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1. Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

Author

Marisol Sampedro-Castañeda, Lucas L. Baltussen, André T. Lopes, Yichen Qiu, Liina Sirvio, Simeon R. Mihaylov, Suzanne Claxton, Jill C. Richardson, Gabriele Lignani, and Sila K. Ultanir

Subjects
Science
Abstract

Abstract Developmental and epileptic encephalopathies (DEEs) are a group of rare childhood disorders characterized by severe epilepsy and cognitive deficits. Numerous DEE genes have been discovered thanks to advances in genomic diagnosis, yet putative molecular links between these disorders are unknown. CDKL5 deficiency disorder (CDD, DEE2), one of the most common genetic epilepsies, is caused by loss-of-function mutations in the brain-enriched kinase CDKL5. To elucidate CDKL5 function, we looked for CDKL5 substrates using a SILAC-based phosphoproteomic screen. We identified the voltage-gated Ca2+ channel Cav2.3 (encoded by CACNA1E) as a physiological target of CDKL5 in mice and humans. Recombinant channel electrophysiology and interdisciplinary characterization of Cav2.3 phosphomutant mice revealed that loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. Our results thus show that CDD is partly a channelopathy. The properties of unphosphorylated Cav2.3 closely resemble those described for CACNA1E gain-of-function mutations causing DEE69, a disorder sharing clinical features with CDD. We show that these two single-gene diseases are mechanistically related and could be ameliorated with Cav2.3 inhibitors.

Published
2023
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2. Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

Author

Alexander Neumann, Olena Ohlei, Fahri Küçükali, Isabelle J. Bos, Jigyasha Timsina, Stephanie Vos, Dmitry Prokopenko, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, Rik Vandenberghe, Philip Scheltens, Charlotte E. Teunissen, Sebastiaan Engelborghs, Giovanni B. Frisoni, Oliver Blin, Jill C. Richardson, Régis Bordet, Alberto Lleó, Daniel Alcolea, Julius Popp, Thomas W. Marsh, Priyanka Gorijala, Christopher Clark, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Christine Van Broeckhoven, Rudolph E. Tanzi, Mara ten Kate, Christina M. Lill, Frederik Barkhof, Carlos Cruchaga, Simon Lovestone, Johannes Streffer, Henrik Zetterberg, Pieter Jelle Visser, Kristel Sleegers, Lars Bertram, and EMIF-AD & ADNI study group

Subjects
Alzheimer’s disease, Dementia, Biomarkers, Cerebrospinal fluid (CSF), Genome-wide association study (GWAS), Multivariate analysis, Medicine, Genetics, QH426-470
Abstract

Abstract Background Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Published
2023
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3. Genome-Wide Association Study of Alzheimer’s Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery Dataset

Author

Jan Homann, Tim Osburg, Olena Ohlei, Valerija Dobricic, Laura Deecke, Isabelle Bos, Rik Vandenberghe, Silvy Gabel, Philip Scheltens, Charlotte E. Teunissen, Sebastiaan Engelborghs, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Regis Bordet, Alberto Lleó, Daniel Alcolea, Julius Popp, Christopher Clark, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Kristel Sleegers, Christine Van Broeckhoven, Michael Wittig, Andre Franke, Christina M. Lill, Kaj Blennow, Henrik Zetterberg, Simon Lovestone, Johannes Streffer, Mara ten Kate, Stephanie J. B. Vos, Frederik Barkhof, Pieter Jelle Visser, and Lars Bertram

Subjects
genome-wide association study, GWAS, X chromosome, Alzheimer’s disease (AD), MRI, imaging, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.

Published
2022
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4. Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context

Author

Evelyn Medawar, Tiffanie A. Benway, Wenfei Liu, Taylor A. Hanan, Peter Haslehurst, Owain T. James, Kenrick Yap, Laurenz Muessig, Fabia Moroni, Muzammil A. Nahaboo Solim, Gaukhar Baidildinova, Rui Wang, Jill C. Richardson, Francesca Cacucci, Dervis A. Salih, Damian M. Cummings, and Frances A. Edwards

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. Methods: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze. Findings: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours. Interpretation: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition. Funding: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC. Keywords: Alzheimer's disease, Dementia, Mouse model, Synaptic transmission, Microglia, Plaque, Neurodegeneration

Published
2019
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5. Modular slowing of resting-state dynamic functional connectivity as a marker of cognitive dysfunction induced by sleep deprivation

Author

Diego Lombardo, Catherine Cassé-Perrot, Jean-Philippe Ranjeva, Arnaud Le Troter, Maxime Guye, Jonathan Wirsich, Pierre Payoux, David Bartrés-Faz, Régis Bordet, Jill C. Richardson, Olivier Felician, Viktor Jirsa, Olivier Blin, Mira Didic, and Demian Battaglia

Subjects
Dynamic functional connectivity, Resting-state, fMRI, Sleep deprivation, Cognitive decline, Cognitive challenge model, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Dynamic Functional Connectivity (dFC) in the resting state (rs) is considered as a correlate of cognitive processing. Describing dFC as a flow across morphing connectivity configurations, our notion of dFC speed quantifies the rate at which FC networks evolve in time. Here we probe the hypothesis that variations of rs dFC speed and cognitive performance are selectively interrelated within specific functional subnetworks.In particular, we focus on Sleep Deprivation (SD) as a reversible model of cognitive dysfunction. We found that whole-brain level (global) dFC speed significantly slows down after 24h of SD. However, the reduction in global dFC speed does not correlate with variations of cognitive performance in individual tasks, which are subtle and highly heterogeneous. On the contrary, we found strong correlations between performance variations in individual tasks –including Rapid Visual Processing (RVP, assessing sustained visual attention)– and dFC speed quantified at the level of functional sub-networks of interest. Providing a compromise between classic static FC (no time) and global dFC (no space), modular dFC speed analyses allow quantifying a different speed of dFC reconfiguration independently for sub-networks overseeing different tasks. Importantly, we found that RVP performance robustly correlates with the modular dFC speed of a characteristic frontoparietal module.

Published
2020
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6. Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors

Author

Giulia Quattrini, Michela Pievani, Jorge Jovicich, Marco Aiello, Núria Bargalló, Frederik Barkhof, David Bartres-Faz, Alberto Beltramello, Francesca B. Pizzini, Olivier Blin, Regis Bordet, Massimo Caulo, Manos Constantinides, Mira Didic, Antonios Drevelegas, Antonio Ferretti, Ute Fiedler, Piero Floridi, Hélène Gros-Dagnac, Tilman Hensch, Karl-Titus Hoffmann, Joost P. Kuijer, Renaud Lopes, Camillo Marra, Bernhard W. Müller, Flavio Nobili, Lucilla Parnetti, Pierre Payoux, Agnese Picco, Jean-Philippe Ranjeva, Luca Roccatagliata, Paolo M. Rossini, Marco Salvatore, Peter Schonknecht, Björn H. Schott, Julien Sein, Andrea Soricelli, Roberto Tarducci, Magda Tsolaki, Pieter J. Visser, Jens Wiltfang, Jill C. Richardson, Giovanni B. Frisoni, and Moira Marizzoni

Subjects
Amygdalar nuclei, Hippocampal subfields, Multicenter MRI study, FreeSurfer, Reliability analysis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults. Methods: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1–90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session. Results: Significant MRI site and vendor effects (p ​0.43, p ​ ​0.80). Conclusion: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

Published
2020
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7. MRI predictors of amyloid pathology: results from the EMIF-AD Multimodal Biomarker Discovery study

Author

Mara ten Kate, Alberto Redolfi, Enrico Peira, Isabelle Bos, Stephanie J. Vos, Rik Vandenberghe, Silvy Gabel, Jolien Schaeverbeke, Philip Scheltens, Olivier Blin, Jill C. Richardson, Regis Bordet, Anders Wallin, Carl Eckerstrom, José Luis Molinuevo, Sebastiaan Engelborghs, Christine Van Broeckhoven, Pablo Martinez-Lage, Julius Popp, Magdalini Tsolaki, Frans R. J. Verhey, Alison L. Baird, Cristina Legido-Quigley, Lars Bertram, Valerija Dobricic, Henrik Zetterberg, Simon Lovestone, Johannes Streffer, Silvia Bianchetti, Gerald P. Novak, Jerome Revillard, Mark F. Gordon, Zhiyong Xie, Viktor Wottschel, Giovanni Frisoni, Pieter Jelle Visser, and Frederik Barkhof

Subjects
Alzheimer’s disease, Mild cognitive impairment, Biomarkers, Magnetic resonance imaging, Amyloid, Machine learning, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background With the shift of research focus towards the pre-dementia stage of Alzheimer’s disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) ε4 genotype, can be used to predict amyloid pathology using machine-learning classification. Methods We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 ± 7.2, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69.1 ± 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 ± 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE ε4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects. Results In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 ± 0.07 in MCI and an AUC of 0.74 ± 0.08 in CN. In CN, selected features for the classifier included APOE ε4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE ε4 information did not improve after additionally adding imaging measures. Conclusions Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.

Published
2018
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8. Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study

Author

Susanna Lopez, Claudio Del Percio, Gianluigi Forloni, Angelisa Frasca, Wilhelmus H. Drinkenburg, Roberta Lizio, Giuseppe Noce, Raffaele Ferri, Andrea Soricelli, Fabrizio Stocchi, Laura Vacca, Règis Bordet, Jill C. Richardson, Claudio Babiloni, and on behalf of PharmaCog Consortium

Subjects
electroencephalography (EEG), Alzheimer’s disease (AD), β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitor, TASTPM mice, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Objective. In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer’s disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods. Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results. Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions. The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.

Published
2020
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9. A Genome-wide Gene-Expression Analysis and Database in Transgenic Mice during Development of Amyloid or Tau Pathology

Author

Mar Matarin, Dervis A. Salih, Marina Yasvoina, Damian M. Cummings, Sebastian Guelfi, Wenfei Liu, Muzammil A. Nahaboo Solim, Thomas G. Moens, Rocio Moreno Paublete, Shabinah S. Ali, Marina Perona, Roshni Desai, Kenneth J. Smith, Judy Latcham, Michael Fulleylove, Jill C. Richardson, John Hardy, and Frances A. Edwards

Subjects
Biology (General), QH301-705.5
Abstract

We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of “amyloid” transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and “TAU” transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.

Published
2015
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10. Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development

Author

Alejo J. Nevado-Holgado, Elena Ribe, Laura Thei, Laura Furlong, Miguel-Angel Mayer, Jie Quan, Jill C. Richardson, Jonathan Cavanagh, NIMA Consortium, and Simon Lovestone

Subjects
Alzheimer, JAK-STAT, multimodal, genomics, transcriptomics, animal models, Cytology, QH573-671
Abstract

As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer’s disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets.

Published
2019
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11. The Effects of Physiological and Methodological Determinants on F-FDG Mouse Brain Imaging Exemplified in a Double Transgenic Alzheimer Model

Author

Steven Deleye MSc, Ann-Marie Waldron MSc, Jill C. Richardson PhD, Mark Schmidt PhD, Xavier Langlois PhD, Sigrid Stroobants MD, PhD, and Steven Staelens PhD

Subjects
Biology (General), QH301-705.5, Medical technology, R855-855.5
Abstract

Introduction: In this study, the influence of physiological determinants on 18F-fluoro- d -glucose ( 18 F-FDG) brain uptake was evaluated in a mouse model of Alzheimer disease. Materials and Methods: TASTPM (Tg) and age-matched C57BL/6 J (WT) mice were fasted for 10 hours, while another group was fasted for 20 hours to evaluate the effect of fasting duration. The effect of repeatedly scanning was evaluated by scanning Tg and WT mice at days 1, 4, and 7. Brain 18 F-FDG uptake was evaluated in the thalamus being the most indicative region. Finally, the cerebellum was tested as a reference region for the relative standard uptake value (rSUV). Results: When correcting the brain uptake for glucose, the effect of different fasting durations was attenuated and the anticipated hypometabolism in Tg mice was demonstrated. Also, with repeated scanning, the brain uptake values within a group and the hypometabolism of the Tg mice only remained stable over time when glucose correction was applied. Finally, hypometabolism was also observed in the cerebellum, yielding artificially higher rSUV values for Tg mice. Conclusion: Corrections for blood glucose levels have to be applied when semiquantifying 18 F-FDG brain uptake in mouse models for AD. Potential reference regions for normalization should be thoroughly investigated to ensure that they are not pathologically affected also by afferent connections.

Published
2016
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12. Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

Author

Marisol Sampedro-Castañeda, Lucas L. Baltussen, Andre T. Lopes, Yichen Qiu, Liina Sirvio, Simeon R. Mihaylov, Suzanne Claxton, Jill C. Richardson, Gabriele Lignani, and Sila Ultanir

Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of rare childhood disorders characterized by severe epilepsy and cognitive deficits. Numerous DEE genes have been discovered thanks to advances in genomic diagnosis, yet putative molecular links between these disorders are unknown. CDKL5 deficiency disorder (CDD, DEE2), one of the most common genetic epilepsies, is caused by loss-of-function mutations in the brain-enriched kinase CDKL5. To elucidate CDKL5 function, we looked for CDKL5 substrates using a SILAC-based phosphoproteomic screen. We identified the voltage-gated Ca2+channel Cav2.3 (encoded byCACNA1E) as a novel physiological target of CDKL5 in mice and humans. Recombinant channel electrophysiology and interdisciplinary characterization of Cav2.3 phosphomutant mice revealed that loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. Our results thus show that CDD is partly a channelopathy. The properties of unphosphorylated Cav2.3 closely resemble those described forCACNA1Egain-of-function mutations causing DEE69, a disorder sharing clinical features with CDD. We show that these two single-gene diseases are mechanistically related and could be ameliorated with Cav2.3 inhibitors.

Published
2022

13. An Alzheimer Disease Challenge Model: 24-Hour Sleep Deprivation in Healthy Volunteers, Impact on Working Memory, and Reversal Effect of Pharmacological Intervention

Author

Jean-Philippe Ranjeva, Romain Truillet, Christine Audebert, Joëlle Micallef, Alexandra Auffret, Jill C. Richardson, Marie-Noëlle Lefebvre, Céline Vervueren, Dominique Deplanque, Laura Lanteaume, David Bartrés-Faz, Anna Chan Kwong, Arnaud Beck, Catherine Cassé-Perrot, Pierre Payoux, Amélie Ponchel, Franck Rouby, Elisabeth Jouve, Marie-Claude Costes-Salon, Olivier Blin, Claudio Babilon, and Régis Bordet

Subjects
Adult, Male, Modafinil, Models, Psychological, Neuropsychological Tests, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Alzheimer Disease, Memantine, law, Reaction Time, medicine, Humans, Cognitive Dysfunction, Donepezil, Pharmacology (medical), Nootropic Agents, Cross-Over Studies, business.industry, medicine.disease, Crossover study, Healthy Volunteers, 030227 psychiatry, 3. Good health, Psychiatry and Mental health, Sleep deprivation, Memory, Short-Term, Anesthesia, Sleep Deprivation, medicine.symptom, Alzheimer's disease, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Purpose/background Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers. Methods/procedure To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task. Findings/results The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459). Implications/conclusions Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.

Published
2020

14. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

Author

Simon Lovestone, Lars Bertram, Pieter Jelle Visser, Dmitry Prokopenko, Isabelle Bos, Régis Bordet, Daniel Alcolea, Sebastiaan Engelborghs, Betty M. Tijms, Silvy Gabel, Charlotte E. Teunissen, Olivier Blin, Jill C. Richardson, Olena Ohlei, Henrik Zetterberg, Richard Dobson, Christina M. Lill, Christopher M. Clark, Giovanni B. Frisoni, Philip Scheltens, Rik Vandenberghe, Johannes Streffer, Valerija Dobricic, Alberto Lleó, Cristina Legido-Quigley, Andre Franke, Mara ten Kate, Gwendoline Peyratout, Christine Van Broeckhoven, Kaj Blennow, Julius Popp, Frederik Barkhof, Stephanie J.B. Vos, Mikel Tainta, Michael Wittig, Pablo Martinez-Lage, Ulf Andreasson, Shengjun Hong, Alzheimer's Disease Neuroimaging Initiative, Kristel Sleegers, Rudolph E. Tanzi, Neuroimaging Initiative, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Pathologic Biochemistry and Physiology, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neurodegeneration, Laboratory Medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Radiology and nuclear medicine

Subjects
0301 basic medicine, Male, Epidemiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, 3&#8208, LOCI, Genome-wide association study, Disease, Bioinformatics, Alzheimer&apos, 0302 clinical medicine, Cerebrospinal fluid, Chitinase-3-like protein 1, like protein 1, Neurofilament Proteins, neurofilament light, Medicine, Nerve Tissue Proteins/genetics, Neurogranin, Biomarker discovery, wide association study, RISK, neurogranin, Health Policy, genome&#8208, Alzheimer's disease, ATLAS, Psychiatry and Mental health, chitinase&#8208, Chitinase-3-Like Protein 1/genetics, Biomarker (medicine), biomarker, Female, Life Sciences & Biomedicine, chitinase-3-like protein 1, PROTEINS, Clinical Neurology, BETA, Nerve Tissue Proteins, cerebrospinal fluid, s disease, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurofilament Proteins/genetics, Alzheimer Disease, Neurogranin/cerebrospinal fluid, Humans, Biomarkers/cerebrospinal fluid, Membrane Proteins/genetics, GENOME-WIDE ASSOCIATION, Genetic association, Aged, Alzheimer Disease/genetics, Science & Technology, business.industry, Membrane Proteins, Genetic architecture, 030104 developmental biology, Neurology (clinical), Human medicine, Neurosciences & Neurology, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study
Abstract

INTRODUCTION: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. METHODS: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. RESULTS: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. DISCUSSION: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD. ispartof: ALZHEIMERS & DEMENTIA vol:17 issue:10 pages:1628-1640 ispartof: location:United States status: published

Published
2021

15. Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients

Author

Marco Salvatore, Marco Aiello, Diego Albani, Ilaria Boscolo Galazzo, Olivier Blin, Pradeep J. Nathan, Francesca B. Pizzini, Melissa Romano, Andrea Soricelli, Mira Didic, Gianluigi Forloni, Jill C. Richardson, Michela Pievani, Giovanni B. Frisoni, Jorge Jovicich, Giulia Quattrini, Moira Marizzoni, Xavier Golay, Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia = University of Brescia (UniBs), University of Brescia, Università degli studi di Verona = University of Verona (UNIVR), IRCCS SDN Napoli, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Università degli Studi di Napoli 'Parthenope' = University of Naples (PARTHENOPE), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], Assistance Publique - Hôpitaux de Marseille (APHM), UCL Institute of Neurology, Queen Square [London], University of Trento [Trento], University of Cambridge [UK] (CAM), GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), and Université de Genève = University of Geneva (UNIGE)

Subjects
0301 basic medicine, Apolipoprotein E, Male, medicine.medical_specialty, Perfusion scanning, Hippocampus, Alzheimer’s disease, arterial spin labeling, brain perfusion, default mode network, limbic network, mild cognitive impairment, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Limbic System, Memory impairment, Humans, Cognitive Dysfunction, Default mode network, Alzheimer's disease, Aged, Amnesia, Biomarkers, Cerebrovascular Circulation, Female, Magnetic Resonance Imaging, Default Mode Network, Perfusion, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, Discriminant validity, General Medicine, Hyperintensity, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Convergent validity, Cerebral blood flow, Cardiology, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

International audience; Background: Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer’s disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL). Objective: To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI. Methods: We collected core AD markers (amyloid-β 42 [Aβ42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks’ perfusion, cerebellar volume, and processing speed. Results: Perfusion was reduced in the DMN (F = 5.486, p = 0.039) and LIN (F = 12.678, p = 0.004) in APOE ɛ4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aβ42 levels (r = 0.678, p = 0.022) and memory impairment (PAL, number of errors, r = –0.779, p = 0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features. Conclusion: Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ɛ4, and memory impairment.

Published
2021

16. Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay

Author

Isabelle Bos, Henrik Zetterberg, Daniel Alcolea, Gwendoline Peyratout, B. Paul Morgan, Susan Baker, Simon Lovestone, Liu Shi, Fabian Kilpert, Lars Bertram, Shengjun Hong, Ellen Elisa De Roeck, Alberto Lleó, Mikel Tainta, Pablo Martinez-Lage, Kaj Blennow, Alison L. Baird, Olivier Blin, Lorena Rami, José Luis Molinuevo, Kristel Sleegers, Yvonne Freund-Levi, Lutz Frölich, Angharad R. Morgan, Pieter Jelle Visser, Rik Vandenberghe, Philip Scheltens, Silvy Gabel, Charlotte E. Teunissen, Petronella Kettunen, Julius Popp, Jill C. Richardson, Noel J. Buckley, Stephanie J. B. Vos, Abdul Hye, Johannes Streffer, Sarah Westwood, Nicholas J. Ashton, Valerija Dobricic, Alejo J. Nevado-Holgado, Magda Tsolaki, Giovanni B. Frisoni, Andre Franke, Frans R.J. Verhey, Sebastiaan Engelborghs, Mara ten Kate, Régis Bordet, Cristina Legido-Quigley, Laura Winchester, Anders Wallin, Karen Meersmans, Frederik Barkhof, Peter Johannsen, University of Oxford, Universität zu Lübeck = University of Lübeck [Lübeck], Christian-Albrechts University of Kiel, King‘s College London, University of Gothenburg (GU), Cardiff University, Maastricht University [Maastricht], VU University Medical Center [Amsterdam], University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Vrije Universiteit Brussel (VUB), University of Antwerp (UA), Université de Genève = University of Geneva (UNIGE), Istituto Centro San Giovanni di Dio Fatebenefratelli, Partenaires INRAE, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM), GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), CHU Lille, Université de Lille, Hospital Clinic (IDIBAPS), Universitat Pompeu Fabra [Barcelona] (UPF), Sahlgrenska Academy at University of Gothenburg [Göteborg], AHEPA University General Hospital [Thessaloniki], Hospital de la Santa Creu i Sant Pau, Lausanne University Hospital, Geneva University Hospital (HUG), Center for Research and Advanced Therapies CITA-Alzheimer Foundation [San Sebastián], Copenhagen University Hospital, Amsterdam UMC - Amsterdam University Medical Center, Vrije Universiteit Amsterdam [Amsterdam] (VU), Karolinska Institutet [Stockholm], Örebro University, Universität Heidelberg [Heidelberg] = Heidelberg University, Institutes of Neurology and Healthcare Engineering, UCL, London, Sahlgrenska University Hospital [Gothenburg], UCL, Institute of Neurology [London], Janssen Research & Development, University of Oslo (UiO), Neurology, Radiology and nuclear medicine, Amsterdam Neuroscience - Neurodegeneration, Clinical chemistry, Faculty of Arts and Philosophy, Clinical sciences, Educational Science, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, Promovendi MHN, and MUMC+: MA Med Staf Spec Psychiatrie (9)

Subjects
0301 basic medicine, Apolipoprotein E, Male, Proteomics, Neurology, Epidemiology, Apolipoprotein E4, Disease, SOMAscan assay, ddc:616.89, BLOOD-BASED BIOMARKERS, 0302 clinical medicine, CASCADE HYPOTHESIS, MARKERS, Tau, Medicine, Biomarker discovery, DRUG, Medicine(all), Health Policy, Age Factors, Brain, Middle Aged, Blood proteins, 3. Good health, Europe, ALZHEIMERS-DISEASE, Psychiatry and Mental health, MENDELIAN RANDOMIZATION, Biomarker (medicine), Female, Life Sciences & Biomedicine, medicine.medical_specialty, Amyloid, MODELS, Clinical Neurology, Replication, Plasma proteomics, Computational biology, Article, SIGNALING PATHWAYS, 03 medical and health sciences, Cellular and Molecular Neuroscience, AGE, Developmental Neuroscience, Alzheimer Disease, Amyloid β, Causal relationship, Mendelian randomization, Humans, Biology, Aged, Science & Technology, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Amyloid beta, 030104 developmental biology, Neurology (clinical), Human medicine, Neurosciences & Neurology, Geriatrics and Gerontology, TAU, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition. This research was conducted as part of the EMIF-AD project, which has received support from 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 Program (FP7/2007-2013), and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007, and #15005). R.V. is a senior clinical investigator of the Flemish Research Foundation (FWO). J.S. is currently an employee of UCB, Braine-l’Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The authors acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIBCMN is funded in part by the University of Antwerp Research Fund. F.B. is supported by the NIHR biomedical research centre at UCLH. L.S. is funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215).

Published
2019

17. Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum

Author

Philip Scheltens, Olivier Blin, Peter Johannsen, Frans R.J. Verhey, Kaj Blennow, Henrik Zetterberg, Rik Vandenberghe, Gwendoline Peyratout, Jill C. Richardson, Yvonne Freund-Levi, Kristel Sleegers, Cristina Legido-Quigley, Sebastiaan Engelborghs, Julius Popp, Sarah Westwood, Pablo Martinez-Lage, Mikel Tainta, Simon Lovestone, Magda Tsolaki, Ulf Andreasson, Valerija Dobricic, Lars Bertram, Régis Bordet, Giovanni B. Frisoni, Charlotte E. Teunissen, Pieter Jelle Visser, Alberto Lleó, Stephanie J.B. Vos, Isabelle Bos, Johannes Streffer, Frederik Barkhof, Lutz Frölich, Neurology, Amsterdam Neuroscience - Neurodegeneration, Laboratory Medicine, Radiology and nuclear medicine, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical sciences, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and MUMC+: MA Med Staf Spec Psychiatrie (9)

Subjects
0301 basic medicine, Apolipoprotein E, MILD COGNITIVE IMPAIRMENT, Epidemiology, Apolipoprotein E4, PROTEIN, Disease, GUIDELINES, 0302 clinical medicine, Cerebrospinal fluid, Cognition, Neurofilament Proteins, Neurogranin, Cognitive decline, ComputingMilieux_MISCELLANEOUS, Medicine(all), Aged, 80 and over, Health Policy, Neurodegeneration, ASSOCIATION, Alzheimer's disease, DEGENERATION, Psychiatry and Mental health, Female, Amyloid-beta, APOE, Neurofilament light, YKL-40, tau Proteins, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Alzheimer Disease, medicine, Humans, Dementia, Amyloid-β, Cognitive Dysfunction, Biology, Aged, NEUROFILAMENT LIGHT, Amyloid beta-Peptides, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, NEUROGRANIN, PATHOLOGY, 030104 developmental biology, Human medicine, Neurology (clinical), Geriatrics and Gerontology, TAU, business, Neuroscience, Biomarkers, 030217 neurology & neurosurgery
Abstract

Introduction: We investigated relations between amyloid-beta (A beta) status, apolipoprotein E (APOE) e4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).Methods: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with A beta status (Ab beta- vs. A beta+), clinical diagnosis APOE epsilon 4 carriership, baseline cognition, and change in cognition.Results: Ng and T-tau distinguished between A beta+ from A beta- individuals in each clinical group, whereas NFL and YKL-40 were associated with A beta+ in nondemented individuals only. APOE epsilon 4 carriership did not influence NFL, Ng, and YKL-40 in A beta+ individuals. NFL was the best predictor of cognitive decline in A beta+ individuals across the cognitive spectrum.Discussion: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Published
2019

18. Genome-wide association study of Alzheimer’s disease brain imaging biomarkers and neuropsychological phenotypes in the EMIF-AD Multimodal Biomarker Discovery dataset

Author

Jan Homann, Tim Osburg, Olena Ohlei, Valerija Dobricic, Laura Deecke, Isabelle Bos, Rik Vandenberghe, Silvy Gabel, Philip Scheltens, Charlotte E. Teunissen, Sebastiaan Engelborghs, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Regis Bordet, Alberto Lleó, Daniel Alcolea, Julius Popp, Christopher Clark, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Kristel Sleegers, Christine Van Broeckhoven, Michael Wittig, Andre Franke, Christina M. Lill, Kaj Blennow, Henrik Zetterberg, Simon Lovestone, Johannes Streffer, Mara ten Kate, Stephanie J. B. Vos, Frederik Barkhof, Pieter Jelle Visser, and Lars Bertram

Abstract

Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, ageing populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e. case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n=931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.

Published
2021

19. Sex-specific metabolic pathways associate with Alzheimer’s Disease (AD) endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery cohort

Author

Min Kim, Charlotte E. Teunissen, Alison L. Baird, Petronella Kettunen, José Luis Molinuevo, Isabelle Bos, Frans R.J. Verhey, Mikel Tainta, Julius Popp, Philip Scheltens, Sarah Westwood, Pieter Jelle Visser, Lutz Frölich, Simon Lovestone, Daniel Alcolea, Cristina Legido-Quigley, Alejo J. Nevado-Holgado, Jin Xu, Lars Bertram, Mara ten Kate, Gwendoline Peyratout, Sebastiaan Engelborghs, Magda Tsolaki, Rebecca Green, Yvonne Freund-Levi, Alberto Lleó, Peter Johannsen, Pablo Martinez-Lage, Karen Meersmans, Valerija Dobricic, Olivier Blin, Amera A. Ebshiana, Jodie Lord, Giovanni B. Frisoni, Silvy Gabel, Rik Vandenberghe, Henrik Zetterberg, Stuart G. Snowden, Kaj Blennow, Régis Bordet, Johannes Streffer, Anders Wallin, Liu Shi, Jill C. Richardson, Petroula Proitsi, Ellen Elisa De Roeck, Lorena Rami, Abdul Hye, Kristel Sleegers, and Stephanie J.B. Vos

Subjects
Oncology, medicine.medical_specialty, business.industry, Disease, Kynurenate, Metabolic pathway, Dopamine, Endophenotype, Internal medicine, Cohort, medicine, Serotonin, Biomarker discovery, business, medicine.drug
Abstract

BACKGROUNDPhysiological differences between males and females could contribute to the development of AD. Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODSWe explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, CSF biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites’ discriminatory performance in AD.RESULTSIn females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (AUC = 0.83, SE = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONSMetabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, associated to females, paving the way to personalised treatment.

Published
2021

20. Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: A European multi-site 3T study

Author

Bernhard W. Müller, Daniele Altomare, Marco Salvatore, Renaud Lopes, Paolo Maria Rossini, Jens Wiltfang, Moira Marizzoni, Martina Montalti, Stéphanie Bombois, Giovanni B. Frisoni, Clarissa Ferrari, Karl Titus Hoffmann, Camillo Marra, Massimo Caulo, Francesca B. Pizzini, David Bartrés-Faz, Ute Fiedler, Antonio Ferretti, Mira Didic, Manos Constantinidis, Andrea Soricelli, Federica Ribaldi, Joost P.A. Kuijer, Carlo Cavaliere, Antonios Drevelegas, Flavio Nobili, Piero Floridi, Luca Roccatagliata, Julien Sein, Régis Bordet, Franco Alessandrini, Pierre Payoux, Roberto Tarducci, Jorge Jovicich, Olivier Blin, Agnese Picco, Jean-Philippe Ranjeva, Frederik Barkhof, Beatriz Bosch, Magda Tsolaki, Pieter Jelle Visser, Lucilla Parnetti, Tilman Hensch, Jill C. Richardson, Núria Bargalló, Anna Mega, Helene Gros-Dagnac, Marco Aiello, Peter Schönknecht, Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia [Brescia], Laboratory of Neuroimaging of aging, Memory clinic and LANVIE, Geneva University Hospital and Geneva University, Center for Mind/Brain Sciences (CIMEC), University of Trento [Trento], Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili [Genova] (DINOGMI), Universita degli studi di Genova, Department of Diagnostics and Public Health [Verona] (UNIVR | DDSP), University of Verona (UNIVR), IRCCS SDN Napoli, Department of Clinic Sciences and Bioimaging, University G. d'Annunzio Chieti-Pescara, Interbalkan Medical Center of Thessaloniki, Dept. of Child and Adolescent Psychiatry and Psychology, Institut Clinic of Neurosciences IDIBAPS (Institut d'Investigacions Biomèdiques August Pi Sunyer), Hospital Clínic Universitari of Barcelona, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Universität Duisburg-Essen [Essen], Department of Neuroscience, Catholic University, Roma, Centre for Medical Image Computing (CMIC), University College of London [London] (UCL), Department of Radiology and Nuclear Medicine [Amsterdam], VU University Medical Center [Amsterdam], Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), University Medical Center Göttingen (UMG), Department of Neuroradiology, University Hospital Leipzig, Section of Neurology, Centre for Memory Disturbances, University of Perugia, Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Neurology Department, Hospital Clinic, IDIBAPS, Facultad de Medicina, Barcelona, Dept. Neuroscience & Neurorehabilitation, IRCCS-San Raffaele-Pisana, Rome, University of Leipzig Medical Center, Neuroradiology Unit, Perugia General Hospital, Perugia, Alzheimer Center Amsterdam, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Medical Physics Unit, Perugia General Hospital, Perugia, Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Leipzig, LVR-Clinic for Psychiatry and Psychotherapy, Institutes and Clinics of the University Duisburg-Essen, Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Università degli Studi di Brescia = University of Brescia (UniBs), Università degli studi di Genova = University of Genoa (UniGe), Università degli studi di Verona = University of Verona (UNIVR), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Leipzig University, Università degli Studi di Perugia = University of Perugia (UNIPG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Adult, Male, Aging, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Image Processing, Medizin, Biomedical Engineering, Biophysics, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Automation, 0302 clinical medicine, Computer-Assisted, Sørensen–Dice coefficient, Image Processing, Computer-Assisted, White matter hyperintensities, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Segmentation, Lesion segmentation toolbox, ComputingMilieux_MISCELLANEOUS, Accuracy, Reproducibility, Lesion segmentation, business.industry, Lesion growth, Automated segmentation algorithms, Multi site, Reproducibility of Results, Gold standard (test), White Matter, Magnetic Resonance Imaging, Hyperintensity, Settore MED/26 - NEUROLOGIA, Cross-Sectional Studies, Algorithms, Female, Nuclear medicine, business, 030217 neurology & neurosurgery
Abstract

Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was −0.22[IQR = 0.50] for LGA-SPM8, −0.12[0.57] for LGA-SPM12, −0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies.

Published
2021

21. Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

Author

Pablo Martinez-Lage, Ulf Andreasson, Richard Dobson, Ellis Niemantsverdriet, Fabian Kilpert, Mikel Tainta, Michael Wittig, Mara ten Kate, Simon Lovestone, Lars Bertram, Henrik Zetterberg, Stephanie J.B. Vos, Dmitry Prokopenko, Frederik Barkhof, Jolien Schaeverbeke, Philip Scheltens, Shengjun Hong, Jill C. Richardson, Olivier Blin, Valerija Dobricic, Pieter Jelle Visser, Silvy Gabel, Cristina Legido-Quigley, Giovanni B. Frisoni, Johannes Streffer, Isabel Sala, Sebastiaan Engelborghs, José Luis Molinuevo, Andre Franke, Alberto Lleó, Isabelle Bos, Rudolph E. Tanzi, Lorena Rami, Kristel Sleegers, Betty M. Tijms, Régis Bordet, Charlotte E. Teunissen, Petronella Kettunen, Rik Vandenberghe, Julius Popp, Isabelle Cleynen, Gwendoline Peyratout, Kaj Blennow, Anders Wallin, Christine Van Broeckhoven, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Alzheimers Dis Neuroimaging Initia, Universität zu Lübeck = University of Lübeck [Lübeck], Massachusetts General Hospital [Boston], Maastricht University [Maastricht], Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Gothenburg (GU), Sahlgrenska University Hospital [Gothenburg], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], University of Antwerp (UA), Vrije Universiteit Brussel (VUB), Université de Genève = University of Geneva (UNIGE), Istituto Centro San Giovanni di Dio Fatebenefratelli, Partenaires INRAE, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), CHU Lille, Université de Lille, Clinic Barcelona Hospital Universitari, University of Oxford, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Geneva University Hospital (HUG), Lausanne University Hospital, Center for Research and Advanced Therapies CITA-Alzheimer Foundation [San Sebastián], King‘s College London, University College of London [London] (UCL), Steno Diabetes Center, VIB [Belgium], Amsterdam UMC - Amsterdam University Medical Center, UCL Institute of Neurology, Queen Square [London], UK Dementia Research Institute (UK DRI), UCB BioPharma [Braine l’Alleud, Belgium], Christian-Albrechts University of Kiel, University of Oslo (UiO), Alzheimer's Disease Neuroimaging Initiative (ADNI), Amsterdam Neuroscience - Neurodegeneration, Neurology, Laboratory Medicine, Radiology and nuclear medicine, Clinical sciences, Neuroprotection & Neuromodulation, and Pathologic Biochemistry and Physiology

Subjects
0301 basic medicine, Male, Genome-wide association study, 0302 clinical medicine, RISK VARIANTS, Biomarker discovery, MIF-AD Multimodal Biomarker Discovery dataset, Psychiatry, Alzheimer's disease, Psychiatry and Mental health, Female, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Neuroscience(all), Single-nucleotide polymorphism, Genomics, tau Proteins, Computational biology, Biology, Molecular neuroscience, elderly, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, medicine, Dementia, SNP, Humans, CSF biomarkers, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Aged, Amyloid beta-Peptides, Science & Technology, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Neurodegenerative disorder, medicine.disease, Personalized medicine, Genetic architecture, Peptide Fragments, 030104 developmental biology, Human medicine, TAU, business, 030217 neurology & neurosurgery, Biomarkers, dementia, Genome-Wide Association Study
Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case–control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case–control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

Published
2020

22. Amygdalar nuclei and hippocampal subfields on MRI: Test‐retest reliability of automated segmentation in old and young healthy volunteers

Author

Agnese Picco, Núria Bargalló, Antonios Drevelegas, Mira Didic, Régis Bordet, Moira Marizzoni, Bernhard W. Müller, Piero Floridi, Björn H. Schott, Michela Pievani, Giovanni B. Frisoni, Jill C. Richardson, Alberto Beltramello, Tilman Hensch, Marco Salvatore, Flavio Nobili, Pierre Payoux, Roberto Tarducci, Jorge Jovicich, Magda Tsolaki, Karl-Titus Hoffmann, Jens Wiltfang, Camillo Marra, Renaud Lopes, Jean-Philippe Ranjeva, Pieter Jelle Visser, Giulia Quattrini, Lucilla Parnetti, Manos Constantinides, Frederik Barkhof, David Bartrés-Faz, Francesca B. Pizzini, Julien Sein, Antonio Ferretti, Olivier Blin, Ute Fiedler, Luca Roccatagliata, Massimo Caulo, Andrea Soricelli, Paolo Maria Rossini, Joost P.A. Kuijer, Helene Gros-Dagnac, Marco Aiello, and Peter Schönknecht

Subjects
medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Automated segmentation, Hippocampal formation, Audiology, Test (assessment), Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, Healthy volunteers, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Brain aging, Reliability (statistics)
Published
2020

23. DNA methylation differences associated with peripheral biomarkers in the EMIF‐AD cohort

Author

Rik Vandenberghe, Philip Scheltens, Julius Popp, Magda Tsolaki, Olivier Blin, Kaj Blennow, Régis Bordet, Stephanie J.B. Vos, Peter Johannsen, Pieter Jelle Visser, Henrik Zetterberg, Alberto Lleó, Isabelle Bos, Katie Lunnon, Frans R.J. Verhey, Johannes Streffer, Jill C. Richardson, Simon Lovestone, Lars Bertram, Yvonne Freund, Lutz Frölich, Pablo Martinez-Lage, Sebastiaan Engelborghs, Ulf Andreasson, Rebecca G. Smith, and Giovanni B. Frisoni

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Peripheral, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, Internal medicine, Cohort, DNA methylation, medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2020

24. Neurofilament light and cognitive performance: Associations with amyloid and vascular pathologies in individuals with mild cognitive impairment

Author

Isabelle Bos, Frans R.J. Verhey, Olivier Blin, Simon Lovestone, Mara ten Kate, Johannes Streffer, Sebastiaan Engelborghs, Giovanni B. Frisoni, Régis Bordet, Ulf Andreasson, Philip Scheltens, Kaj Blennow, Pieter Jelle Visser, Julius Popp, Henrik Zetterberg, Magda Tsolaki, Stephanie J.B. Vos, Frederik Barkhof, and Jill C. Richardson

Subjects
Amyloid, Epidemiology, business.industry, Health Policy, Neurofilament light, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Effects of sleep deprivation on cognitive performance, Geriatrics and Gerontology, Cognitive impairment, business, Neuroscience
Published
2020

25. Identification of plasma proteome signatures associated with ATN framework using SOMAscan

Author

Isabelle Bos, Simon Lovestone, Mara ten Kate, Ellen De Roeck, Lars Bertram, Giovanni B. Frisoni, Daniel Alcolea, Nicholas J. Ashton, Frederik Barkhof, Gwendoline Peyratout, Frans R.J. Verhey, Yvonne Freund, Noel J. Buckley, Sebastiaan Engelborghs, Fabian Kilpert, Valerija Dobricic, Régis Bordet, Paul Morgan, Mikel Tainta, Johannes Streffer, José Luis Molinuevo, Silvy Gabel, Kaj Blennow, Rik Vandenberghe, Kristel Sleegers, Olivier Blin, Cristina Legido-Quigley, Alberto Lleó, Abdul Hye, Andreas G. Franke, Alejo J. Nevado-Holgado, Julius Popp, Lutz Frölich, Sarah Westwood, Magda Tsolaki, Karen Meersmans, Laura Winchester, Liu Shi, Anders Wallin, Lorena Rami, Jill C. Richardson, Henrik Zetterberg, Stephanie J.B. Vos, Philip Scheltens, Alison L. Baird, Pablo Martinez-Lage, Peter Johannsen, Angharad R. Morgan, Pieter Jelle Visser, Charlotte E. Teunissen, Petronella Kettunen, and Shengjun Hong

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Proteome, Identification (biology), Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology
Published
2020

26. Ongoing Electroencephalographic Rhythms Related to Exploratory Movements in Transgenic TASTPM Mice

Author

Ditte Zerlang Christensen, Sophie Dix, Giuseppe Bertini, Fabrizio Stocchi, Maria Teresa Pascarelli, Bettina Laursen, Francesco Infarinato, Jill C. Richardson, Gianluigi Forloni, Jonathan Kelley, Andrea Soricelli, Paolo F. Fabene, Claudio Babiloni, Jan Torleif Pedersen, Giuseppe Noce, Valeria Colavito, Raffaele Ferri, Roberta Lizio, Susanna Lopez, Jesper F. Bastlund, Claudio Del Percio, Marina Bentivoglio, Francesco Noé, Wilhelmus Drinkenburg, and Angelisa Frasca

Subjects
0301 basic medicine, medicine.medical_specialty, Future studies, Transgene, Movement, Mice, Transgenic, Electroencephalography, Audiology, Active and passive state in wakefulness, TASTPM mice, wild type mice, 03 medical and health sciences, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Rhythm, Alzheimer Disease, PSEN1, Medicine, Animals, Cognitive Dysfunction, Wakefulness, Alzheimer’s disease, electroencephalography, medicine.diagnostic_test, business.industry, General Neuroscience, Brain, Reproducibility of Results, Cognition, General Medicine, Amyloidosis, Quiet wakefulness, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Eeg rhythms, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Background: The European PharmaCog study (http://www.pharmacog.org) has reported a reduction in delta (1–6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer’s disease (AD) amyloidosis and cognitive deficits. Objective: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. Methods: Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched “wild type” C57 mice (range of age: 12–24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. Results: Compared with the “wild type” group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p

Published
2020

27. Amygdalar nuclei and hippocampal subfields on MRI

Author

Michela Pievani, Agnese Picco, Jean-Philippe Ranjeva, Giovanni B. Frisoni, Lucilla Parnetti, Piero Floridi, Frederik Barkhof, Jens Wiltfang, Marco Salvatore, Helene Gros-Dagnac, Antonio Ferretti, Julien Sein, Massimo Caulo, Alberto Beltramello, Pierre Payoux, Marco Aiello, Joost P.A. Kuijer, Roberto Tarducci, Tilman Hensch, Renaud Lopes, Björn H. Schott, Peter Schönknecht, Luca Roccatagliata, Camillo Marra, David Bartrés-Faz, Jill C. Richardson, Jorge Jovicich, Flavio Nobili, Antonios Drevelegas, Pieter Jelle Visser, Olivier Blin, Paolo Maria Rossini, Karl Titus Hoffmann, Mira Didic, Régis Bordet, Bernhard W. Müller, Francesca B. Pizzini, Magda Tsolaki, Ute Fiedler, Manos Constantinides, Giulia Quattrini, Moira Marizzoni, Andrea Soricelli, Núria Bargalló, Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia [Brescia], Center for Mind/Brain Sciences, University of Trento, Corso Bettini, 31, 38068, Rovereto, TN, Italy, IRCCS SDN Napoli, Department of Neuroradiology and Image Research Platform, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Department of Radiology and Nuclear Medicine [Amsterdam], VU University Medical Center [Amsterdam], Institute of Neurology, Queen Square, London, Department of Medicine and Health Sciences, Faculty of Medicine, Universitat de Barcelona and IDIBAPS, Barcelona, Department of Radiology, IRCCS 'Sacro Cuore-Don Calabria', Negrar, Verona, Radiology, Department of Diagnostic and Public Health, University of Verona, Verona, Centre investigation clinique - Unité de pharmacologie clinique et d'évaluations thérapeutiques (CIC-UPCET), Assistance Publique - Hôpitaux de Marseille (APHM), Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University 'G. d'Annunzio' of Chieti-Pescara [Chieti], Interbalkan Medical Center of Thessaloniki, LVR-Clinic for Psychiatry and Psychotherapy, Institutes and Clinics of the University Duisburg-Essen, Neuroradiology Unit, Perugia General Hospital, Perugia, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Leipzig, Department of Neuroradiology, University Hospital Leipzig, LVR-Hospital Essen, Department for Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg-Essen, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, 16132 Genova, Section of Neurology, Department of Medicine, University of Perugia, Perugia, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), IRCCS, Ospedale Policlinico San Martino, Genova, Italy, Department of Health Science (DISSAL), University of Genoa, Genoa, Dept. Neuroscience & Rehabilitation, IRCCS San Raffaele-Pisana, Rome, Department of Psychiatry and Psychotherapy, University Medical Center Goettingen (UMG), Göttingen, Leibniz Institute for Neurobiology, Magdeburg, Center for Neurodegenerative Diseases (DZNE), Goettingen, Medical Physics Unit, Perugia General Hospital, Perugia, Aristotle University of Thessaloniki, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Netherlands, Maastricht University, Maastricht, Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, German Center for Neurodegenerative Diseases (DZNE), Goettingen, GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Laboratory of Neuroimaging of aging, Memory clinic and LANVIE, Geneva University Hospital and Geneva University, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Amsterdam Neuroscience - Brain Imaging, Radiology and nuclear medicine, Neurology, Università degli Studi di Brescia = University of Brescia (UniBs), Università degli Studi di Trento (UNITN), Università degli studi di Verona = University of Verona (UNIVR), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Leipzig University, Università degli studi di Genova = University of Genoa (UniGe), Università degli Studi di Perugia = University of Perugia (UNIPG), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), and Leibniz Institute for Neurobiology [Magdeburg] (LIN)

Subjects
Male, STRUCTURAL DIFFERENCES, Neurology, genetic structures, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, FreeSurfer, Medizin, Hippocampus, Hippocampal formation, Amygdalar nuclei, Hippocampal subfields, Multicenter MRI study, Reliability analysis, 0302 clinical medicine, methods [Magnetic Resonance Imaging], hippocampal subfields, multicenter MRI study, reliability analysis, methods [Image Processing, Computer-Assisted], Image Processing, Computer-Assisted, METHODS FREESURFER, ELDERLY-PATIENTS, ComputingMilieux_MISCELLANEOUS, 05 social sciences, Subiculum, BORDERLINE PERSONALITY-DISORDER, Middle Aged, Amygdala, HUMAN BRAIN, Magnetic Resonance Imaging, ALZHEIMERS-DISEASE, standards [Image Processing, Computer-Assisted], Settore MED/26 - NEUROLOGIA, MANUAL SEGMENTATION, medicine.anatomical_structure, Brain size, Cohort, Female, methods [Neuroimaging], Adult, medicine.medical_specialty, Cognitive Neuroscience, anatomy & histology [Hippocampus], Neuroimaging, Cognitive neuroscience, SURFACE-BASED ANALYSIS, 050105 experimental psychology, lcsh:RC321-571, 03 medical and health sciences, medicine, Humans, 0501 psychology and cognitive sciences, ddc:610, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Aged, standards [Magnetic Resonance Imaging], business.industry, Reproducibility of Results, SAMPLE-SIZE CALCULATIONS, ddc:616.8, nervous system, anatomy & histology [Amygdala], Nuclear medicine, business, 030217 neurology & neurosurgery, standards [Neuroimaging], Software, FUNCTIONAL-ORGANIZATION
Abstract

Background: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults.Methods: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (epsilon) and spatial overlapping coefficient (DICE) between test and retest session.Results: Significant MRI site and vendor effects (p 0.43, p 0.80).Conclusion: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

Published
2020

28. CSF cutoffs for MCI due to AD depend on APOEε4 carrier status

Author

Jean-Philippe Ranjeva, Frederik Barkhof, Jorge Jovicich, Régis Bordet, Jill C. Richardson, Elena Rolandi, Magda Tsolaki, Andrea Soricelli, Olivier Blin, Lucilla Parnetti, Marco Salvatore, Claudio Babiloni, Tilman Hensch, Jens Wiltfang, Camillo Marra, José Luis Molinuevo, Libera Cavaliere, Samantha Galluzzi, Moira Marizzoni, Diego Albani, Mira Didic, Clarissa Ferrari, Flavio Nobili, Federica Fusco, Paolo Maria Rossini, Giovanni B. Frisoni, Gianluigi Forloni, Federica Ribaldi, Pierre Payoux, Pieter Jelle Visser, Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia [Brescia], Department of Physiology and Pharmacology 'Vittorio Erspamer', Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Neuroscience Department, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Department of Radiology and Nuclear Medicine [Amsterdam], VU University Medical Center [Amsterdam], Institutes of Neurology and Healthcare Engineering, UCL, London, Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Leipzig, Center for Mind/Brain Sciences, University of Trento, Corso Bettini, 31, 38068, Rovereto, TN, Italy, Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Rome, Alzheimer's Disease Unit and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Dipartimento di Neuroscienze, riabilitazione, oftalmologia, genetica e scienze materno-infantili [Genova] (DINOGMI), Universita degli studi di Genova, Section of Neurology, Centre for Memory Disturbances, University of Perugia, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Area Neuroscience, IRCCS San Raffaele, Rome, IRCCS SDN Napoli, Department of Neurology (Aristotle University of Thessaloniki), Aristotle University of Thessaloniki, Alzheimer Center Amsterdam, LVR-Clinic for Psychiatry and Psychotherapy, Institutes and Clinics of the University Duisburg-Essen, GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre investigation clinique - Unité de pharmacologie clinique et d'évaluations thérapeutiques (CIC-UPCET), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratory of Neuroimaging of aging, Memory clinic and LANVIE, Geneva University Hospital and Geneva University, Amsterdam Neuroscience - Neurodegeneration, Radiology and nuclear medicine, Università degli Studi di Brescia = University of Brescia (UniBs), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Leipzig University, Università degli Studi di Trento (UNITN), Università degli studi di Genova = University of Genoa (UniGe), Università degli Studi di Perugia = University of Perugia (UNIPG), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), and Lille Neurosciences & Cognition - U 1172 (LilNCog)

Subjects
Male, 0301 basic medicine, Oncology, Apolipoprotein E, Aging, Medizin, Cohort Studies, 0302 clinical medicine, Cerebrospinal fluid, Cutoff, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, biology, General Neuroscience, Alzheimer's disease, 3. Good health, Settore MED/26 - NEUROLOGIA, Biomarker (medicine), Female, Heterozygote, medicine.medical_specialty, CSF cutoff, Disease progression, Mild cognitive impairment, Tau protein, tau Proteins, 03 medical and health sciences, Apolipoproteins E, Neuroimaging, Alzheimer Disease, Internal medicine, mental disorders, medicine, Humans, Cognitive Dysfunction, Aged, Amyloid beta-Peptides, Receiver operating characteristic, business.industry, medicine.disease, Peptide Fragments, ddc:616.8, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, biology.protein, Neurology (clinical), Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aβ42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis.

Published
2020

29. Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology

Author

Simon Lovestone, Lars Bertram, Ruth Frikke-Schmidt, Patrizia Mecocci, Jill C. Richardson, Giovanni B. Frisoni, Fabian Kilpert, B. Paul Morgan, Abdul Hye, Stephanie J.B. Vos, Olivier Blin, Valerija Dobricic, Silvy Gabel, Richard Dobson, Mikel Tainta, Shengjun Hong, Frederik Barkhof, Cristina Legido-Quigley, Frans R.J. Verhey, Liu Shi, Børge G. Nordestgaard, Katrine L. Rasmussen, Pablo Martinez-Lage, Alejo J. Nevado-Holgado, Steven J. Kiddle, Charlotte E. Teunissen, Iwona Kłoszewska, Nicholas J. Ashton, Sebastiaan Engelborghs, Noel J. Buckley, Antonio Cuadrado, Petronella Kettunen, Bruno Vellas, José Luis Molinuevo, Kristel Sleegers, Alison L. Baird, Isabelle Bos, Angharad R. Morgan, Pieter Jelle Visser, Martina Sattlecker, Benjamine Y Liu, Mara ten Kate, Daniel Alcolea, Alberto Lleó, Ellen Elisa De Roeck, Lorena Rami, Elena M. Ribe, Andre Franke, Rik Vandenberghe, Julius Popp, Sarah Westwood, Régis Bordet, Magda Tsolaki, Yvonne Freund-Levi, Kaj Blennow, Philip Scheltens, Sune F. Nielsen, Gwendoline Peyratout, Peter Johannsen, Henrik Zetterberg, Hilkka Soininen, Johannes Streffer, Lutz Frölich, Karen Meersmans, Laura Winchester, Anders Wallin, Richard Killick, Neurology, Amsterdam Neuroscience - Neurodegeneration, Radiology and nuclear medicine, Clinical chemistry, European Commission, Research Foundation - Flanders, Eusko Jaurlaritza, University of Antwerp, National Institute for Health Research (UK), NHS Foundation Trust, NIHR Biomedical Research Centre (UK), Medical Research Council (UK), University of Oxford, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), Faculty of Arts and Philosophy, Clinical sciences, Neuroprotection & Neuromodulation, and Educational Science

Subjects
0301 basic medicine, Apolipoprotein E, Male, Pathology, PATHOGENESIS, ATN framework, Gene Expression, ACTIVATION, PATHWAY, 0302 clinical medicine, INDUCTION, General Neuroscience, Neurodegeneration, NEURODEGENERATION, Wnt signaling pathway, Aged, Alzheimer Disease/blood, Alzheimer Disease/genetics, Alzheimer Disease/pathology, Biomarkers/blood, Female, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins/biosynthesis, Intercellular Signaling Peptides and Proteins/blood, Intercellular Signaling Peptides and Proteins/genetics, Middle Aged, Dickkopf-1, SomaScan, Wnt signaling, replication, General Medicine, DEGENERATION, 3. Good health, Psychiatry and Mental health, Clinical Psychology, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, Life Sciences & Biomedicine, Research Article, musculoskeletal diseases, medicine.medical_specialty, BETA-AMYLOID TOXICITY, Amyloid, Neuroscience(all), MODELS, Clinical Neurology, Biology, 03 medical and health sciences, In vivo, Alzheimer Disease, medicine, METAANALYSIS, Science & Technology, [SCCO.NEUR]Cognitive science/Neuroscience, Neurosciences, Albumin, medicine.disease, In vitro, 030104 developmental biology, DKK1, Neurosciences & Neurology, Human medicine, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Biomarkers
Abstract

© 2020 – IOS Press and the authors., [Background]: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer’s disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. [Objective]: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. [Methods]: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). [Results]: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T–N–, A+T+N–, A+T–N+, and A+T+N+) from no AD pathology (A–T–N–) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. [Conclusions]: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo., This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 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. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007 and #15005). The Lausanne cohort study was supported by a grant from the Swiss National Research Foundation to JP (SNF 320030_141179). RV is a senior clinical investigator of the Flemish Research Foundation (FWO). JS is currently an employee of UCB, Braine-l’Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIB-CMN is funded in part by the University of Antwerp Research Fund. FB is supported by the NIHR biomedical research centre at UCLH. RD is supported by Health Data Research UK, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London, Maudsley NHS Foundation Trust, King’s College London and the NIHR University College London Hospitals Biomedical Research Centre. LS is funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). Also support was received from the NIHR Biomedical Research Centre at Oxford Health NHS Foundation Trust.

Published
2020

30. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer’s disease biomarker levels

Author

Mikel Tainta, Olivier Blin, Richard Dobson, Isabelle Bos, Julius Popp, Betty M. Tijms, Daniel Alcolea, Michael Wittig, Jill C. Richardson, Christopher M. Clark, Alberto Lleó, Shengjun Hong, Pieter Jelle Visser, Pablo Martinez-Lage, Ulf Andreasson, Valerija Dobricic, Sebastiaan Engelborghs, Johannes Streffer, Kristel Sleegers, Rik Vandenberghe, Andre Franke, Kaj Blennow, Cristina Legido-Quigley, Gwendoline Peyratout, Christine Van Broeckhoven, Mara ten Kate, Rudolph E. Tanzi, Giovanni B. Frisoni, Frederik Barkhof, Régis Bordet, Dmitry Prokopenko, Silvy Gabel, Charlotte E. Teunissen, Simon Lovestone, Henrik Zetterberg, Lars Bertram, Philip Scheltens, and Stephanie J. B. Vos

Subjects
Cerebrospinal fluid, Genotype, Genome-wide association study, Computational biology, Neurogranin, Biomarker discovery, Quantitative trait locus, Biology, Phenotype, Genetic architecture
Abstract

BackgroundNeurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimer’s disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome.MethodsDNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates.FindingsWe identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1.InterpretationOur study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

Published
2020

31. Validation of plasma proteomic biomarkers relating to brain amyloid burden in the EMIF-Alzheimer's disease multimodal biomarker discovery cohort

Author

Isabelle Bos, Gwendoline Peyratout, Yvonne Freund-Levi, Ellen Elisa De Roeck, Mara ten Kate, Kristel Sleegers, Susan Baker, Mikel Tainta, Lutz Frölich, Giovanni B. Frisoni, Cristina Legido-Quigley, Karen Meersmans, Andrey Kormilitzin, Abdul Hye, Valerija Dobricic, Alison L. Baird, Alberto Lleó, Régis Bordet, Johannes Streffer, Isabel Sala, Sneha N Anand, Lorena Rami, B. Paul Morgan, Silvy Gabel, Julius Popp, Noel J. Buckley, Olivier Blin, José Luis Molinuevo, Sarah Westwood, Angharad R. Morgan, Frans R.J. Verhey, Pieter Jelle Visser, Magda Tsolaki, Martinez-Lage P, Rik Vandenberghe, Alejo J. Nevado-Holgado, Simon Lovestone, Lars Bertram, Henrik Zetterberg, Anders Wallin, Philip Scheltens, Peter Johannsen, Nicholas J. Ashton, Charlotte E. Teunissen, Petronella Kettunen, Sebastiaan Engelborghs, Stephanie J.B. Vos, Frederik Barkhof, Liu Shi, Jill C. Richardson, University of Oxford, King‘s College London, University of Gothenburg (GU), Cardiff University, Maastricht University [Maastricht], Janssen Research & Development, VU University Medical Center [Amsterdam], University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Antwerp (UA), Vrije Universiteit Brussel (VUB), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Université de Genève = University of Geneva (UNIGE), Istituto Centro San Giovanni di Dio Fatebenefratelli, Partenaires INRAE, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM), GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Université de Lille, CHU Lille, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Universitat Pompeu Fabra [Barcelona] (UPF), Sahlgrenska Academy at University of Gothenburg [Göteborg], AHEPA University General Hospital [Thessaloniki], Hospital de la Santa Creu i Sant Pau, Lausanne University Hospital, Center for Research and Advanced Therapies CITA-Alzheimer Foundation [San Sebastián], Copenhagen University Hospital, Karolinska University Hospital [Stockholm], Universität Heidelberg [Heidelberg] = Heidelberg University, Universität zu Lübeck = University of Lübeck [Lübeck], Steno Diabetes Center, University of Oslo (UiO), Institutes of Neurology and Healthcare Engineering, UCL, London, Sahlgrenska University Hospital [Gothenburg], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), UCL, Institute of Neurology [London], UCB Pharma S.A.[Braine-l'Alleud], UCB Pharma [Brussels], Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), Faculty of Arts and Philosophy, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Educational Science, Rissman, R, Radiology and nuclear medicine, and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, Apolipoprotein E, Oncology, Male, MILD COGNITIVE IMPAIRMENT, Alzheimer’s disease, amyloid-β, biomarkers, plasma, proteomics, Apolipoprotein E4, PROGRESSION, Disease, Proteomics, GUIDELINES, Cohort Studies, ddc:616.89, 0302 clinical medicine, MARKERS, BLOOD-BASED BIOMARKER, Biomarker discovery, Medicine(all), biology, General Neuroscience, DEMENTIA, General Medicine, Blood Proteins, Middle Aged, CEREBROSPINAL-FLUID BIOMARKERS, Alzheimer's disease, Blood proteins, Magnetic Resonance Imaging, amyloid-beta, 3. Good health, Psychiatry and Mental health, Clinical Psychology, Body Burden, Female, Sample collection, Life Sciences & Biomedicine, Research Article, EXPRESSION, medicine.medical_specialty, Amyloid beta, tau Proteins, 03 medical and health sciences, Alzheimer Disease, Internal medicine, medicine, Dementia, Humans, Amyloid-β, Cognitive Dysfunction, Biology, Aged, Science & Technology, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Neurosciences, LECTIN, medicine.disease, Cerebral Amyloid Angiopathy, PATHOLOGY, 030104 developmental biology, ROC Curve, Positron-Emission Tomography, biology.protein, Neurosciences & Neurology, Human medicine, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure. ispartof: JOURNAL OF ALZHEIMERS DISEASE vol:74 issue:1 pages:213-225 ispartof: location:Netherlands status: published

Published
2020

32. MRI predictors of amyloid pathology: results from the EMIF-AD Multimodal Biomarker Discovery study

Author

Christine Van Broeckhoven, Isabelle Bos, Pablo Martinez-Lage, Frans R.J. Verhey, Frederik Barkhof, Alison L. Baird, Magdalini Tsolaki, Régis Bordet, Jolien Schaeverbeke, Sebastiaan Engelborghs, Pieter Jelle Visser, Olivier Blin, Zhiyong Xie, Mark Forrest Gordon, Silvy Gabel, Mara ten Kate, Carl Eckerström, Rik Vandenberghe, Jérôme Revillard, Julius Popp, Cristina Legido-Quigley, Alberto Redolfi, Giovanni B. Frisoni, Simon Lovestone, Gerald Novak, Lars Bertram, Jill C. Richardson, Johannes Streffer, Silvia Bianchetti, José Luis Molinuevo, Anders Wallin, Enrico Peira, Viktor Wottschel, Valerija Dobricic, Philip Scheltens, Henrik Zetterberg, Stephanie J.B. Vos, Radiology and nuclear medicine, Amsterdam Neuroscience - Neurodegeneration, Neurology, Clinical sciences, Pathologic Biochemistry and Physiology, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, Promovendi MHN, MUMC+: MA Med Staf Spec Psychiatrie (9), VU University Medical Center [Amsterdam], Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia = University of Brescia (UniBs), Maastricht University [Maastricht], University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Hôpital de la Timone [CHU - APHM] (TIMONE), CIC-CPCET, GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, University of Gothenburg (GU), Pasqual Maragall Foundation, University of Antwerp (UA), Hospital Network Antwerp Middelheim and Hoge Beuken, Center for Research and Advanced Therapies CITA-Alzheimer Foundation [San Sebastián], Lausanne University Hospital, Geneva University Hospital (HUG), Aristotle University of Thessaloniki, University of Oxford, King‘s College London, Universität zu Lübeck = University of Lübeck [Lübeck], Imperial College London, University of Oslo (UiO), UCL, Institute of Neurology [London], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Sahlgrenska University Hospital [Gothenburg], UCB Pharma S.A.[Braine-l'Alleud], UCB Pharma [Brussels], Janssen Research & Development, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Pfizer Global Research and Development [Cambridge, MA, USA], Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Genève = University of Geneva (UNIGE), and Institutes of Neurology and Healthcare Engineering, UCL, London

Subjects
0301 basic medicine, Apolipoprotein E, Oncology, Male, MILD COGNITIVE IMPAIRMENT, Neurology, Support vector machine, European Medical Information Framework for Alzheimer's Disease, Apolipoprotein E4, lcsh:RC346-429, ddc:616.89, 0302 clinical medicine, Biomarker discovery, Medicine(all), medicine.diagnostic_test, DEMENTIA, Brain, Cognition, Alzheimer's disease, Middle Aged, European Medical Information Framework for Alzheimer’s Disease, 3. Good health, ALZHEIMERS-DISEASE, Female, Life Sciences & Biomedicine, PROJECT, Alzheimer’s disease, medicine.medical_specialty, Amyloid, Aged, Alzheimer Disease/diagnostic imaging, Alzheimer Disease/genetics, Alzheimer Disease/pathology, Amyloid beta-Peptides/cerebrospinal fluid, Amyloid beta-Peptides/metabolism, Apolipoprotein E4/genetics, Biomarkers, Brain/diagnostic imaging, Brain/pathology, Cognitive Dysfunction/diagnostic imaging, Cognitive Dysfunction/pathology, Humans, Magnetic Resonance Imaging, ROC Curve, Support Vector Machine, Machine learning, Magnetic resonance imaging, Mild cognitive impairment, Cognitive Neuroscience, Clinical Neurology, ATROPHY, lcsh:RC321-571, 03 medical and health sciences, Atrophy, Alzheimer Disease, Internal medicine, BETA DEPOSITION, mental disorders, medicine, Dementia, Cognitive Dysfunction, support vector machine, Biology, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, SELECTION BIAS, DECLINE, Science & Technology, Amyloid beta-Peptides, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Research, Neurosciences, medicine.disease, PREVENTION, MACHINE, 030104 developmental biology, Neurology (clinical), Neurosciences & Neurology, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Background With the shift of research focus towards the pre-dementia stage of Alzheimer’s disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) ε4 genotype, can be used to predict amyloid pathology using machine-learning classification. Methods We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 ± 7.2, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69.1 ± 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 ± 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE ε4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects. Results In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 ± 0.07 in MCI and an AUC of 0.74 ± 0.08 in CN. In CN, selected features for the classifier included APOE ε4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE ε4 information did not improve after additionally adding imaging measures. Conclusions Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.

Published
2018

33. Sex-Specific Metabolic Pathways Were Associated with Alzheimer’s Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort

Author

Kristel Sleegers, Frans R.J. Verhey, Giovanni B. Frisoni, Abdul Hye, Ellen Elisa De Roeck, Lorena Rami, José Luis Molinuevo, Cristina Legido-Quigley, Alison L. Baird, Pablo Martinez-Lage, Charlotte E. Teunissen, Lutz Frölich, Petronella Kettunen, Rebecca Green, Pieter Jelle Visser, Jill C. Richardson, Mara ten Kate, Petroula Proitsi, Stuart G. Snowden, Sarah Westwood, Henrik Zetterberg, Gwendoline Peyratout, Magda Tsolaki, Amera A. Ebshiana, Karen Meersmans, R. Vandenberghe, Alberto Lleó, Kaj Blennow, Isabelle Bos, Valerija Dobricic, Daniel Alcolea, Stephanie J.B. Vos, Julius Popp, Anders Wallin, Alejo J. Nevado-Holgado, Liu Shi, Philip Scheltens, Johannes Streffer, Peter Johannsen, Min Kim, Régis Bordet, Mikel Tainta, Sebastiaan Engelborghs, Simon Lovestone, Lars Bertram, Jodie Lord, Yvonne Freund-Levi, Olivier Blin, Jin Xu, Silvy Gabel, European Medical Information Framework Consortium, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Clinical chemistry, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Radiology and nuclear medicine

Subjects
Oncology, medicine.medical_specialty, QH301-705.5, tryptophan betaine, Medicine (miscellaneous), Disease, Kynurenate, Article, General Biochemistry, Genetics and Molecular Biology, SERUM, Metabolomics, CEREBROSPINAL-FLUID, MARKERS, blood, Dopamine, Internal medicine, KYNURENINE, sex, Medicine, OLDER-PEOPLE, Biology (General), BRAIN, Biomarker discovery, Biology, METAANALYSIS, business.industry, neurology, DEMENTIA, Pharmacology. Therapy, metabolic pathway, vanillylmandelate, Alzheimer's disease, metabolomics, Chemistry, Endophenotype, Cohort, Human medicine, Serotonin, business, Alzheimer’s disease, medicine.drug
Abstract

Altres ajuts: Fundació Bancària Obra Social La Caixa, Fundació Catalana Síndrome de Down, Fundació La Marató de TV3, Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica, Fundación BBVA i Fundació Víctor Grífols i Lucas Background: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives. Methods: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD. Results: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046). Conclusions: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.

Published
2021

34. Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model

Author

Mark E. Schmidt, Leonie Wyffels, Ann-Marie Waldron, Xavier Langlois, Steven Staelens, Jill C. Richardson, Jeroen Verhaeghe, and Sigrid Stroobants

Subjects
Male, Genetically modified mouse, medicine.medical_specialty, [18F]-AV45, Time Factors, longitudinal, Transgene, [18F]-FDG, Mice, Transgenic, transgenic mice, 030218 nuclear medicine & medical imaging, Amyloid beta-Protein Precursor, Mice, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Fluorodeoxyglucose F18, small animal imaging, Internal medicine, Presenilin-1, medicine, Multiple time, Animals, Humans, Amyloid burden, Longitudinal Studies, Brain function, Aniline Compounds, Chemistry, General Neuroscience, Amyloidosis, Brain, General Medicine, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Psychiatry and Mental health, Clinical Psychology, Endocrinology, Amyloid deposition, Positron-Emission Tomography, Mutation, Ethylene Glycols, Human medicine, Geriatrics and Gerontology, Alzheimer’s disease, 030217 neurology & neurosurgery, Ex vivo, Research Article
Abstract

We aimed to monitor the timing of amyloid-beta deposition in relation to changes in brain function using in vivo imaging with [F-18]-AV45 and [F-18]-FDG in a mouse model of Alzheimer's disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [F-18]-AV45 and [F-18]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [F-18]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [F-18]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [F-18]-AV45. The observed trajectory of [F-18]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [F-18]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [F-18]-FDG was not associated with aging in TASTPM mice. Moreover, [F-18]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-beta is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

Published
2016

35. Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

Author

Dmitry Prokopenko, Simon Lovestone, Lars Bertram, Silvy Gabel, Isabelle Bos, Charlotte E. Teunissen, Petronella Kettunen, Fabian Kilpert, Pablo Martinez-Lage, Jill C. Richardson, Betty M. Tijms, Richard Dobson, Mikel Tainta, Ulf Andreasson, Mara ten Kate, Sebastiaan Engelborghs, Michael Wittig, Anders Wallin, Alzheimer’s Disease Neuroimaging Initiative, Johannes Streffer, Rudolph E. Tanzi, Frederik Barkhof, Isabel Sala, Giovanni B. Frisoni, Henrik Zetterberg, Isabelle Cleynen, Jolien Schaeverbeke, Olivier Blin, Pieter Jelle Visser, Shengjun Hong, Gwendoline Peyratout, Andre Franke, Philip Scheltens, Lorena Rami, Valerija Dobricic, Kaj Blennow, Kristel Sleegers, Rik Vandenberghe, Stephanie J. B. Vos, Alberto Lleó, Julius Popp, Christine Van Broeckhoven, José Luis Molinuevo, Cristina Legido-Quigley, Ellis Niemantsverdriet, and Régis Bordet

Subjects
0303 health sciences, Genomics, Single-nucleotide polymorphism, Genome-wide association study, Disease, Computational biology, Biology, medicine.disease, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, SNP, Biomarker discovery, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

Published
2019
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36. Sleep deprivation and Modafinil affect cortical sources of resting state electroencephalographic rhythms in healthy young adults

Author

Jill C. Richardson, Pierre Payoux, Nicolas Chauveau, Claire Thalamas, Juergen Dukart, Maria Teresa Pascarelli, Raffaele Ferri, Philippe Derambure, Déborah Méligne, J.L. Bourriez, Claudio Del Percio, Roberta Lizio, Olivier Blin, Giuseppe Noce, Claudio Babiloni, Catherine Cassé-Perrot, David Bartrés-Faz, Laura Lanteaume, Dominique Deplanque, Régis Bordet, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), CHU Lille, Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), IRCCS SDN Napoli, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU 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 de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU 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), Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), F. Hoffmann-La Roche [Basel], Istituto di Ricovero e Cura a Carattere Scientifico [Troina, Italy] (IRCCS), Oasi Maria Santissima Srl [Troina, Italy], GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU 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 (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Otten, Lisa

Subjects
wakefulness-promoting agents, Alzheimer’s disease (AD), Modafinil, Audiology, Resting state electroencephalographic (rsEEG) rhythms, 0302 clinical medicine, Alzheimer's disease (AD), exact low-resolution brain electromagnetic source tomography (eLORETA), resting state electroencephalographic (rsEEG) rhythms, sleep deprivation, adult, alpha rhythm, beta rhythm, brain waves, cerebral cortex, cross-over studies, delta rhythm, electroencephalography, functional laterality, camma rhythm, healthy volunteers, humans, male, rest, sample size, theta rhythm, wakefulness, Gamma Rhythm, media_common, medicine.diagnostic_test, 05 social sciences, Neuropsychological test, Sensory Systems, Sleep deprivation, Neurology, medicine.symptom, medicine.drug, Vigilance (psychology), medicine.medical_specialty, media_common.quotation_subject, 050105 experimental psychology, Arousal, 03 medical and health sciences, Physiology (medical), medicine, Exact low-resolution brain electromagnetic source tomography (eLORETA), 0501 psychology and cognitive sciences, Resting state fMRI, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Alertness, Delta Rhythm, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Objective It has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project ( www.pharmacog.org ): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers. Methods rsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware. Results In the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2–4 Hz) and alpha (8–13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities. Conclusions The present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness. Significance Future research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia.

Published
2019

37. O5‐05‐03: ASSOCIATIONS BETWEEN CEREBROSPINAL FLUID NEURODEGENERATIVE MARKERS, NEUROFILAMENT‐LIGHT AND TOTAL TAU AND CEREBROVASCULAR IMAGING MARKERS

Author

Isabelle Bos, Olivier Blin, Pablo Martinez-Lage, Ulf Andreasson, Jill C. Richardson, Cristina Legido-Quigley, Sebastiaan Engelborghs, Johannes Streffer, Mara ten Kate, Giovanni B. Frisoni, Frans R.J. Verhey, Pieter Jelle Visser, Simon Lovestone, Lars Bertram, Rik Vandenberghe, Régis Bordet, Henrik Zetterberg, Philip Scheltens, Stephanie J.B. Vos, Julius Popp, Sarah Westwood, Magda Tsolaki, Kaj Blennow, Frederik Barkhof, and Willemijn J. Jansen

Subjects
Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Neurofilament light, Total tau, Cerebrovascular imaging, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Cerebrospinal fluid, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2019

38. Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort

Author

Lutz Frölich, Kaj Blennow, Karen Meersmans, Kristel Sleegers, Cristina Legido-Quigley, Mara ten Kate, Tommi Suvitaival, Julius Popp, Frederik Barkhof, Sarah Westwood, Tahmina Ahmad, Petra Proitsi, Jill C. Richardson, Magda Tsolaki, José Luis Molinuevo, Mikel Tainta, Alison L. Baird, Pablo Martinez-Lage, Philip Scheltens, Abdul Hye, Yvonne Freund-Levi, Lorena Rami, Adnan Ali, Stephanie J.B. Vos, Frans R.J. Verhey, Stuart G. Snowden, Rik Vandenberghe, Valerija Dobricic, Charlotte E. Teunissen, Pieter Jelle Visser, Petronella Kettunen, Min Kim, Peter Johannsen, Régis Bordet, David J. Merkler, Nicholas J. Ashton, Alberto Lleó, Henrik Zetterberg, Gwendoline Peyratout, Alejo J. Nevado-Holgado, Anders Wallin, Sebastiaan Engelborghs, Olivier Blin, Johannes Streffer, Isabel Sala, Isabelle Bos, Simon Lovestone, Ellen De Roeck, Lars Bertram, Silvy Gabel, Giovanni B. Frisoni, King‘s College London, University of Cambridge [UK] (CAM), Steno Diabetes Center of Copenhagen [Gentofte, Denmark], University of South Florida [Tampa] (USF), University of Oxford, Maastricht University [Maastricht], University Hospitals Leuven [Leuven], Amsterdam UMC - Amsterdam University Medical Center, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM), GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), University of Antwerp (UA), Troubles cognitifs vasculaires et dégénératifs, Université de Lille, Sciences et Technologies, CHU Lille, Hospital Clinic (IDIBAPS), University of Gothenburg (GU), AHEPA University General Hospital [Thessaloniki], Hospital de la Santa Creu i Sant Pau, Lausanne University Hospital, Center for Research and Advanced Therapies CITA-Alzheimer Foundation [San Sebastián], Copenhagen University Hospital, Karolinska University Hospital [Stockholm], Universität Heidelberg [Heidelberg] = Heidelberg University, Universität zu Lübeck = University of Lübeck [Lübeck], Université de Genève = University of Geneva (UNIGE), Geneva University Hospital (HUG), Sahlgrenska University Hospital [Gothenburg], UCL, Institute of Neurology [London], Janssen Pharmaceutica [Beerse], Universität Heidelberg [Heidelberg], Otten, Lisa, Clinical sciences, Neurology, Amsterdam Neuroscience - Neurodegeneration, Laboratory Medicine, Radiology and nuclear medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and MUMC+: MA Med Staf Spec Psychiatrie (9)

Subjects
0301 basic medicine, Oncology, Male, Neurology, Epidemiology, Neuropsychological Tests, Hippocampus, RECOMMENDATIONS, Cohort Studies, ddc:616.89, 0302 clinical medicine, Cerebrospinal fluid, MARKERS, Biomarker discovery, Brain volume measurements, Medicine(all), OLEAMIDE, biology, medicine.diagnostic_test, Health Policy, Brain, INDUCED LIPOKINE, EMIF-AD, Amyloidosis, Middle Aged, Alzheimer's disease, Magnetic Resonance Imaging, PERTURBATIONS, 3. Good health, Psychiatry and Mental health, ACID, Female, Alzheimer’s disease, Life Sciences & Biomedicine, medicine.medical_specialty, Amyloid, Tau protein, Clinical Neurology, tau Proteins, CSF, METABOLISM, Article, Aged, Amyloid beta-Peptides/blood, Amyloid beta-Peptides/cerebrospinal fluid, Amyloidosis/blood, Amyloidosis/cerebrospinal fluid, Amyloidosis/metabolism, Biomarkers/blood, Biomarkers/cerebrospinal fluid, Brain/pathology, Cognitive Dysfunction/diagnosis, Hippocampus/metabolism, Humans, Memory/physiology, Metabolomics, tau Proteins/blood, tau Proteins/cerebrospinal fluid, Biomarkers, Cognitive function measurements, Dementia, Tau, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Memory, Internal medicine, 12,13-DIHOME, medicine, 13-DIHOME, Cognitive Dysfunction, BIOSYNTHESIS, Biology, Mini–Mental State Examination, Amyloid beta-Peptides, Science & Technology, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, medicine.disease, 030104 developmental biology, ddc:618.97, biology.protein, Human medicine, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Introduction: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.Methods: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.Results: Eight metabolites were associated with amyloid b and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.Discussion: PFAMs have been found increased and associated with amyloid b burden in CSF and clinical measures. Crown Copyright (C) 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

Published
2019

39. Two-year longitudinal monitoring of amnestic mild cognitive impairment patients with prodromal Alzheimer's disease using topographical biomarkers derived from functional magnetic resonance imaging and electroencephalographic activity

Author

Jill C. Richardson, Flavio Nobili, Libera Cavaliere, Moira Marizzoni, Claudio Babiloni, Gianluigi Forloni, Giovanni B. Frisoniand, Mira Didic, Régis Bordet, Ludovico Minati, Jorge Jovicich, Susanna Lopez, Marco Salvatore, Jens Wiltfang, David Bartrés Faz, Claudio Del Percio, Camillo Marra, Giuseppe Noce, Andrea Soricelli, Diego Albani, Clarissa Ferrari, Tilman Hensch, Lucilla Parnetti, José Luis Molinuevo, Olivier Blin, Pierre Payoux, Cinzia Costa, Peter Schönknecht, Roberta Lizio, Pieter Jelle Visser, Magda Tsolaki, Lucia Farotti, Paolo Maria Rossini, Samantha Galluzzi, Ute Fiedler, Daniele Orlandi, Davide V. Moretti, University of Trento [Trento], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia = University of Brescia (UniBs), IRCCS SDN Napoli, IRCCS Istituto Nazionale dei Tumori [Milano], Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Universität Leipzig, Pasqual Maragall Foundation, Universitat de Barcelona (UB), Università degli studi di Genova = University of Genoa (UniGe), Università degli Studi di Perugia = University of Perugia (UNIPG), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Aristotle University of Thessaloniki, VU University Medical Center [Amsterdam], GlaxoSmithKline, Glaxo Smith Kline, Université de Lille, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), Universität Duisburg-Essen [Essen], Universität Leipzig [Leipzig], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, University of Duisburg-Essen, Otten, Lisa, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, Male, pharma cog project, Medizin, Prodromal Alzheimer's Disease, Electroencephalography, Audiology, Neuropsychological Tests, Amnesic Mild Cognitive Impairment (aMCI), 0302 clinical medicine, PharmaCog project, Alpha rhythms, prodromal alzheimer’s disease, Longitudinal Studies, Default mode network, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, General Neuroscience, Brain, clinical trial, General Medicine, Middle Aged, Magnetic Resonance Imaging, Clinical Trial, Psychiatry and Mental health, Clinical Psychology, Settore MED/26 - NEUROLOGIA, Resting State, alpha rhythms, amnesic mild cognitive impairment, biomarkers, electroencephalography, functional magnetic resonance imaging, oddball event-related potentials, resting state, Functional Magnetic Resonance Imaging (fMRI), Disease Progression, Evoked Potentials, Auditory, Female, prodromal Alzheimer’s disease, medicine.medical_specialty, Posterior parietal cortex, 03 medical and health sciences, Alzheimer Disease, medicine, Dementia, Humans, Cognitive Dysfunction, Electroencephalography (EEG), Aged, prodromal Alzheimer's disease, Resting state fMRI, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, medicine.disease, Cortex (botany), 030104 developmental biology, Posterior cingulate, Amnesia, Geriatrics and Gerontology, Functional magnetic resonance imaging, business, 030217 neurology & neurosurgery, Oddball Event-Related Potentials (ERPs), Biomarkers
Abstract

Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer's disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: "positive" (i.e., "prodromal AD" n=81) or "negative" (n=63) based on a diagnostic marker of AD derived from cerebrospinal samples (Aβ 42 /P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group×Time effects adjusted by nuisance covariates (only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects ("positive" versus "negative", p

Published
2019

40. Improving Mouse Models for Dementia. Are All the Effects in Tau Mouse Models Due to Overexpression?

Author

Jill C. Richardson, Z Joel, Frances A. Edwards, Damian M. Cummings, Dervis A. Salih, and Pablo Izquierdo

Subjects
0301 basic medicine, Transgene, Neurodegeneration, Tau protein, Neurofibrillary tangle, Biology, medicine.disease, Biochemistry, Tangle, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, mental disorders, Genetics, medicine, biology.protein, PSEN1, Dementia, Molecular Biology, Gene, 030217 neurology & neurosurgery
Abstract

Mouse models of Alzheimer's disease have commonly used transgenic overexpression of genes involved in production of amyloid β (APP and/or PSEN1/2) or Tau (MAPT) with mutations that result in familial forms of dementia. We discuss possible improvements that may create full models while avoiding the problems of overexpression and report synaptic results in APPKI models. We stress use of inappropriate controls without overexpression of the normal human protein and the mismatch between the learning deficits reported in mice with plaques but no tangles and the human condition. We focus on Tau overexpression, including new data that support previous reports of the grossly nonlinear relationship between Tau overexpression and neurofibrillary tangle load, with a twofold increase in Tau protein, resulting in a 100-fold increase in tangle density. These data also support the hypothesis that a high concentration of soluble Tau, in overexpression models, plays an important direct role in neurodegeneration, rather than only via aggregation. Finally, we hypothesize that there is an optimal concentration range over which Tau can bind to microtubules and a threshold beyond which much of the overexpressed protein is unable to bind. The excess thus causes toxicity in ways not necessarily related to the process in human dementias.

Published
2019

41. Biomarker matrix to track short term disease progression in amnestic mild cognitive impairment patients with prodromal Alzheimer's disease

Author

Ulrich Hegerl, Gianluigi Forloni, Paolo Maria Rossini, Andrea Soricelli, Jill C. Richardson, Francesca B. Pizzini, Diego Albani, Ambra Macis, Magda Tsolaki, Mira Didic, Giovanni B. Frisoni, Jorge Jovicich, Lucilla Parnetti, Marco Salvatore, Pierre Payoux, Régis Bordet, Flavio Nobili, Pieter Jelle Visser, Libera Cavaliere, Clarissa Ferrari, Jens Wiltfang, Tilman Hensch, José Luis Molinuevo, Moira Marizzoni, Claudio Babiloni, Olivier Blin, Samantha Galluzzi, Karl-Titus Hoffmann, Claudio Del Percio, Peter Schönknecht, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, Oncology, Male, Medizin, Neuropsychological Tests, ddc:616.89, biomarker matrices, 0302 clinical medicine, magnetic resonance imaging, Longitudinal Studies, Cognitive decline, Alzheimer's disease, clinical trial, mild cognitive impairment, General Neuroscience, Brain, General Medicine, Human brain, Middle Aged, Clinical trial, Psychiatry and Mental health, Clinical Psychology, medicine.anatomical_structure, Biomarker matrices, Disease Progression, Biomarker (medicine), Female, Alzheimer’s disease, medicine.medical_specialty, tau Proteins, Alzheimer’s disease, biomarker matrices, clinical trial, magnetic resonance imaging, mild cognitive impairment, 03 medical and health sciences, Atrophy, Magnetic resonance imaging, Alzheimer Disease, Internal medicine, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Aged, Amyloid beta-Peptides, Resting state fMRI, business.industry, Dentate gyrus, Mild cognitive impairment, medicine.disease, Peptide Fragments, 030104 developmental biology, Positron-Emission Tomography, Amnesia, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Background: Assessment of human brain atrophy in temporal regions using magnetic resonance imaging (MRI), resting state functional MRI connectivity in the left parietal cortex, and limbic electroencephalographic (rsEEG) rhythms as well as plasma amyloid peptide 42 (Aβ 42 ) has shown that each is a promising biomarker of disease progression in amnestic mild cognitive impairment (aMCI) patients with prodromal Alzheimer's disease (AD). However, the value of their combined use is unknown. Objective: To evaluate the association with cognitive decline and the effect on sample size calculation when using a biomarker composite matrix in prodromal AD clinical trials. Methods: Multicenter longitudinal study with follow-up of 2 years or until development of incident dementia. APOE ϵ4-specific cerebrospinal fluid (CSF) Aβ 42 /P-tau cut-offs were used to identify aMCI with prodromal AD. Linear mixed models were performed 1) with repeated matrix values and time as factors to explain the longitudinal changes in ADAS-cog13, 2) with CSF Aβ 42 /P-tau status, time, and CSF Aβ 42 /P-tau status×time interaction as factors to explain the longitudinal changes in matrix measures, and 3) to compute sample size estimation for a trial implemented with the selected matrices. Results: The best composite matrix included the MRI volumes of hippocampal dentate gyrus and lateral ventricle. This matrix showed the best sensitivity to track disease progression and required a sample size 31% lower than that of the best individual biomarker (i.e., volume of hippocampal dentate gyrus). Conclusion: Optimal matrices improved the statistical power to track disease development and to measure clinical progression in the short-term period. This might contribute to optimize the design of future clinical trials in MCI.

Published
2019

42. A metabolite-based machine learning approach to diagnose Alzheimer’s-type dementia in blood: Results from the European Medical Information Framework for Alzheimer’s Disease biomarker discovery cohort

Author

Charlotte E. Teunissen, Petronella Kettunen, Ellen Elisa De Roeck, Daniel Stamate, Cristina Legido-Quigley, Kaj Blennow, Abdul Hye, Valerija Dobricic, Lorena Rami, Alison L. Baird, Frans R.J. Verhey, Johannes Streffer, Min Kim, Olivier Blin, Pieter Jelle Visser, Gwendoline Peyratout, Simon Lovestone, Henrik Zetterberg, Julius Popp, Kristel Sleegers, Régis Bordet, Jill C. Richardson, José Luis Molinuevo, Lutz Frölich, Lars Bertram, Petroula Proitsi, Sarah Westwood, Pablo Martinez-Lage, Isabelle Bos, Karen Meersmans, Philip Scheltens, Mikel Tainta, R. Vandenberghe, Sebastiaan Engelborghs, Magda Tsolaki, Mara ten Kate, Giovanni B. Frisoni, Peter Johannsen, Alejo J. Nevado-Holgado, Alberto Lleó, Silvy Gabel, Daniel Alcolea, Anders Wallin, Yvonne Freund-Levi, and Stephanie J.B. Vos

Subjects
0303 health sciences, business.industry, Metabolite, Medical information, Disease, medicine.disease, Machine learning, computer.software_genre, Alzheimer s type dementia, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Cohort, Csf biomarkers, Medicine, Dementia, Disease biomarker, Artificial intelligence, business, computer, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

INTRODUCTIONMachine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer’s Disease (AD). Here we set out to test the performance of metabolites in blood to categorise AD when compared to CSF biomarkers.METHODSThis study analysed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n=883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).RESULTSOn the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.DISCUSSIONThis study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders

Published
2019

43. A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort

Author

Alison L. Baird, Pieter Jelle Visser, Giovanni B. Frisoni, Mikel Tainta, José Luis Molinuevo, Gwendoline Peyratout, Johannes Streffer, Yvonne Freund-Levi, Daniel Stamate, Min Kim, Kaj Blennow, Abdul Hye, Mara ten Kate, Alejo J. Nevado-Holgado, Stephanie J.B. Vos, Henrik Zetterberg, Lorena Ramit, Régis Bordet, Isabelle Bos, Daniel Alcolea, Philip Scheltens, Lutz Frölich, Valerija Dobricic, Rik Vandenberghe, Cristina Legido-Quigley, Karen Meersmans, Julius Popp, Ellen Elisa De Roeck, Sarah Westwood, Kristel Sleegers, Peter Johannsen, Anders Wallin, Magda Tsolaki, Pablo Martinez-Lage, Silvy Gabel, Simon Lovestone, Lars Bertram, Olivier Blin, Alberto Lleó, Sebastiaan Engelborghs, Jill C. Richardson, Petroula Proitsi, Frans R.J. Verhey, Charlotte E. Teunissen, Petronella Kettunen, Neurology, Amsterdam Neuroscience - Neurodegeneration, Laboratory Medicine, Radiology and nuclear medicine, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, Promovendi MHN, MUMC+: MA Med Staf Spec Psychiatrie (9), Faculty of Arts and Philosophy, Educational Science, Clinical sciences, and Neuroprotection & Neuromodulation

Subjects
0301 basic medicine, medicine.medical_specialty, Metabolite, Clinical Neurology, Short Report, Machine-Learning, Medical information, Alzheimer type dementia, Bioinformatics, ddc:616.89, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolomics, Medicine, Biomarker discovery, Biology, Medicine(all), Geriatrics, Science & Technology, business.industry, Neurosciences, EMIF-AD, Alzheimer's disease, medicine.disease, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, chemistry, Cohort, Biomarkers, Human medicine, Neurosciences & Neurology, Neurology (clinical), business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery
Abstract

Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers. This study analyzed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV). On the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively. This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders. The present study was conducted as part of the EMIF-AD project, which has received support from 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 Program (FP7/2007–2013) and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the fifth framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01. 41142.001.H). Kristel Sleegers is supported by the Research Fund of the University of Antwerp. Daniel Stamate is supported by the Alzheimer’s Research UK (ARUK-PRRF2017-012).

Published
2019

44. Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic mice

Author

Peter Haslehurst, Damian M. Cummings, Francesca Cacucci, Tiffanie A. Benway, Gaukhar Baidildinova, Owain T. James, Jill C. Richardson, Wenfei Liu, Fabia Moroni, Frances A. Edwards, Muzammil A. Nahaboo Solim, Dervis A. Salih, Evelyn Medawar, Taylor A. Hanan, and Laurenz Muessig

Subjects
Genetically modified mouse, Male, Research paper, Mice, Transgenic, Hippocampal formation, Neurotransmission, Biology, Hippocampus, Synaptic Transmission, Mouse model, Amyloid beta-Protein Precursor, Mice, Cognition, medicine, Neuropil, Presenilin-1, Animals, Humans, Neurodegeneration, Maze Learning, Cognitive deficit, Plaque, Hemizygote, Amyloid beta-Peptides, Microglia, Behavior, Animal, Long-term potentiation, Alzheimer's disease, medicine.disease, Disease Models, Animal, medicine.anatomical_structure, Dementia, medicine.symptom, Neuroscience
Abstract

BackgroundProgression of Alzheimer’s disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes.MethodsCA1 Synaptic transmission and plasticity were investigated using in vitro electrophysiology. Migroglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze.FindingsThe most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours.InterpretationThe pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition.Research in contextEvidence before this studyThere is a large body of research examining many aspects of phenotypes associated with mouse models of Alzheimer’s disease – a PubMed search for the terms Alzheimer* AND mouse returns in excess of 21000 articles. However, there are few systematic articles pulling together pathological, functional (electrophysiological), and behavioural analyses across the life-span of such models. There is also a number of conflicting outcomes, for example reports of impaired versus enhanced synaptic plasticity; cognitive impairments or not.Recently, the importance of microglia in Alzheimer’s disease has come to the fore in human Genome Wide Association Studies (GWAS), with variants of a number of microglial genes identified as risk-factors for developing the disease. Interestingly, we have recently reported that Trem2 and other genes identified as risk-factors in humans are strongly up regulated in close association to plaque development in the mouse model used in this study. Moreover, this previous study predicted two of the most recently identified genes that were identified in GWAS since the publication of our paper.We have previously used this model to identify the earliest synaptic changes and shown changes in release of glutamate, the primary excitatory neurotransmitter in the brain, to occur even before plaques are detectable.Added value of this studyBy studying this transgenic mouse model of Alzheimer’s disease, throughout the development of plaques, from prior to detection through to heavy plaque loads, we have been able to identify a clear time course of key phenotypic changes associated with early disease. In particular, this study identifies the very early changes in microglia and can separate the time course of the microglial phenotype. In addition, we detail the changes in synaptic plasticity over time and importantly identify that, like in humans in the absence of Tau tangles or neurodegeneration, considerable synaptic changes can occur and a heavy plaque load without resulting in substantial cognitive loss.Implications of all the available evidenceOur data indicate that rising amyloid beta prior to detectable plaque deposition results in changes in synaptic function that likely reflects an enhanced physiological effect of amyloid beta. At this stage, microglia proliferate but do not activate. Once plaques begin to appear, microglia migrate to surround the plaque and become phagocytic, likely targeting dystrophic synapses and neurites caused by the cloud of highly-toxic amyloid beta around the plaque. Similarly to humans, who have plaques but no tangles and have yet to develop substantial neurodegeneration, cognitive deficits are not seen, even with a heavy plaque load; behavioural changes are limited to anxiety-like effects.This investigation of the parallel time-course of events highlights the probability that, if progression of disease can be reversed or slowed early enough, before Tau tangles and substantial neurodegeneration occur, the symptoms of cognitive decline could be very largely avoided. Moreover, it suggests that the substantial increases in microglia number and upregulation of their specific gene expression in association with plaques, is not associated with cognitive loss and may indeed be protective.

Published
2019

45. Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study

Author

Wilhelmus Drinkenburg, Laura Vacca, Angelisa Frasca, Giuseppe Noce, Gianluigi Forloni, Claudio Babiloni, Jill C. Richardson, Raffaele Ferri, Susanna Lopez, Claudio Del Percio, Fabrizio Stocchi, Régis Bordet, Roberta Lizio, Andrea Soricelli, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), IRCCS Istituto Nazionale dei Tumori [Milano], Janssen Pharmaceutica [Beerse], Università degli Studi di Napoli 'Parthenope' = University of Naples (PARTHENOPE), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, GlaxoSmithKline [Stevenage, UK] (GSK), GlaxoSmithKline [Headquarters, London, UK] (GSK), CHU Lille, Inserm, Université de Lille, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] [UNIROMA], Lille Neurosciences & Cognition (LilNCog) - U 1172, Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS San Raffaele Pisana], and GlaxoSmithKline [Stevenage, UK] [GSK]

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Alzheimer’s disease (AD), s disease (AD), Electroencephalography, Hippocampal formation, Inbred C57BL, TASTPM mice, Transgenic, lcsh:Chemistry, Amyloid beta-Protein Precursor, Mice, Computer-Assisted, 0302 clinical medicine, Amyloid precursor protein, PSEN1, Aspartic Acid Endopeptidases, site amyloid precursor protein cleaving enzyme (BACE-1) inhibitor, Enzyme Inhibitors, lcsh:QH301-705.5, Spectroscopy, &#946, biology, medicine.diagnostic_test, β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitor, Signal Processing, Computer-Assisted, General Medicine, electroencephalography (EEG), Alzheimer’ β TASTPM mice, Computer Science Applications, Wakefulness, medicine.medical_specialty, Amyloid, Mice, Transgenic, Neuropathology, Electroencephalography (EEG), Amyloid Precursor Protein Secretases, Animals, Electrodes, Electromyography, Mice, Inbred C57BL, Mutation, Presenilin-1, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Internal medicine, mental disorders, medicine, Physical and Theoretical Chemistry, Alzheimer&#8217, Molecular Biology, business.industry, Organic Chemistry, Wild type, 030104 developmental biology, Endocrinology, lcsh:Biology (General), lcsh:QD1-999, Signal Processing, Settore BIO/14 - Farmacologia, biology.protein, business, 030217 neurology & neurosurgery
Abstract

Objective. In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1, ER-901356, Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer’s disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods. Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males, aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results. Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p &lt, 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions. The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.

Published
2020

46. A TauP301L mouse model of dementia; development of pathology, synaptic transmission, microglial response and cognition throughout life

Author

Yap K, Marion Roberts, Chloe M. Hall, Spowart E, RA Desai, Dervis A. Salih, Kenneth Smith, Pablo Izquierdo, Jill C. Richardson, Seamus J. Martin, Nick A, Steinberg R, Laurenz Muessig, Wei Liu, Z Joel, Damian M. Cummings, Francesca Cacucci, and Frances A. Edwards

Subjects
Pathology, medicine.medical_specialty, Microglia, Transgene, Neurodegeneration, Neurotransmission, Biology, medicine.disease, Open field, Tangle, Immune system, medicine.anatomical_structure, medicine, Dementia
Abstract

BackgroundLate stage Alzheimer’s disease and other dementias are associated with neurofibrillary tangles and neurodegeneration. Here we describe a mouse (TauD35) carrying human Tau with the P301L mutation that results in Tau hyperphosphorylation and tangles. Previously we have compared gene expression in TauD35 mice to mice which develop plaques but no tangles. A similar comparison of other pathological features throughout disease progression is made here between amyloidβ and Tau mice described in Parts I and II of this study.MethodsIn vitro CA1 patch clamp and field recordings were used to investigate synaptic transmission and plasticity. Plaque load and microglia were investigated with immunohistochemistry. Cognition, locomotor activity and anxiety-related behaviours were assessed with a forced-alternation T-maze, open field and light/dark box.ResultsTransgene copy number in TauD35 mice fell into two groups (HighTAU and LowTAU), allowing assessment of dose-dependent effects of overexpression and resulting in tangle load increasing 100-fold for a 2-fold change in protein levels. Tangles were first detected at 8 (HighTAU) or 13 months (LowTAU) but the effects on synaptic transmission and plasticity and behaviour were subtle. However, severe neurodegeneration occurred in HighTAU mice at around 17 months, preceded by considerable proliferation and activation of microglia at 13 months of age; both increasing further at 17 months. LowTAU mice at 24 months of age showed a comparable tangle load and microglial proliferation to that occurring at 13 months in HighTAU mice. However, LowTAU mice showed no neurodegeneration at this stage and considerable microglial activation, stressing the dependence of these effects on overexpression and/or age.ConclusionsComparison of the effects of amyloidβ and plaques without tangles in a model of preclinical Alzheimer’s disease to the effects of tangles without amyloidβ plaques in the late stage model described here may clarify the progressive stages of Alzheimer’s disease. While Tau hyperphosphorylation and neurofibrillary tangles are eventually sufficient to cause severe neurodegeneration, initial effects on synaptic transmission and the immune response are subtle. In contrast while even with a heavy plaque load little if any neurodegeneration occurs, considerable effects on synaptic transmission and the immune system result, even before plaques are detectable.

Published
2018

47. F1‐02‐01: RELATING CSF MARKERS NEUROGRANIN, NEUROFILAMENT‐LIGHT AND YKL‐40 TO Aβ, APOE ε4 AND COGNITION: RESULTS FROM THE EMIF‐AD MULTIMODAL BIOMARKER DISCOVERY STUDY

Author

Pablo Martinez-Lage, Ulf Andreasson, Frederik Barkhof, Rik Vandenberghe, Henrik Zetterberg, Régis Bordet, Stephanie J.B. Vos, Cristina Legido-Quigley, Alberto Lleó, Frans R.J. Verhey, Philip Scheltens, Jill C. Richardson, Alison L. Baird, Peter Johannsen, Giovanni B. Frisoni, Lutz Frölich, Simon Lovestone, Lars Bertram, Pieter Jelle Visser, Johannes Streffer, Isabelle Bos, Olivier Blin, Yvonne Freund-Levi, Kaj Blennow, Sebastiaan Engelborghs, Julius Popp, and Magda Tsolaki

Subjects
Epidemiology, business.industry, Health Policy, Neurofilament light, Cognition, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Neurogranin, Geriatrics and Gerontology, Biomarker discovery, business, Neuroscience
Published
2018

48. P2‐458: PREDICTING COGNITIVE DECLINE THROUGH STRUCTURAL MRI BIOMARKERS: RESULTS FROM THE EMIF‐AD BIOMARKER DISCOVERY STUDY

Author

Viktor Wottschel, Enrico Peira, Jérôme Revillard, Mark Forrest Gordon, Rik Vandenberghe, Gerald Novak, Anders Wallin, Zhiyong Xie, Jill C. Richardson, Stephanie J.B. Vos, Philip Scheltens, Frans R.J. Verhey, Giovanni B. Frisoni, Silvia Ingala, Sebastiaan Engelborghs, Julius Popp, Simon Lovestone, José Luis Molinuevo, Lars Bertram, Henrik Zetterberg, Alison L. Baird, Olivier Blin, Magda Tsolaki, Pieter Jelle Visser, Mara ten Kate, Frederik Barkhof, Pablo Martinez-Lage, Régis Bordet, Johannes Streffer, Isabelle Bos, Cristina Legido-Quigley, and Alberto Redolfi

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, Medicine, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, Biomarker discovery, business
Published
2018

49. F1‐02‐04: GENOMICS AND EPIGENOMICS ANALYSES IN THE EMIF‐AD MULTIMODAL BIOMARKER DISCOVERY STUDY

Author

Johannes Streffer, Isabelle Bos, Katie Lunnon, Pablo Martinez-Lage, Fahri Küçükali, Giovanni B. Frisoni, Simon Lovestone, Kristel Sleegers, Lars Bertram, Frederik Barkhof, Rik Vandenberghe, Lutz Frölich, Sebastiaan Engelborghs, Julius Popp, Frans R.J. Verhey, Henrik Zetterberg, Alison L. Baird, Olivier Blin, Rebecca G. Smith, Valerija Dobricic, Magda Tsolaki, Shengjun Hong, Christine Van Broeckhoven, Régis Bordet, Alberto Lleó, Philip Scheltens, Peter Johannsen, Fabian Kilpert, Stephanie J.B. Vos, Cristina Legido Quigley, Pieter Jelle Visser, and Jill C. Richardson

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genomics, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biomarker discovery, Biology, Epigenomics
Published
2018

50. P3‐368: PREDICTING AND MONITORING SHORT‐TERM DISEASE PROGRESSION IN A‐MCI PATIENTS WITH PRODROMAL AD USING MRI STRUCTURAL BRAIN BIOMARKERS

Author

Pierre Payoux, Giovanni B. Frisoni, Andrea Soricelli, Libera Cavaliere, Jill C. Richardson, Jorge Jovicich, Pieter Jelle Visser, Jens Wiltfang, Gianluigi Forloni, Clarissa Ferrari, Régis Bordet, Flavio Nobili, Magda Tsolaki, Lucilla Parnetti, Federica Ribaldi, Paolo Maria Rossini, Peter Schönknecht, Moira Marizzoni, Mira Didic, Olivier Blin, and José Luis Molinuevo

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease progression, Term (time), Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2018

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