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1. Elevated Lipoprotein(a) in Perinatally HIV-Infected Children Compared With Healthy Ethnicity-Matched Controls

Author

Van den Hof, Malon, Haneveld, Mirthe J Klein, Blokhuis, Charlotte, Scherpbier, Henriette J, Jansen, Hans PG, Kootstra, Neeltje A, Dallinga-Thie, Geesje M, Van Deventer, Sander JH, Tsimikas, Sotirios, Pajkrt, Dasja, Van den Hof, M, Blokhuis, C, Cohen, S, Pajkrt, D, Scherpbier, HJ, Kuijpers, TW, van der Plas, A, Weijsenfeld, A, Stege, JS ter, Kootstra, NA, Caan, MWA, Mutsaerts, HJMM, Majoie, CBLM, Demirkaya, N, Verbraak, FD, Schmand, B, Geurtsen, G, Mathot, RAA, Wit, FWNM, Reiss, P, Teunissen, CE, Kuhle, J, and Meijer, JCM

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cardiovascular, Pediatric, Clinical Research, Atherosclerosis, Prevention, Infectious Diseases, Heart Disease, Good Health and Well Being, cardiovascular disease risk, lipids, lipoprotein(a), MRI, perinatal HIV infection, NOVICE study group, Clinical sciences, Medical microbiology
Abstract

BackgroundHIV-associated cardiovascular disease (CVD) risk in combination antiretroviral therapy (cART)-treated perinatally HIV-infected patients (PHIV+) remains unknown due to the young age of this population. Lipoprotein(a) (Lp(a)) has been established as an independent causal risk factor for CVD in the general population but has not been well established in the population of PHIV+.MethodsWe cross-sectionally compared lipid profiles, including nonfasting Lp(a), together with total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides between 35 cART-treated PHIV+ children aged 8-18 years and 37 controls who were matched for age, sex, ethnicity, and socioeconomic status. We explored associations between Lp(a) and disease- and treatment-related factors (inflammation, monocyte activation, and vascular), biomarkers, and neuroimaging outcomes using linear regression models.ResultsPHIV+ children had significantly higher levels of Lp(a) compared with controls (median, 43.6 [21.6-82.4] vs 21.8 [16.8-46.6] mg/dL; P = .033). Other lipid levels were comparable between groups. Additional assessment of apolipoprotein B, apolipoprotein CIII, apolipoprotein E, and APOE genotype revealed no significant differences. Higher Lp(a) levels were associated with higher plasma apoB levels and with lower monocyte chemoattractant protein-1 and TG levels in PHIV+ children. Lp(a) was not associated with HIV- or cART-related variables or with neuroimaging outcomes.ConclusionscART-treated PHIV+ children appear to have higher levels of Lp(a) compared with ethnicity-matched controls, which may implicate higher CVD risk in this population. Future research should focus on the association between Lp(a) and (sub)clinical CVD measurements in cART-treated PHIV+ patients.Dutch trial register numberNRT4074.

Published
2019

2. Deciphering Protein Secretion from the Brain to Cerebrospinal Fluid for Biomarker Discovery

Author

Waury, K, de WIt, Renske, Verberk, IMW, Teunissen, CE, Abeln, S, Waury, K, de WIt, Renske, Verberk, IMW, Teunissen, CE, and Abeln, S

Abstract

Cerebrospinal fluid (CSF) is an essential matrix for the discovery of neurological disease biomarkers. However, the high dynamic range of protein concentrations in CSF hinders the detection of the least abundant protein biomarkers by untargeted mass spectrometry. It is thus beneficial to gain a deeper understanding of the secretion processes within the brain. Here, we aim to explore if and how the secretion of brain proteins to the CSF can be predicted. By combining a curated CSF proteome and the brain elevated proteome of the Human Protein Atlas, brain proteins were classified as CSF or non-CSF secreted. A machine learning model was trained on a range of sequence-based features to differentiate between CSF and non-CSF groups and effectively predict the brain origin of proteins. The classification model achieves an area under the curve of 0.89 if using high confidence CSF proteins. The most important prediction features include the subcellular localization, signal peptides, and transmembrane regions. The classifier generalized well to the larger brain detected proteome and is able to correctly predict novel CSF proteins identified by affinity proteomics. In addition to elucidating the underlying mechanisms of protein secretion, the trained classification model can support biomarker candidate selection.

Published
2023

4. Long-term tactile hypersensitivity after nerve crush injury in mice is characterized by the persistence of intact sensory axons

Author

Kim, HW, Shim, SW, Zhao, AM, Roh, D, Han, HM, Middleton, S, Kim, W, Chung, S, Johnson, E, Prentice, J, Tacon, M, Koel-Simmelink, MJA, Wieske, L, Teunissen, CE, Bae, YC, Bennett, D, Rinaldi, S, Davies, A, and Oh, SB

Abstract

Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel, effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (i.e. crush), yet the neuropathic phenotype of ‘painful’ nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custommodified hemostats resulting in either complete (‘full’) or incomplete (‘partial’) axonotmesis in adult mice. Assays of thermal and mechanically-evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; in contrast, partial crush of the nerve resulted in the early return of pin-prick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, that was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers (IENF), fewer dorsal root ganglia (DRG) expressing the injury marker ATF3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury

Published
2023

5. Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview

Author

Delaby, C, Teunissen, CE, Blennow, K, Alcolea, D, Arisi, I, Amar, EB, Beaume, A, Bedel, A, Bellomo, G, Bigot-Corbel, E, Bjerke, M, Blanc-Quintin, M-C, Boada, M, Bousiges, O, Chapman, MD, DeMarco, ML, D'Onofrio, M, Dumurgier, J, Dufour-Rainfray, D, Engelborghs, S, Esselmann, H, Fogli, A, Gabelle, A, Galloni, E, Gondolf, C, Grandhomme, F, Grau-Rivera, O, Hart, M, Ikeuchi, T, Jeromin, A, Kasuga, K, Keshavan, A, Khalil, M, Koertvelyessy, P, Kulczynska-Przybik, A, Laplanche, J-L, Lewczuk, P, Li, Q-X, Lleo, A, Malaplate, C, Marquie, M, Masters, CL, Mroczko, B, Nogueira, L, Orellana, A, Otto, M, Oudart, J-B, Paquet, C, Paoletti, FP, Parnetti, L, Perret-Liaudet, A, Peoc'h, K, Poesen, K, Puig-Pijoan, A, Quadrio, I, Quillard-Muraine, M, Rucheton, B, Schraen, S, Schott, JM, Shaw, LM, Suarez-Calvet, M, Tsolaki, M, Tumani, H, Udeh-Momoh, CT, Vaudran, L, Verbeek, MM, Verde, F, Vermunt, L, Vogelgsang, J, Wiltfang, J, Zetterberg, H, Lehmann, S, Delaby, C, Teunissen, CE, Blennow, K, Alcolea, D, Arisi, I, Amar, EB, Beaume, A, Bedel, A, Bellomo, G, Bigot-Corbel, E, Bjerke, M, Blanc-Quintin, M-C, Boada, M, Bousiges, O, Chapman, MD, DeMarco, ML, D'Onofrio, M, Dumurgier, J, Dufour-Rainfray, D, Engelborghs, S, Esselmann, H, Fogli, A, Gabelle, A, Galloni, E, Gondolf, C, Grandhomme, F, Grau-Rivera, O, Hart, M, Ikeuchi, T, Jeromin, A, Kasuga, K, Keshavan, A, Khalil, M, Koertvelyessy, P, Kulczynska-Przybik, A, Laplanche, J-L, Lewczuk, P, Li, Q-X, Lleo, A, Malaplate, C, Marquie, M, Masters, CL, Mroczko, B, Nogueira, L, Orellana, A, Otto, M, Oudart, J-B, Paquet, C, Paoletti, FP, Parnetti, L, Perret-Liaudet, A, Peoc'h, K, Poesen, K, Puig-Pijoan, A, Quadrio, I, Quillard-Muraine, M, Rucheton, B, Schraen, S, Schott, JM, Shaw, LM, Suarez-Calvet, M, Tsolaki, M, Tumani, H, Udeh-Momoh, CT, Vaudran, L, Verbeek, MM, Verde, F, Vermunt, L, Vogelgsang, J, Wiltfang, J, Zetterberg, H, and Lehmann, S

Abstract

INTRODUCTION: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. METHODS: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. RESULTS: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. DISCUSSION: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.

Published
2022

6. Amyloid Pathology is Associated with Semantic Loss in Patients with Subjective Cognitive Decline

Author

van den Berg, RL, de Boer, C, Zwan, MD, van Harten, AC, Dubbelman, MA, Mank, A, Kroeze, Lior A., Verberk, IMW, van Berckel, BNM, Teunissen, CE, van der Flier, WM, Sikkes, SAM, Amsterdam Neuroscience - Neurodegeneration, Neurology, Clinical chemistry, Amsterdam Neuroscience - Brain Imaging, Radiology and nuclear medicine, and Amsterdam Neuroscience - Neuroinfection & -inflammation

Published
2022

7. New developments of biofluid-based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia

Author

del Campo, M, Zetterberg, H, Gandy, S, Onyike, CU, Oliveira, F, Udeh-Momoh, C, Lleo, A, Teunissen, CE, and Pijnenburg, Y

Abstract

Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with different phenotypes, genetic backgrounds, and pathological states. Its clinicopathological diversity challenges the diagnostic process and the execution of clinical trials, calling for specific diagnostic biomarkers of pathologic FTD types. There is also a need for biomarkers that facilitate disease staging, quantification of severity, monitoring in clinics and observational studies, and for evaluation of target engagement and treatment response in clinical trials. This review discusses current FTD biofluid-based biomarker knowledge taking into account the differing applications. The limitations, knowledge gaps, and challenges for the development and implementation of such markers are also examined. Strategies to overcome these hurdles are proposed, including the technologies available, patient cohorts, and collaborative research initiatives. Access to robust and reliable biomarkers that define the exact underlying pathophysiological FTD process will meet the needs for specific diagnosis, disease quantitation, clinical monitoring, and treatment development.

Published
2022

8. State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease

Author

Hampel, H, Shaw, LM, Aisen, P, Chen, C, Lleo, A, Iwatsubo, T, Iwata, A, Yamada, M, Ikeuchi, T, Jia, JP, Wang, HL, Teunissen, CE, Peskind, E, Blennow, K, Cummings, J, and Vergallo, A

Subjects
system readiness, diagnosis, biomarker, lumbar puncture, Alzheimer's disease, evidence-based guidelines, cerebrospinal fluid
Abstract

Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.

Published
2022
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9. Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease (vol 17, pg 1, 2022)

Author

Visser, PJ, Reus, LM, Gobom, J, Jansen, I, Dicks, E, van der Lee, SJ, Tsolaki, M, Verhey, FRJ, Popp, J, Martinez-Lage, P, Vandenberghe, R, Lleo, A, Molinuevo, JL, Engelborghs, S, Freund-Levi, Y, Froelich, L, Sleegers, K, Dobricic, V, Lovestone, S, Streffer, J, Vos, SJB, Bos, I, Smit, AB, Blennow, K, Scheltens, P, Teunissen, CE, Bertram, L, Zetterberg, H, and Tijms, BM

Published
2022

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

Author

Hong, SJ, Dobricic, V, Ohlei, O, Bos, I, Vos, SJB, Prokopenko, D, Tijms, BM, Andreasson, U, Blennow, K, Vandenberghe, R, Gabel, S, Scheltens, P, Teunissen, CE, Engelborghs, S, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Lleo, A, Alcolea, D, Popp, J, Clark, C, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Sleegers, K, Van Broeckhoven, C, Tanzi, RE, ten Kate, M, Wittig, M, Franke, A, Lill, CM, Barkhof, F, Lovestone, S, Streffer, J, Zetterberg, H, Visser, PJ, Bertram, L, and Neuroimaging Initiative

Subjects
s disease, wide association study, chitinase&#8208, like protein 1, neurogranin, neurofilament light, 3&#8208, biomarker, genome&#8208, Alzheimer&apos, cerebrospinal fluid
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.

Published
2021

11. Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview

Author

Delaby, C, Teunissen, CE, Blennow, K, Alcolea, D, Arisi, I, Amar, EB, Beaume, A, Bedel, A, Bellomo, G, Bigot‐Corbel, E, Bjerke, M, Blanc, M, Boada, M, Bousiges, O, Chapman, MD, DeMarco, ML, D'Onofrio, M, Dumurgier, J, Dufour‐Rainfray, D, Engelborgs, S, Esselmann, H, Fogli, A, Gabelle, A, Galloni, E, Gondolf, C, Grandhomme, F, Grau‐Rivera, O, Hart, M, Ikeuchi, T, Jeromin, A, Kasuga, K, Keshavan, A, Khalil, M, Koertvelyessy, P, Kulczynska‐Przybik, A, Laplanche, J, Lewczuk, P, Li, Q, Lleó, A, Malaplate, C, Marquié, M, Masters, CL, Mroszko, B, Nogueira, L, Orellana, A, Otto, M, Oudart, J, Paquet, C, Paoletti, FP, Parnetti, L, Perret‐Liaudet, A, Poec’h, K, Poesen, K, Puig‐Pijoan, A, Quadrio, I, Quillard‐Muraine, M, Rucheton, B, Schraen, S, Schott, JM, Shaw, LM, Suarez‐Calvet, M, Tsolaki, M, Tumani, H, Udeh‐Momoh, CT, Vaudran, L, Verbeek, MM, Verde, F, Vermunt, L, Vogelgsang, J, Wiltfang, J, Zetterberg, H, Lehmann, S, Delaby, C, Teunissen, CE, Blennow, K, Alcolea, D, Arisi, I, Amar, EB, Beaume, A, Bedel, A, Bellomo, G, Bigot‐Corbel, E, Bjerke, M, Blanc, M, Boada, M, Bousiges, O, Chapman, MD, DeMarco, ML, D'Onofrio, M, Dumurgier, J, Dufour‐Rainfray, D, Engelborgs, S, Esselmann, H, Fogli, A, Gabelle, A, Galloni, E, Gondolf, C, Grandhomme, F, Grau‐Rivera, O, Hart, M, Ikeuchi, T, Jeromin, A, Kasuga, K, Keshavan, A, Khalil, M, Koertvelyessy, P, Kulczynska‐Przybik, A, Laplanche, J, Lewczuk, P, Li, Q, Lleó, A, Malaplate, C, Marquié, M, Masters, CL, Mroszko, B, Nogueira, L, Orellana, A, Otto, M, Oudart, J, Paquet, C, Paoletti, FP, Parnetti, L, Perret‐Liaudet, A, Poec’h, K, Poesen, K, Puig‐Pijoan, A, Quadrio, I, Quillard‐Muraine, M, Rucheton, B, Schraen, S, Schott, JM, Shaw, LM, Suarez‐Calvet, M, Tsolaki, M, Tumani, H, Udeh‐Momoh, CT, Vaudran, L, Verbeek, MM, Verde, F, Vermunt, L, Vogelgsang, J, Wiltfang, J, Zetterberg, H, and Lehmann, S

Abstract

Background The quantification of cerebrospinal fluid (CSF) biomarkers (Amyloid beta peptides [Aß1‐40 and Aß1‐42], t‐tau and p‐tau(181)) is progressively implemented in specialized laboratories as an aid for the multidisciplinary diagnosis of Alzheimer’s disease (AD). There is however a diversity of practices between centers related to pre‐analytical and analytical conditions, the calculation of ratios between analytes, the applied cut‐off, or the use of interpretation scales. Finally, for the same biochemical profile, the interpretation and reporting of results may differ from one center to another, which may raise questions about the commutability of the tests. So far, no consensus has been reached between the different laboratories involved to define the most appropriate conclusions/comments based on the profile of the quantified biomarkers. This work is an essential step towards a consensual harmonization of clinical reporting after CSF analysis in the context of AD diagnosis, as advocated by the "Biofluid Based Biomarkers PIA" working group of the Alzheimer's Association. Method We obtained, by means of a questionnaire, a description of the pre‐analytical and analytical protocols and examples of reporting from 40 centers located in 15 countries, i.e. in the majority of countries that have implemented clinical CSF tests for the diagnosis of AD. We then adopted a consensus approach to propose harmonized comments corresponding to different AD CSF biomarker profiles observed in patients. Result Pre‐analytical procedures were very similar, among the centers. Regarding the analytical part, more than 88% of the laboratories use automatized immunoassays and more than 83% measure Aß1‐40 and compute the Aß1‐42/Aß1‐40 ratio, in addition to the three core biomarkers (Aß1‐42, t‐tau and p‐tau(181)). The cut‐off values of biomarkers used by the different laboratories are widely dispersed. Delay before sending back the results is lower than 1 week in more than 34% of t

Published
2021

12. Circulating metabolites are associated with brain atrophy and white matter hyperintensities

Author

de Leeuw, FA, Comic, Hata, Tijms, BM, Peeters, CFW, Kester, MI, Scheltens, P, Ahmad, Shahzad, Vojinovic, Dina, Adams, Hieab, Hankemeier, T, Bos, Daniel, van der Lugt, Aad, Vernooij, Meike, Ikram, Arfan, Amin, Najaf, Barkhof, F, Teunissen, CE, Duijn, Cornelia, van der Flier, WM, de Leeuw, FA, Comic, Hata, Tijms, BM, Peeters, CFW, Kester, MI, Scheltens, P, Ahmad, Shahzad, Vojinovic, Dina, Adams, Hieab, Hankemeier, T, Bos, Daniel, van der Lugt, Aad, Vernooij, Meike, Ikram, Arfan, Amin, Najaf, Barkhof, F, Teunissen, CE, Duijn, Cornelia, and van der Flier, WM

Abstract

Introduction: Our aim was to study whether systemic metabolites are associated with magnetic resonance imaging (MRI) measures of brain and hippocampal atrophy and white matter hyperintensities (WMH). Methods: We studied associations of 143 plasma-based metabolites with MRI measures of brain and hippocampal atrophy and WMH in three independent cohorts (n = 3962). We meta-analyzed the results of linear regression analyses to determine the association of metabolites with MRI measures. Results: Higher glucose levels and lower levels of three small high density lipoprotein (HDL) particles were associated with brain atrophy. Higher glucose levels were associated with WMH. Discussion: Glucose levels were associated with brain atrophy and WMH, and small HDL particle levels were associated with brain atrophy. Circulating metabolites may aid in developing future intervention trials.

Published
2021

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

Author

Hong, SJ, Prokopenko, D, Dobricic, V, Kilpert, F, Bos, I, Vos, SJB, Tijms, BM, Andreasson, U, Blennow, K, Vandenberghe, R, Cleynen, I, Gabel, S, Schaeverbeke, J, Scheltens, P, Teunissen, CE, Niemantsverdriet, E, Engelborghs, S, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Molinuevo, JL, Rami, L, Kettunen, P, Wallin, A, Lleo, A, Sala, I, Popp, J, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Sleegers, K, Van Broeckhoven, C, ten Kate, M, Barkhof, F, Zetterberg, H, Lovestone, S, Streffer, J, Wittig, M, Franke, A, Tanzi, RE, Visser, PJ, Bertram, L, and Alzheimers Dis Neuroimaging Initia

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 (A beta) 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 A beta 42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-A beta 38 and CSF-A beta 40 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-A beta 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

15. Decline in cognitively complex everyday activities accelerates along the Alzheimer's disease continuum

Author

Dubbelman, MA, Jutten, RJ, Tomaszewski Farias, SE, Amariglio, RE, Buckley, RF, Visser, PJ, Rentz, DM, Johnson, KA, Properzi, MJ, Schultz, A, Donovan, N, Gatchell, JR, Teunissen, CE, Van Berckel, BNM, Van der Flier, WM, Sperling, RA, Papp, KV, Scheltens, P, Marshall, GA, Sikkes, SAM, Dubbelman, MA, Jutten, RJ, Tomaszewski Farias, SE, Amariglio, RE, Buckley, RF, Visser, PJ, Rentz, DM, Johnson, KA, Properzi, MJ, Schultz, A, Donovan, N, Gatchell, JR, Teunissen, CE, Van Berckel, BNM, Van der Flier, WM, Sperling, RA, Papp, KV, Scheltens, P, Marshall, GA, and Sikkes, SAM

Abstract

BACKGROUND: Impairment in daily functioning is a clinical hallmark of dementia. Difficulties with "instrumental activities of daily living" (IADL) seem to increase gradually over the course of Alzheimer's disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD. METHODS: In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging-Alzheimer's Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized. RESULTS: The rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = - 0.32 [- 0.55, - 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (- 1.06 [- 1.27, - 0.85], p < .001) and nearly two SD units per year in stage 4+ (1.93 [- 2.19, - 1.67], p < .001). Overall, results were similar between community-based and memory clinic study cohorts. CONCLUSIONS: Our results suggest that the rate of functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive NIA-AA clinical stage. These results impl

Published
2020

16. Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach

Author

van Steenoven, I, Koel-Simmelink, MJ, Vergouw, Leonie, Tijms, BM, Piersma, SR, Pham, TV, Bridel, C, Ferri, GL, Cocco, C, Noli, B, Worley, PF, Xiao, MF, Xu, DS, Oeckl, P, Otto, M, Flier, WMD, de Jong, Frank jan, Jimenez, CR, Lemstra, AW, Teunissen, CE, van Steenoven, I, Koel-Simmelink, MJ, Vergouw, Leonie, Tijms, BM, Piersma, SR, Pham, TV, Bridel, C, Ferri, GL, Cocco, C, Noli, B, Worley, PF, Xiao, MF, Xu, DS, Oeckl, P, Otto, M, Flier, WMD, de Jong, Frank jan, Jimenez, CR, Lemstra, AW, and Teunissen, CE

Published
2020

17. Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

Author

van der Ende, Emma, Xiao, MF, Xu, DS, Poos, Jackie, Panman, Jessica, Jiskoot, Lize, Meeter, Lieke, Dopper, Elise, Papma, Janne, Heller, C, Convery, H, Moore, K, Bocchetta, M, Neason, M, Peakman, G, Cash, D, Teunissen, CE, Graff, C, Synofzik, M, Moreno, F, Finger, E, Sanchez-Valle, R, Vandenberghe, R, Laforce, R, Jr, Masellis, M, Carmela Tartaglia, M, Rowe, JB, Butler, CR, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Pijnenburg, YAL, Otto, M, Borroni, B, Tagliavini, F, De Mendonca, A, Santana, I, Galimberti, D, Seelaar, Harro, Rohrer, JD, Worley, PF, van Swieten, J.C., van der Ende, Emma, Xiao, MF, Xu, DS, Poos, Jackie, Panman, Jessica, Jiskoot, Lize, Meeter, Lieke, Dopper, Elise, Papma, Janne, Heller, C, Convery, H, Moore, K, Bocchetta, M, Neason, M, Peakman, G, Cash, D, Teunissen, CE, Graff, C, Synofzik, M, Moreno, F, Finger, E, Sanchez-Valle, R, Vandenberghe, R, Laforce, R, Jr, Masellis, M, Carmela Tartaglia, M, Rowe, JB, Butler, CR, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Pijnenburg, YAL, Otto, M, Borroni, B, Tagliavini, F, De Mendonca, A, Santana, I, Galimberti, D, Seelaar, Harro, Rohrer, JD, Worley, PF, and van Swieten, J.C.

Published
2020

18. CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE epsilon 4 carriers

Author

Ahmad, Shahzad, Milan, MD, Hansson, O, Demirkan, Ayse, Agustin, R, Saez, ME, Giagtzoglou, N, Cabrera-Socorro, A, Bakker, M, Ramirez, A, Hankemeier, T, Stomrud, E, Mattsson-Carlgren, N, Scheltens, P, Flier, WMD, Ikram, Arfan, Malarstig, A, Teunissen, CE, Amin, Najaf, Duijn, Cornelia, Ahmad, Shahzad, Milan, MD, Hansson, O, Demirkan, Ayse, Agustin, R, Saez, ME, Giagtzoglou, N, Cabrera-Socorro, A, Bakker, M, Ramirez, A, Hankemeier, T, Stomrud, E, Mattsson-Carlgren, N, Scheltens, P, Flier, WMD, Ikram, Arfan, Malarstig, A, Teunissen, CE, Amin, Najaf, and Duijn, Cornelia

Published
2020

19. Liquorbiomarkers voor de ziekte van Alzheimer; huidige praktijk en toekomstperspectieven

Author

Duits, FH, Bouwman, FH, Teunissen, CE, van der Flier, WM, Neurology, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation, Clinical chemistry, Epidemiology and Data Science, APH - Personalized Medicine, and APH - Methodology

Abstract

Sinds het ontdekken van de eiwitten in liquor die verantwoordelijkzijn voor de hersenafwijkingen bij deziekte van Alzheimer, amyloid-beta (1-42) en (gehyperfosforyleerd)tau, is het biomarkeronderzoek ineen stroomversnelling geraakt. In de jaren 90 van devorige eeuw werden assays ontwikkeld voor het bepalenvan deze eiwitten in de liquor, en in 2011 zijnde liquorbiomarkers als bewijs voor onderliggendeziekte van Alzheimer in de nieuwe wetenschappelijkediagnostische criteria van de National Institute onAging - Alzheimer’s Association (NIA-AA) en van deInternational Working Group (IWG) opgenomen. Indit artikel wordt ingegaan op de ontwikkeling van dehuidige liquorbiomarkers, het onderzoek naar potentiëlenieuwe biomarkers, en het gebruik van biomarkersin klinische trials. Ook worden aanwijzingen gegevenvoor het gebruik van de biomarkers in dedagelijkse praktijk van een geheugenpolikliniek.

Published
2018

21. Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

Author

Meeter, Lieke, Steketee, Rebecca, Salkovic, Dina, Vos, ME, Grossman, M, McMillan, CT, Irwin, DJ, Boxer, AL, Rojas, JC, Olney, NT, Karydas, A, Miller, BL, Pijnenburg, YA, Barkhof, F, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Diehl-Schmid, J, Grimmer, T, Goldhardt, O, Santillo, AF, Hansson, O, Vestberg, S, Borroni, B, Padovani, A, Galimberti, D, Scarpini, E, Rohrer, JD, Woollacott, IOC, Synofzik, M, Wilke, C, De Mendonca, A, Vandenberghe, R, Benussi, L, Ghidoni, R, Binetti, G, Niessen, Wiro, Papma, Janne, Seelaar, Harro, Jiskoot, Lize, de Jong, Frank jan, Donker Kaat, Laura, Del Campo, M, Teunissen, CE, Bron, Esther, van den Berg, Esther, van Swieten, J.C., Meeter, Lieke, Steketee, Rebecca, Salkovic, Dina, Vos, ME, Grossman, M, McMillan, CT, Irwin, DJ, Boxer, AL, Rojas, JC, Olney, NT, Karydas, A, Miller, BL, Pijnenburg, YA, Barkhof, F, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Diehl-Schmid, J, Grimmer, T, Goldhardt, O, Santillo, AF, Hansson, O, Vestberg, S, Borroni, B, Padovani, A, Galimberti, D, Scarpini, E, Rohrer, JD, Woollacott, IOC, Synofzik, M, Wilke, C, De Mendonca, A, Vandenberghe, R, Benussi, L, Ghidoni, R, Binetti, G, Niessen, Wiro, Papma, Janne, Seelaar, Harro, Jiskoot, Lize, de Jong, Frank jan, Donker Kaat, Laura, Del Campo, M, Teunissen, CE, Bron, Esther, van den Berg, Esther, and van Swieten, J.C.

Published
2019

22. Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry

Author

Lewczuk, P, Riederer, P, O'Bryant, SE, Verbeek, MM, Dubois, B, Visser, PJ, Jellinger, KA, Engelborghs, S, Ramirez, A, Parnetti, L, Jack, CR, Teunissen, CE, Hampel, H, Lleo, A, Jessen, F, Glodzik, L, de Leon, MJ, Fagan, AM, Molinuevo, JL, Jansen, WJ, Winblad, B, Shaw, LM, Andreasson, U, Otto, M, Mollenhauer, B, Wiltfang, J, Turner, MR, Zerr, I, Handels, R, Thompson, AG, Johansson, G, Ermann, N, Trojanowski, JQ, Karaca, I, Wagner, H, Oeckl, P, van Doorn, LV, Bjerke, M, Kapogiannis, D, Kuiperij, HB, Farotti, L, Li, Y, Gordon, BA, Epelbaum, S, Vos, SJB, Klijn, CJM, Van Nostrand, WE, Minguillon, C, Schmitz, M, Gallo, C, Mato, AL, Thibaut, F, Lista, S, Alcolea, D, Zetterberg, H, Blennow, K, Kornhuber, J, WFSBP Task Force, Clinical sciences, Neurology, Faculty of Economic and Social Sciences and Solvay Business School, and WFSBP Task Force

Subjects
0301 basic medicine, PRECLINICAL ALZHEIMERS-DISEASE, MILD COGNITIVE IMPAIRMENT, CREUTZFELDT-JAKOB-DISEASE, AMYOTROPHIC-LATERAL-SCLEROSIS, 0302 clinical medicine, Biological Psychiatry/standards, standards [Societies, Medical], Medicine, Societies, Medical, Medicine(all), blood [Biomarkers], cerebrospinal fluid [Dementia], Neurodegenerative Diseases, Alzheimer's disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, cerebrospinal fluid [Biomarkers], Dementia/blood, Psychiatry and Mental Health, GAMMA-SECRETASE INHIBITOR, Biological psychiatry, Alzheimer’s disease, medicine.medical_specialty, purl.org/pe-repo/ocde/ford#3.02.24 [https], Societies, Medical/standards, diagnosis [Neurodegenerative Diseases], CEREBRAL AMYLOID ANGIOPATHY, Article, cerebrospinal fluid, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, POSITRON-EMISSION-TOMOGRAPHY, NEUROFILAMENT LIGHT-CHAIN, Medical/standards, Dementia, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Psychiatry, Biological Psychiatry, FRONTOTEMPORAL LOBAR DEGENERATION, business.industry, Task force, Alzheimerâ s disease, standards [Biological Psychiatry], biomarkers, medicine.disease, blood [Dementia], diagnosis [Dementia], 030104 developmental biology, Blood biomarkers, blood [Neurodegenerative Diseases], consensus, cerebrospinal fluid [Neurodegenerative Diseases], Human medicine, Neurodegenerative Diseases/blood, business, Societies, Alzheimer’s disease, dementia, 030217 neurology & neurosurgery, Biomarkers/blood
Abstract

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimers disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.

Published
2018
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23. Maximising the Potential of Longitudinal Cohorts for Research in Neurodegenerative Diseases: A Community Perspective

Author

Brayne, CEG, Moody, CJ, Mitchell, D, Kiser, G, Aarsland, D, Berg, D, Brayne, C, Costa, A, Ikram, MA, Mountain, G, Rohrer, JD, Teunissen, CE, van den Berg, LH, Wardlaw, JM, Brayne, Carol [0000-0001-5307-663X], and Apollo - University of Cambridge Repository

Subjects
joint programming, research, flexible funding mechanism, neurodegenerative disease, longitudinal cohort studies, transnational working groups
Abstract

Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND), and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND) recently developed a novel funding mechanism to rapidly mobilise scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape (Alzheimer’s, Parkinson’s, frontotemporal degeneration, amyotrophic lateral sclerosis, Lewy-body and vascular dementia) were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online.

Published
2017
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24. Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: Emergence of the Solution to an Important Unmet Need

Author

Teunissen, CE and Willemse, EAJ

Subjects
biobanking, biomarker, standardisation, Abeta(1–42), Tau, Alzheimer’s disease, cerebrospinal fluid, Research Article
Abstract

Alzheimer's Disease (AD) represents an increasing problem as the overall population ages. The identification of reliable biomarkers of AD has, therefore, become increasingly important. This is not only for risk prediction and diagnosis in order to provide appropriate care, but also to identify those patients at high risk of AD development who may be eligible for inclusion in clinical trials of novel therapies. Treatment in the early stages of the disease are urgently needed, as these are expected to yield the greatest benefits. The cerebrospinal fluid biomarkers amyloid beta (1-42), hyperphosphorylated Tau and total Tau have been most extensively evaluated. Their combination has been shown to be valuable in identifying AD patients, including those who will progress to AD among a wider group of subjects with only subjective memory complaints or in very early disease stages. While commercially available diagnostic tests for these biomarkers are available, implementation in clinical practice is associated with a number of problems, such as absorption of amyloid beta (1-42) to laboratory tubes, a high degree of batch-to-batch variation with the current test, and the lack of certified reference material. Therefore, there is a need for increased automation and implementation on routine diagnostic platforms in order to support the cost-effective and reliable introduction of the tests on a wider scale. As the use of these biomarkers in research and in clinical practice continues to expand, extensive standardisation efforts are being put in place to address the challenges associated with the use of these biomarkers. Together with the development of additional biomarkers for early and differential diagnosis, this casts good foresight to serve the needs of an increasing patient population.

Published
2014

25. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study

Author

Scheltens, P, Hallikainen, M, Grimmer, T, Duning, T, Gouw, AA, Teunissen, CE, Wink, AM, Maruff, P, Harrison, J, van Baal, CM, Bruins, S, Lues, I, Prins, ND, Scheltens, P, Hallikainen, M, Grimmer, T, Duning, T, Gouw, AA, Teunissen, CE, Wink, AM, Maruff, P, Harrison, J, van Baal, CM, Bruins, S, Lues, I, and Prins, ND

Abstract

BACKGROUND: PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. METHODS: This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naïve at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses. RESULTS: There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestin

Published
2018

26. Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Author

Del Campo, M, Galimberti, D, Elias, N, Boonkamp, L, Pijnenburg, YA, van Swieten, J.C., Watts, K, Paciotti, S, Beccari, T, Hu, W, Teunissen, CE, Del Campo, M, Galimberti, D, Elias, N, Boonkamp, L, Pijnenburg, YA, van Swieten, J.C., Watts, K, Paciotti, S, Beccari, T, Hu, W, and Teunissen, CE

Published
2018

28. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Author

Meeter, Lieke, Gendron, TF, Sias, AC, Jiskoot, Lize, Russo, SP, Donker Kaat, Laura, Papma, Janne, Panman, Jessica, van der Ende, Emma, Dopper, Elise, Franzen, Sanne, Graff, C, Boxer, AL, Rosen, HJ, Sanchez-Valle, R, Galimberti, D, Pijnenburg, YAL, Benussi, L, Ghidoni, R, Borroni, B, Laforce, R, Del Campo, M, Teunissen, CE, van Minkelen, Rick, Rojas, JC, Coppola, G, Geschwind, DH, Rademakers, R, Karydas, AM, Oijerstedt, L, Scarpini, E, Binetti, G, Padovani, A, Cash, DM, Dick, K M, Bocchetta, M, Miller, BL, Rohrer, JD, Petrucelli, L, van Swieten, J.C., Lee, SE, Meeter, Lieke, Gendron, TF, Sias, AC, Jiskoot, Lize, Russo, SP, Donker Kaat, Laura, Papma, Janne, Panman, Jessica, van der Ende, Emma, Dopper, Elise, Franzen, Sanne, Graff, C, Boxer, AL, Rosen, HJ, Sanchez-Valle, R, Galimberti, D, Pijnenburg, YAL, Benussi, L, Ghidoni, R, Borroni, B, Laforce, R, Del Campo, M, Teunissen, CE, van Minkelen, Rick, Rojas, JC, Coppola, G, Geschwind, DH, Rademakers, R, Karydas, AM, Oijerstedt, L, Scarpini, E, Binetti, G, Padovani, A, Cash, DM, Dick, K M, Bocchetta, M, Miller, BL, Rohrer, JD, Petrucelli, L, van Swieten, J.C., and Lee, SE

Published
2018

29. Association of Cerebrospinal Fluid (CSF) Insulin with Cognitive Performance and CSF Biomarkers of Alzheimer's Disease

Author

Geijselaers, SLC, Aalten, P, Ramakers, I, de Deyn, PP, Heijboer, AC, Koek, HL, OldeRikkert, MGM, Papma, Janne, Reesink, FE, Smits, LL, Stehouwer, CDA, Teunissen, CE, Verhey, FRJ, van der Flier, WM, Biessels, GJ, Geijselaers, SLC, Aalten, P, Ramakers, I, de Deyn, PP, Heijboer, AC, Koek, HL, OldeRikkert, MGM, Papma, Janne, Reesink, FE, Smits, LL, Stehouwer, CDA, Teunissen, CE, Verhey, FRJ, van der Flier, WM, and Biessels, GJ

Published
2018

31. Design of the ExCersion-VCI study: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment

Author

Leeuwis, AE, Hooghiemstra, AM, Amier, R, Ferro, DA, Franken, L, Nijveldt, R, Kuijer, JPA, Bronzwaer, A-SGT, van Lieshout, JJ, Rietberg, MB, Veerbeek, JM, Huijsmans, RJ, Backx, FJG, Teunissen, CE, Bron, Esther, Barkhof, F, Prins, ND, Shahzad, R, Niessen, Wiro, de Roos, A, van Osch, MJP, van Rossum, AC, Biessels, GJ, van der Flier, WM, Heart Brain Connection study, g, Leeuwis, AE, Hooghiemstra, AM, Amier, R, Ferro, DA, Franken, L, Nijveldt, R, Kuijer, JPA, Bronzwaer, A-SGT, van Lieshout, JJ, Rietberg, MB, Veerbeek, JM, Huijsmans, RJ, Backx, FJG, Teunissen, CE, Bron, Esther, Barkhof, F, Prins, ND, Shahzad, R, Niessen, Wiro, de Roos, A, van Osch, MJP, van Rossum, AC, Biessels, GJ, van der Flier, WM, and Heart Brain Connection study, g

Published
2017

33. Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS

Author

Bruinsma, IB, van Dijk, M, Bridel, C, de Lisdonk, TV, Haverkort, SQ, Runia, Tessel, Steinman, L, Hintzen, Rogier, Killestein, J, Verbeek, MM, Teunissen, CE, de Jong, BA, Bruinsma, IB, van Dijk, M, Bridel, C, de Lisdonk, TV, Haverkort, SQ, Runia, Tessel, Steinman, L, Hintzen, Rogier, Killestein, J, Verbeek, MM, Teunissen, CE, and de Jong, BA

Published
2017

34. Neurofilament light chain: a biomarker for genetic frontotemporal dementia

Author

Meeter, Lieke, Dopper, Elise, Jiskoot, Lize, Sanchez-Valle, R, Graff, C, Benussi, L, Ghidoni, R, Pijnenburg, YA, Borroni, B, Galimberti, D, Laforce, R, Masellis, M, Vandenberghe, R, Le Ber, I, Otto, M, van Minkelen, Rick, Papma, Janne, Rombouts, SA, Balasa, M, Oijerstedt, L, Jelic, V, Dick, K M, Cash, DM, Harding, S R, Cardoso, MJ, Ourselin, S, Rossor, MN, Padovani, A, Scarpini, E, Fenoglio, C, Tartaglia, MC, Lamari, F, Barro, C, Kuhle, J, Rohrer, JD, Teunissen, CE, van Swieten, J.C., Meeter, Lieke, Dopper, Elise, Jiskoot, Lize, Sanchez-Valle, R, Graff, C, Benussi, L, Ghidoni, R, Pijnenburg, YA, Borroni, B, Galimberti, D, Laforce, R, Masellis, M, Vandenberghe, R, Le Ber, I, Otto, M, van Minkelen, Rick, Papma, Janne, Rombouts, SA, Balasa, M, Oijerstedt, L, Jelic, V, Dick, K M, Cash, DM, Harding, S R, Cardoso, MJ, Ourselin, S, Rossor, MN, Padovani, A, Scarpini, E, Fenoglio, C, Tartaglia, MC, Lamari, F, Barro, C, Kuhle, J, Rohrer, JD, Teunissen, CE, and van Swieten, J.C.

Published
2016

35. A consensus protocol for the standardisation of cerebrospinal fluid collection and biobanking

Author

Teunissen, CE, Petzold, A, Bennett, JL, Berven, FS, Brundin, L, Comabella, M, Franciotta, D, Federiksen, JL, Fleming, JO, Furlan, R, Hintzen, Rogier, Hughes, SG, Johnson, MH, Krasulova, E, Kuhle, J, Magnone, MC, Rajda, C, Rejdak, K, Schmidt, HK, van Pesch, V, Waubant, E, Wolf, C, Giovannoni, G, Deisenhammer, F, Hegen, H, Hemmer, B, Tumani, HT, Molecular cell biology and Immunology, Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases

Abstract

There is a long history of research on body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only very few biomarkers in cerebrospinal fluid (CSF) are being used in clinical practice. One of the most critical factors in CSF biomarker research is the inadequate powering of Studies owing to the lack of sufficient samples that call be obtained in sin-le-centre studies. Therefore, collaboration between investigators is needed to establish lame biobanks of well-defined samples. Standardised protocols for biobanking are a prerequisite to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by preanalytical factors. Here. a consensus report on guidelines of CSF collection and biobanking is presented. formed by the European network for Biomarkers in MS for CSF biomarker research in Multiple sclerosis. In this paper, we FOCUS on CSF collection procedures, preanalytical factors, and high quality clinical and paraclinical information. The biobanking protocols are applicable for CSF biobanks For research targeting any neurological disease.

Published
2010
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36. The Dutch Parelsnoer Institute - Neurodegenerative diseases; methods, design and baseline results

Author

Aalten, P, Ramakers, IHGB, Biessels, GJ, de Deyn, PP, Koek, HL, OldeRikkert, MGM, Oleksik, AM, Richard, E, Smits, LL, van Swieten, J.C., Teune, LK, van der Lugt, Aad, Barkhof, F, Teunissen, CE, Rozendaal, N, Verhey, FRJ, van der Flier, WM, Aalten, P, Ramakers, IHGB, Biessels, GJ, de Deyn, PP, Koek, HL, OldeRikkert, MGM, Oleksik, AM, Richard, E, Smits, LL, van Swieten, J.C., Teune, LK, van der Lugt, Aad, Barkhof, F, Teunissen, CE, Rozendaal, N, Verhey, FRJ, and van der Flier, WM

Abstract

Background: The Parelsnoer Institute is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called "Pearls") are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer's disease. The objective of this paper is to describe the design and methods of the Pearl Neurodegenerative Diseases, as well as baseline descriptive variables, including their biomarker profile. Methods: The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%). Discussion: The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset.

Published
2014

39. Biomarker report from the phase II lamotrigine trial in secondary progressive MS – neurofilament as a surrogate of disease progression

Author

Gnanapavan, S, Grant, D, Morant, S, Furby, J, Hayton, T, Teunissen, C, Leoni, V, Marta, M, Brenner, R, Palace, J, Miller, D, Kapoor, R, Giovannoni, G, Teunissen, CE, Miller, DH, Gnanapavan, S, Grant, D, Morant, S, Furby, J, Hayton, T, Teunissen, C, Leoni, V, Marta, M, Brenner, R, Palace, J, Miller, D, Kapoor, R, Giovannoni, G, Teunissen, CE, and Miller, DH

Abstract

Objective:Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.Methods:SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.Results:Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p = 0.043, Nfh 0-24 months p = 0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.Conclusions:The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration

Published
2013

41. CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome

Author

Khalil, M, primary, Enzinger, C, additional, Langkammer, C, additional, Ropele, S, additional, Mader, A, additional, Trentini, A, additional, Vane, MLG, additional, Wallner-Blazek, M, additional, Bachmaier, G, additional, Archelos, J-J, additional, Koel-Simmelink, MJA, additional, Blankenstein, MA, additional, Fuchs, S, additional, Fazekas, F, additional, and Teunissen, CE, additional

Published
2012
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44. Short commentary on ‘a consensus protocol for the standardization of cerebrospinal fluid collection and biobanking’

Author

Teunissen, CE, primary, Tumani, HT, additional, Bennett, JL, additional, Berven, FS, additional, Brundin, L., additional, Comabella, M., additional, Franciotta, D., additional, Federiksen, JL, additional, Fleming, JO, additional, Furlan, R., additional, Hintzen, RQ, additional, Hughes, SG, additional, Johnson, MH, additional, Krasulova, E., additional, Kuhle, J., additional, Magnone, Maria-Chiara, additional, Petzold, A., additional, Rajda, C., additional, Rejdak, K., additional, Schmidt, HK, additional, van Pesch, V., additional, Waubant, E., additional, Wolf, C., additional, Hemmer, B., additional, Deisenhammer, F., additional, and Giovannoni, G., additional

Published
2009
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45. Application of serum natalizumab levels during plasma exchange in MS patients with progressive multifocal leukoencephalopathy.

Author

Vennegoor, A, Rispens, T, Van Oosten, BW, Wattjes, MP, Wondergem, MJ, Teunissen, CE, Van der Kleij, D, Uitdehaag, BMJ, Polman, CH, and Killestein, J

Subjects
NATALIZUMAB, MULTIPLE sclerosis, PLASMAPHERESIS, IMMUNOADSORPTION, PLASMA exchange (Therapeutics), PATIENTS
Abstract

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML. [ABSTRACT FROM AUTHOR]

Published
2015
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46. Oxysterols and cholesterol precursors correlate to magnetic resonance imaging measures of neurodegeneration in multiple sclerosis.

Author

van de Kraats, C, Killestein, J, Popescu, V, Rijkers, E, Vrenken, H, Lütjohann, D, Barkhof, F, Polman, CH, and Teunissen, CE

Subjects
SERUM, CEREBROSPINAL fluid, STEROLS, MULTIPLE sclerosis, MAGNETIC resonance imaging, HYDROXYCHOLESTEROLS
Abstract

The article presents a study which examines the differences of serum and cerebrospinal fluid (CSF) sterol levels between 105 multiple sclerosis (MS) and 49 control patients. The study correlated sterol levels to magnetic resonance imaging (MRI) markers of disease activity. It found more decreased serum 24OHC and 27-hydroxycholesterol (27OHC) and increased CSF lathosterol in MS patients than in control patients.

Published
2014
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47. CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome.

Author

Khalil, M, Enzinger, C, Langkammer, C, Ropele, S, Mader, A, Trentini, A, Vane, MLG, Wallner-Blazek, M, Bachmaier, G, Archelos, J-J, Koel-Simmelink, MJA, Blankenstein, MA, Fuchs, S, Fazekas, F, and Teunissen, CE

Subjects
CEREBROSPINAL fluid, BIOMARKERS, AXONAL transport, MAGNETIC resonance imaging, CYTOPLASMIC filaments
Abstract

The article presents a study which assessed the reflection and prediction for cerebrospinal spinal fluid (CSF) biomarkers for axonal damage. The study performed baseline magnetic resonance imaging (MRI) to patients with clinically isolated syndrome (CIS). The result of the study shows that there was an increase neurofilament levels in CIS.

Published
2013
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50. Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's disease.

Author

van Rossum IA, Visser PJ, Knol DL, van der Flier WM, Teunissen CE, Barkhof F, Blankenstein MA, Scheltens P, van Rossum, Ineke A, Visser, Pieter Jelle, Knol, Dirk L, van der Flier, Wiesje M, Teunissen, Charlotte E, Barkhof, Frederik, Blankenstein, Marinus A, and Scheltens, Philip

Abstract

Alzheimer's disease (AD) is a common cause of mild cognitive impairment (MCI). However, the time between the diagnosis of MCI and the diagnosis of dementia is highly variable. In this study we investigated which known risk factors and biomarkers of AD pathology were associated with rapid progression from MCI to dementia. Of the 203 subjects with MCI, 91 progressed to AD-type dementia and were considered to have MCI-AD at baseline. Subjects with MCI-AD were older, more frequently female and carrier of the APOE-ε4 allele, had lower scores on the Mini-Mental State Examination (MMSE), more medial temporal lobe atrophy (MTA) and lower levels of Aβ1-42 and increased levels of t-tau and p-tau in the cerebrospinal fluid (CSF) compared to subjects without AD-type dementia at follow up. Of the 91 subjects with MCI-AD, we had data available of CSF (n = 56), MTA (n = 76), and APOE-genotype (n = 63). Among the subjects with MCI-AD, MTA (hazard ratio (HR) 2.2, p = 0.004) and low MMSE score (HR 2.0 p = 0.007) were associated with rapid progression to dementia. High CSF t-tau (HR 1.7, p = 0.07) and p-tau (1.7, p = 0.08) tended to be associated with rapid progression to dementia. CSF Aβ1-42, APOE status, age, gender, and educational level were not associated with time to dementia. Our findings implicate a different role for biomarkers in diagnosis and prognosis of MCI-AD. While amyloid markers can be used to identify MCI-AD, injury markers may predict rapid progression to dementia. [ABSTRACT FROM AUTHOR]

Published
2012
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