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4. New insights into the genetic etiology of Alzheimer’s disease and related dementias

Author

Bellenguez, Céline, Küçükali, Fahri, Jansen, Iris E, Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C, Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A, Boland, Anne, Damotte, Vincent, van der Lee, Sven J, Costa, Marcos R, Kuulasmaa, Teemu, Yang, Qiong, de Rojas, Itziar, Bis, Joshua C, Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcón-Martín, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Álvarez, Victoria, Armstrong, Nicola J, Tsolaki, Anthoula, Antúnez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Pastor, Alfonso Arias, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belén, Below, Jennifer E, Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Céline, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Mercè, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossù, Paola, Bråthen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J, Brusco, Luis Ignacio, Buiza-Rueda, Dolores, Bûrger, Katharina, Burholt, Vanessa, Bush, William S, Calero, Miguel, Cantwell, Laura B, Chene, Geneviève, Chung, Jaeyoon, Cuccaro, Michael L, Carracedo, Ángel, Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen AHR, Clark, Christopher, Conti, Elisa, Corma-Gómez, Anaïs, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-François, de Deyn, Peter Paul, de Paiva Lopes, Katia, de Witte, Lot D, Debette, Stéphanie, Deckert, Jürgen, and del Ser, Teodoro

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurodegenerative, Alzheimer's Disease, Human Genome, Prevention, Aging, Brain Disorders, Acquired Cognitive Impairment, Neurosciences, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer Disease, Cognitive Dysfunction, Genome-Wide Association Study, Humans, tau Proteins, EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Published
2022

9. The association between antibodies to neurotropic pathogens and bipolar disorder : A study in the Dutch Bipolar (DB) Cohort and meta-analysis.

Author

Snijders, Gijsje JLJ, van Mierlo, Hans C, Boks, Marco P, Begemann, Marieke JH, Sutterland, Arjen L, Litjens, Manja, Ophoff, Roel A, Kahn, René S, and de Witte, Lot D

Subjects
Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Exposure to neurotropic pathogens has been hypothesized to be a risk factor for the development of bipolar disorder (BD). However, evidence so far is inconsistent. We, therefore, analyzed the seroprevalence and titer levels of IgG antibodies against several herpesviruses and Toxoplasma gondii (T. gondii) in plasma of 760 patients with a bipolar disorder, 144 first-degree matched relatives and 132 controls of the Dutch Bipolar (DB) Cohort using ELISA. In addition, we performed a literature-based meta-analysis on the seroprevalence of IgG antibodies against these pathogens (n = 14). Our results in the DB Cohort and subsequent meta-analysis (n = 2364 BD patients, n = 5101 controls) show no association between exposure to herpesviruses and bipolar disorder (HSV-1 [adjusted OR 0.842, 95% CI 0.567-1.230], HSV-2 [adjusted OR 0.877, 95% CI 0.437-1.761], CMV [adjusted OR 0.884 95% CI 0.603-1.295], EBV [adjusted OR 0.968 95% CI 0.658-1.423]). In the DB Cohort, we did not find an association between bipolar disorder and T. gondii titer or seroprevalence either [adjusted OR 1.018, 95% CI 0.672-1.542]. The overall OR was not significant for T. gondii [OR: 1.4, 95% CI 0.95-1.90, p = 0.09), but subgroup analyses in age groups below 40 years showed a significantly increased seroprevalence of T. gondii IgGs in BD [OR: 1.8 (95% CI 1.10-2.89, p = 0.021]. Our meta-analysis indicates that T. gondii exposure may be a risk factor for BD in certain subpopulations.

Published
2019

12. Diagnostic model development for schizophrenia based on peripheral blood mononuclear cell subtype-specific expression of metabolic markers

Author

Zaki, Jihan K., Lago, Santiago G., Rustogi, Nitin, Gangadin, Shiral S., Benacek, Jiri, van Rees, Geertje F., Haenisch, Frieder, Broek, Jantine A., Suarez-Pinilla, Paula, Ruland, Tillmann, Auyeung, Bonnie, Mikova, Olya, Kabacs, Nikolett, Arolt, Volker, Baron-Cohen, Simon, Crespo-Facorro, Benedicto, Drexhage, Hemmo A., de Witte, Lot D., Kahn, René S., Sommer, Iris E., Bahn, Sabine, and Tomasik, Jakub

Published
2022
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14. Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies

Author

Lopes, Katia de Paiva, Snijders, Gijsje J. L., Humphrey, Jack, Allan, Amanda, Sneeboer, Marjolein A. M., Navarro, Elisa, Schilder, Brian M., Vialle, Ricardo A., Parks, Madison, Missall, Roy, van Zuiden, Welmoed, Gigase, Frederieke A. J., Kübler, Raphael, van Berlekom, Amber Berdenis, Hicks, Emily M., Bӧttcher, Chotima, Priller, Josef, Kahn, René S., de Witte, Lot D., and Raj, Towfique

Published
2022
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15. Navigating Human Astrocyte Differentiation: Direct and Rapid one-step Differentiation of Induced Pluripotent Stem Cells to Functional Astrocytes Supporting Neuronal Network development

Author

Schuurmans, Imke M. E., primary, Mordelt, Annika, additional, Linda, Katrin, additional, Puvogel, Sofia, additional, Duineveld, Denise, additional, Hommersom, Marina P, additional, Rahm, Lisa, additional, Dyke, Emma, additional, Scholten, Gijs-Jan, additional, Knorz, Caroline, additional, Oudakker, Astrid, additional, van Bokhoven, Hans, additional, de Witte, Lot D, additional, van Karnebeek, Clara D.M., additional, Garanto, Alejandro, additional, and Kasri, Nael Nadif, additional

Published
2024
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16. The effect of SARS-CoV-2 infection and vaccination on Th17 and regulatory T cells in a pregnancy cohort in NYC

Author

Gigase, Frederieke A. J., primary, Graziani, Mara, additional, Castro, Juliana, additional, Lesseur, Corina, additional, Rommel, Anna-Sophie, additional, Flores, Tammy, additional, Perez-Rodriguez, M. Mercedes, additional, Dolan, Siobhan, additional, Stone, Joanne, additional, Janevic, Teresa, additional, Lieb, Whitney, additional, Bergink, Veerle, additional, and de Witte, Lot D., additional

Published
2024
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18. Clinical symptoms and psychosocial functioning in patients with schizophrenia spectrum disorders testing seropositive for anti-NMDAR antibodies: a case–control comparison with patients testing negative

Author

Luykx, Jurjen J, Visscher, Robbert, Winter-van Rossum, Inge, Waters, Patrick, de Witte, Lot D, Fleischhacker, W Wolfgang, Lin, Bochao Danae, de Boer, Nini, van der Horst, Marte, Yeeles, Ksenija, Davidson, Michael, Pollak, Thomas A, Hasan, Alkomiet, and Lennox, Belinda R

Abstract

Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach. We aimed to assess the seroprevalence of anti-NMDAR antibodies in schizophrenia, and compare symptoms and psychosocial functioning between patients with schizophrenia who were seropositive and seronegative for these antibodies.

Published
2024
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19. Transcriptomic and morphological maturation of human astrocytes in cerebral organoids

Author

TN groep Hol, Brain, AIOS Psychiatrie, Translational Neuroscience, Regenerative Medicine and Stem Cells, Cancer, Verkerke, Marloes, Berdenis van Berlekom, Amber, Donega, Vanessa, Vonk, Daniëlle, Sluijs, Jacqueline A, Butt, Nayab F, Kistemaker, Lois, de Witte, Lot D, Pasterkamp, R Jeroen, Middeldorp, Jinte, Hol, Elly M, TN groep Hol, Brain, AIOS Psychiatrie, Translational Neuroscience, Regenerative Medicine and Stem Cells, Cancer, Verkerke, Marloes, Berdenis van Berlekom, Amber, Donega, Vanessa, Vonk, Daniëlle, Sluijs, Jacqueline A, Butt, Nayab F, Kistemaker, Lois, de Witte, Lot D, Pasterkamp, R Jeroen, Middeldorp, Jinte, and Hol, Elly M

Published
2024

20. Exploring peripheral biomarkers of response to simvastatin supplementation in schizophrenia

Author

Onderzoeksgroep 11, Brain, Zaki, Jihan K, Lago, Santiago G, Spadaro, Benedetta, Rustogi, Nitin, Gangadin, Shiral S, Benacek, Jiri, Drexhage, Hemmo A, de Witte, Lot D, Kahn, René S, Sommer, Iris E C, Bahn, Sabine, Tomasik, Jakub, Onderzoeksgroep 11, Brain, Zaki, Jihan K, Lago, Santiago G, Spadaro, Benedetta, Rustogi, Nitin, Gangadin, Shiral S, Benacek, Jiri, Drexhage, Hemmo A, de Witte, Lot D, Kahn, René S, Sommer, Iris E C, Bahn, Sabine, and Tomasik, Jakub

Published
2024

26. A Pharmacological Toolkit for Human Microglia Identifies Topoisomerase I Inhibitors as Immunomodulators for Alzheimer's Disease

Author

Haage, Verena Claudia, primary, Tuddenham, John F., additional, Comandante-Lou, Natacha, additional, Bautista, Alex, additional, Monzel, Anna, additional, Chiu, Rebecca, additional, Fujita, Masashi, additional, Garcia, Frankie G., additional, Bhattarai, Prabesh, additional, Patel, Ronak, additional, Buonfiglioli, Alice, additional, Idiarte, Juan, additional, Herman, Mathieu, additional, Rinderspacher, Alison, additional, Mela, Angeliki, additional, Zhao, Wenting, additional, Argenziano, Michael, additional, Furnari, Julia L., additional, Banu, Matei A., additional, Landry, Donald W., additional, Bruce, Jeffrey N., additional, Canoll, Peter, additional, Zhang, Ya, additional, Nuriel, Tal, additional, Kizil, Caghan, additional, Sproul, Andrew, additional, de Witte, Lot D., additional, Sims, Peter A., additional, Menon, Vilas, additional, Picard, Martin, additional, and De Jager, Philip L., additional

Published
2024
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31. Association between doxycycline use and long-term functioning in patients with schizophrenia.

Author

de Witte, Lot D., Munk Laursen, Thomas, Corcoran, Cheryl M., Munk-Olsen, Trine, and Bergink, Veerle

Subjects
*DOXYCYCLINE, *DISABILITY retirement, *PEOPLE with schizophrenia, *TETRACYCLINE, *TETRACYCLINES
Abstract

• Tetracyclines have been proposed as candidate drugs for schizophrenia. • Potential long-term effects of doxycycline were explored using Danish Registry data. • 11,157 schizophrenia patients were analyzed, of which 718 redeemed a prescription of doxycycline. • The incidence of disability pension was selected as proxy measure of functioning. • Doxycycline prescription was associated with a lower incidence rate of disability pension. The brain-penetrant tetracycline antibiotics, minocycline and doxycycline, have been proposed as potential candidate drugs for treatment of schizophrenia, based on preclinical studies and clinical trials. A potential long-term beneficial effect of these antibiotics for schizophrenia patients has not been investigated. This study was designed to determine if redemption of doxycycline prescription in schizophrenia is associated with decreased incidence of disability pension, a proxy for long-term functioning. We performed a population-based cohort study with data from schizophrenia patients available through the Danish registers. Survival analysis models with time-varying covariates were constructed to assess incidence rate ratios (IRR) of disability pension after exposure to doxycycline or a non-brain penetrant tetracycline, defined as at least one filled prescription. The analysis was adjusted for age, sex, calendar year, parental psychiatric status and educational level. We used data from 11,157 individuals with schizophrenia (4,945 female and 6,212 male; average age 22.4 years old, standard deviation (std) 4.50). 718 of these were exposed to brain-penetrant doxycycline, and 1,498 individuals redeemed a prescription of one or more of the non-brain-penetrant tetracyclines. The average years at risk per person in this cohort was 4.9, and 2,901 individuals received disability pension in the follow-up period. There was a significantly lower incidence rate of disability pension in schizophrenia patients who had redeemed doxycycline compared to patients who did not redeem a prescription of any tetracycline antibiotics (Incidence rate ratio (IRR) 0.68; 95 % CI 0.56, 0.83). There was also a significant lower rate of disability pension in schizophrenia patients who redeemed doxycycline compared to individuals who redeemed a prescription of one of the non-brain penetrant tetracycline antibiotics (IRR 0.69 95 % CI 0.55, 0.87). In this observational study, doxycycline exposure is associated with a reduced incidence of disability pension. These data support further studies on the potential long term neuroprotective effects of doxycycline and level of functioning in schizophrenia patients. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Long-term effects of prenatal infection on the human brain:a prospective multimodal neuroimaging study

Author

Suleri, Anna, Cecil, Charlotte, Rommel, Anna Sophie, Hillegers, Manon, White, Tonya, de Witte, Lot D., Muetzel, Ryan L., Bergink, Veerle, Suleri, Anna, Cecil, Charlotte, Rommel, Anna Sophie, Hillegers, Manon, White, Tonya, de Witte, Lot D., Muetzel, Ryan L., and Bergink, Veerle

Abstract

There is convincing evidence from rodent studies suggesting that prenatal infections affect the offspring's brain, but evidence in humans is limited. Here, we assessed the occurrence of common infections during each trimester of pregnancy and examined associations with brain outcomes in adolescent offspring. Our study was embedded in the Generation R Study, a large-scale sociodemographically diverse prospective birth cohort. We included 1094 mother-child dyads and investigated brain morphology (structural MRI), white matter microstructure (DTI), and functional connectivity (functional MRI), as outcomes at the age of 14. We focused on both global and focal regions. To define prenatal infections, we composed a score based on the number and type of infections during each trimester of pregnancy. Models were adjusted for several confounders. We found that prenatal infection was negatively associated with cerebral white matter volume (B = -0.069, 95% CI -0.123 to -0.015, p = 0.011), and we found an association between higher prenatal infection scores and smaller volumes of several frontotemporal regions of the brain. After multiple testing correction, we only observed an association between prenatal infections and the caudal anterior cingulate volume (B = -0.104, 95% CI -0.164 to -0.045, p < 0.001). We did not observe effects of prenatal infection on other measures of adolescent brain morphology, white matter microstructure, or functional connectivity, which is reassuring. Our results show potential regions of interest in the brain for future studies; data on the effect of severe prenatal infections on the offspring's brain in humans are needed.

Published
2023

39. Gene expression profiling of monocytes in recent-onset schizophrenia

Author

Onderzoeksgroep 5, Affectieve & Psychotisch Ond., Onderzoeksgroep 11, Brain, AIOS Psychiatrie, Kübler, Raphael, Ormel, Paul R, Sommer, Iris E C, Kahn, René S, de Witte, Lot D, Onderzoeksgroep 5, Affectieve & Psychotisch Ond., Onderzoeksgroep 11, Brain, AIOS Psychiatrie, Kübler, Raphael, Ormel, Paul R, Sommer, Iris E C, Kahn, René S, and de Witte, Lot D

Published
2023

42. Inflammatory monocyte gene signature predicts beneficial within group effect of simvastatin in patients with schizophrenia spectrum disorders in a secondary analysis of a randomized controlled trial

Author

Aichholzer, Mareike, primary, Gangadin, Shiral S., additional, Sommer, Iris E.C., additional, Wijkhuis, Annemarie, additional, de Witte, Lot D., additional, Kahn, René S., additional, Bahn, Sabine, additional, Drexhage, Hemmo A., additional, and Schiweck, Carmen, additional

Published
2022
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45. Shock and kill within the CNS: A promising HIV eradication approach?

Author

Nühn, Marieke M, primary, Gumbs, Stephanie B H, additional, Buchholtz, Ninée V E J, additional, Jannink, Lisanne M, additional, Gharu, Lavina, additional, de Witte, Lot D, additional, Wensing, Annemarie M J, additional, Lewin, Sharon R, additional, Nijhuis, Monique, additional, and Symons, Jori, additional

Published
2022
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46. Microglia innately develop within cerebral organoids

Author

Ormel, Paul R., Vieira de Sá, Renata, van Bodegraven, Emma J., Karst, Henk, Harschnitz, Oliver, Sneeboer, Marjolein A. M., Johansen, Lill Eva, van Dijk, Roland E., Scheefhals, Nicky, Berdenis van Berlekom, Amber, Ribes Martínez, Eduardo, Kling, Sandra, MacGillavry, Harold D., van den Berg, Leonard H., Kahn, René S., Hol, Elly M., de Witte, Lot D., and Pasterkamp, R. Jeroen

Published
2018
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48. Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model

Author

Berdenis van Berlekom, Amber, primary, Kübler, Raphael, additional, Hoogeboom, Jeske W., additional, Vonk, Daniëlle, additional, Sluijs, Jacqueline A., additional, Pasterkamp, R. Jeroen, additional, Middeldorp, Jinte, additional, Kraneveld, Aletta D., additional, Garssen, Johan, additional, Kahn, René S., additional, Hol, Elly M., additional, de Witte, Lot D., additional, and Boks, Marco P., additional

Published
2022
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49. Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model

Author

Afd Pharmacology, Pharmacology, Berdenis van Berlekom, Amber, Kübler, Raphael, Hoogeboom, Jeske W, Vonk, Daniëlle, Sluijs, Jacqueline A, Pasterkamp, R Jeroen, Middeldorp, Jinte, Kraneveld, Aletta D, Garssen, Johan, Kahn, René S, Hol, Elly M, de Witte, Lot D, Boks, Marco P, Afd Pharmacology, Pharmacology, Berdenis van Berlekom, Amber, Kübler, Raphael, Hoogeboom, Jeske W, Vonk, Daniëlle, Sluijs, Jacqueline A, Pasterkamp, R Jeroen, Middeldorp, Jinte, Kraneveld, Aletta D, Garssen, Johan, Kahn, René S, Hol, Elly M, de Witte, Lot D, and Boks, Marco P

Published
2022

50. Inflammatory monocyte gene signature predicts beneficial within group effect of simvastatin in patients with schizophrenia spectrum disorders in a secondary analysis of a randomized controlled trial

Author

Aichholzer, Mareike, Gangadin, Shiral S., Sommer, Iris E.C., Wijkhuis, Annemarie, de Witte, Lot D., Kahn, René S., Bahn, Sabine, Drexhage, Hemmo A., Schiweck, Carmen, Aichholzer, Mareike, Gangadin, Shiral S., Sommer, Iris E.C., Wijkhuis, Annemarie, de Witte, Lot D., Kahn, René S., Bahn, Sabine, Drexhage, Hemmo A., and Schiweck, Carmen

Abstract

Immune dysregulation has been reported in schizophrenia spectrum disorders (SSD). In the past decade, several trials using anti-inflammatory agents for treatment of SSD have been completed, with so far limited success. One such anti-inflammatory agent used is simvastatin. A recent, large-scale, randomized controlled trial with simvastatin augmentation failed to show improvement in the predefined primary outcome. However, baseline inflammatory profiles were not taken into account. Here we employed a data-driven clustering approach to investigate whether patients with an inflammatory monocyte gene signature respond better to add-on simvastatin treatment than those without such a signature, over a treatment period of 2 years. In 61 patients (60 randomized, 1:1 placebo:simvastatin) and healthy controls, a previously validated monocyte gene expression signature was assessed using quantitative polymerase chain reaction. Resulting delta cycle threshold values were used to identify patient clusters. Two major patient clusters with either up- or downregulated pro-inflammatory factors were detected. Linear mixed models showed a significant three-way interaction between the inflammatory cluster, treatment, and time for psychotic symptoms. Only patients treated with simvastatin who were in the inflammatory group, showed a consistent improvement: symptom severity gradually decreased after 3 months and reached significance after 12 and 24 months compared to baseline (p.adj<0.05). The effects were small, and overall between-group effects were not significant. Here, we show that patient stratification based on inflammatory gene expression might be useful to select appropriate treatment augmentation for patients with SSD, highlighting the need for precision medicine approaches. Our findings corroborate the results of the primary analyses, showing that in the overall group, simvastatin was not effective; however, at the individual level the treatment might make a difference.

Published
2022

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