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1. Cardiac troponin T as a serum biomarker of respiratory impairment in amyotrophic lateral sclerosis.

Author

Koch T, Fabian R, Weinhold L, Koch FW, Barakat S, Castro-Gomez S, Grehl T, Bernsen S, and Weydt P

Subjects
Humans, Male, Middle Aged, Female, Aged, Retrospective Studies, Vital Capacity physiology, Respiratory Insufficiency blood, Respiratory Insufficiency etiology, Adult, Neurofilament Proteins blood, Amyotrophic Lateral Sclerosis blood, Amyotrophic Lateral Sclerosis diagnosis, Amyotrophic Lateral Sclerosis physiopathology, Troponin T blood, Biomarkers blood
Abstract

Objective: Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis., Methods: In this retrospective observation, we analyzed two independent hospital-based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (n d  = 298; n v  = 49), serum neurofilament light chain (n d  = 117; n v  = 17), and respiratory tests (n d  = 93; n v  = 49)., Results: Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = -0.45, p = 0.001) and slow vital capacity % (r = -0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62-0.84) and <50% (AUC 0.80, 95% CI 0.68-0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61-0.83) and <50% (AUC 0.79, 95% CI 0.67-0.91)., Interpretation: Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2024
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2. Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies.

Author

van der Lee SJ, Teunissen CE, Pool R, Shipley MJ, Teumer A, Chouraki V, Melo van Lent D, Tynkkynen J, Fischer K, Hernesniemi J, Haller T, Singh-Manoux A, Verhoeven A, Willemsen G, de Leeuw FA, Wagner H, van Dongen J, Hertel J, Budde K, Willems van Dijk K, Weinhold L, Ikram MA, Pietzner M, Perola M, Wagner M, Friedrich N, Slagboom PE, Scheltens P, Yang Q, Gertzen RE, Egert S, Li S, Hankemeier T, van Beijsterveldt CEM, Vasan RS, Maier W, Peeters CFW, Jörgen Grabe H, Ramirez A, Seshadri S, Metspalu A, Kivimäki M, Salomaa V, Demirkan A, Boomsma DI, van der Flier WM, Amin N, and van Duijn CM

Subjects
Adult, Aged, Alzheimer Disease metabolism, Cohort Studies, Female, Humans, Life Style, Male, Middle Aged, Reproducibility of Results, Risk Factors, Biomarkers metabolism, Cognitive Dysfunction metabolism, Dementia metabolism
Abstract

Introduction: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions., Methods: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined., Results: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors., Discussion: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2018
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3. Levels of Alzheimer's disease blood biomarkers are altered after food intake—A pilot intervention study in healthy adults.

Author

Huber, Hanna, Ashton, Nicholas J., Schieren, Alina, Montoliu‐Gaya, Laia, Molfetta, Guglielmo Di, Brum, Wagner S., Lantero‐Rodriguez, Juan, Grötschel, Lana, Stoffel‐Wagner, Birgit, Coenen, Martin, Weinhold, Leonie, Schmid, Matthias, Blennow, Kaj, Stehle, Peter, Zetterberg, Henrik, and Simon, Marie‐Christine

Abstract

INTRODUCTION: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD‐related biomarkers in cognitively healthy, obese adults at high metabolic risk. METHODS: One‐hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid‐beta (Aβ) 42/40, phosphorylated tau (p‐tau) 181 and 231, and total‐tau were measured via single molecule array assays. RESULTS: Significant differences were found for NfL, GFAP, Aβ42/40, p‐tau181, and p‐tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p‐tau181 (120 min postprandially, p < 0.0001). CONCLUSION: Our data suggest that AD‐related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. Highlights: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults.We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations.Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Published
2023
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4. Association between urinary iodine excretion, genetic disposition and fluid intelligence in children, adolescents and young adults: the DONALD study.

Author

Schulz, Christina-Alexandra, Weinhold, Leonie, Schmid, Matthias, Nöthen, Markus M., and Nöthlings, Ute

Subjects
*BIOMARKERS, *FOOD consumption, *REGRESSION analysis, *INTELLECT, *DESCRIPTIVE statistics, *RESEARCH funding, *COGNITIVE testing, *IODINE, *GENETIC profile, *INTELLIGENCE tests, *CHILDREN, *ADULTS, *ADOLESCENCE
Abstract

Purpose: Iodine deficiency increases the risk of cognitive impairment and delayed physical development in children. It is also associated with cognitive impairment in adults. Cognitive abilities are among the most inheritable behavioural traits. However, little is known about the consequences of insufficient postnatal iodine intake and whether the individual genetic disposition modifies the association between iodine intake and fluid intelligence in children and young adults. Methods: The cultural fair intelligence test was used to assess fluid intelligence in the participants of the DONALD study (n = 238; mean age, 16.5 [SD = 7.7] years). Urinary iodine excretion, a surrogate iodine intake marker, was measured in 24-h urine. Individual genetic disposition (n = 162) was assessed using a polygenic score, associated with general cognitive function. Linear regression analyses were conducted to determine whether Urinary iodine excretion was associated with fluid intelligence and whether this association was modified by individual genetic disposition. Results: Urinary iodine excretion above the age-specific estimated average requirement was associated with a five-point higher fluid intelligence score than that below the estimated average requirement (P = 0.02). The polygenic score was positively associated with the fluid intelligence score (β = 2.3; P = 0.03). Participants with a higher polygenic score had a higher fluid intelligence score. Conclusion: Urinary iodine excretion above the estimated average requirement in childhood and adolescence is beneficial for fluid intelligence. In adults, fluid intelligence was positively associated with a polygenic score for general cognitive function. No evidence showed that the individual genetic disposition modifies the association between Urinary iodine excretion and fluid intelligence. [ABSTRACT FROM AUTHOR]

Published
2023
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5. Validation of the web-based self-administered 24-h dietary recall myfood24-Germany: comparison with a weighed dietary record and biomarkers

Author

Koch, Stefanie A. J., Conrad, Johanna, Cade, Janet E., Weinhold, Leonie, Alexy, Ute, and Nöthlings, Ute

Subjects
Male, Potassium intake, Dietary assessment, Concordance, Medicine (miscellaneous), Diet Surveys, Animal science, Germany, Surveys and Questionnaires, Humans, Medicine, Web-based 24-h dietary recall, Internet, Nutrition and Dietetics, business.industry, Validation study, Reproducibility of Results, Myfood24, Original Contribution, Protein intake, Diet Records, Diet, Nutrition Assessment, Dietary recall, Method comparison, Mental Recall, Biomarker (medicine), Female, Energy Intake, business, Biomarkers, Kappa
Abstract

Purpose We aimed to validate myfood24-Germany, a web-based 24-h dietary recall (24HDR), by comparing its performance with a weighed dietary record (WDR) and biomarkers. Methods 97 adults (77% female) completed a 3-day WDR with a 24-h urine collection on day 3, followed by at least one 24HDR with myfood24-Germany (corresponding to day 3 of the WDR). Intake of energy and 32 nutrients assessed by myfood24-Germany and the WDR for the same day were compared (method comparison). Intakes of protein and potassium assessed by myfood24-Germany/WDR were compared with intake estimated from urinary biomarkers for protein and potassium (biomarker comparison). Results In the method comparison, significant correlations were found for energy and all tested nutrients (range 0.45–0.87). There was no significant difference between both methods in the assessed mean energy and macronutrient intake. However, myfood24-Germany underestimated mean intake of 15 nutrients. In the biomarker comparison, protein intake reported by myfood24-Germany/WDR was on average 10%/8% lower than estimated by biomarker. There was no significant difference in mean potassium intake assessed by myfood24-Germany/WDR and biomarker. However, a shared bias in the assessment of potassium intake was observed for both instruments. Concordance correlation coefficients (pc) and weighted Kappa coefficients (κ) confirmed good agreement with the biomarker estimates for myfood24-Germany/WDR in case of protein (pc = 0.58/0.66, κ = 0.51/0.53) and moderate agreement in case of potassium (pc = 0.44/0.51; κ = 0.30/0.33). Conclusion Our results suggest that myfood24-Germany is of comparable validity to traditional dietary assessment methods.

Published
2021

6. Replication and mediation of the association between the metabolome and clinical markers of metabolic health in an adolescent cohort study.

Author

Brachem, Christian, Weinhold, Leonie, Alexy, Ute, Schmid, Matthias, Oluwagbemigun, Kolade, and Nöthlings, Ute

Subjects
*BIOMARKERS, *BETAINE, *COHORT analysis, *BODY mass index, *BLOOD lipids, *YOUNG adults, *FAT
Abstract

Metabolomics-derived metabolites (henceforth metabolites) may mediate the relationship between modifiable risk factors and clinical biomarkers of metabolic health (henceforth clinical biomarkers). We set out to study the associations of metabolites with clinical biomarkers and a potential mediation effect in a population of young adults. First, we conducted a systematic literature review searching for metabolites associated with 11 clinical biomarkers (inflammation markers, glucose, blood pressure or blood lipids). Second, we replicated the identified associations in a study population of n = 218 (88 males and 130 females, average age of 18 years) participants of the DONALD Study. Sex-stratified linear regression models adjusted for age and BMI and corrected for multiple testing were calculated. Third, we investigated our previously reported metabolites associated with anthropometric and dietary factors mediators in sex-stratified causal mediation analysis. For all steps, both urine and blood metabolites were considered. We found 41 metabolites in the literature associated with clinical biomarkers meeting our inclusion criteria. We were able to replicate an inverse association of betaine with CRP in women, between body mass index and C-reactive protein (CRP) and between body fat and leptin. There was no evidence of mediation by lifestyle-related metabolites after correction for multiple testing. We were only able to partially replicate previous findings in our age group and did not find evidence of mediation. The complex interactions between lifestyle factors, the metabolome, and clinical biomarkers warrant further investigation. [ABSTRACT FROM AUTHOR]

Published
2023
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7. Polygenic risk for obsessive-compulsive disorder (OCD) predicts brain response during working memory task in OCD, unaffected relatives, and healthy controls

Author

Heinzel, Stephan, Kaufmann, Christian, Grützmann, Rosa, Klawohn, Julia, Riesel, Anja, Bey, Katharina, Heilmann-Heimbach, Stefanie, Weinhold, Leonie, Ramirez, Alfredo, and Wagner, Michael

Subjects
FOS: Psychology, Risk factors, FOS: Biological sciences, mental disorders, Genetics, Psychology, 100 Philosophie und Psychologie::150 Psychologie::150 Psychologie, behavioral disciplines and activities, humanities, Biomarkers, Neuroscience
Abstract

Alterations in frontal and parietal neural activations during working memory task performance have been suggested as a candidate endophenotype of obsessive-compulsive disorder (OCD) in studies involving first-degree relatives. However, the direct link between genetic risk for OCD and neuro-functional alterations during working memory performance has not been investigated to date. Thus, the aim of the current functional magnetic resonance imaging (fMRI) study was to test the direct association between polygenic risk for OCD and neural activity during the performance of a numeric n-back task with four working memory load conditions in 128 participants, including patients with OCD, unaffected first-degree relatives of OCD patients, and healthy controls. Behavioral results show a significant performance deficit at high working memory load in both patients with OCD and first-degree relatives (p

Published
2021
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8. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Author

KLEINEIDAM, Luca, Chouraki, Vincent, Próchnicki, Tomasz, van der Lee, Sven, Madrid‑Márquez, Laura, Wagner-Thelen, Holger, Karaca, Ilker, WEINHOLD, Leonie, Wolfsgruber, Steffen, Boland, Anne, Martino Adami, Pamela, Lewczuk, Piotr, POPP, Julius, Brosseron, Frederic, Jansen, Iris, HULSMAN, Marc, Kornhuber, Johannes, Peters, Oliver, Berr, Claudine, Heun, Reinhard, Frölich, Lutz, Tzourio, Christophe, Dartigues, Jean-François, Hüll, Michael, Espinosa, Ana, Hernández, Isabel, de Rojas, Itziar, ORELLANA, Adelina, VALERO, Sergi, STRINGA, Najada, Van Schoor, Natasja, Huisman, Martijn, Scheltens, Philip, For The Alzheimer'S Disease Neuroimaging Initiative, (ADNI), Rüther, Eckart, Deleuze, Jean-François, Wiltfang, Jens, Tarraga, Lluis, Schmid, Matthias, Scherer, Martin, Riedel-Heller, Steffi, Heneka, Michael, Amouyel, Philippe, Jessen, Frank, Boada, Merce, Maier, Wolfgang, Schneider, Anja, González‑Pérez, Antonio, van der Flier, Wiesje, Wagner, Michael, Lambert, Jean-Charles, Holstege, Henne, Saez, Mª Eugenia, Latz, Eicke, Ruiz, Agustin, Ramirez, Alfredo, University Hospital Bonn, Universität zu Köln, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), 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-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Epidémiologie et de Santé Publique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Amsterdam UMC, Vrije Universiteit Amsterdam [Amsterdam] (VU), Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] (CAEBi), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), 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), Universitätsklinikum Erlangen [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of Bialystok, Lausanne University Hospital, University hospital of Zurich [Zurich], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universität Heidelberg [Heidelberg], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Albert-Ludwigs-Universität Freiburg, Universitat Internacional de Catalunya [Barcelona] (UIC), Instituto de Salud Carlos III [Madrid] (ISC), University Medical Center Göttingen (UMG), Universidade de Aveiro, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Universität Leipzig [Leipzig], University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434, grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project 'Diet-Body-Brain: from epidemiology to evidence-based communication'. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica, Inc., Biogen, Bristol-Myers Squibb Company, CereSpir, Inc., Cogstate, Eisai Inc., ElanPharmaceuticals, Inc., Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc., Fujirebio, GE Healthcare, IXICO Ltd., Janssen Alzheimer Immunotherapy Research and Development, LLC., Johnson and Johnson Pharmaceutical Research and Development LLC., Lumosity, Lundbeck, Merck and Co., Inc., Meso Scale Diagnostics, LLC., NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc., Piramal Imaging, Servier, Takeda Pharmaceutical Company, and transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND, PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. Additional funding for the 3C Study was also obtained from the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai. Fundacio ACE cohort receives support from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme (ADAPTED Grant No. 115975). A. Ruiz’s research is also supported by Instituto de Salud Carlos III (ISCIII) grants PI13/02434, PI16/01861, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de Hacer Europa'), by Fundación bancaria 'La Caixa' and Grifols SA (GR@ACE project). For the Longitudinal Aging Study Amsterdam (LASA) supports was largely obtained from a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project 'New Cohorts of young old in the twenty-first century' (File Number 480-10-014). Genotyping using Axiom-NL array was financially supported by EMGO+ Research Institute. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. JW is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal. JP was supported by a grant from the Swiss National Science Foundation (320030L_141179)., Universität zu Köln = University of Cologne, Amsterdam UMC - Amsterdam University Medical Center, Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Leipzig, Alzheimer's Disease Neuroimaging Initiative (ADNI), Kleineidam, L., Karaca, I., Heneka, M.T., Maier, W., Schneider, A., Wagner, M., Chouraki, V., Amouyel, P., Lambert, J.C., Próchnicki, T., Latz, E., van der Lee, S.J., Jansen, I.E., Hulsman, M., Scheltens, P., van der Flier, W.M., Holstege, H., Madrid-Márquez, L., González-Pérez, A., Sáez, M.E., Wagner-Thelen, H., Martino Adami, P.V., Jessen, F., Ramirez, A., Weinhold, L., Schmid, M., Wolfsgruber, S., Brosseron, F., Boland, A., Deleuze, J.F., Lewczuk, P., Kornhuber, J., Popp, J., Peters, O., Berr, C., Heun, R., Frölich, L., Tzourio, C., Dartigues, J.F., Hüll, M., Espinosa, A., Hernández, I., de Rojas, I., Orellana, A., Valero, S., Ruiz, A., Tarraga, L., Boada, M., Stringa, N., van Schoor, N.M., Huisman, M., Rüther, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Neurology, Human genetics, Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, APH - Methodology, Sociology, and The Social Context of Aging (SoCA)

Subjects
Apolipoprotein E, Male, pathology [Cognitive Dysfunction], Cognitive decline, genetics [Alzheimer Disease], Disease, SEPIA, pathology [Alzheimer Disease], 0302 clinical medicine, Cognition, genetics [Amyloid beta-Peptides], Medicine, Aged, 80 and over, 0303 health sciences, education.field_of_study, Microglia, physiology [Cognition], Middle Aged, medicine.anatomical_structure, Disease Progression, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], analysis [Biomarkers], Alzheimer’s disease, Amyloid, Phospholipase C gamma 2, Population, tau Proteins, Pathology and Forensic Medicine, PLCG2, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, Humans, Cognitive Dysfunction, ddc:610, education, Mild cognitive impairment, HEALTHY, 030304 developmental biology, Aged, metabolism [Phospholipase C gamma], Original Paper, Amyloid beta-Peptides, TREM2, business.industry, Phospholipase C gamma, genetics [Cognitive Dysfunction], metabolism [tau Proteins], cerebrospinal fluid [tau Proteins], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Published
2020

9. Blood Metabolomic Profiling Confirms and Identifies Biomarkers of Food Intake.

Author

Langenau, Julia, Oluwagbemigun, Kolade, Brachem, Christian, Lieb, Wolfgang, Giuseppe, Romina di, Artati, Anna, Kastenmüller, Gabi, Weinhold, Leonie, Schmid, Matthias, and Nöthlings, Ute

Subjects
METABOLOMICS, INGESTION, BIOMARKERS, METABOLITES, BLOOD, COFFEE drinks
Abstract

Metabolomics can be a tool to identify dietary biomarkers. However, reported food-metabolite associations have been inconsistent, and there is a need to explore further associations. Our aims were to confirm previously reported food-metabolite associations and to identify novel food-metabolite associations. We conducted a cross-sectional analysis of data from 849 participants (57% men) of the PopGen cohort. Dietary intake was obtained using FFQ and serum metabolites were profiled by an untargeted metabolomics approach. We conducted a systematic literature search to identify previously reported food-metabolite associations and analyzed these associations using linear regression. To identify potential novel food-metabolite associations, datasets were split into training and test datasets and linear regression models were fitted to the training datasets. Significant food-metabolite associations were evaluated in the test datasets. Models were adjusted for covariates. In the literature, we identified 82 food-metabolite associations. Of these, 44 associations were testable in our data and confirmed associations of coffee with 12 metabolites, of fish with five, of chocolate with two, of alcohol with four, and of butter, poultry and wine with one metabolite each. We did not identify novel food-metabolite associations; however, some associations were sex-specific. Potential use of some metabolites as biomarkers should consider sex differences in metabolism. [ABSTRACT FROM AUTHOR]

Published
2020
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