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The correlation between neuropathology levels and cognitive performance in centenarians

Zhang, M. (author), Ganz, Andrea B. (author), Rohde, Susan (author), Lorenz, Linda (author), Rozemuller, Annemieke J.M. (author), Reinders, M.J.T. (author), Hulsman, M. (author), Hoozemans, Jeroen J.M. (author), Holstege, H. (author)

INTRODUCTION: Neuropathological substrates associated with neurodegeneration occur in brains of the oldest old. How does this affect cognitive performance?. METHODS: The 100-plus Study is an ongoing longitudinal cohort study of centenarians who self-report to be cognitively healthy; post mortem brain donation is optional. In 85 centenarian...

journal article 2023

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

van der Lee, S.J. (author), De Rojas, I. (author), Holstege, H. (author), Hulsman, M. (author), Reinders, M.J.T. (author), Tesi, N. (author), van Rooij, Jeroen (author), Zhao, Y. (author), Zhang, X. (author)

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<br/>genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found...

journal article 2022

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Resilience and resistance to the accumulation of amyloid plaques and neurofibrillary tangles in centenarians: An age-continuous perspective

Zhang, M. (author), Ganz, Andrea B. (author), Rohde, Susan (author), Rozemuller, Annemieke J.M. (author), Bank, Netherlands Brain (author), Reinders, M.J.T. (author), Scheltens, Philip (author), Hulsman, M. (author), Hoozemans, Jeroen J.M. (author), Holstege, H. (author)

Introduction: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals—are they resilient, or resistant to AD-associated neuropathologies?. Methods: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and...

journal article 2022

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SnpXplorer: A web application to explore human SNP-associations and annotate SNP-sets

Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Holstege, H. (author), Reinders, M.J.T. (author)

Genetic association studies are frequently used to study the genetic basis of numerous human phenotypes. However, the rapid interrogation of how well a certain genomic region associates across traits as well as the interpretation of genetic associations is often complex and requires the integration of multiple sources of annotation, which...

journal article 2021

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Polygenic Risk Score of Longevity Predicts Longer Survival across an Age Continuum

Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), Holstege, H. (author)

Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with...

journal article 2021

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The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

Tesi, N. (author), Hulsman, M. (author), van der Lee, S.J. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, Natasja M. (author), Scheltens, Philip (author), Reinders, M.J.T. (author), Holstege, H. (author)

Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in...

journal article 2021

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Dynamic clonal hematopoiesis and functional T-cell immunity in a supercentenarian

van den Akker, E.B. (author), Makrodimitris, S. (author), Hulsman, M. (author), Brugman, Martijn H. (author), Nikolic, Tatjana (author), Bradley, Ted (author), Waisfisz, Quinten (author), Baas, Frank (author), Reinders, M.J.T. (author), Holstege, H. (author)

journal article 2020

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Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Scheltens, Philip (author), van der Flier, Wiesje M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), Holstege, H. (author)

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what...

journal article 2020

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Centenarian controls increase variant effect sizes by an average twofold in an extreme case–extreme control analysis of Alzheimer’s disease

Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Meijers-Heijboer, Hanne (author), Reinders, M.J.T. (author), Holstege, H. (author)

The detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be...

journal article 2019

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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

van der Lee, S.J. (author), Conway, Olivia J. (author), Hansen, Iris (author), Carrasquillo, Minerva M. (author), Kleineidam, Luca (author), van den Akker, E.B. (author), Hulsman, M. (author), Tesi, N. (author), Reinders, M.J.T. (author)

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer’s disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven...

journal article 2019

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Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: A clinical interpretation strategy

Holstege, H. (author), van der Lee, S.J. (author), Hulsman, M. (author), Hang Wong, Tsz (author), van Rooij, Jeroen G.J. (author), Weiss, Marjan (author), Louwersheimer, Eva (author), Wolters, Frank J, (author), Amin, Najaf (author), Reinders, M.J.T. (author)

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1...

journal article 2017

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Improved intra-array and interarray normalization of peptide microarray phosphorylation for phosphorylome and kinome profiling by rational selection of relevant spots

Scholma, Jetse (author), Fuhler, G.M. (author), Joore, Jos (author), Hulsman, M. (author), Schivo, Stefano (author), List, Alan F. (author), Reinders, M.J.T. (author), Peppelenbosch, M.P. (author), Post, Janine N. (author)

Massive parallel analysis using array technology has become the mainstay for analysis of genomes and transcriptomes. Analogously, the predominance of phosphorylation as a regulator of cellular metabolism has fostered the development of peptide arrays of kinase consensus substrates that allow the charting of cellular phosphorylation events (often...

journal article 2016

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Unbiased Quantitative Models of Protein Translation Derived from Ribosome Profiling Data

Gritsenko, A.A. (author), Hulsman, M. (author), Reinders, M.J.T. (author), De Ridder, D. (author)

Translation of RNA to protein is a core process for any living organism. While for some steps of this process the effect on protein production is understood, a holistic understanding of translation still remains elusive. In silico modelling is a promising approach for elucidating the process of protein synthesis. Although a number of...

journal article 2015

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Hi-C Chromatin Interaction Networks Predict Co-expression in the Mouse Cortex

Babaei, S. (author), Mahfouz, A.M.E.T.A. (author), Hulsman, M. (author), Lelieveldt, B.P.F. (author), De Ridder, J. (author), Reinders, M.J.T. (author)

The three dimensional conformation of the genome in the cell nucleus influences important biological processes such as gene expression regulation. Recent studies have shown a strong correlation between chromatin interactions and gene co-expression. However, predicting gene co-expression from frequent long-range chromatin interactions remains...

journal article 2015

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Switching from a Unicellular to Multicellular Organization in an Aspergillus niger Hypha

Bleichrodt, R.J. (author), Hulsman, M. (author), Wösten, H.A.B. (author), Reinders, A.J.T. (author)

Pores in fungal septa enable cytoplasmic streaming between hyphae and their compartments. Consequently, the mycelium can be considered unicellular. However, we show here that Woronin bodies close ~50% of the three most apical septa of growing hyphae of Aspergillus niger. The incidence of closure of the 9th and 10th septa was even ?94%....

journal article 2015

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Meta-analysis on blood transcriptomic studies identifies consistently coexpressed protein–protein interaction modules as robust markers of human aging

Van den Akker, E.B. (author), Passtoors, W.M. (author), Jansen, R. (author), Van Zwet, E.W. (author), Goeman, J.J. (author), Hulsman, M. (author), Emilsson, V. (author), Perola, M. (author), Willemsen, G. (author), Penninx, B.W.J.H. (author), Heijmans, B.T. (author), Maier, A.B. (author), Boomsma, D.I. (author), Kok, J.N. (author), Slagboom, P.E. (author), Reinders, M.J.T. (author), Beekman, M. (author)

The bodily decline that occurs with advancing age strongly impacts on the prospects for future health and life expectancy. Despite the profound role of age in disease etiology, knowledge about the molecular mechanisms driving the process of aging in humans is limited. Here, we used an integrative network-based approach for combining multiple...

journal article 2013

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Detecting recurrent gene mutation in interaction network context using multi-scale graph diffusion

Babaei, S. (author), Hulsman, M. (author), Reinders, M.J.T. (author), De Ridder, J. (author)

Background Delineating the molecular drivers of cancer, i.e. determining cancer genes and the pathways which they deregulate, is an important challenge in cancer research. In this study, we aim to identify pathways of frequently mutated genes by exploiting their network neighborhood encoded in the protein-protein interaction network. To this end...

journal article 2013

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Exploring Sequence Characteristics Related to High- Level Production of Secreted Proteins in Aspergillus niger

Van den Berg, B.A. (author), Reinders, M.J.T. (author), Hulsman, M. (author), Wu, L. (author), Pel, H.J. (author), Roubos, J.A. (author), De Ridder, D. (author)

Protein sequence features are explored in relation to the production of over-expressed extracellular proteins by fungi. Knowledge on features influencing protein production and secretion could be employed to improve enzyme production levels in industrial bioprocesses via protein engineering. A large set, over 600 homologous and nearly 2,000...

journal article 2012

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Detecting recurrent gene mutation in interaction network context using multi-scale graph diffusion

Babaei, S. (author), Hulsman, M. (author), Reinders, M.J.T. (author), de Ridder, J. (author)

We introduce a multi-scale kernel diffusion framework and apply it to a large collection of murine retroviral insertional mutagenesis data. The diffusion strength plays the role of scale parameter. As a result, in addition to detecting genes with frequent mutations in their genomic vicinity (red nodes in the interaction graph) we can also find...

poster 2012

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Data mining the TopoChip

Hulsman, M. (author), Unadkat, HV (author), Cornelissen, Kamiel (author), de Boer, Jan (author), Reinders, M.J.T. (author)

poster 2011