19 results on '"Verbeek, Marcel M."'
Search Results
2. Plasma amyloid beta 42 is a biomarker for patients with hereditary, but not sporadic, cerebral amyloid angiopathy.
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de Kort, Anna M., Kuiperij, H. Bea, Jäkel, Lieke, Kersten, Iris, Rasing, Ingeborg, van Etten, Ellis S., van Rooden, Sanneke, van Osch, Matthias J. P., Wermer, Marieke J. H., Terwindt, Gisela M., Schreuder, Floris H. B. M., Klijn, Catharina J. M., and Verbeek, Marcel M.
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CEREBRAL amyloid angiopathy ,AMYLOID ,BIOMARKERS - Abstract
Background: The diagnosis of probable cerebral amyloid angiopathy (CAA) is currently mostly based on characteristics of brain MRI. Blood biomarkers would be a cost-effective, easily accessible diagnostic method that may complement diagnosis by MRI and aid in monitoring disease progression. We studied the diagnostic potential of plasma Aβ38, Aβ40, and Aβ42 in patients with hereditary Dutch-type CAA (D-CAA) and sporadic CAA (sCAA). Methods: All Aβ peptides were quantified in the plasma by immunoassays in a discovery cohort (11 patients with presymptomatic D-CAA and 24 patients with symptomatic D-CAA, and 16 and 24 matched controls, respectively) and an independent validation cohort (54 patients with D-CAA, 26 presymptomatic and 28 symptomatic, and 39 and 46 matched controls, respectively). In addition, peptides were quantified in the plasma in a group of 61 patients with sCAA and 42 matched controls. We compared Aβ peptide levels between patients and controls using linear regression adjusting for age and sex. Results: In the discovery cohort, we found significantly decreased levels of all Aβ peptides in patients with presymptomatic D-CAA (Aβ38: p < 0.001; Aβ40: p = 0.009; Aβ42: p < 0.001) and patients with symptomatic D-CAA (Aβ38: p < 0.001; Aβ40: p = 0.01; Aβ42: p < 0.001) compared with controls. In contrast, in the validation cohort, plasma Aβ38, Aβ40, and Aβ42 were similar in patients with presymptomatic D-CAA and controls (Aβ38: p = 0.18; Aβ40: p = 0.28; Aβ42: p = 0.63). In patients with symptomatic D-CAA and controls, plasma Aβ38 and Aβ40 were similar (Aβ38: p = 0.14; Aβ40: p = 0.38), whereas plasma Aβ42 was significantly decreased in patients with symptomatic D-CAA (p = 0.033). Plasma Aβ38, Aβ40, and Aβ42 levels were similar in patients with sCAA and controls (Aβ38: p = 0.092; Aβ40: p = 0.64. Aβ42: p = 0.68). Conclusions: Plasma Aβ42 levels, but not plasma Aβ38 and Aβ40, may be used as a biomarker for patients with symptomatic D-CAA. In contrast, plasma Aβ38, Aβ40, and Aβ42 levels do not appear to be applicable as a biomarker in patients with sCAA. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline
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Bos, Isabelle, Verhey, Frans R., Ramakers, Inez H.G.B., Jacobs, Heidi I. L., Soininen, Hilkka, Freund-Levi, Yvonne, Hampel, Harald, Tsolaki, Magda, Wallin, Åsa K., van Buchem, Mark A., Oleksik, Ania, Verbeek, Marcel M., Olde Rikkert, Marcel, van der Flier, Wiesje M., Scheltens, Philip, Aalten, Pauline, Visser, Pieter Jelle, and Vos, Stephanie J. B.
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- 2017
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4. Heat Shock Proteins and Amateur Chaperones in Amyloid-Beta Accumulation and Clearance in Alzheimer’s Disease
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Wilhelmus, Micha M. M., de Waal, Robert M. W., and Verbeek, Marcel M.
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- 2007
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5. Prevalence of cerebral amyloid angiopathy: A systematic review and meta-analysis.
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Jäkel, Lieke, De Kort, Anna M., Klijn, Catharina J. M., Schreuder, Floris H. B. M., and Verbeek, Marcel M.
- Abstract
Reported prevalence estimates of sporadic cerebral amyloid angiopathy (CAA) vary widely. CAA is associated with cognitive dysfunction and intracerebral hemorrhage, and linked to immunotherapy-related side-effects in Alzheimer’s disease (AD). Given ongoing efforts to develop AD immunotherapy, accurate estimates of CAA prevalence are important. CAA can be diagnosed neuropathologically or during life using MRI markers including strictly lobar microbleeds. In this meta-analysis of 170 studies including over 73,000 subjects, we show that in patients with AD, CAA prevalence based on pathology (48%) is twice that based on presence of strictly lobar cerebral microbleeds (22%); in the general population this difference is three-fold (23% vs 7%). Both methods yield similar estimated prevalences of CAA in cognitively normal elderly (5% to 7%), in patients with intracerebral hemorrhage (19% to 24%), and in patients with lobar intracerebral hemorrhage (50% to 57%). However, we observed large heterogeneity among neuropathology and MRI protocols, which calls for standardized assessment and reporting of CAA. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Reply to "Decreased Cerebrospinal Fluid Amyloid Beta 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy".
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de Kort, Anna M., Kuiperij, H. Bea, Schreuder, Floris H. B. M., Klijn, Catharina J. M., and Verbeek, Marcel M.
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CEREBRAL amyloid angiopathy ,CEREBROSPINAL fluid ,AMYLOID - Abstract
We thank Dr Kuhlenbäumer and colleagues for their interest in our recent study[1] in which we demonstrate that the cerebrospinal fluid (CSF) panel of the amyloid beta (A ) peptides 38, 40, 42, and 43 discriminates patients with sporadic cerebral amyloid angiopathy (sCAA) from patients with Alzheimer disease (AD) with high accuracy. However, we would like to point out that, despite using decreased CSF A 42 (in combination with increased phospho-tau and total tau) as a criterion for AD, CSF A 42 levels were lower in sCAA than in AD. The area under the curve (AUC) for the combination of CSF A 38, A 40, and A 43 is 0.92 (95% CI: 0.85-0.98), instead of the earlier reported AUC of 0.96 (95% confidence interval [CI] = 0.92-1.00). [Extracted from the article]
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- 2023
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7. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia A Meta-analysis
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Jansen, Willemijn J, Ossenkoppele, Rik, Alcolea, Daniel, Rodríguez-Rodríguez, Eloy, Roe, Catherine M, Rot, Uros, Rowe, Christopher C, Rüther, Eckart, Sabri, Osama, Sanchez-Juan, Páscual, Santana, Isabel, Sarazin, Marie, Schröder, Johannes, Alexander, Myriam, Schütte, Christin, Seo, Sang W, Soetewey, Femke, Soininen, Hilkka, Spiru, Luiza, Struyfs, Hanne, Teunissen, Charlotte E, Tsolaki, Magda, Vandenberghe, Rik, Verbeek, Marcel M, Almdahl, Ina S, Villemagne, Victor L, Vos, Stephanie J B, van Waalwijk van Doorn, Linda J C, Waldemar, Gunhild, Wallin, Anders, Wallin, Åsa K, Wiltfang, Jens, Wolk, David A, Zboch, Marzena, Zetterberg, Henrik, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart N M, Bibeau, Kristen, Blennow, Kaj, Brooks, David J, Knol, Dirk L, van Buchem, Mark A, Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D, Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M, Fladby, Tormod, Tijms, Betty M, Fleisher, Adam S, van der Flier, Wiesje M, Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S, Freund-Levi, Yvonne, Frisoni, Giovanni B, Froelich, Lutz, Scheltens, Philip, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Verhey, Frans R J, Hildebrandt, Helmut, Ishihara, Lianna, Ivanoiu, Adrian, Jagust, William J, Johannsen, Peter, Kandimalla, Ramesh, Kapaki, Elisabeth, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E, Köhler, Sebastian, Visser, Pieter Jelle, Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G, Van Laere, Koen, Landau, Susan M, Lee, Dong Young, de Leon, Mony, Lisetti, Viviana, Lleó, Alberto, Madsen, Karine, Group, Amyloid Biomarker Study, Maier, Wolfgang, Marcusson, Jan, Mattsson, Niklas, de Mendonça, Alexandre, Meulenbroek, Olga, Meyer, Philipp T, Mintun, Mark A, Mok, Vincent, Molinuevo, José Luis, Møllergård, Hanne M, Aalten, Pauline, Morris, John C, Mroczko, Barbara, Van der Mussele, Stefan, Na, Duk L, Newberg, Andrew, Nordberg, Agneta, Nordlund, Arto, Novak, Gerald P, Paraskevas, George P, Parnetti, Lucilla, Aarsland, Dag, Perera, Gayan, Peters, Oliver, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D, Ramakers, Inez H G B, Rami, Lorena, Resende de Oliveira, Catarina, Rinne, Juha O, Rodrigue, Karen M, Clinical sciences, Neurology, Promovendi MHN, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Neuroscience Campus Amsterdam - Neurodegeneration, Amyloid Biomarker Study Group, Frisoni, Giovanni, Popp, Julius, Radiology and nuclear medicine, Epidemiology and Data Science, and NCA - neurodegeneration
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Apolipoprotein E ,Male ,Pediatrics ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neurology ,pathology [Cognitive Dysfunction] ,Apolipoprotein E4 ,pathology [Dementia] ,Biomarkers/analysis ,ddc:616.89 ,Risk Factors ,pathology [Brain] ,chemistry [Cerebrospinal Fluid] ,80 and over ,Prevalence ,Medicine ,risk factors ,Apolipoprotein E4/genetics ,genetics [Apolipoprotein E4] ,Cerebrospinal Fluid ,Cerebrospinal Fluid/chemistry ,Aged, 80 and over ,Medicine(all) ,pathology [Mild Cognitive Impairment] ,Adult ,Age Factors ,Aged ,Amyloid beta-Peptides ,Biomarkers ,Brain ,Cognitive Dysfunction ,Dementia ,Female ,Genotype ,Humans ,Middle Aged ,Positron-Emission Tomography ,Medicine (all) ,Cognitive Dysfunction/pathology ,Cognition ,General Medicine ,analysis [Amyloid beta-Peptides] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,3. Good health ,Amyloid beta-Peptides/analysis ,Meta-analysis ,Alzheimer's disease ,analysis [Biomarkers] ,medicine.medical_specialty ,Amyloid ,Dementia/pathology ,ta3112 ,Article ,mental disorders ,Brain/pathology ,ddc:610 ,Psychiatry ,Pathological ,Mild Cognitive Impairment/pathology ,analysis [Biological Markers] ,business.industry ,Biological Markers/analysis ,medicine.disease ,ta3124 ,business ,aged, 80 and over - Abstract
Item does not contain fulltext IMPORTANCE: Cerebral amyloid-beta aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-epsilon4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE epsilon4epsilon4 carriers, 50 years for epsilon2epsilon4 carriers, 55 years for epsilon3epsilon4 carriers, 65 years for epsilon3epsilon3 carriers, and 95 years for epsilon2epsilon3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.
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- 2015
8. Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study.
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Lleó, Alberto, Alcolea, Daniel, Martínez‐Lage, Pablo, Scheltens, Philip, Parnetti, Lucilla, Poirier, Judes, Simonsen, Anja H., Verbeek, Marcel M., Rosa‐Neto, Pedro, Slot, Rosalinde E.R., Tainta, Mikel, Izaguirre, Andrea, Reijs, Babette L.R., Farotti, Lucia, Tsolaki, Magda, Vandenbergue, Rik, Freund‐Levi, Yvonne, Verhey, Frans R.J., Clarimón, Jordi, and Fortea, Juan
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Introduction: Within‐person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined. Methods: We included 467 subjects from the BIOMARKAPD study with at least two serial CSF samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow‐up CSF levels of total tau (t‐tau), phosphorylated tau (p‐tau), YKL‐40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years. Results: CSF levels of t‐tau, p‐tau, NfL, and YKL‐40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t‐tau levels were 1% lower (P <.001) and p‐tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL‐40 (P <.02) increased during the study period. Discussion: All four CSF biomarkers increase with age, but this effect deviates in AD for t‐tau and p‐tau. [ABSTRACT FROM AUTHOR]
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- 2019
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9. Multicenter Analytical Validation of Aβ40 Immunoassays.
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van Waalwijk van Doorn, Linda J. C., Kulic, Luka, Koel-Simmelink, Marleen J. A., Kuiperij, H. Bea, Versleijen, Alexandra A. M., Struyfs, Hanne, Twaalfhoven, Harry A. M., Fourier, Anthony, Engelborghs, Sebastiaan, Perret-Liaudet, Armand, Lehmann, Sylvain, Verbeek, Marcel M., Vanmechelen, Eugeen J. M., and Teunissen, Charlotte E.
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AMYLOID ,CEREBROSPINAL fluid ,STANDARD operating procedure ,IMMUNOASSAY ,PHYSICIAN practice patterns - Abstract
Background: Before implementation in clinical practice, biomarker assays need to be thoroughly analytically validated. There is currently a strong interest in implementation of the ratio of amyloid-β peptide 1-42 and 1-40 (Aβ42/Aβ40) in clinical routine. Therefore, in this study, we compared the analytical performance of six assays detecting Aβ40 in cerebrospinal fluid (CSF) in six laboratories according to a recently standard operating procedure (SOP) developed for implementation of ELISA assays for clinical routine. Methods: Aβ40 assays of six vendors were validated in up to three centers per assay according to recently proposed international consensus validation protocols. The performance parameters included sensitivity, precision, dilutional linearity, recovery, and parallelism. Inter-laboratory variation was determined using a set of 20 CSF samples. In addition, test results were used to critically evaluate the SOPs that were used to validate the assays. Results: Most performance parameters of the different Aβ40 assays were similar between labs and within the predefined acceptance criteria. The only exceptions were the out-of-range results of recovery for the majority of experiments and of parallelism by three laboratories. Additionally, experiments to define the dilutional linearity and hook-effect were not executed correctly in part of the centers. The inter-laboratory variation showed acceptable low levels for all assays. Absolute concentrations measured by the assays varied by a factor up to 4.7 for the extremes. Conclusion: All validated Aβ40 assays appeared to be of good technical quality and performed generally well according to predefined criteria. A novel version of the validation SOP is developed based on these findings, to further facilitate implementation of novel immunoassays in clinical practice. [ABSTRACT FROM AUTHOR]
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- 2017
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10. Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study.
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Hilal, Saima, Akoudad, Saloua, van Duijn, Cornelia M., Niessen, Wiro J., Verbeek, Marcel M., Vanderstichele, Hugo, Stoops, Erik, Ikram, M. Arfan, and Vernooij, Meike W.
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CEREBRAL small vessel diseases ,BLOOD plasma ,AMYLOID ,COGNITION ,VASCULAR diseases ,BRAIN diseases ,BRAIN ,LONGITUDINAL method ,MAGNETIC resonance imaging ,NEUROPSYCHOLOGICAL tests ,META-analysis ,PEPTIDES ,REGRESSION analysis ,PSYCHOLOGY - Abstract
Background: Plasma amyloid-β (Aβ) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Aβ isoforms, i.e., Aβ1-40 and Aβ1-42 have been linked with risk of Alzheimer's disease. However, it remains under-explored whether plasma Aβ levels including novel Aβ1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementiaObjective:To examine the association of plasma Aβ levels (i.e., Aβ1-38, Aβ1-40, and Aβ1-42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting.Methods: We analyzed plasma Aβ1 levels in 1201 subjects from two independent cohorts of the Rotterdam Study. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Aβ levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-analysis with fixed effects.Results: Higher levels of plasma Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-40/ Aβ1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels of Aβ1-40 and Aβ1-40/ Aβ1-42 were significantly associated with larger WMH volumes. With regard to cognition, a higher level of Aβ1-38 Aβ1-40 and Aβ1-40/ Aβ1-42 was related to worse performance on cognitive test specifically in memory domain.Conclusion: Higher plasma levels of Aβ levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Aβ levels thus mark the presence of vascular brain pathology. [ABSTRACT FROM AUTHOR]- Published
- 2017
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11. Dickkopf-related protein 3 is a potential Aβ-associated protein in Alzheimer's Disease.
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Bruggink, Kim A., Kuiperij, H. Bea, Gloerich, Jolein, Otte‐Höller, Irene, Rozemuller, Annemieke J.M., Claassen, Jurgen A.H.R., Küsters, Benno, and Verbeek, Marcel M.
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AMYLOID beta-protein ,AMYLOID plaque ,ALZHEIMER'S disease research ,ENZYME-linked immunosorbent assay ,PATHOLOGICAL physiology ,BLOOD serum analysis ,PROTEOMICS - Abstract
Amyloid-β (Aβ) is the most prominent protein in Alzheimer's disease ( AD) senile plaques. In addition, Aβ interacts with a variety of Aβ-associated proteins (AAPs), some of which can form complexes with Aβ and influence its clearance, aggregation or toxicity. Identification of novel AAPs may shed new light on the pathophysiology of AD and the metabolic fate of Aβ. In this study, we aimed to identify new AAPs by searching for proteins that may form soluble complexes with Aβ in CSF, using a proteomics approach. We identified the secreted Wnt pathway protein Dickkopf-related protein 3 (Dkk-3) as a potential Aβ-associated protein. Using immunohistochemistry on human AD brain tissue, we observed that (i) Dkk-3 co-localizes with Aβ in the brain, both in diffuse and classic plaques. (ii) Dkk-3 is expressed in neurons and in blood vessel walls in the brain and (iii) is secreted by leptomeningeal smooth muscle cells in vitro. Finally, measurements using ELISA revealed that (iv) Dkk-3 protein is abundantly present in both cerebrospinal fluid and serum, but its levels are similar in non-demented controls and patients with AD, Lewy body dementia, and frontotemporal dementia. Our study demonstrates that Dkk-3 is a hitherto unidentified Aβ-associated protein which, given its relatively high cerebral concentrations and co-localization with Aβ, is potentially involved in AD pathology. [ABSTRACT FROM AUTHOR]
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- 2015
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12. An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter.
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Lucey, Brendan P., Gonzales, Celedon, Das, Ujjwas, Jinhe Li, Siemers, Eric R., Slemmon, J. Randall, Bateman, Randall J., Yafei Huang, Fox, Gerard B., Claassen, Jurgen A. H. R., Slats, Diane, Verbeek, Marcel M., Gary Tong, Soares, Holly, Savage, Mary J., Kennedy, Matthew, Forman, Mark, Sjögren, Magnus, Margolin, Richard, and Xia Chen
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CEREBROSPINAL fluid examination ,LUMBAR puncture ,CATHETERIZATION ,BIOMARKERS ,TARGETED drug delivery ,AMYLOID ,THERAPEUTICS - Abstract
Introduction: Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time. Methods: Grouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time. Results: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors' studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection. Conclusions: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs. [ABSTRACT FROM AUTHOR]
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- 2015
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13. Cerebral Level of vGlut1 is Increased and Level of Glycine is Decreased in TgSwDI Mice.
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Timmer, Nienke M., Metaxas, Athanasios, van der Stelt, Inge, Kluijtmans, Leo A.J., van Berckel, Bart N., and Verbeek, Marcel M.
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ALZHEIMER'S disease ,GLUTAMATE transporters ,AMINO acids ,AUTORADIOGRAPHY ,AMYLOID ,GLYCOPROTEINS ,GLYCINE - Abstract
Amyloid-β (Aβ) deposition, one of the main hallmarks of Alzheimer's disease (AD), has been linked to glutamatergic dysfunction, i.e., increased stimulation of synaptic glutamate receptors that may ultimately result in neuronal loss. It was our aim to study the effect of Aβ on multiple components of the glutamatergic system, and therefore we assessed the expression of several glutamate-related proteins and amino acids in the TgSwDI mouse model for Aβ pathology. We determined that in TgSwDI mice, levels of several amino acids are altered, in particular that of glycine. Protein changes were only found in 9-month-old TgSwDI mice with extensive Aβ deposits, with the most prominent change an increased expression of vesicular glutamate transporter 1 (vGlut1). Autoradiography experiments demonstrated that, while the number of activated N-methyl-D-aspartic acid (NMDA) receptors was unchanged in TgSwDI mice, binding of the NMDA receptor radioligand [3H]MDL-105,519 to the glycine-binding site of these receptors was increased. Although there are some discrepancies between our results and those found in AD patients, our results suggest that several components of the glutamatergic system might serve as meaningful markers to monitor the progression of AD. [ABSTRACT FROM AUTHOR]
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- 2014
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14. Cerebral Amyloid Angiopathy with Severe Secondary Vascular Pathology: A Histopathological Study.
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Van Horssen, Jack, De Jong, Danielle, De Waal, Robert M. W., Maass, Cathy, Otte-Höller, Irene, Kremer, Berry, Verbeek, Marcel M., and Wesseling, Pieter
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AMYLOID ,NEUROLOGICAL disorders ,PATIENTS ,SMOOTH muscle ,HEMORRHAGE ,PATHOLOGY ,DEMENTIA - Abstract
Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and is characterized by deposition of fibrillar amyloid in cortical and leptomeningeal vessels. In this study we describe the macroscopic and microscopic neuropathological findings of 5 patients with severe CAA-associated secondary vascular changes, including smooth muscle cell degeneration, hyalinization, ‘double-barreling’ phenomenon, macrophage infiltration, and aneurysmal dilatation of the vessel wall. In 3 of the 5 patients these vascular changes were associated with multiple small hemorrhages, whereas in 2 patients areas of ischemic necrosis were observed. However, none of these patients suffered from large (lobar) hemorrhagic accidents. Nevertheless, severe CAA, particularly when associated with secondary vascular pathology, may lead to vascular dementia-like ischemic changes. Hence, the distinction between patients with severe CAA and secondary vascular abnormalities from those suffering from vascular dementia can be difficult. We speculate that CAA, particularly when associated with secondary vascular pathology, although not resulting in large hemorrhages, may contribute to cognitive decline. The functional impact of CAA and CAA-related secondary vascular changes on cognitive performance warrants further exploration. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2005
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15. Apolipoprotein E Genotype Regulates Amyloid-β Cytotoxicity.
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Wilhelmus, Micha M. M., Otte-Höller, Irene, De Waal, Robert M. W., Davis, Judianne, Van Nostrand, William E., and Verbeek, Marcel M.
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APOLIPOPROTEIN E ,ALZHEIMER'S disease ,CELL-mediated cytotoxicity ,GENETIC polymorphisms ,AMYLOID ,CEREBROVASCULAR disease - Abstract
The ∈4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimer's disease (AD), whereas the ∈2 allele may be relatively protective. Both alleles are risk factors for cerebral amyloid angiopathy (CAA)-related hemorrhages. CAA is associated with degeneration of smooth muscle cells and pericytes. Previously, we described that synthetic amyloid-β
1-40 peptide (Aβ1-40 ) with the22 Glu→Gln "Dutch" mutation caused pericyte death in vitro by a mechanism that involves Aβ fibril-like assembly at the cell surface. It is known that ApoE binds to Aβ and may modify its biological activities. In the present study, we evaluated the effect of ApoE on Aβ-mediated toxicity of cerebrovascular cells. We observed that cultured cells with an ∈4/∈4 genotype were more vulnerable to Aβ than cultures with an ∈3/∈3 or ∈3/∈4 genotype. The one cell culture with the ∈2/∈3 genotype was relatively resistant to Aβ compared with other cultures. Furthermore, we observed a dose-dependent protective effect of native ApoE against Aβ-mediated toxicity of cerebrovascular cells and, in addition, ApoE ∈2/∈3 cells secreted more ApoE protein compared with cells with other ApoE genotypes, in particular, compared with ∈4/∈4 cells. Thus, the disparity between ApoE genotype and Aβ-mediated toxicity might be related to differences in the cellular capacity to secrete ApoE. The present data suggest that one mechanism by which ApoE may alter the risk for AD is a genotype-dependent regulation of Aβ cytotoxicity, possibly via variations in its secretion levels, whereby extracellular ApoE may bind to Aβ and thereby modify Aβ-mediated cell death. [ABSTRACT FROM AUTHOR]- Published
- 2005
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16. Amyloid-β oligomer detection by ELISA in cerebrospinal fluid and brain tissue
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Bruggink, Kim A., Jongbloed, Wesley, Biemans, Elisanne A.L.M., Veerhuis, Rob, Claassen, Jurgen A.H.R., Kuiperij, H. Bea, and Verbeek, Marcel M.
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AMYLOID , *OLIGOMERS , *ENZYME-linked immunosorbent assay , *CEREBROSPINAL fluid , *BRAIN physiology , *ALZHEIMER'S disease diagnosis , *TRANSGENIC mice - Abstract
Abstract: Amyloid-β (Aβ) deposits are important pathological hallmarks of Alzheimer’s disease (AD). Aβ aggregates into fibrils; however, the intermediate oligomers are believed to be the most neurotoxic species and, therefore, are of great interest as potential biomarkers. Here, we have developed an enzyme-linked immunosorbent assay (ELISA) specific for Aβ oligomers by using the same capture and (labeled) detection antibody. The ELISA predominantly recognizes relatively small oligomers (10–25kDa) and not monomers. In brain tissue of APP/PS1 transgenic mice, we found that Aβ oligomer levels increase with age. However, for measurements in human samples, pretreatment to remove human anti-mouse antibodies (HAMAs) was required. In HAMA-depleted human hippocampal extracts, the Aβ oligomer concentration was significantly increased in AD compared with nondemented controls. Aβ oligomer levels could also be quantified in pretreated cerebrospinal fluid (CSF) samples; however, no difference was detected between AD and control groups. Our data suggest that levels of small oligomers might not be suitable as biomarkers for AD. In addition, we demonstrate the importance of avoiding HAMA interference in assays to quantify Aβ oligomers in human body fluids. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
17. Pathogenesis of cerebral amyloid angiopathy
- Author
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Rensink, Annemieke A.M., de Waal, Robert M.W., Kremer, Berry, and Verbeek, Marcel M.
- Subjects
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AMYLOID , *PROTEINS , *ALZHEIMER'S disease , *DEMENTIA - Abstract
Cerebral amyloid angiopathy (CAA) is the result of the deposition of an amyloidogenic protein in cortical and leptomeningeal vessels. The most common type of CAA is caused by amyloid β-protein (Aβ), which is particularly associated with Alzheimer''s disease (AD). Excessive Aβ-CAA formation can be caused by several mutations in the Aβ precursor protein and presenilin genes. The origin of Aβ in CAA is likely to be neuronal, although cerebrovascular cells or the circulation cannot be excluded as a source. Despite the apparent similarity, the pathogenesis of CAA appears to differ from that of senile plaques in several aspects, including the mechanism of Aβ-induced cellular toxicity, the extent of inflammatory reaction and the role of oxidative stress. Therefore, therapeutic strategies for AD should, at least in part, also target CAA. Moreover, CAA and cerebrovascular disease (CVD) may set a lower threshold for AD-like changes to cause dementia and may even cause dementia on its own, since patients with AD and CAA and/or CVD appear to be more cognitively impaired than patients with only AD. In conclusion, the precise impact of CAA on AD or dementia remains unclear, however, its role may have been underestimated in the past, and more extensive studies of in vitro and in vivo models for CAA will be needed to elucidate the importance of CAA-specific approaches in designing intervention strategies for AD. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
18. Heparan sulphate proteoglycans in Alzheimer's disease and amyloid-related disorders
- Author
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van Horssen, Jack, Wesseling, Pieter, van den Heuvel, Lambert PWJ, de Waal, Robert MW, Verbeek, Marcel M, van den Heuvel, Lambert P W J, and de Waal, Robert M W
- Subjects
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PROTEOGLYCANS , *ALZHEIMER'S disease , *PRESENILE dementia , *AMYLOID , *HUMAN physiology - Abstract
Proteoglycans are associated with all kinds of amyloid deposits in the human body. These complex macromolecules, in particular heparan sulphate proteoglycans, have also been implicated in several features of the pathogenesis of Alzheimer''s disease (AD), including the genesis of senile plaques, cerebrovascular amyloid, and neurofibrillary tangles. In this review we focus on the role of proteoglycans and glycosaminoglycans in amyloidogenesis in general and in AD in particular. Heparan sulphate proteoglycans may promote amyloid-β peptide (Aβ) or tau fibrillisation on the one hand, and provide resistance against proteolytic breakdown on the other. Knowledge about the role of proteoglycans in AD pathology may eventually be of therapeutic use, because small polysulphated compounds, which can interfere with the interaction between proteoglycan and Aβ, have been shown to stop or even prevent amyloidogenesis. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
19. CSF α-synuclein concentrations do not fluctuate over hours and are not correlated to amyloid β in humans
- Author
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Spies, Petra E., Slats, Diane, Olde Rikkert, Marcel G.M., Tseng, Jack, Claassen, Jurgen A.H.R., and Verbeek, Marcel M.
- Subjects
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AMYLOID , *HUMAN beings , *CEREBROSPINAL fluid , *BIOMARKERS , *LEWY body dementia , *PARKINSON'S disease , *PROTEINS - Abstract
Abstract: Reports on the value of cerebrospinal fluid (CSF) α-synuclein as a biomarker for dementia with Lewy bodies and Parkinson disease are contradicting. This may be explained by fluctuating CSF α-synuclein concentrations over time. Such fluctuations have been suggested for CSF amyloid β concentrations. Furthermore, a physiological relationship between α-synuclein and amyloid β has been suggested based on in vitro research. We performed repeated CSF sampling in healthy elderly and AD patients and showed that sinusoidal fluctuations in CSF α-synuclein concentrations were not present. Furthermore, we did not find evidence for an interaction between amyloid β and α-synuclein concentrations in CSF. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
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