clinic College of Medicine, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurology, University of Pennsylvania [Philadelphia], Centres d'addictologies - Région Centre, CHU Clermont-Ferrand, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux - Clermont Auvergne (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne (UCA), Service de neurologie, Hôpital Gabriel Montpied, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Neurologie [CHU Clermont-Ferrand], Hospices Civils de Lyon (HCL), Neurosciences précliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Le Kremlin Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, CIC - Biotherapie - Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Toulouse, Laboratoire Mouvement Adaptation Cognition (MAC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Inter-universitaire de Psychologie : Personnalité, Cognition, Changement Social (LIP-PC2S ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Grenoble Alpes (UGA), Laboratoire de Psychologie Sociale et Cognitive - Clermont Auvergne (LAPSCO), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), and Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)

Subjects
Adult, Male, Cognitive bias modification, Ecological validity, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Mental processes, education, Craving, Pilot Projects, Alcohol use disorder, Attentional bias, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Memory, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Tablet dosage form, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Cognitive Behavioral Therapy, Ethanol, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Play behavior, Cognition, General Medicine, Middle Aged, medicine.disease, Cognitive bias, 030227 psychiatry, Alcoholism, Inhibition, Psychological, Treatment Outcome, Therapy, Computer-Assisted, [SCCO.PSYC]Cognitive science/Psychology, Female, medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Clinical psychology
Abstract

Aims Cognitive bias modification (CBM) training has been considered a promising and effective intervention tool for reducing cognitive biases toward alcohol. However, the link between the cognitive process and actual behavior remains statistically insignificant because computerized tasks do not have sufficient ecological validity and suffer from high dropout rates. The recent development of ‘serious games’ has shown encouraging results in maintaining adherence to health-related interventions. We aim to evaluate a CBM program using a gamified attentional bias (AB) training procedure on a touchpad for individuals with alcohol use disorders. Methods Forty-one patients were included in this study, 33 of whom displayed an AB and were randomly assigned into the ‘CBM group’ (N = 18, 16.7% women) or ‘Memory group’—which involved playing a memory game—(N = 15, no woman). Eight other participants (12.5% women) with no AB comprised the ‘Without AB group’. Efficacy was assessed for AB, craving, and inhibition and attentional capacities before and after the program. Results We observed that the reduction of AB was higher for the ‘CBM group’ (Mbefore = 153.61, SD = 172.21; Mafter = 18.00, SD = 77.71; t (17) = 4.21, P = 0.001) than for the ‘Memory group’ (Mbefore = 73.20, SD = 66.65; Mafter =42.47, SD = 113.77; ts Conclusions This study demonstrated an increased reduction of AB for patients included in the CBM program on a touchpad than for patients playing only a memory game.

Published
2020

13. Obesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II Study

Author

Singh-Manoux, Archana, Dugravot, Aline, Shipley, Martin, Brunner, Eric J., Elbaz, Alexis, Sabia, Séverine, and Kivimaki, Mika

Subjects
Male, Waist-to-hip ratio, Age Factors, Middle Aged, Neuropsychological Tests, Weight Gain, Severity of Illness Index, Article, Body Mass Index, Cohort Studies, BMI, mental disorders, Waist circumference, Humans, Dementia, Female, Obesity, Adiposity, Aged, Proportional Hazards Models
Abstract

Introduction We examined whether obesity at ages 50, 60, and 70 years is associated with subsequent dementia. Changes in body mass index (BMI) for more than 28 years before dementia diagnosis were compared with changes in BMI in those free of dementia. Methods A total of 10,308 adults (33% women) aged 35 to 55 years in 1985 were followed up until 2015. BMI was assessed six times and 329 cases of dementia were recorded. Results Obesity (BMI ≥30 kg/m2) at age 50 years (hazard ratio = 1.93; 1.35–2.75) but not at 60 or 70 years was associated with risk of dementia. Trajectories of BMI differed in those with dementia compared with all others (P

Published
2018

14. Global, regional, and national burden of motor neuron diseases 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Author

Logroscino, Giancarlo, Piccininni, Marco, Marin, Benoît, Nichols, Emma, Abd-Allah, Foad, Abdelalim, Ahmed, Alahdab, Fares, Asgedom, Solomon Weldegebreal, Awasthi, Ashish, Chaiah, Yazan, Daryani, Ahmad, Do, Huyen Phuc, Dubey, Manisha, Elbaz, Alexis, Eskandarieh, Sharareh, Farhadi, Farzaneh, Farzadfar, Farshad, Fereshtehnejad, Seyed-Mohammad, Fernandes, Eduarda, Filip, Irina, Foreman, Kyle J., Gebre, Abadi Kahsu, Gnedovskaya, Elena V., Hamidi, Samer, Hay, Simon I., Irvani, Seyed Sina Naghibi, Ji, John S., Kasaeian, Amir, Kim, Yun Jin, Mantovani, Lorenzo Giovanni, Mashamba-Thompson, Tivani Phosa, Mehndiratta, Man Mohan, Mokdad, Ali H., Nagel, Gabriele, Nguyen, Trang Huyen, Nixon, Molly R, Olagunju, Andrew T, Owolabi, Mayowa Ojo, Piradov, Michael A, Qorbani, Mostafa, Radfar, Amir, Reiner, Robert C, Sahraian, Mohammad Ali, Sarvi, Shahabeddin, Sharif, Mehdi, Temsah, Omar, Tran, Bach Xuan, Truong, Nu Thi, Venketasubramanian, Narayanaswamy, Winkler, Andrea Sylvia, Yimer, Ebrahim M, Feigin, Valery L., Vos, Theo, Murray, Christopher J L, Università degli studi di Bari, Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Laboratoire de Biostatistique et d'Informatique Médicale, Université de Limoges (UNILIM), Institute for Health Metrics and Evaluation [University of Washington], University of Washington [Seattle], Department of Neurology [Egypte], Cairo University - Faculty of Medicine, Mayo Clinic [Rochester], Public Health Directorate, Saudi Ministry of Health, WHO Collaborating Center for Mass Gathering Medicine, Riyadh, Saudi Arabia, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia., Neuroépidémiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Spatial Ecology and Epidemiology Group, Department of Zoology, Ludwig-Maximilians-University of Munich-Grosshadern, Department of Neurology, Università degli studi di Bari Aldo Moro (UNIBA), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Département santé travail (DST-InVS), Institut de Veille Sanitaire (INVS), Institute of Epidemiology, Universität Ulm - Ulm University [Ulm, Allemagne], University of Tehran, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Logroscino, G, Piccininni, M, Marin, B, Nichols, E, Abd-Allah, F, Abdelalim, A, Alahdab, F, Asgedom, S, Awasthi, A, Chaiah, Y, Daryani, A, Do, H, Dubey, M, Elbaz, A, Eskandarieh, S, Farhadi, F, Farzadfar, F, Fereshtehnejad, S, Fernandes, E, Filip, I, Foreman, K, Gebre, A, Gnedovskaya, E, Hamidi, S, Hay, S, Irvani, S, Ji, J, Kasaeian, A, Kim, Y, Mantovani, L, Mashamba-Thompson, T, Mehndiratta, M, Mokdad, A, Nagel, G, Nguyen, T, Nixon, M, Olagunju, A, Owolabi, M, Piradov, M, Qorbani, M, Radfar, A, Reiner, R, Sahraian, M, Sarvi, S, Sharif, M, Temsah, O, Tran, B, Truong, N, Venketasubramanian, N, Winkler, A, Yimer, E, Feigin, V, Vos, T, and Murray, C

Subjects
Aged, 80 and over, Male, Incidence, Amyotrophic Lateral Sclerosis, Bayes Theorem, Middle Aged, Article, Global Burden of Disease, Age Distribution, Life Expectancy, Cause of Death, Prevalence, Humans, Disabled Persons, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Motor Neuron Disease, Aged
Abstract

Summary Background Understanding how prevalence, incidence, and mortality of motor neuron diseases change over time and by location is crucial for understanding the causes of these disorders and for health-care planning. Our aim was to produce estimates of incidence, prevalence, and disability-adjusted life-years (DALYs) for motor neuron diseases for 195 countries and territories from 1990 to 2016 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016. Methods The motor neuron diseases included in this study were amyotrophic lateral sclerosis, spinal muscular atrophy, hereditary spastic paraplegia, primary lateral sclerosis, progressive muscular atrophy, and pseudobulbar palsy. Incidence, prevalence, and DALYs were estimated using a Bayesian meta-regression model. We analysed 14 165 site-years of vital registration cause of death data using the GBD 2016 cause of death ensemble model. The 84 risk factors quantified in GBD 2016 were tested for an association with incidence or death from motor neuron diseases. We also explored the relationship between Socio-demographic Index (SDI; a compound measure of income per capita, education, and fertility) and age-standardised DALYs of motor neuron diseases. Findings In 2016, globally, 330 918 (95% uncertainty interval [UI] 299 522–367 254) individuals had a motor neuron disease. Motor neuron diseases have caused 926 090 (881 566–961 758) DALYs and 34 325 (33 051–35 364) deaths in 2016. The worldwide all-age prevalence was 4·5 (4·1–5·0) per 100 000 people, with an increase in age-standardised prevalence of 4·5% (3·4–5·7) over the study period. The all-age incidence was 0·78 (95% UI 0·71–0·86) per 100 000 person-years. No risk factor analysed in GBD showed an association with motor neuron disease incidence. The largest age-standardised prevalence was in high SDI regions: high-income North America (16·8, 95% UI 15·8–16·9), Australasia (14·7, 13·5–16·1), and western Europe (12·9, 11·7–14·1). However, the prevalence and incidence were lower than expected based on SDI in high-income Asia Pacific. Interpretation Motor neuron diseases have low prevalence and incidence, but cause severe disability with a high fatality rate. Incidence of motor neuron diseases has geographical heterogeneity, which is not explained by any risk factors quantified in GBD, suggesting other unmeasured risk factors might have a role. Between 1990 and 2016, the burden of motor neuron diseases has increased substantially. The estimates presented here, as well as future estimates based on data from a greater number of countries, will be important in the planning of services for people with motor neuron diseases worldwide. Funding Bill & Melinda Gates Foundation.

Published
2018

15. Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis

Author

Moisan, Frédéric, Kab, Sofiane, Mohamed, Fatima, Canonico, Marianne, Le Guern, Morgane, Quintin, Cécile, Carcaillon, Laure, Nicolau, Javier, Duport, Nicolas, Singh-Manoux, Archana, Boussac-Zarebska, Marjorie, and Elbaz, Alexis

Subjects
Adult, Male, Risk, Movement Disorders, Databases, Factual, Parkinson Disease, Middle Aged, STATISTICS, Antiparkinson Agents, Cohort Studies, Prevalence, EPIDEMIOLOGY, Humans, Female, France, Sex Distribution, PARKINSON'S DISEASE, Algorithms
Abstract

Background Parkinson’s disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M–F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies. Methods We used French national drug claims databases to identify PD cases using a validated algorithm. We computed M–F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M–F ratios. Results On the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M–F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M–F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M–F ratio 0.20), and over 1.6 (p

Published
2015

16. Prediction of cognition in Parkinson's disease with a clinical–genetic score: a longitudinal analysis of nine cohorts

Author

Liu, Ganqiang, Locascio, Joseph J, Winder-Rhodes, Sophie, Vidailhet, Marie, Bonnet, Anne-Marie, Bonnet, Cecilia, Corvol, Jean-Christophe, Elbaz, Alexis, Grabli, David, Hartmann, Andreas, Klebe, Stephan, Lacomblez, Lucette, Mangone, Graziella, Tanner, Caroline M, Bourdain, Frédéric, Brandel, Jean-Philippe, Derkinderen, Pascal, Durif, Franck, Mesnage, Valérie, Pico, Fernando, Rascol, Olivier, Brefel-Courbon, Christine, Ory-Magne, Fabienne, Lang, Anthony E, Forlani, Sylvie, Lesage, Suzanne, Tahiri, Khadija, Albin, Roger, Alcalay, Roy, Ascherio, Alberto, Bowman, Dubois, Chen-Plotkin, Alice, Dawson, Ted, Eberly, Shirley, Dewey, Richard, German, Dwight, Saunders-Pullman, Rachel, Scherzer, Clemens, Vaillancourt, David, Petyuk, Vladislav, West, Andy, Zhang, Jing, Brice, Alexis, Ravina, Bernard, Shoulson, Ira, Cormier-Dequaire, Florence, Heutink, Peter, van Hilten, Jacobus J, Barker, Roger A, Williams-Gray, Caroline H, Marinus, Johan, Scherzer, Clemens R, HBS, CamPaIGN, PICNICS, PROPARK, Boot, Brendon, PSG, DIGPD, PDBP, Hyman, Bradley T, Ivinson, Adrian J, Trisini-Lipsanopoulos, Ana, Franco, Daly, Burke, Kyle, Sudarsky, Lewis R, Liao, Zhixiang, Hayes, Michael T, Umeh, Chizoba C, Sperling, Reisa, Growdon, John H, Schwarzschild, Michael A, Hung, Albert Y, Flaherty, Alice W, Blacker, Deborah, Wills, Anne-Marie, Sohur, U Shivraj, Page, Kara, Mejia, Nicte I, Viswanathan, Anand, Gomperts, Stephen N, Khurana, Vikram, Albers, Mark W, Alora-Palli, Maria, McGinnis, Scott, Sharma, Nutan, Dickerson, Bradford, Frosch, Matthew, Gomez-Isla, Teresa, Greenberg, Steven, Gusella, James, Hedden, Trey, Hedley-Whyte, E Tessa, Koenig, Aaron, Marquis-Sayagues, Marta, Marshall, Gad, Okereke, Olivia, Stemmer-Rachaminov, Anat, Kloppenburg, Jessica, Schlossmacher, Michael G, Selkoe, Dennis J, Yi, Thomas, Li, Haining, Stalberg, Gabriel, Jansen, Iris E, Barker, Roger, Foltynie, Tom, Williams-Gray, Caroline, Robbins, Trevor, Brayne, Carol, Mason, Sarah, Breen, David P, Cummins, Gemma, Evans, Jonathan, Mallet, Alain, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Human genetics

Subjects
0301 basic medicine, Gerontology, Male, medicine.medical_specialty, Population, etiology [Cognitive Dysfunction], 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Dementia, Humans, Cognitive Dysfunction, ddc:610, Longitudinal Studies, Cognitive decline, education, Aged, Proportional Hazards Models, Aged, 80 and over, education.field_of_study, Mini–Mental State Examination, Framingham Risk Score, medicine.diagnostic_test, Proportional hazards model, Hazard ratio, Parkinson Disease, Middle Aged, medicine.disease, Prognosis, diagnosis [Dementia], 030104 developmental biology, diagnosis [Cognitive Dysfunction], Quartile, Disease Progression, Female, Neurology (clinical), etiology [Dementia], complications [Parkinson Disease], Psychology, diagnosis [Parkinson Disease], 030217 neurology & neurosurgery, Algorithms
Abstract

Summary Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment in patients with the disease. Methods In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. Findings 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6–4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase ( GBA ) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1–7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82–0·90) and replication (95% CI 0·78–0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4–36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79–0·94) and a negative predictive value of 0·92 (95% 0·88–0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. Funding National Institutes of Health, US Department of Defense.

Published
2017

17. Contribution of cognitive performance and cognitive decline to associations between socioeconomic factors and dementia : a cohort study

Author

Rusmaully, Jennifer, Dugravot, Aline, Moatti, Jean-Paul, Marmot, Michael G., Elbaz, Alexis, Kivimaki, Mika, Sabia, Séverine, Singh-Manoux, Archana, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD), Department of Epidemiology and Public Health, University College of London [London] (UCL), The Whitehall II study is supported by grants from the US National Institute on Aging (R01AG013196, R01AG034454), the UK Medical Research Council (MRC K013351), and British Heart Foundation. MK is supported by the UK Medical Research Council (K013351), NordForsk (75021), and Horizon2020 (Lifepath 633666). ASM and JPM are supported by Horizon2020 (Fresher 643357)., European Project: 633666,H2020,H2020-PHC-2014-two-stage,LIFEPATH(2015), Bodescot, Myriam, Lifecourse biological pathways underlying social differences in healthy ageing - LIFEPATH - - H20202015-05-01 - 2019-04-30 - 633666 - VALID, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Male, Cognitive Neuroscience, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cardiology, Social Sciences, Cardiovascular Medicine, Research and Analysis Methods, Cohort Studies, Cognition, Risk Factors, Mental Health and Psychiatry, London, Medicine and Health Sciences, Psychology, Humans, Public and Occupational Health, Cognitive Dysfunction, Aged, Retrospective Studies, Cognitive Impairment, Aged, 80 and over, Cognitive Neurology, Cognitive Psychology, Biology and Life Sciences, Middle Aged, Socioeconomic Aspects of Health, Health Care, Neurology, Socioeconomic Factors, Research Design, Cardiovascular Diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cognitive Science, Medicine, Dementia, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Behavioral and Social Aspects of Health, Research Article, Neuroscience
Abstract

Background Socioeconomic disadvantage is a risk factor for dementia, but longitudinal studies suggest that it does not affect the rate of cognitive decline. Our objective is to understand the manner in which socioeconomic disadvantage shapes dementia risk by examining its associations with midlife cognitive performance and cognitive decline from midlife to old age, including cognitive decline trajectories in those with dementia. Methods and findings Data are drawn from the Whitehall II study (N = 10,308 at study recruitment in 1985), with cognitive function assessed at 4 waves (1997, 2002, 2007, and 2012). Sociodemographic, behavioural, and cardiometabolic risk factors from 1985 and chronic conditions until the end of follow-up in 2015 (N dementia/total = 320/9,938) allowed the use of inverse probability weighting to take into account data missing because of loss to follow-up between the study recruitment in 1985 and the introduction of cognitive tests to the study in 1997. Generalized estimating equations and Cox regression were used to assess associations of socioeconomic markers (height, education, and midlife occupation categorized as low, intermediate, and high to represent hierarchy in the socioeconomic marker) with cognitive performance, cognitive decline, and dementia (N dementia/total = 195/7,499). In those with dementia, we examined whether retrospective trajectories of cognitive decline (backward timescale) over 18 years prior to diagnosis differed as a function of socioeconomic markers. Socioeconomic disadvantage was associated with poorer cognitive performance (all p < 0.001). Using point estimates for the effect of age, the differences between the high and low socioeconomic groups corresponded to an age effect of 4, 15, and 26 years, for height, education, and midlife occupation, respectively. There was no evidence of faster cognitive decline in socioeconomically disadvantaged groups. Low occupation, but not height or education, was associated with risk of dementia (hazard ratio [HR] = 2.03 [95% confidence interval (CI) 1.23–3.36]) in an analysis adjusted for sociodemographic factors; the excess risk was unchanged after adjustment for cognitive decline but was completely attenuated after adjustment for cognitive performance. In further analyses restricted to those with dementia, retrospective cognitive trajectories over 18 years prior to dementia diagnosis showed faster cognitive decline in the high education (p = 0.006) and occupation (p = 0.001) groups such that large differences in cognitive performance in midlife were attenuated at dementia diagnosis. A major limitation of our study is the use of electronic health records rather than comprehensive dementia ascertainment. Conclusions Our results support the passive or threshold cognitive reserve hypothesis, in that high cognitive reserve is associated with lower risk for dementia because of its association with cognitive performance, which provides a buffer against clinical expression of dementia., In a cohort study including patients from the Whitehall II study, Archana Singh-Manoux and colleagues examine whether cognitive reserve is associated with cognitive performance and rate of cognitive decline., Author summary Why was this study done? Socioeconomic disadvantage is associated with greater risk of dementia, but the manner in which socioeconomic factors shape risk of dementia is unclear. Previous studies show lower socioeconomic status, a proxy for cognitive reserve, to be associated with lower cognitive function and increased risk of dementia, but not faster cognitive decline. What did the researchers do and find? We used data from 7,499 participants from the Whitehall II study, aged 45–69 years in 1997, who were administered cognitive tests 4 times between 1997 and 2012 and followed for incidence of dementia until 2015. We found socioeconomic disadvantage (measured using height, education, and midlife occupational position) to be associated with poorer cognitive performance but not with faster cognitive decline. Midlife occupation was associated with risk of dementia, and the excess risk was explained by lower midlife cognitive performance and not faster cognitive decline. Analyses restricted to those with dementia showed that the large socioeconomic differences in cognitive performance in midlife were completely attenuated over a period of 18 years leading to dementia diagnosis. What do these findings mean? Our analysis supports the passive or threshold cognitive reserve hypothesis, in that high cognitive reserve is associated with lower risk for dementia because of its association with cognitive performance, which provides a buffer against clinical expression of dementia. We found no evidence that high cognitive reserve is associated with a slower rate of cognitive decline; in fact, cognitive decline in the preclinical phase of dementia was more rapid in the high reserve group. The main limitation of our study is that analyses are based on dementia ascertained from medical records, likely missing out on milder forms of dementia.

Published
2017

18. Accelerometer assessed moderate-to-vigorous physical activity and successful ageing: results from the Whitehall II study

Author

Menai, Mehdi, van Hees, Vincent T., Elbaz, Alexis, Kivimaki, Mika, Singh-Manoux, Archana, and Sabia, Séverine

Subjects
Adult, Aged, 80 and over, Male, Aging, Middle Aged, Motor Activity, Article, Cross-Sectional Studies, Surveys and Questionnaires, Accelerometry, Humans, Female, Self Report, human activities, Exercise, Aged
Abstract

Physical activity is key for successful ageing, but questions remain regarding the optimal physical activity pattern. We examined the cross-sectional association between physical activity and successful ageing using data on 3,749 participants (age range = 60-83years) of the Whitehall II study. The participants underwent a clinical assessment, completed a 20-item physical activity questionnaire, and wore a wrist-mounted accelerometer for 9 days. Successful ageing was defined as good cognitive, motor, and respiratory functioning, along with absence of disability, mental health problems, and major chronic diseases. Time spent in moderate-to-vigorous physical activity (MVPA) episodes assessed by accelerometer was classified as "short" (1-9.59 minutes) and "long" (≥10 minutes) bouts. Linear multivariate regression showed that successful agers (N = 789) reported 3.79 (95% confidence interval (CI): 1.39-6.19) minutes more daily MVPA than other participants. Accelerometer data showed this difference to be 3.40 (95% CI:2.44-4.35) minutes for MVPA undertaken in short bouts, 4.16 (95% CI:3.11-5.20) minutes for long bouts, and 7.55 (95% CI:5.86-9.24) minutes for all MVPA bouts lasting 1 minute or more. Multivariate logistic regressions showed that participants undertaking ≥150 minutes of MVPA per week were more likely to be successful agers with both self-reported (Odd Ratio (OR) = 1.29,95% (CI):1.09-1.53) and accelerometer data (length bout ≥1 minute:OR = 1.92, 95%CI:1.60-2.30). Successful agers practice more MVPA, having both more short and long bouts, than non-successful agers.

Published
2017
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19. Alcohol consumption and cognitive decline in early old age

Author

Sabia, Séverine, Elbaz, Alexis, Britton, Annie, Bell, Steven, Dugravot, Aline, Shipley, Martin, Kivimaki, Mika, Singh-Manoux, Archana, Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de Gérontologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), The Whitehall II study is supported by the British Medical ResearchCouncil (K013351), British Heart Foundation, National Heart, Lung,and Blood Institute (R01HL036310), and US NIH National Instituteon Aging (R01AG013196, R01AG034454)., Bell, Steven [0000-0001-6774-3149], Apollo - University of Cambridge Repository, SZTAJNBOK, Pascale, and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Aging, Alcohol Drinking, Middle Aged, Neuropsychological Tests, Article, Cohort Studies, Executive Function, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Memory, Surveys and Questionnaires, Linear Models, Humans, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cognition Disorders, Aged
Abstract

OBJECTIVE: To examine the association between alcohol consumption in midlife and subsequent cognitive decline. METHODS: Data are from 5,054 men and 2,099 women from the Whitehall II cohort study with a mean age of 56 years (range 44-69 years) at first cognitive assessment. Alcohol consumption was assessed 3 times in the 10 years preceding the first cognitive assessment (1997-1999). Cognitive tests were repeated in 2002-2004 and 2007-2009. The cognitive test battery included 4 tests assessing memory and executive function; a global cognitive score summarized performances across these tests. Linear mixed models were used to assess the association between alcohol consumption and cognitive decline, expressed as z scores (mean = 0, SD = 1). RESULTS: In men, there were no differences in cognitive decline among alcohol abstainers, quitters, and light or moderate alcohol drinkers (

Published
2014

20. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Author

Liu, Ganqiang, Boot, Brendon, Cormier-Dequaire, Florence, Corvol, Jean-Christophe, Barker, Roger A, Heutink, Peter, Marinus, Johan, Williams-Gray, Caroline H, Scherzer, Clemens R, Progression, International Genetics of Parkinson Disease, Scherzer, C., Hyman, B. T., Locascio, Joseph J, Ivinson, A. J., Trisini-Lipsanopoulos, A., Franco, D., Burke, K., Sudarsky, L. R., Hayes, M. T., Umeh, C. C., Growdon, J. H., Schwarzschild, M. A., Hung, A. Y., Jansen, Iris E, Flaherty, A. W., Wills, A-M, Mejia, N. I., Gomperts, S. N., Khurana, V., Selkoe, D. J., Yi, T., Page, K., Liao, Z., Barker, R., Winder-Rhodes, Sophie, Foltynie, T., Williams-Gray, C. H., Mason, S., Winder-Rhodes, S., Breen, D., Cummins, G., Evans, J., Eberly, Shirley, Corvol, J-C, Brice, A., Elbaz, A., Mallet, A., Vidailhet, M., Bonnet, A-M, Bonnet, C., Grabli, D., Hartmann, A., Klebe, S., Elbaz, Alexis, Lacomblez, L., Mangone, G., Bourdain, F., Brandel, J-P, Derkinderen, P., Durif, F., Mesnage, V., Pico, F., Rascol, O., Forlani, S., Brice, Alexis, Lesage, S., Tahiri, K., van Hilten, J. J., Marinus, J., Duong, K., Ravina, Bernard, Dong, X., Hutten, S. J., Amr, S. S., Shoulson, I., Tanner, C. M., Lang, A. E., Nalls, M. A., van Hilten, Jacobus J, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease, medicine.disease_cause, genetics [Glucosylceramidase], etiology [Cognitive Dysfunction], 03 medical and health sciences, 0302 clinical medicine, Parkinson Disease/complications, genetics [Parkinson Disease], Internal medicine, Genetic variation, medicine, Humans, Cognitive Dysfunction/etiology, ddc:610, Longitudinal Studies, Cognitive decline, Allele, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Genetics, genetics [Gaucher Disease], Mutation, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Proportional hazards model, [SCCO.NEUR]Cognitive science/Neuroscience, Hazard ratio, genetics [Cognitive Dysfunction], [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Middle Aged, Confidence interval, 3. Good health, 030104 developmental biology, Neurology, Glucosylceramidase/genetics, Disease Progression, Glucosylceramidase, Female, Neurology (clinical), complications [Gaucher Disease], complications [Parkinson Disease], Gaucher Disease/complications, Psychology, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates.METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance.INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685.

Published
2016

21. Association of body mass index and waist circumference with successful ageing: 16 year follow-up of the Whitehall II study

Author

Singh-Manoux, Archana, Sabia, Séverine, Bouillon, Kim, Brunner, Eric J, Grodstein, Francine, Elbaz, Alexis, and Kivimaki, Mika

Subjects
Adult, Male, obesity, Aging, Health Status, Body Weight, body mass index, Middle Aged, waist circumference, Article, Logistic Models, ageing, Humans, Female, Longitudinal Studies, Adiposity, Follow-Up Studies
Abstract

Objective We examined whether midlife body mass index (BMI) and waist circumference (WC) predict successful ageing. Design and Methods BMI/WC were assessed in 4869 persons (mean age 51.2, range 42–63 in 1991/93) and survival and successful ageing (alive, no chronic disease at age >60 years, not in the worst age- and sex-standardized quintile of cognitive, physical, respiratory, and cardiovascular, and mental health) ascertained over a 16-year follow-up, analysed using logistic regression adjusted for socio-demographic factors and health behaviours. Results 507 participants died, 1008 met the criteria for successful ageing. Those with BMI≥30 kg/m2 had lower odds of successful ageing (Odds Ratio (OR)=0.37; 95% Confidence Interval (CI): 0.27, 0.50) and survival (OR=0.55; 95% CI: 0.41, 0.74) compared to BMI between 18.5–25 kg/m2. Those with a large waist circumference (≥102/88 cm in men/women) had lower odds of successful ageing (OR=0.41; 95% CI: 0.31, 0.54) and survival (OR=0.57; 95% CI: 0.44, 0.73) compared to those with a small waist (

Published
2013

22. Identification of common variants associated with human hippocampal and intracranial volumes

Author

Stein, Jason L, Medland, Sarah E, Bernard, Manon, Nauck, Matthias, Nöthen, Markus M., Olvera, Rene L, Pandolfo, Massimo, Pike, G Bruce, Puls, Ralf, Reinvang, Ivar, Rentería, Miguel E, Rietschel, Marcella, Roffman, Joshua L, Brown, Andrew A, Royle, Natalie A, Rujescu, Dan, Savitz, Jonathan, Schnack, Hugo G, Schnell, Knut, Seiferth, Nina, Smith, Colin, Steen, Vidar M, Valdés Hernández, Maria C, Van den Heuvel, Martijn, Cannon, Dara M, van der Wee, Nic J, Van Haren, Neeltje E M, Veltman, Joris A, Völzke, Henry, Walker, Robert, Westlye, Lars T, Whelan, Christopher D, Agartz, Ingrid, Boomsma, Dorret I, Cavalleri, Gianpiero L, Chakravarty, M Mallar, Dale, Anders M, Djurovic, Srdjan, Drevets, Wayne C, Hagoort, Peter, Hall, Jeremy, Heinz, Andreas, Jack, Clifford R, Foroud, Tatiana M, Le Hellard, Stephanie, Macciardi, Fabio, Christoforou, Andrea, Montgomery, Grant W, Poline, Jean Baptiste, Porteous, David J, Sisodiya, Sanjay M, Starr, John M, Sussmann, Jessika, Toga, Arthur W, Veltman, Dick J, Walter, Henrik, Weiner, Michael W, Domin, Martin, Initiative, Alzheimer's Disease Neuroimaging, Consortium, EPIGEN, Consortium, IMAGEN, Group, Saguenay Youth Study, Bis, Joshua C, Ikram, M Arfan, Smith, Albert V, Gudnason, Vilmundur, Tzourio, Christophe, Vernooij, Meike W, Grimm, Oliver, Launer, Lenore J, DeCarli, Charles, Seshadri, Sudha, Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Andreassen, Ole A, Apostolova, Liana G, Bastin, Mark E, Blangero, John, Brunner, Han G, Buckner, Randy L, Hollinshead, Marisa, Cichon, Sven, Coppola, Giovanni, de Zubicaray, Greig I, Deary, Ian J, Donohoe, Gary, de Geus, Eco J C, Espeseth, Thomas, Fernández, Guillén, Glahn, David C, Grabe, Hans J, Holmes, Avram J, Hardy, John, Hulshoff Pol, Hilleke E, Jenkinson, Mark, Kahn, René S, McDonald, Colm, McIntosh, Andrew M, McMahon, Francis J, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morris, Derek W, Homuth, Georg, Müller-Myhsok, Bertram, Nichols, Thomas E, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W, Potkin, Steven G, Sämann, Philipp G, Saykin, Andrew J, Schumann, Gunter, Vasquez, Alejandro Arias, Hottenga, Jouke-Jan, Smoller, Jordan W, Wardlaw, Joanna M, Weale, Michael E, Martin, Nicholas G, Franke, Barbara, Wright, Margaret J, Thompson, Paul M, Consortium, Enhancing Neuro Imaging Genetics through Meta-Analysis, Weiner, Michael, Aisen, Paul, Langan, Camilla, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Green, Robert C, Morris, John, Liu, Enchi, Lopez, Lorna M, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Hansell, Narelle K, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Hwang, Kristy S, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Kim, Sungeun, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Laje, Gonzalo, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lee, Phil H, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Liu, Xinmin, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Loth, Eva, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Hibar, Derrek P, Lourdusamy, Anbarasu, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, Mattingsdal, Morten, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Coleman, R Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Mohnke, Sebastian, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Mulnard, Ruth A, Thai, Gaby, Maniega, Susana Muñoz, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Nho, Kwangsik, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Lu, Po H, Bartzokis, George, Silverman, Daniel H S, Graff-Radford, Neill R, Nugent, Allison C, Parfitt, Francine, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, O'Brien, Carol, Bergman, Howard, Hosei, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Papmeyer, Martina, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Pütz, Benno, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Ramasamy, Adaikalavan, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Senstad, Rudy E, Rasmussen, Jerod, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Rijpkema, Mark, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Risacher, Shannon L, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Roddey, J Cooper, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Schwartz, Eben S, Sink, Kaycee M, Rose, Emma J, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Ryten, Mina, Miller, Bruce L, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabeth, Rachinsky, Irina, Drost, Dick, Cavalleri, Gianpiero, Alhusaini, Saud, Delanty, Norman, Whelan, Christopher, Sisodiya, Sanjay, Kasperaviciute, Dalia, Matarin, Mar, Depondt, Chantal, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Sprooten, Emma, Radtke, Rodney, Ottmann, Ruth, Sergievsky, G. H., Schumann, G., Conrod, P., Reed, L., Barker, G., Williams, S., Loth, E., Struve, M., Strengman, Eric, Lourdusamy, A., Cattrell, A., Nymberg, C., Topper, L., Smith, L., Havatzias, S., Stueber, K., Mallik, C., Stacey, D., Wong, C Peng, Teumer, Alexander, Werts, H., Andrew, C., Desrivieres, S., Heinz, A., Gallinat, J., Häke, I., Ivanov, N., Klär, A., Reuter, J., Winkler, Anderson M, Trabzuni, Daniah, Palafox, C., Hohmann, C., Schilling, C., Lüdemann, K., Romanowski, A., Ströhle, A., Wolff, E., Rapp, M., Ittermann, B., Brühl, R., Turner, Jessica, Ihlenfeld, A., Walaszek, B., Schubert, F., Garavan, H., Connolly, C., Jones, J., Lalor, E., McCabe, E., Ní Shiothcháin, A., Whelan, R., van Eijk, Kristel, Spanagel, R., Leonardi-Essmann, F., Sommer, W., Flor, H., Vollstaedt-Klein, S., Nees, F., Banaschewski, T., Poustka, L., Steiner, S., Mann, K., van Erp, Theo G M, Buehler, M., Rietschel, M., Stolzenburg, E., Schmal, C., Schirmbeck, F., Paus, T., Gowland, P., Heym, N., Lawrence, C., Newman, C., van Tol, Marie-Jose, Pausova, Z., Smolka, M., Huebner, T., Ripke, S., Mennigen, E., Muller, K., Ziesch, V., Büchel, C., Bromberg, U., Fadai, T., Wittfeld, Katharina, Lueken, L., Yacubian, J., Finsterbusch, J., Martinot, J. L., Artiges, E., Bordas, N., de Bournonville, S., Bricaud, Z., Gollier Briand, F., Lemaitre, H., Wolf, Christiane, Massicotte, J., Miranda, R., Paillère Martinot, M. L., Penttilä, J., Poline, J. B., Barbot, A., Schwartz, Y., Lalanne, C., Frouin, V., Thyreau, B., Woudstra, Saskia, Dalley, J., Mar, A., Robbins, T., Subramaniam, N., Theobald, D., Richmond, N., de Rover, M., Molander, A., Jordan, E., Robinson, E., Aleman, Andre, Hipolata, L., Moreno, M., Arroyo, M., Stephens, D., Ripley, T., Crombag, H., Pena, Y., Lathrop, M., Zelenika, D., Heath, S., Lanzerath, D., Heinrichs, B., Spranger, T., Fuchs, B., Speiser, C., Resch, F., Haffner, J., Parzer, P., Brunner, R., Klaassen, A., Toro, Roberto, Almasy, Laura, Klaassen, I., Constant, P., Mignon, X., Thomsen, T., Zysset, S., Vestboe, A., Ireland, J., Rogers, J., Binder, Elisabeth B, Chakravarty, Mallar, Smith, Albert Vernon, van der Lijn, Fedde, Crivello, Fabrice, Fornage, Myriam, Shulman, Joshua M, Brohawn, David G, Schmidt, Helena, Srikanth, Velandai, Schuur, Maaike, Yu, Lei, Choi, Seung-Hoan, Sigurdsson, Sigurdur, Verhaaren, Benjamin F J, DeStefano, Anita L, Lambert, Jean-Charles, Cantor, Rita M, Struchalin, Maksim, Stankovich, Jim, Ibrahim-Verbaas, Carla A, Fleischman, Debra, Zijdenbos, Alex, den Heijer, Tom, Mazoyer, Bernard, Coker, Laura H, Enzinger, Christian, Danoy, Patrick, Carless, Melanie A, Amin, Najaf, Arfanakis, Konstantinos, van Buchem, Mark A, de Bruijn, Renée F A G, Beiser, Alexa, Dufouil, Carole, Huang, Juebin, Cavalieri, Margherita, Thomson, Russell, Niessen, Wiro J, Corvin, Aiden, Chibnik, Lori B, Gislason, Gauti K, Hofman, Albert, Pikula, Aleksandra, Amouyel, Philippe, Freeman, Kevin B, Phan, Thanh G, Oostra, Ben A, Nalls, Michael A, Uitterlinden, Andre G, Czisch, Michael, Au, Rhoda, Elbaz, Alexis, Beare, Richard J, van Swieten, John C, Lopez, Oscar, Harris, Tamara B, Chouraki, Vincent, Breteler, Monique M B, De Jager, Philip L, Becker, James T, Curran, Joanne E, Knopman, David, Fazekas, Franz, Wolf, Philip A, van der Lugt, Aad, Longstreth, W. T., Brown, Mathew A, Bennett, David A, van Duijn, Cornelia M, Davies, Gail, Mosley, Thomas H, Schmidt, Reinhold, de Almeida, Marcio A A, Appel, Katja, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fagerness, Jesen, Fox, Peter T, Freimer, Nelson B, Gill, Michael, Göring, Harald H H, Bartecek, Richard, Hagler, Donald J, Hoehn, David, Holsboer, Florian, Hoogman, Martine, Hosten, Norbert, Jahanshad, Neda, Johnson, Matthew P, Kent, Jack W, Kochunov, Peter, Bergmann, Ørjan, Lancaster, Jack L, Lawrie, Stephen M, Liewald, David C, Mandl, René, Mattheisen, Manuel, Meisenzahl, Eva, Melle, Ingrid, Moses, Eric K, Mühleisen, Thomas W, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Queensland Institute of Medical Research, Radboud University Medical Center [Nijmegen], Yale University School of Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universität Greifswald - University of Greifswald, Universität Heidelberg [Heidelberg], University Medical Center [Utrecht], University of Oslo (UiO), University of Toronto, National University of Ireland [Galway] (NUI Galway), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], University of Bergen (UiB), Harvard University [Cambridge], VU University Amsterdam, University of Edinburgh, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], National Institutes of Health [Bethesda] (NIH), Department of Forensic and Neurodevelopmental Sciences, King‘s College London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Georgia State University, University System of Georgia (USG), Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Leiden University Medical Center (LUMC), Dundee Technopole, CXR Biosciences Ltd, University of Groningen [Groningen], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Department of Genetics, Southwest Foundation for Biomedical Research, Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, The University of Texas Health Science Center at Houston (UTHealth), Center for Neurobehavioral Genetics, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Computer Science, Durham University, Laboratoire des symbioses tropicales et méditerranéennes (UMR LSTM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of California, Institute of Neurology [London], University College of London [London] (UCL), University of California [San Francisco] (UCSF), Department of Medicine, University of Washington [Seattle], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Émile Durkheim (CED), Sciences Po Bordeaux - Institut d'études politiques de Bordeaux (IEP Bordeaux)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Salermo, Università degli Studi di Salerno (UNISA), School of Psychology, University of Queensland, University of Queensland [Brisbane], Hartford Hospital, Lancaster University, Centre for Advanced Imaging, McConnell Brain Imaging Centre (MNI), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Faculteit Medische Wetenschappen/UMCG, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Biological Psychology, Neuroscience Campus Amsterdam - Brain Imaging, EMGO+ - Mental Health, EPIGEN Consortium, IMAGENConsortium, Saguenay Youth Study Group, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium, Psychiatry, NCA - Brain Imaging, EMGO - Mental health, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Virology, Epidemiology, Clinical Chemistry, Erasmus MC other, Radiology & Nuclear Medicine, University of California (UC)-University of California (UC), Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg] = Heidelberg University, Harvard University, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of California [Irvine] (UC Irvine), Universiteit Leiden, University of California (UC), University of California [San Francisco] (UC San Francisco), Università degli Studi di Salerno = University of Salerno (UNISA), University of Iceland [Reykjavik], McGill University, University of Bergen (UIB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Bijvoet Center of Biomolecular Research, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, UMR5116, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and McGill University-McGill University

Subjects
Netherlands Twin Register (NTR), Pathology, 110 012 Social cognition of verbal communication, [SDV]Life Sciences [q-bio], Hippocampus, Genome-wide association study, DCN PAC - Perception action and control, Hippocampal formation, physiopathology [Brain], Bioinformatics, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, TEMPORAL-LOBE EPILEPSY, 110 014 Public activities, Renal disorder [IGMD 9], 0303 health sciences, medicine.diagnostic_test, Translational research Immune Regulation [ONCOL 3], Brain, Human brain, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], ALZHEIMERS-DISEASE, medicine.anatomical_structure, Brain size, genetics [Chromosomes, Human, Pair 12], genetics [Polymorphism, Single Nucleotide], Biomarker (medicine), NA+/H+ EXCHANGER, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetic Markers, medicine.medical_specialty, 110 000 Neurocognition of Language, DCN MP - Plasticity and memory, A neurocomputational model for the Processing of Linguistic Utterances based on the Unification-Space architecture [110 007 PLUS], BRAIN VOLUME, UNIFIED APPROACH, 110 013 Binding and the MUC-model, Neuroimaging, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, AUTOMATED SEGMENTATION, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, ddc:570, FUNCTIONAL IMPLICATIONS, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Chromosomes, Human, Pair 12, Magnetic resonance imaging, Genetic Loci, physiopathology [Hippocampus], 110 009 The human brain and Chinese prosody, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 108202.pdf (Publisher’s version ) (Closed access) Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 x 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 x 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 x 10(-7)). 01 mei 2012

Published
2012

23. Physical activity and adiposity markers at older ages: accelerometer vs questionnaire data

Author

Sabia, Séverine, Cogranne, Pol, van Hees, Vincent, Bell, Joshua, Elbaz, Alexis, Kivimaki, Mika, Singh-Manoux, Archana, Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), MoveLab— Physical Activity and Exercise Research, Institute of Cellular Medicine, Newcastle University, Centre de Gérontologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by the US National Institutes of Health (R01AG013196, R01AG034454, R01HL036310),theUKMedical ResearchCouncil (K013351),the BritishHeart Foundation (PG/29605), and the Economic and Social Research Council (ES/J023299)., SZTAJNBOK, Pascale, and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Medicine(all), Aged, 80 and over, Male, adiposity, Physical activity, Health Policy, questionnaire, Health Behavior, Nursing(all), body mass index, Middle Aged, Motor Activity, waist circumference, accelerometer, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Surveys and Questionnaires, Accelerometry, Humans, Female, Original Study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Self Report, Aged, Monitoring, Physiologic
Abstract

Objective Physical activity is critically important for successful aging, but its effect on adiposity markers at older ages is unclear as much of the evidence comes from self-reported data on physical activity. We assessed the associations of questionnaire-assessed and accelerometer-assessed physical activity with adiposity markers in older adults. Design/Setting/Participants This was a cross-sectional study on 3940 participants (age range 60-83 years) of the Whitehall II study who completed a 20-item physical activity questionnaire and wore a wrist-mounted accelerometer for 9 days in 2012 and 2013. Measurements Total physical activity was estimated using metabolic equivalent hours/week for the questionnaire and mean acceleration for the accelerometer. Time spent in moderate-and-vigorous physical activity (MVPA) was also assessed by questionnaire and accelerometer. Adiposity assessment included body mass index, waist circumference, and fat mass index. Fat mass index was calculated as fat mass/height² (kg/m²), with fat mass estimated using bioimpedance. Results Greater total physical activity was associated with lower adiposity for all adiposity markers in a dose-response manner. In men, the strength of this association was 2.4 to 2.8 times stronger with the accelerometer than with questionnaire data. In women, it was 1.9 to 2.3 times stronger. For MVPA, questionnaire data in men suggested no further benefit for adiposity markers past 1 hour/week of activity. This was not the case for accelerometer-assessed MVPA where, for example, compared with men undertaking

Published
2015

24. Cumulative Associations Between Midlife Health Behaviors and Physical Functioning in Early Old Age: A 17-Year Prospective Cohort Study

Author

Sabia, Séverine, Elbaz, Alexis, Rouveau, Nicolas, Brunner, Eric, Kivimaki, Mika, Singh-Manoux, Archana, Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris Descartes - Paris 5 (UPD5), Centre de Gérontologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Sainte Perine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), A.S-M is supported by the National Institute on Aging, National Institutes of Health (NIH, R01AG013196, R01AG034454). M.K is supported by the Medical Research Council (K013351), the Economic and Social Research Council, the NIH (R01HL036310, R01AG034454), and the Academy of Finland. A.E has received funding from the FrenchAgence Nationale de la Recherche (2009–2012). E.J.B is supported by the British Heart Foundation(RG/13/2/30098)., University College of London [London], Université Paris-Sud - Paris 11 (UP11) - Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Hôpital Paul Brousse - Assistance publique - Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Sainte-Perine, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and SZTAJNBOK, Pascale

Subjects
Male, Alcohol Drinking, Health Behavior, Clinical Investigations, Walking, Motor Activity, walking speed, Body Mass Index, Cohort Studies, Upper Extremity, physical function, London, Vegetables, Humans, Longitudinal Studies, Muscle Strength, Geriatric Assessment, Aged, Hand Strength, Smoking, Middle Aged, upper-limb strength, Diet, health behaviors, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Fruit, Linear Models, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

Objectives To examine cumulative associations between midlife health behaviors and walking speed and upper-limb strength in early old age. Design Prospective cohort study. Setting Whitehall II Study. Participants Individuals (mean age 49.1 ± 5.9 in 1991–93) with health behavior data for at least two of the three assessments (1991–93, 1997–99, 2002–04) and physical functioning measures in 2007–09 (mean age 65.9 ± 5.9) (N = 5,671). Measurements A trained nurse assessed walking speed and upper-limb strength. Unhealthy behaviors were defined as current or recent smoking, nonmoderate alcohol consumption (abstinence or heavy drinking), fruit and vegetable consumption less than twice per day, and physical inactivity (

Published
2014

25. Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Author

Heckman, Michael G, Elbaz, Alexis, Brighina, Laura, Pastor, Pao, Payami, Haydeh, Pchelina, Sofya N, Petersen, Maria Skaalum, Puschmann, Andrea, Ritz, Beate, Rogaeva, Ekaterina, Sazci, Ali, Slawek, Jaroslaw, Stefanis, Leonidas, Chartier-Harlin, Marie-Christine, Tan, Eng-King, Toda, Tatsushi, Toft, Mathias, Van Broeckhoven, Christine, Wirdefeldt, Karin, Woitalla, Dirk, Wszolek, Zbigniew K, Zimprich, Alexander, Dardiotis, Efthimios, Destée, Alain, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gispert, Suzana, Hadjigeorgiou, Georgios M, Hattori, Nobutaka, Soto-Ortolaza, Alexandra I, Ioannidis, John P A, Jasinska-Myga, Barbara, Jeon, Beom S, Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lin, Chin-Hsien, Lohmann, Katja, Loriot, Marie-Anne, Serie, Daniel J, Lynch, Timothy, Mellick, George D, Mutez, Eugénie, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A, Sohn, Young Ho, Aasly, Jan O, Tadic, Vera, Tomiyama, Hiroyuki, Uitti, Ryan J, Valente, Enza Maria, Vassilatis, Demetrios K, Vilariño-Güell, Carles, White, Linda R, Annesi, Grazia, Wu, Ruey-Meei, Xiromerisiou, Georgia, Maraganore, Demetrius M, Farrer, Matthew J, Ross, Owen A, Disease, Genetic Epidemiology Of Parkinson's, Auburger, Georg, Ioannidis, John P, Annesi, Grazie, Bentivoglio, Annarita, Bozi, Maria, Brice, Alexis, Carmine-Belin, Andrea, Carr, Jonathan, Bacon, Justin A, Carroll, Camille, Chase, Bruce, Checkoway, Harvey, Chen, Sheng-Di, Chung, Sun Ju, Cosentino, Carlos, Cresswell, Silke, Deutschlaender, Angela, Boczarska-Jedynak, Magdalena, Foroud, Tatiana, Garraux, Gaëtan, Goldwurm, Stefano, Hadjigeorgiou, George, Jeon, Beom Seok, Kawakami, Hideshi, Kishore, Asha, Krainc, Dimitri, Krygowska-Wajs, Anna, Lay-Son, Luis, Lin, Jeui-Jueng, Mellick, George, Morrison, Karen E, Munhoz, Renato P, Okubadejo, Njide U, Van Broeckhoven, Christine, Heckman, M, Elbaz, A, Soto Ortolaza, A, Serie, D, Aasly, J, Annesi, G, Auburger, G, Bacon, J, Boczarska Jedynak, M, Bozi, M, Brighina, L, Chartier Harlin, M, Dardiotis, E, Destée, A, Ferrarese, C, Ferraris, A, Fiske, B, Gispert, S, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lin, C, Lohmann, K, Loriot, M, Lynch, T, Mellick, G, Mutez, E, Opala, G, Park, S, Petrucci, S, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Tomiyama, H, Uitti, R, Valente, E, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Xiromerisiou, G, Maraganore, D, Farrer, M, and Ross, O

Subjects
Male, Aging, Parkinson's disease, european continental ancestry group, chemistry.chemical_compound, genetics [Parkinson Disease], Genotype, 80 and over, MAPT, genetics, genetics [Genetic Predisposition to Disease], Genetics, Aged, 80 and over, biology, General Neuroscience, LRRK2, Parkinson Disease, Middle Aged, Protein-Serine-Threonine Kinases, genetics [European Continental Ancestry Group], genetics [alpha-Synuclein], alpha-Synuclein, Medical genetics, Female, interaction, lrrk2, mapt, parkinson's disease, snca, adolescent, adult, aged, aged, 80 and over, asian continental ancestry group, female, genetic predisposition to disease, genotype, haplotypes, humans, leucine-rich repeat serine-threonine protein kinase-2, male, middle aged, parkinson disease, protein-serine-threonine kinases, risk, young adult, alpha-synuclein, tau proteins, genetic variation, Adult, Risk, medicine.medical_specialty, Interaction, Adolescent, Tau protein, MAPT protein, human, tau Proteins, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, genetics [Protein-Serine-Threonine Kinases], White People, Article, Young Adult, Genetic, Asian People, Genetic variation, genetics [Haplotypes], medicine, Humans, Genetic Predisposition to Disease, ddc:610, LRRK2 protein, human, SNCA protein, human, Biology, Aged, Alpha-synuclein, genetics [Asian Continental Ancestry Group], Haplotype, Genetic Variation, medicine.disease, nervous system diseases, genetics [tau Proteins], Haplotypes, chemistry, biology.protein, prevention & control [Parkinson Disease], SNCA, Neurology (clinical), Human medicine, Geriatrics and Gerontology, Developmental Biology
Abstract

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotypedefining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

Published
2014

26. Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

Author

Theuns, Jessie, Verstraeten, Aline, Krüger, Rejko, Puschmann, Andrea, Ritz, Beate, Rogaeva, Ekaterina, Sazci, Ali, Slawek, Jaroslaw, Stefanis, Leonidas, Tan, Eng-King, Toda, Tatsushi, Toft, Matthias, Van Broeckhoven, Christine, Lesage, Suzanne, Wirdefeldt, Karin, Woitalla, Dirk, Wszolek, Zbigniew K, Zimprich, Alexander, Brice, Alexis, Chung, Sun Ju, Kim, Mi-Jung, Kim, Young Jin, Ross, Owen A, Xi, Zhengrui, Sleegers, Kristel, Lang, Anthony E, Klein, Christine, Weissbach, Anne, Mellick, George D, Silburn, Peter A, Hadjigeorgiou, Georgios M, Dardiotis, Efthimios, Hattori, Nobutaka, Ogaki, Kotaro, Wauters, Eline, Zhao, Yi, Aasly, Jan, Valente, Enza Maria, Petrucci, Simona, Annesi, Grazia, Quattrone, Aldo, Ferrarese, Carlo, Brighina, Laura, Deutschländer, Angela, Puschmann, Andreas, Gijselinck, Ilse, Nilsson, Christer, Garraux, Gaëtan, LeDoux, Mark S, Pfeiffer, Ronald F, Boczarska-Jedynak, Magdalena, Opala, Grzegorz, Maraganore, Demetrius M, Engelborghs, Sebastiaan, De Deyn, Peter Paul, Cras, Patrick, Smolders, Stefanie, Cruts, Marc, Consortium, GEO-PD, Farrer, Matthew J, Aasly, Jan O, Elbaz, Alexis, Ioannidis, John P, Annesi, Grazie, Crosiers, David, Bozi, Maria, Curie, Marie, Carmine-Belin, Andrea, Carr, Jonathan, Carroll, Camille, Chen, Sheng-Di, Cosentino, Carlos, Cresswell, Silke, Corsmit, Ellen, Deutschlaender, Angela, Foroud, Tatiana, Goldwurm, Stefano, Hadjigeorgiou, George, Chartier-Harlin, Marie-Christine, Hassan, Anhar, Hentati, Faycal, Elinck, Ellen, Jeon, Beom Seok, Kawakami, Hideshi, Kim, Yun Joong, Kishore, Asha, Koks, Sulev, Krainc, Dimitri, Krygowska-Wajs, Anna, Lin, Juei-Jueng, Lynch, Tim, Sharma, Manu, Mellick, George, Morrison, Karen E, Munhoz, Renato P, Pastor, Pao, Payami, Haydeh, Pchelina, Sofya N, Petersburg, Saint, Petersen, Maria Skaalum, Theuns, J, Verstraeten, A, Sleegers, K, Wauters, E, Gijselinck, I, Smolders, S, Crosiers, D, Corsmit, E, Elinck, E, Sharma, M, Krüger, R, Lesage, S, Brice, A, Chung, S, Kim, M, Kim, Y, Ross, O, Wszolek, Z, Rogaeva, E, Xi, Z, Lang, A, Klein, C, Weissbach, A, Mellick, G, Silburn, P, Hadjigeorgiou, G, Dardiotis, E, Hattori, N, Ogaki, K, Tan, E, Zhao, Y, Aasly, J, Valente, E, Petrucci, S, Annesi, G, Quattrone, A, Ferrarese, C, Brighina, L, Deutschländer, A, Puschmann, A, Nilsson, C, Garraux, G, Ledoux, M, Pfeiffer, R, Boczarska Jedynak, M, Opala, G, Maraganore, D, Engelborghs, S, De Deyn, P, Cras, P, Cruts, M, Van Broeckhoven, C, Clinical sciences, Neurology, Physiotherapy, Human Physiology and Anatomy, and Pathologic Biochemistry and Physiology

Subjects
Male, Pathology, Parkinson's disease, Internationality, Gastroenterology, Cohort Studies, 0302 clinical medicine, C9orf72, genetics [Parkinson Disease], dna repeat expansion, Amyotrophic lateral sclerosis, Family history, Parkinson Disease/ diagnosis/epidemiology/ genetics, Proteins/ genetics, Medicine(all), 0303 health sciences, Frontotemporal lobar degeneration, Middle Aged, 3. Good health, c9orf72 protein, cohort studies, female, humans, internationality, male, middle aged, parkinson disease, proteins, Neurology, repeat-primed, Proteins/genetics, Cohort studies, Female, epidemiology [Parkinson Disease], diagnosis [Parkinson Disease], medicine.medical_specialty, short tandem repeat, genetics [DNA Repeat Expansion], Article, DNA Repeat Expansion/genetics, 03 medical and health sciences, Internal medicine, medicine, Humans, ddc:610, 030304 developmental biology, DNA Repeat Expansion/ genetics, C9orf72 Protein, business.industry, Parkinson Disease/diagnosis, Proteins, medicine.disease, genetics [Proteins], Genetic epidemiology, Genetic Epidemiology of Parkinson's Disease, Attributable risk, Etiology, Human medicine, Neurology (clinical), C9orf72 protein, human, business, 030217 neurology & neurosurgery
Abstract

Objectives: The objective of this study is to clarify the role of (G 4 C 2 ) n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson9s Disease (GEO-PD) cohort. Methods: C9orf72 (G 4 C 2 ) n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. Results: A pathogenic (G 4 C 2 ) n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G 4 C 2 ) n repeats; however, we could not detect a robust association between the C9orf72 (G 4 C 2 ) n repeat and PD, and the population attributable risk was low. Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

Published
2014

27. No evidence of a longitudinal association between diurnal cortisol patterns and cognition

Author

Singh-Manoux, Archana, Dugravot, Aline, Elbaz, Alexis, Shipley, Martin, Kivimaki, Mika, Kumari, Meena, Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre de Gérontologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ste Périne, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), This research is supported by the US National Institutes of Health(R01AG013196 to A. S-M, R01AG034454 toA. S-M and M.K, R01HL036310 toM. K), the UK Medical Research Council (K013351to M. K), the Economic and Social Research Council (toM. K) and the British Heart Foundation, which supportsM.J. S., Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and SZTAJNBOK, Pascale

Subjects
Male, Aging, Hypothalamo-Hypophyseal System, Time Factors, Hydrocortisone, Neuroscience(all), Clinical Neurology, Pituitary-Adrenal System, Cognitive decline, Cortisol, Cognition, Glucocorticoid, Humans, Longitudinal Studies, Saliva, Regular Article, Middle Aged, Circadian Rhythm, Ageing, Cross-Sectional Studies, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, Geriatrics and Gerontology, Cognition Disorders, Developmental Biology
Abstract

International audience; We examined the effect of salivary cortisol on cognitive performance and decline in 3229 adults (79% men), mean age 61 years. Six saliva samples over the day along with a cognition test battery were administered twice in 5 years. In fully-adjusted cross-sectional analyses from 2002 to 2004, higher waking cortisol was associated with higher reasoning score (β = 0.08, 95% confidence interval: 0.01, 0.15) but this finding was not replicated using data from 2007 to 2009. Over the mean 5 years follow-up there was decline in all cognitive tests but this decline did not vary as a function of cortisol levels; the exception was among APOE e4 carriers where a flatter diurnal slope and higher bedtime cortisol were associated with faster decline in verbal fluency. Changes in cortisol measures between 2002/2004 and 2007/2009 or chronically elevated levels were not associated with cognitive performance in 2007/2009. These results, based on a large sample of community-dwelling adults suggest that variability in hypothalamic-pituitary-adrenal function is not a strong contributor to cognitive aging.

Published
2013

28. Association between Parkinson's disease and the HLA-DRB1 locus.: Parkinson's Disease and HLADRB1

Author

Ismaïl Ahmed, Tamouza, Ryad, Delord, Marc, Krishnamoorthy, Rajagopal, Tzourio, Christophe, Mulot, Claire, Nacfer, Magali, Lambert, Jean-Charles, Beaune, Philippe, Laurent-Puig, Pierre, Loriot, Marie-Anne, Charron, Dominique, Elbaz, Alexis, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Pharmacogénétique et abords thérapeutiques des maladies héréditaires, Université des Antilles et de la Guyane (UAG)-Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epigenetec, Centre de Ressources Biologiques (CRB), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), A. Elbaz has been funded for the present work (money paid to his institution) by grants from Agence Nationale de la Recherche (ANR), Agence Française de Sécurité Sanitaire de l'Environnement et du Travail (AFSSET), and France Parkinson., Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme biostatistique/bioinformatique, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Université des Antilles et de la Guyane ( UAG ) -Université Paris Diderot - Paris 7 ( UPD7 ) -IFR2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Bases moléculaires de la réponse aux xénobiotiques ( U775 (IFR95) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
Adult, Aged, 80 and over, Male, Genotype, Parkinson Disease, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, DNA, Middle Aged, Polymorphism, Single Nucleotide, Haplotypes, Socioeconomic Factors, Humans, Female, Genetic Predisposition to Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Aged, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

International audience; Two genome-wide association studies (GWASs) recently highlighted the HLA-DRA and HLA-DRB5 genes as associated with Parkinson disease (PD). However, because HLA-DRA displays a low level of polymorphisms and HLA-DRB5 is only present in approximately 20% of the population, these findings are difficult to interpret. Our aims were: (1) to replicate and investigate in greater detail the association between PD and the HLA-DR region; (2) to identify PD-associated HLA alleles; and (3) to perform a meta-analysis of our top finding. As part of 2 French population-based case-control studies of PD including highly ethnically homogeneous participants, we investigated the association between PD and 51 Single-nucleotide polymorphisms (SNPs) in the HLA-DR region. HLA-DRB1 alleles were imputed using the HLA(*) IMP software. HLA typing was performed in a subsample of the participants. We performed a meta-analysis of our top finding based on 4 GWAS data sets. Among 499 cases and 1123 controls, after correction for multiple testing, we found an association with rs660895 (OR/minor allele, 0.70; 95% CI, 0.57-0.87) within the HLA-DRB1 gene, which encodes the most polymorphic HLA-DR chain (DRβ). A meta-analysis (7996 cases, 36455 controls) confirmed this association (OR, 0.86; 95% CI, 0.82-0.91; P < .0001). SNP-based imputation of HLA alleles showed an inverse association between PD and the HLA-DRB1(*) 04 allele. We replicated an association between PD and the HLA-DR region and provided further insight into the loci and alleles involved. The highly polymorphic HLA-DRB1 locus contains rs660895, which represents a more legitimate candidate than previous ones. Our finding is in agreement with the hypothesis of an immune component in PD pathophysiology. © 2012 Movement Disorder Society.

Published
2012

29. Common variants at 12q14 and 12q24 are associated with hippocampal volume

Author

Bis, Joshua C, DeCarli, Charles, Schuur, Maaike, Grimm, Oliver, Hollinshead, Marisa, Holmes, Avram J, Homuth, Georg, Hottenga, Jouke-Jan, Langan, Camilla, Lopez, Lorna M, Hansell, Narelle K, Hwang, Kristy S, Kim, Sungeun, Yu, Lei, Laje, Gonzalo, Lee, Phil H, Liu, Xinmin, Loth, Eva, Lourdusamy, Anbarasu, Maniega, Susana Muñoz, Mattingsdal, Morten, Mohnke, Sebastian, Nho, Kwangsik, Nugent, Allison C, Choi, Seung-Hoan, O'Brien, Carol, Papmeyer, Martina, Pütz, Benno, Ramasamy, Adaikalavan, Rasmussen, Jerod, Rijpkema, Mark, Risacher, Shannon L, Roddey, J Cooper, Rose, Emma J, Ryten, Mina, Sigurdsson, Sigurdur, Shen, Li, Sprooten, Emma, Strengman, Eric, Teumer, Alexander, Trabzuni, Daniah, Turner, Jessica, van Eijk, Kristel, van Erp, Theo G M, van Tol, Marie-Jose, Wittfeld, Katharina, Verhaaren, Benjamin F J, Wolf, Christiane, Woudstra, Saskia, Aleman, Andre, Alhusaini, Saud, Almasy, Laura, Binder, Elisabeth B, Brohawn, David G, Cantor, Rita M, Carless, Melanie A, Corvin, Aiden, DeStefano, Anita L, Czisch, Michael, Curran, Joanne E, Davies, Gail, de Almeida, Marcio A A, Delanty, Norman, Depondt, Chantal, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fagerness, Jesen, Lambert, Jean-Charles, Fox, Peter T, Freimer, Nelson B, Gill, Michael, Göring, Harald H H, Hagler, Donald J, Hoehn, David, Holsboer, Florian, Hoogman, Martine, Hosten, Norbert, Jahanshad, Neda, Jack, Clifford R, Johnson, Matthew P, Kasperaviciute, Dalia, Kent, Jack W, Kochunov, Peter, Lancaster, Jack L, Lawrie, Stephen M, Liewald, David C, Mandl, René, Matarin, Mar, Mattheisen, Manuel, Struchalin, Maksim, Meisenzahl, Eva, Melle, Ingrid, Moses, Eric K, Mühleisen, Thomas W, Nauck, Matthias, Nöthen, Markus M, Olvera, Rene L, Pandolfo, Massimo, Pike, G Bruce, Puls, Ralf, Stankovich, Jim, Reinvang, Ivar, Rentería, Miguel E, Rietschel, Marcella, Roffman, Joshua L, Royle, Natalie A, Rujescu, Dan, Savitz, Jonathan, Schnack, Hugo G, Schnell, Knut, Seiferth, Nina, Smith, Albert Vernon, Ibrahim-Verbaas, Carla A, Smith, Colin, Steen, Vidar M, Valdés Hernández, Maria C, Van den Heuvel, Martijn, van der Wee, Nic J, Van Haren, Neeltje E M, Veltman, Joris A, Völzke, Henry, Walker, Robert, Westlye, Lars T, Fleischman, Debra, Whelan, Christopher D, Agartz, Ingrid, Boomsma, Dorret I, Cavalleri, Gianpiero L, Dale, Anders M, Djurovic, Srdjan, Drevets, Wayne C, Hagoort, Peter, Hall, Jeremy, Heinz, Andreas, Zijdenbos, Alex, Foroud, Tatiana M, Le Hellard, Stephanie, Macciardi, Fabio, Montgomery, Grant W, Poline, Jean Baptiste, Porteous, David J, Sisodiya, Sanjay M, Starr, John M, Sussmann, Jessika, den Heijer, Tom, Toga, Arthur W, Veltman, Dick J, Walter, Henrik, Weiner, Michael W, Andreassen, Ole A, Apostolova, Liana G, Bastin, Mark E, Blangero, John, Brunner, Han G, Buckner, Randy L, Mazoyer, Bernard, Cichon, Sven, Coppola, Giovanni, de Zubicaray, Greig I, Deary, Ian J, Donohoe, Gary, de Geus, Eco J C, Espeseth, Thomas, Fernández, Guillén, Glahn, David C, Grabe, Hans J, Coker, Laura H, Hardy, John, Hulshoff Pol, Hilleke E, Jenkinson, Mark, Kahn, René S, McDonald, Colm, McIntosh, Andrew M, McMahon, Francis J, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morris, Derek W, Enzinger, Christian, Müller-Myhsok, Bertram, Nichols, Thomas E, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W, Potkin, Steven G, Sämann, Philipp G, Saykin, Andrew J, Schumann, Gunter, Danoy, Patrick, Smoller, Jordan W, Wardlaw, Joanna M, Weale, Michael E, Martin, Nicholas G, Franke, Barbara, Wright, Margaret J, Thompson, Paul M, Amin, Najaf, Arfanakis, Konstantinos, van der Lijn, Fedde, van Buchem, Mark A, de Bruijn, Renée F A G, Beiser, Alexa, Dufouil, Carole, Huang, Juebin, Cavalieri, Margherita, Thomson, Russell, Niessen, Wiro J, Chibnik, Lori B, Gislason, Gauti K, Crivello, Fabrice, Hofman, Albert, Pikula, Aleksandra, Amouyel, Philippe, Freeman, Kevin B, Phan, Thanh G, Oostra, Ben A, Stein, Jason L, Medland, Sarah E, Vasquez, Alejandro Arias, Hibar, Derrek P, Fornage, Myriam, Consortium, Enhancing Neuro Imaging Genetics through Meta-Analysis, Nalls, Michael A, Uitterlinden, Andre G, Au, Rhoda, Elbaz, Alexis, Beare, Richard J, Debette, Stephanie, van Swieten, John C, Lopez, Oscar L, Harris, Tamara B, Chouraki, Vincent, Breteler, Monique M B, De Jager, Philip L, Becker, James T, Vernooij, Meike W, Knopman, David, Fazekas, Franz, Shulman, Joshua M, Wolf, Philip A, van der Lugt, Aad, Gudnason, Vilmundur, Longstreth, W. T., Brown, Matthew A, Bennett, David A, van Duijn, Cornelia M, Mosley, Thomas H, Schmidt, Reinhold, Tzourio, Christophe, Schmidt, Helena, Launer, Lenore J, Ikram, M Arfan, Seshadri, Sudha, Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Arias Vasquez, Alejandro, Senstad, Rudy E, Winkler, Anderson M, Srikanth, Velandai, Toro, Roberto, Appel, Katja, Bartecek, Richard, Bergmann, Ørjan, Bernard, Manon, Brown, Andrew A, Cannon, Dara M, Chakravarty, Mallar, Christoforou, Andrea, Domin, Martin, University of Washington [Seattle], University of California [Davis] (UC Davis), University of California, Center for Neuroscience, University of California-University of California, Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, The University of Texas Health Science Center at Houston (UTHealth), Human Genetics Center, Institut National de la Santé et de la Recherche Médicale (INSERM), U708, Neuroepidemiology, Paris, France, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institute of Molecular Biology and Biochemistry, Medical University Graz, Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Monash University [Melbourne], Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, University of Tasmania [Hobart, Australia] (UTAS), Rush University Medical Center [Chicago], Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Université Lille Nord de France (COMUE), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Radiology, Mayo Clinic, Biospective [Montréal], Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands, Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Department of Neurology, Medical University Graz, Graz, Austri, University of Queensland, Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia, Department of Biomedical Engineering, Illinois Institute of Technology (IIT), Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands, University of Mississippi Medical Center (UMMC), Delft University of Technology (TU Delft), Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Queensland Institute of Medical Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], National Institutes of Health [Bethesda] (NIH), Unité de recherche Neuroépidémiologie [CHU Pitié-Salpêtrière], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Murdoch Children's Research Institute (MCRI), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Harvard University [Cambridge], Harvard Medical School [Boston] (HMS), Mayo Clinic [Rochester], Human Genetics Group, University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia, Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, University of Bordeaux, U708, Bordeaux, France, INSERM, Neuroepidemiology U708, Bordeaux, France, University of California (UC), University of California (UC)-University of California (UC), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), University of Queensland [Brisbane], Radboud University [Nijmegen], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Harvard University, Other departments, Human genetics, EMGO - Mental health, NCA - Attention & Cognition, Radiology & Nuclear Medicine, Epidemiology, Neurology, Cardiothoracic Surgery, Clinical Genetics, Internal Medicine, Biological Psychology, Neuroscience Campus Amsterdam - Attention & Cognition, and EMGO+ - Mental Health

Subjects
Netherlands Twin Register (NTR), genetics [Alzheimer Disease], Genome-wide association study, DCN PAC - Perception action and control, genetics [Cognition Disorders], Hippocampal formation, Hippocampus, 0302 clinical medicine, Polymorphism (computer science), Cognitive decline, Genetics, 0303 health sciences, Translational research Immune Regulation [ONCOL 3], Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], genetics [Chromosomes, Human, Pair 12], genetics [Polymorphism, Single Nucleotide], Alzheimer's disease, Genetic Markers, medicine.medical_specialty, DCN MP - Plasticity and memory, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, genetics [Dementia], Alzheimer Disease, ddc:570, Internal medicine, medicine, Humans, SNP, Chromosome 12, 030304 developmental biology, Chromosomes, Human, Pair 12, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Endocrinology, Genetic Loci, physiopathology [Hippocampus], Dementia, Cognition Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 110608.pdf (Publisher’s version ) (Closed access) Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of

Published
2012

30. The relation between type of farming and prevalence of Parkinson's disease among agricultural workers in five French districts.: Parkinson's disease and type of farming

Author

Moisan, Frédéric, Spinosi, Johan, Dupupet, Jean-Luc, Delabre, Laurène, Mazurie, Jean-Louis, Goldberg, Marcel, Imbernon, Ellen, Tzourio, Christophe, Elbaz, Alexis, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département santé travail (DST-InVS), Institut de Veille Sanitaire (INVS), Unité Mixte de Recherche Epidémiologique et de Surveillance Transport Travail Environnement (UMRESTTE UMR T9405), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Caisse centrale, Mutualité sociale agricole, Caisse départementale de la Gironde, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), This work was supported by Institut national de la santé et de la recherche médicale (Inserm), Agence nationale de la recherche, Agence française de sécurité sanitaire de l'environnement et du travail (Afsset) and France Parkinson. Frédéric Moisan was supported by a scholarship from the Ministère de l'enseignement supérieur et de la recherche., Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national de la santé et de la recherche médicale (Inserm), Agence nationale de la recherche, Agence française de sécurité sanitaire de l'environnement et du travail (Afsset) and France Parkinson. Frédéric Moisan was supported by a scholarship from the Ministère de l'enseignement supérieur et de la recherche, ANR-05-SEST-0004,Etude cas-témoin sur la maladie de Parkinson parmi des sujets affiliés à la Mutualité Sociale Agricole : rôle de l'exposition professionnelle aux pesticides et de la susceptibilité génétique(2005), and Schmaus, Annie

Subjects
Male, MESH: Humans, MESH: Environmental Exposure, prevalence, environmental exposure, pesticides, Article, MESH: Male, MESH: Occupational Exposure, Agricultural Workers' Diseases, MESH: France, Parkinson disease, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Occupational Exposure, Humans, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, MESH: Pesticides, MESH: Agricultural Workers' Diseases, MESH: Female, MESH: Parkinson Disease, MESH: Prevalence, MESH: Agriculture, agriculture
Abstract

International audience; Retrospective assessment of pesticide exposure is complex; however, patterns of pesticide use strongly depend on farming type, which is easier to assess than pesticide exposure. Our aim was to estimate Parkinson's disease (PD) prevalence in five French districts in 2007 among affiliates of Mutualité Sociale Agricole (MSA) and to investigate the relation between PD prevalence and farming type. We identified PD cases from administrative files as persons who used levodopa and/or benefited from free health care for PD. Densities of 16 farming types were defined at the canton of residence level (1988 French agricultural census). We used logistic regression to study the relation between PD prevalence and density of farming types and a semi-Bayes approach to deal with correlated exposures. We identified 1,659 PD cases, yielding an age- and sex-standardized PD prevalence of 3.01/1,000. Prevalence increased with age and was higher in men than women. We found a higher PD prevalence among affiliates living in cantons characterized by a higher density of farms specialized in fruits and permanent crops (multivariable semi-Bayes model: OR(4+5 vs 1+2+3 quintiles) = 1.21, 95% CI = 1.08-1.36; test for trend, P = 0.035). In France, farms specialized in fruits and permanent crops rank first in terms of insecticide use per hectare. Our findings are consistent with studies reporting an association between PD and insecticide use and show that workers in farms specialized in fruits or permanent crops may be an occupational group at higher PD risk. © 2010 Movement Disorder Society.

Published
2011

31. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study

Author

Ross, Owen A, Soto-Ortolaza, Alexandra I, Brighina, Laura, Riess, Olaf, Klein, Christine, Djarmati, Ana, Hagenah, Johann, Lohmann, Katja, van de Loo, Simone, Abahuni, Nadine, Gispert-Sánchez, Suzana, Hilker, Rüdiger, Auburger, Georg, Van Broeckhoven, Christine, Xiromerisiou, Georgia, Tsimourtou, Vaia, Ralli, Styliani, Kountra, Persa, Markou, Katerina, Patramani, Gianna, Vogiatzi, Christina, Lynch, Tim, Gibson, J Mark, Craig, Dr David, Carr, Jonathan, Valente, Enza Maria, Ferraris, Alessandro, Bentivoglio, Anna Rita, Ialongo, Tamara, Guidubaldi, Arianna, Piano, Carla, Ferrarese, Carlo, Tarantino, Patrizia, Annesi, Ferdinanda, Chartier-Harlin, Marie-Christine, Annesi, Grazia, Quattrone, Aldo, Hattori, Nobutaka, Tomiyama, Hiroyuki, Funayama, Manabu, Yoshino, Hiroyo, Li, Yuanzhe, Imamichi, Yoko, Toda, Tatsushi, Satake, Wataru, Dardiotis, Efthimios, Aasly, J., Opala, Grzegorz, Jasinska-Myga, Barbara, Boczarska-Jedynak, Magdalena, Tan, Eng King, Bardien, Soraya, Jeon, Beom Seok, Park, Sung Sup, Kim, Yun Joong, Dickson, Dennis W, Sohn, Young Ho, Belin, Andrea Carmine, Olson, Lars, Galter, Dagmar, Westerlund, Marie, Sydow, Olof, Pedersen, Nancy L, Wirdefeldt, Karin, Nilsson, Christer, Puschmann, Andreas, Diehl, Nancy N, Wu, Ruey-Meei, Maraganore, Demetrius M, Ahlskog, Eric, de Andrade, Mariza, Lesnick, Timothy G, Rocca, Walter A, Checkoway, Harvey, Farrer, M., Elbaz, Alexis, Heckman, Michael G, Fiske, Brian, Gibson, Rachel, Hadjigeorgiou, Georgios M, Ioannidis, John P A, Jeon, Beom S, Aasly, Jan O, Kruger, Rejko, Kyratzi, Elli, Lesage, Suzanne, Lin, Chin-Hsien, Lynch, Timothy, Mellick, George D, Mutez, Eugénie, Sharma, Manu, Silburn, Peter A, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Uitti, Ryan J, Vassilatis, Demetrios K, Vilariño-Güell, Carles, White, Linda R, Wszolek, Zbigniew K, Farrer, Matthew J, Bacon, Justin A, Disease, Genetic Epidemiology Of Parkinson's, Sutherland, G. T., Siebert, G. A., Nuytemans, Karen, Meeus, Bram, Crosiers, David, Pickut, Barbara, Engelborghs, Sebastiaan, De Deyn, Peter P, Cras, Patrick, Rogaeve, Ekaterina, Destée, A., Agid, Y., Anheim, M., Bonnet, A-M, Borg, M., Bozi, Maria, Brice, A., Broussolle, E., Corvol, J. C., Damier, P., Dürr, A., Durif, F., Lesage, S., Lohmann, E., Pollak, P., Brice, Alexis, Rascol, O., Tison, F., Tranchant, C., Viallet, F., Vidailhet, M., Gasser, Thomas, Krüger, Rejko, Berg, Daniela, Schulte, Claudia, Ross, O, Soto Ortolaza, A, Heckman, M, Aasly, J, Abahuni, N, Annesi, G, Bacon, J, Bardien, S, Bozi, M, Brice, A, Brighina, L, Van Broeckhoven, C, Carr, J, Chartier Harlin, M, Dardiotis, E, Dickson, D, Diehl, N, Elbaz, A, Ferrarese, C, Ferraris, A, Fiske, B, Gibson, J, Gibson, R, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lesage, S, Lin, C, Lynch, T, Maraganore, D, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Park, S, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Theuns, J, Tomiyama, H, Uitti, R, Valente, E, van de Loo, S, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Farrer, M, Engelborghs, Sebastiaan, De Deyn, Peter Paul, Cras, Patrick, Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium, Pathologic Biochemistry and Physiology, and Pollak, Pierre

Subjects
Male, Polymorphism, Single Nucleotide/*genetics, International Cooperation, Ethnic Groups/genetics, Ethnic Group, Genome-wide association study, Protein-Serine-Threonine Kinase, methods [Genome-Wide Association Study], genetics [Ethnic Groups], 0302 clinical medicine, Gene Frequency, genetics [Parkinson Disease], Risk Factors, Exons/genetics, Ethnicity, Parkinson Disease/genetics, Medicine(all), Genetics, Aged, 80 and over, 0303 health sciences, Parkinson Disease, Exons, genetics [Exons], Middle Aged, Polymorphism, Single Nucleotide/genetics, Protein-Serine-Threonine Kinases, LRRK2, 3. Good health, genetics [Polymorphism, Single Nucleotide], Genome-Wide Association Study/methods, Female, Case-Control Studie, Human, Adult, Parkinson Disease/*genetics, Genotype, Adolescent, Protein-Serine-Threonine Kinases/*genetics, Protein-Serine-Threonine Kinases/genetics, Exon, Protein Serine-Threonine Kinases, Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, genetics [Protein-Serine-Threonine Kinases], Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Humans, Genetic Predisposition to Disease, ddc:610, LRRK2 protein, human, Risk factor, Allele frequency, 030304 developmental biology, Aged, Risk Factor, Case-control study, Exons/*genetics, Odds ratio, nervous system diseases, ddc:616.8, Minor allele frequency, Genetic epidemiology, Case-Control Studies, Neurology (clinical), Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

BACKGROUND: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS: LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS: 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 1.33-15.09; p=0.012). INTERPRETATION: The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING: Michael J Fox Foundation and National Institutes of Health. Lancet Neurol

Published
2011

32. Independent and joint effects of the MAPT and SNCA genes in Parkinson disease

Author

Elbaz, Alexis, Ross, Owen A, Destée, Alain, Ferrarese, Carlo, Ferraris, Alessandro, Gibson, J Mark, Gispert, Suzana, Hadjigeorgiou, Georgios M, Jasinska-Myga, Barbara, Klein, Christine, Krüger, Rejko, Lambert, Jean-Charles, Ioannidis, John P A, Lohmann, Katja, van de Loo, Simone, Loriot, Marie-Anne, Lynch, Timothy, Mellick, George D, Mutez, Eugénie, Nilsson, Christer, Opala, Grzegorz, Puschmann, Andreas, Quattrone, Aldo, Soto-Ortolaza, Alexandra I, Sharma, Manu, Silburn, Peter A, Stefanis, Leonidas, Uitti, Ryan J, Valente, Enza Maria, Vilariño-Güell, Carles, Wirdefeldt, Karin, Wszolek, Zbigniew K, Xiromerisiou, Georgia, Maraganore, Demetrius M, Moisan, Frédéric, Farrer, Matthew J, Disease, Genetic Epidemiology of Parkinson's, Amouyel, Philippe, Tzourio, Christophe, Mulot, Claire, Bacon, Justin A, Cobb, Stephanie A, Sutherland, Greg T, Siebert, Gerhard A, Dissanayaka, Nadeeka, Aasly, Jan, O'Sullivan, John D, Boyle, Richard S, Pasquier, Florence, Bordet, Régis, Legendre, Jean-Philippe, Auburger, Georg, Hilker, Rüdiger, Abahuni, Nadine, Geisen, Christof, Winkler, Susen, Annesi, Grazia, Gasser, Thomas, Riess, Olaf, Berg, Daniela, Schulte, Claudia, Vassilatis, Demitris, Stamboulis, Eleftherios, Dardiotis, Efthimios, Patramani, Ioanna, Kountra, Persa-Maria, Vogiatzi, Christina, Bozi, Maria, Markou, Katerina, Tarantino, Patrizia, Annesi, Ferdinanda, Bentivoglio, Anna Rita, Guidubaldi, Arianna, Caccialupi, Matilde, De Nigris, Francesca, Riva, Chiara, Pedersen, Nancy L, Nilsson, Karin, Brighina, Laura, Reimer, Jan, Van Gerpen, Jay, Lash, Jennifer, Searcy, Jill, Strongosky, Audrey, Chartier-Harlin, Marie-Christine, Elbaz, A, Ross, O, Ioannidis, J, Soto Ortolaza, A, Moisan, F, Aasly, J, Annesi, G, Bozi, M, Brighina, L, Chartier Harlin, M, Destée, A, Ferrarese, C, Ferraris, A, Gibson, J, Gispert, S, Hadjigeorgiou, G, Jasinska Myga, B, Klein, C, Krüger, R, Lambert, J, Lohmann, K, van de Loo, S, Loriot, M, Lynch, T, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Stefanis, L, Uitti, R, Valente, E, Vilariño Güell, C, Wirdefeldt, K, Wszolek, Z, Xiromerisiou, G, Maraganore, D, and Farrer, M

Subjects
Adult, Male, Parkinson Disease/*genetics, Logistic Model, Polymorphism, Single Nucleotide/*genetics, Single-nucleotide polymorphism, Genome-wide association study, MAPT protein, human, tau Proteins, Biology, alpha-Synuclein/*genetics, Polymorphism, Single Nucleotide, Article, Gene interaction, genetics [Parkinson Disease], Retrospective Studie, Genotype, Odds Ratio, SNP, Humans, genetics, Genetic Predisposition to Disease, ddc:610, SNCA protein, human, Age of Onset, Retrospective Studies, Aged, Genetics, Aged, 80 and over, Haplotype, tau Protein, Parkinson Disease, Middle Aged, genetics [tau Proteins], Settore MED/26 - NEUROLOGIA, Logistic Models, Neurology, Genetic epidemiology, Case-Control Studies, Multiple comparisons problem, genetics [Polymorphism, Single Nucleotide], genetics [alpha-Synuclein], alpha-Synuclein, Female, Neurology (clinical), tau Proteins/*genetics, Case-Control Studie, Human
Abstract

Objective: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. Methods: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. Results: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 30 end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. Interpretation: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. ANN NEUROL 2011; 69: 778-792

Published
2011

33. Low disease risk in relatives of north african lrrk2 Parkinson disease patients

Author

Troiano, André, Elbaz, Alexis, Lohmann, E., Belarbi, S., Vidailhet, Marie, Bonnet, A.-M., Lesage, Suzanne, Pollak, Pierre, Cazeneuve, Cécile, Borg, Michel, Feingold, Josué, Dürr, Alexandra, Tazir, M., Brice, Alexis, Study Group, For The French Parkinson Disease Genetic, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche en Neurosciences, CHU Mustapha, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie, Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), ANR-05-NEUR-0019,LRRK2 in PD,Pathologie moléculaire et modèles murins du gène LRRK2, impliqué dans la maladie de Parkinson(2005), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Lesage, Suzanne, and Neurosciences, neurologie et psychiatrie - Pathologie moléculaire et modèles murins du gène LRRK2, impliqué dans la maladie de Parkinson - - LRRK2 in PD2005 - ANR-05-NEUR-0019 - NEURO - VALID

Subjects
Proband, Risk, Pediatrics, medicine.medical_specialty, Protein-Serine-Threonine Kinases/genetics, Population, Disease, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, 03 medical and health sciences, 0302 clinical medicine, Africa, Northern, Informed consent, Medicine, Outpatient clinic, Humans, Genetic Predisposition to Disease, Family, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Family history, Parkinson Disease/genetics, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Genetic Predisposition to Disease/genetics, Parkinson Disease, LRRK2, Penetrance, 3. Good health, ddc:616.8, Mutation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Currently, mutations in the leucine repeat–rich kinase 2 (LRRK2) gene are the main identifiable genetic cause of Parkinson disease (PD). The Gly2019Ser (G2019S) substitution is the most common mutation and is frequent among North African (40%) and Jewish (30%) patients with familial PD. Reduced G2019S penetrance has been documented in several reports.1–3 The identification of LRRK2 mutations in numerous North African patients without PD family history prompted us to investigate disease risk in presumed mutation carriers in this population. ### Methods. PD cases were recruited by a national French network (French PD Genetic Study Group) and collaborators from Algeria at their outpatient clinic (September 1994 through August 2007). Blood samples were collected from participants after obtaining written informed consent, and molecular analyses were performed.4 For this study, we included probands of North African ancestry who were heterozygous or homozygous G2019S carriers (figure e-1 on the Neurology ® Web site at www.neurology.org). They were interviewed to obtain information on their first-degree relatives. Relatives were analyzed from birth through 1 of the following events, whichever occurred first: PD onset or last contact or death without PD. The cumulative risk of PD until age 80 years in first-degree relatives was estimated using the Kaplan-Meier …

Published
2010

34. [Treatment of information on personal health data for research purposes: nobody should ignore the law.]

Author

Bonaïti-Pellié, Catherine, Arveux, Patrick, Billette De Villemeur, Agathe, Dantchev, Nicolas, Elbaz, Alexis, Fabre-Guillevin, Elisabeth, Fresson, Jeanne, Saura, Christine, Saurel-Cubizolles, Marie-Josèphe, Serre, Jean-Louis, Simon, Dominique, Stücker, Isabelle, Thélot, Bertrand, Tubert-Bitter, Pascale, Zureik, Mahmoud, Bonaïti-Pellié, Catherine, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé, and CCTIRS

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Research, Legislation as Topic, Humans, Health Promotion, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioethics, [SDV.ETH] Life Sciences [q-bio]/Ethics, Confidentiality, [SDV.ETH]Life Sciences [q-bio]/Ethics
Abstract

National audience; pas de résumé

Published
2009

35. [Parkinson's disease and rural environment]

Author

Elbaz, Alexis, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Tzourio, Christophe

Subjects
Rural Population, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Occupational Exposure, Humans, Parkinson Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Rural Health, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Parkinson Disease, Secondary, Pesticides, Agricultural Workers' Diseases
Abstract

International audience; Parkinson's disease, the primary cause of parkinsonian syndrome, is, after Alzheimer's disease, the most frequent neurodegenerative disorder. Parkinson's disease is currently considered as a multifactorial disease resulting from the effect of genetic and environmental susceptibility. Several epidemiological studies have shown a moderate association between Parkinson's disease and farmer occupation or exposure to pesticides. Nevertheless, no product has been incriminated in a repeatable manner in these studies. The main methodological difficulty of these studies is associated with the complexity in assessing the occupational exposure to pesticides. The results of the toxicological studies point equally in this direction and provide arguments in favor of this relationship. However, some questions remain to be answered, particularly the role of low-dose exposure, the gene-environment interactions and the implied biological mechanisms.

Published
2007

36. Risk of cancer after the diagnosis of Parkinson's disease: a historical cohort study

Author

Elbaz, Alexis, Peterson, Brett, Yang, Ping, Bower, James, Maraganore, Demetrius, Mcdonnell, Shannon, Ahlskog, J. Eric, Rocca, Walter, Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Department of Neurology, Mayo Clinic [Rochester], and Tzourio, Christophe

Subjects
Male, Risk, Parkinson's disease, etiology, MESH: Antiparkinson Agents, Antiparkinson Agents, Cohort Studies, MESH: Aged, 80 and over, MESH: Demography, Reference Values, Neoplasms, cohort study, Confidence Intervals, cancer, risk factors, Humans, MESH: Neoplasms, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Cohort Studies, Aged, Demography, Retrospective Studies, MESH: Aged, Aged, 80 and over, MESH: Risk, MESH: Humans, skin cancer, MESH: Reference Values, MESH: Retrospective Studies, Parkinson Disease, MESH: Follow-Up Studies, MESH: Confidence Intervals, MESH: Case-Control Studies, MESH: Male, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, MESH: Female, MESH: Parkinson Disease, Follow-Up Studies
Abstract

International audience; We investigated the risk of cancer after the diagnosis of Parkinson's disease (PD) through a historical cohort study. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of PD in Olmsted County, Minnesota from 1976 through 1995. Patients with PD were matched by age (+/- 1 year) and gender to referent subjects from the same population. For 196 patients and 185 referent subjects, we ascertained the incidence of cancer through medical records abstraction between the date of diagnosis (or index date) and death, loss to follow-up, or end of study. The risk of cancer was higher among patients than in referent subjects (relative risk [RR] = 1.64; 95% confidence interval [CI] = 1.15-2.35; P = 0.007). The RR did not change noticeably after adjustment for smoking. The increased risk was significant for nonmelanoma skin cancer (RR = 1.76; 95% CI = 1.07-2.89; P = 0.03), but not for other more severe types of cancer; therefore, we cannot exclude the occurrence of a surveillance bias. Among PD patients, there was no relation between the risk of cancer and the cumulative dose of levodopa received or the use of other PD medications.

Published
2005

37. S18Y polymorphism in the UCH-L1 gene and Parkinson's disease: evidence for an age-dependent relationship

Author

Elbaz, Alexis, Levecque, Clotilde, Clavel, Jacqueline, Vidal, Jean-Sébastien, Richard, Florence, Corrèze, Jean-René, Delemotte, Bernard, Amouyel, Philippe, Alpérovitch, Annick, Chartier-Harlin, Marie-Christine, Tzourio, Christophe, Recherches épidémiologiques en neurologie et psychopathologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des maladies chroniques: impact des intéractions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Recherches épidémiologiques et statistiques sur l'environnement et la santé., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Mutualité sociale agricole, Secretariat, U754, and Service de neurologie [CHU Saint-Antoine]

Subjects
Adult, Male, MESH: Smoking, Adolescent, Genotype, MESH: Age of Onset, MESH: Environmental Exposure, MESH: Insurance, Health, MESH: Genotype, Risk Factors, MESH: Risk Factors, Surveys and Questionnaires, MESH: Polymorphism, Genetic, Humans, MESH: Pesticides, Age of Onset, Pesticides, Alleles, Aged, MESH: Adolescent, MESH: Age Factors, MESH: Aged, Insurance, Health, Polymorphism, Genetic, MESH: Humans, MESH: Middle Aged, MESH: Questionnaires, MESH: Alleles, Smoking, Age Factors, Parkinson Disease, MESH: Adult, Environmental Exposure, Middle Aged, MESH: Ubiquitin Thiolesterase, MESH: Case-Control Studies, MESH: Male, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Thiolester Hydrolases, MESH: Thiolester Hydrolases, Ubiquitin Thiolesterase, MESH: Female, MESH: Parkinson Disease
Abstract

International audience; We studied the relationship between Parkinson's disease (PD) and the S18Y polymorphism in the UCH-L1 gene and the effect on this relationship of age at onset, smoking, and pesticides. Patients requested free health coverage for PD to the Mutualit?ociale Agricole (MSA), the French health insurance organization for people whose work is related to agriculture. Controls requested reimbursement of health expenses to the MSA. A maximum of three controls were matched to each case. Analyses included participants with both parents born in Europe. There were no differences in S18Y genotypes between patients (n = 209; 67% SS, 32% SY, 1% YY) and controls (n = 488; 66% SS, 30% SY, 4% YY). The relationship between PD and S18Y was modified by age at onset (P = 0.03). The Y allele was inversely associated with PD for patients with onset before 61 years (odds ratio [OR] = 0.53; 95% confidence interval [CI], 0.29-0.99); there was no association for older patients (62-68 years: OR = 1.21; 95% CI, 0.67-2.20; >68 years: OR = 1.24; 95% CI, 0.67-2.31). Among patients, Y carriers had a later onset than noncarriers (P = 0.04). These findings were not modified or confounded by smoking and pesticides. In this community-based case-control study, carriers of the Y allele were at decreased risk of developing PD at a young age, independently of pesticides and smoking.

Published
2003

38. Trajectories of the Framingham general cardiovascular risk profile in midlife and poor motor function later in life: The Whitehall II study

Author

Elbaz, Alexis, Shipley, Martin, Nabi, Hermann, Brunner, Eric, Kivimaki, Mika, Singh-Manoux, Archana, SZTAJNBOK, Pascale, Department of Epidemiology and Public Health, University College of London [London] (UCL), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Gérontologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Sainte Perine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ASM is supported by a 'European Young Investigator Award' fromthe European Science Foundation. EJB and MS are supported by the BritishHeart Foundation. MK is supported by the BUPA Foundation, UK, theAcademy of Finland, Finland, and an ESRC professorship. The WhitehallII study has been supported by grants from the British Medical ResearchCouncil (MRC), the British Heart Foundation, the British Health andSafety Executive, the British Department of Health, the NationalHeart, Lung, and Blood Institute (R01HL036310), and the National Instituteon Aging (R01AG013196 and R01AG034454)., and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Male, Aging, MESH: Cardiovascular Diseases/epidemiology, BMI, body mass index, Myocardial Infarction, MESH: Myocardial Infarction/prevention & control, Coronary Disease, Disability Evaluation, Risk Factors, MESH: Risk Factors, MESH: Aging, MESH: Aged, MESH: Middle Aged, Hand Strength, MESH: Stroke/epidemiology, MESH: Disability Evaluation, SES, socioeconomic status, Middle Aged, MESH: Myocardial Infarction/epidemiology, Stroke, MESH: Cognition Disorders/epidemiology, MESH: Hand Strength, Cardiovascular Diseases, Motor Skills, Female, Cardiology and Cardiovascular Medicine, Cohort study, Adult, MESH: Coronary Disease/prevention & control, Cardiovascular risk score, FRS, Framingham general cardiovascular disease risk score, MESH: Psychomotor Performance, CVD, cardiovascular disease, MESH: Cardiovascular Diseases/prevention & control, Article, Fingers, MESH: Cognition Disorders/prevention & control, Age Distribution, MESH: Mobility Limitation, Humans, Mobility Limitation, MESH: Age Distribution, Motor function, MESH: Stroke/prevention & control, Aged, MESH: Humans, MESH: Coronary Disease/epidemiology, MESH: Male, MESH: Fingers, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, SD, standard deviation, Cognition Disorders, MESH: Female, Psychomotor Performance, MESH: Motor Skills
Abstract

Background Vascular risk factors are associated with increased risk of cognitive impairment and dementia, but their association with motor function, another key feature of aging, has received little research attention. We examined the association between trajectories of the Framingham general cardiovascular disease risk score (FRS) over midlife and motor function later in life. Methods A total of 5376 participants of the Whitehall II cohort study (29% women) who had up to four repeat measures of FRS between 1991–1993 (mean age = 48.6 years) and 2007–2009 (mean age = 65.4 years) and without history of stroke or coronary heart disease in 2007–2009 were included. Motor function was assessed in 2007–2009 through objective tests (walking speed, chair rises, balance, finger tapping, grip strength). We used age- and sex-adjusted linear mixed models. Results Participants with poorer performances for walking speed, chair rises, and balance in 2007–2009 had higher FRS concurrently and also in 1991–1993, on average 16 years earlier. These associations were robust to adjustment for cognition, socio-economic status, height, and BMI, and not explained by incident mobility limitation prior to motor assessment. No association was found with finger tapping and grip strength. Conclusions Cardiovascular risk early in midlife is associated with poor motor performances later in life. Vascular risk factors play an important and under-recognized role in motor function, independently of their impact on cognition, and suggest that better control of vascular risk factors in midlife may prevent physical impairment and disability in the elderly.

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39. Alcohol consumption and cognitive decline in early old age

Author

Sabia, Séverine, Elbaz, Alexis, Britton, Annie, Bell, Steven, Dugravot, Aline, Shipley, Martin, Kivimaki, Mika, and Singh-Manoux, Archana

Subjects
Adult, Male, Aging, Alcohol Drinking, Middle Aged, Neuropsychological Tests, 3. Good health, Cohort Studies, Executive Function, Memory, Surveys and Questionnaires, Linear Models, Humans, Female, Cognition Disorders, Aged
Abstract

OBJECTIVE: To examine the association between alcohol consumption in midlife and subsequent cognitive decline. METHODS: Data are from 5,054 men and 2,099 women from the Whitehall II cohort study with a mean age of 56 years (range 44-69 years) at first cognitive assessment. Alcohol consumption was assessed 3 times in the 10 years preceding the first cognitive assessment (1997-1999). Cognitive tests were repeated in 2002-2004 and 2007-2009. The cognitive test battery included 4 tests assessing memory and executive function; a global cognitive score summarized performances across these tests. Linear mixed models were used to assess the association between alcohol consumption and cognitive decline, expressed as z scores (mean = 0, SD = 1). RESULTS: In men, there were no differences in cognitive decline among alcohol abstainers, quitters, and light or moderate alcohol drinkers (

40. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Author

Liu, Ganqiang, Boot, Brendon, Locascio, Joseph J, Jansen, Iris E, Winder-Rhodes, Sophie, Eberly, Shirley, Elbaz, Alexis, Brice, Alexis, Ravina, Bernard, Van Hilten, Jacobus J, Cormier-Dequaire, Florence, Corvol, Jean-Christophe, Barker, Roger A, Heutink, Peter, Marinus, Johan, Williams-Gray, Caroline H, Scherzer, Clemens R, and International Genetics Of Parkinson Disease Progression (IGPP) Consortium

Subjects
Aged, 80 and over, Male, Gaucher Disease, Disease Progression, Glucosylceramidase, Humans, Cognitive Dysfunction, Female, Parkinson Disease, Longitudinal Studies, Middle Aged, 3. Good health, Aged
Abstract

OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685.

41. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease

Author

Roger A. Barker, Claudia Trenkwalder, Sami S. Amr, Anne-Marie Wills, Christine Klein, Meike Kasten, Florence Cormier-Dequaire, Thomas G. Beach, Todd M. Herrington, Ganqiang Liu, Suzanne Lesage, Ole-Bjørn Tysnes, Clemens R. Scherzer, Jacobus J. van Hilten, Michael A. Schwarzschild, Meghan C. Campbell, Jodi Maple-Grødem, Albert Y. Hung, Zhixiang Liao, Michael T. Hayes, Jean-Christophe Corvol, Alexis Elbaz, Guido Alves, Frank Zhu, John H. Growdon, Pille Taba, Peter Heutink, Johan Marinus, Brit Mollenhauer, Joseph J. Locascio, Caroline H. Williams-Gray, Xianjun Dong, Joel S. Perlmutter, Bernard Ravina, Graziella Mangone, Alexis Brice, Ira Shoulson, Sulev Kõks, Jiajie Peng, Liu, Ganqiang [0000-0002-1921-9542], Dong, Xianjun [0000-0002-8052-9320], Maple-Grødem, Jodi [0000-0001-7142-0078], Elbaz, Alexis [0000-0001-9724-5490], Hung, Albert Y [0000-0003-3658-571X], Kõks, Sulev [0000-0001-6087-6643], Alves, Guido [0000-0003-0630-2870], Heutink, Peter [0000-0001-5218-1737], Scherzer, Clemens R [0000-0002-0567-9193], and Apollo - University of Cambridge Repository

Subjects
Oncology, Multifactorial Inheritance, Parkinson's disease, Apolipoprotein E4, Genome-wide association study, Disease, genetics [Cognition Disorders], genetics [Glucosylceramidase], Cognition, 0302 clinical medicine, genetics [Parkinson Disease], Risk Factors, Longitudinal Studies, GBA protein, human, genetics [Multifactorial Inheritance], genetics [Apolipoprotein E4], 0303 health sciences, education.field_of_study, Hazard ratio, Parkinson Disease, genetics [Synapses], Disease Progression, Glucosylceramidase, physiopathology [Parkinson Disease], medicine.medical_specialty, Population, genetics [Mutation], Biology, Article, 03 medical and health sciences, ddc:570, Internal medicine, Genetics, medicine, Humans, Dementia, Genetic Predisposition to Disease, education, Survival analysis, Proportional Hazards Models, 030304 developmental biology, Proportional hazards model, medicine.disease, Survival Analysis, pathology [Parkinson Disease], Genetic Loci, Mutation, Synapses, Cognition Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 x 10(-11)), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 x 10(-8)) and WWOX (HR = 2.12, P = 2.37 x 10(-8)) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.A genome-wide survival study identifies variants at RIMS2 associated with progression of Parkinson's disease to dementia and highlights divergence in the genetic architecture of disease onset and progression.

Published
2021

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