Publications by authors named "Hanne Struyfs"

33 Publications

Automated MRI volumetry as a diagnostic tool for Alzheimer's disease: Validation of icobrain dm.

Neuroimage Clin 2020 12;26:102243. Epub 2020 Mar 12.

icometrix, Leuven, Belgium.

Brain volumes computed from magnetic resonance images have potential for assisting with the diagnosis of individual dementia patients, provided that they have low measurement error and high reliability. In this paper we describe and validate icobrain dm, an automatic tool that segments brain structures that are relevant for differential diagnosis of dementia, such as the hippocampi and cerebral lobes. Experiments were conducted in comparison to the widely used FreeSurfer software. The hippocampus segmentations were compared against manual segmentations, with significantly higher Dice coefficients obtained with icobrain dm (25-75th quantiles: 0.86-0.88) than with FreeSurfer (25-75th quantiles: 0.80-0.83). Other brain structures were also compared against manual delineations, with icobrain dm showing lower volumetric errors overall. Test-retest experiments show that the precision of all measurements is higher for icobrain dm than for FreeSurfer except for the parietal cortex volume. Finally, when comparing volumes obtained from Alzheimer's disease patients against age-matched healthy controls, all measures achieved high diagnostic performance levels when discriminating patients from cognitively healthy controls, with the temporal cortex volume measured by icobrain dm reaching the highest diagnostic performance level (area under the receiver operating characteristic curve = 0.99) in this dataset.
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http://dx.doi.org/10.1016/j.nicl.2020.102243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082216PMC
February 2021

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [F]THK5351 uptake in progressive supranuclear palsy.

Neuroimage Clin 2019 13;24:102091. Epub 2019 Nov 13.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, 6825 Boulevard LaSalle, Verdun, Montreal, QC H4H 1R3, Canada; Alzheimer's Disease Research Unit, Douglas Hospital, McGill University, Montreal, Canada. Electronic address:

Background: [F]THK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). However, the interpretation of [F]THK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD.

Objectives: To test the hypothesis that the MAO-B inhibitor, rasagiline reduces [F]THK5351 uptake in PSP.

Methods: Six individuals (4: PSP; 2: cognitively unimpaired, CU) underwent [F]THK5351 and [F]AZD4694 to quantify baseline tau and amyloid deposition, respectively. Following a 10-day course of 1 mg rasagiline, all participants received a post-challenge [F]THK5351 scan. The baseline and post-rasagiline challenge standardized uptake value (SUV) were generated normalized for patient weight and injected radioactivity.

Results: The post-rasagiline regional SUV was reduced on average by 69-89% in PSP, and 53-81% in CU. The distributions of post-rasagiline [F]THK5351 SUV among PSP individuals were not consistent with the typical pattern of tau aggregates in PSP.

Conclusions: Similar to AD, the interpretation of [F]THK5351 uptake in PSP is likely confounded by off-target binding to MAO-B binding sites. [F]THK5351 is not sufficient in quantifying tau aggregates in PSP using the proposed rasagiline dosing regimen.
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http://dx.doi.org/10.1016/j.nicl.2019.102091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889764PMC
September 2020

Association of short-term cognitive decline and MCI-to-AD dementia conversion with CSF, MRI, amyloid- and F-FDG-PET imaging.

Neuroimage Clin 2019 13;22:101771. Epub 2019 Mar 13.

Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium. Electronic address:

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on F-FDG SUVR. CSF measures included Aβ, Aβ, T-tau, P-tau, and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p < 0.001] and + 0.37 [p = 0.005], resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aβ burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: β = -0.28 [p = 0.020]). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters.
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http://dx.doi.org/10.1016/j.nicl.2019.101771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444289PMC
January 2020

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER).

J Alzheimers Dis 2018 ;63(4):1509-1522

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Background: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD).

Objective: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression.

Methods: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available.

Results: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment.

Conclusion: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.
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http://dx.doi.org/10.3233/JAD-171140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004934PMC
June 2019

Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease.

Authors:
Niklas Mattsson Colin Groot Willemijn J Jansen Susan M Landau Victor L Villemagne Sebastiaan Engelborghs Mark M Mintun Alberto Lleo José Luis Molinuevo William J Jagust Giovanni B Frisoni Adrian Ivanoiu Gaël Chételat Catarina Resende de Oliveira Karen M Rodrigue Johannes Kornhuber Anders Wallin Aleksandra Klimkowicz-Mrowiec Ramesh Kandimalla Julius Popp Pauline P Aalten Dag Aarsland Daniel Alcolea Ina S Almdahl Inês Baldeiras Mark A van Buchem Enrica Cavedo Kewei Chen Ann D Cohen Stefan Förster Juan Fortea Kristian S Frederiksen Yvonne Freund-Levi Kiran Dip Gill Olymbia Gkatzima Timo Grimmer Harald Hampel Sanna-Kaisa Herukka Peter Johannsen Koen van Laere Mony J de Leon Wolfgang Maier Jan Marcusson Olga Meulenbroek Hanne M Møllergård John C Morris Barbara Mroczko Arto Nordlund Sudesh Prabhakar Oliver Peters Lorena Rami Eloy Rodríguez-Rodríguez Catherine M Roe Eckart Rüther Isabel Santana Johannes Schröder Sang W Seo Hilkka Soininen Luiza Spiru Erik Stomrud Hanne Struyfs Charlotte E Teunissen Frans R J Verhey Stephanie J B Vos Linda J C van Waalwijk van Doorn Gunhild Waldemar Åsa K Wallin Jens Wiltfang Rik Vandenberghe David J Brooks Tormod Fladby Christopher C Rowe Alexander Drzezga Marcel M Verbeek Marie Sarazin David A Wolk Adam S Fleisher William E Klunk Duk L Na Pascual Sánchez-Juan Dong Young Lee Agneta Nordberg Magda Tsolaki Vincent Camus Juha O Rinne Anne M Fagan Henrik Zetterberg Kaj Blennow Gil D Rabinovici Oskar Hansson Bart N M van Berckel Wiesje M van der Flier Philip Scheltens Pieter Jelle Visser Rik Ossenkoppele

Alzheimers Dement 2018 07 28;14(7):913-924. Epub 2018 Mar 28.

Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden; Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands. Electronic address:

Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location.

Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.

Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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http://dx.doi.org/10.1016/j.jalz.2018.02.009DOI Listing
July 2018

Anosognosia predicts default mode network hypometabolism and clinical progression to dementia.

Neurology 2018 03 14;90(11):e932-e939. Epub 2018 Feb 14.

From the Translational Neuroimaging Laboratory (J.T., K.P.N., T.A.P., S.M., M.S.K., H.S., M.S., A.L.B., P.R.-N.) and Alzheimer's Disease Research Unit (K.P.N., S.G., P.R.-N.), The McGill University Research Centre for Studies in Aging, Montreal, Canada; Department of Neurology (K.P.N.), National Neuroscience Institute, Singapore; Reference Center for Biological Markers of Dementia (BIODEM) (H.S.), University of Antwerp, Belgium; Center for Mind and Brain (I.C.W.), University of Sydney, Australia; Douglas Hospital Research Centre (V.N.), Department of Psychiatry (V.N.), and Department of Neurology and Neurosurgery (P.R.-N.), McGill University; and Montreal Neurological Institute (P.R.-N.), Canada.

Objective: To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.

Methods: We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia.

Results: We found that participants with impaired awareness had lower [F]fluorodeoxyglucose uptake and increased [F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame.

Conclusions: Our results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.
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http://dx.doi.org/10.1212/WNL.0000000000005120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858945PMC
March 2018

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.

Authors:
Willemijn J Jansen Rik Ossenkoppele Betty M Tijms Anne M Fagan Oskar Hansson William E Klunk Wiesje M van der Flier Victor L Villemagne Giovanni B Frisoni Adam S Fleisher Alberto Lleó Mark A Mintun Anders Wallin Sebastiaan Engelborghs Duk L Na Gäel Chételat José Luis Molinuevo Susan M Landau Niklas Mattsson Johannes Kornhuber Osama Sabri Christopher C Rowe Lucilla Parnetti Julius Popp Tormod Fladby William J Jagust Pauline Aalten Dong Young Lee Rik Vandenberghe Catarina Resende de Oliveira Elisabeth Kapaki Lutz Froelich Adrian Ivanoiu Tomasz Gabryelewicz Marcel M Verbeek Páscual Sanchez-Juan Helmut Hildebrandt Vincent Camus Marzena Zboch David J Brooks Alexander Drzezga Juha O Rinne Andrew Newberg Alexandre de Mendonça Marie Sarazin Gil D Rabinovici Karine Madsen Milica G Kramberger Agneta Nordberg Vincent Mok Barbara Mroczko David A Wolk Philipp T Meyer Magda Tsolaki Philip Scheltens Frans R J Verhey Pieter Jelle Visser Dag Aarsland Daniel Alcolea Myriam Alexander Ina S Almdahl Steven E Arnold Inês Baldeiras Henryk Barthel Bart N M van Berckel Kaj Blennow Mark A van Buchem Enrica Cavedo Kewei Chen Elena Chipi Ann D Cohen Stefan Förster Juan Fortea Kristian S Frederiksen Yvonne Freund-Levi Olymbia Gkatzima Mark Forrest Gordon Timo Grimmer Harald Hampel Lucrezia Hausner Sabine Hellwig Sanna-Kaisa Herukka Peter Johannsen Aleksandra Klimkowicz-Mrowiec Sebastian Köhler Norman Koglin Koen van Laere Mony de Leon Viviana Lisetti Wolfgang Maier Jan Marcusson Olga Meulenbroek Hanne M Møllergård John C Morris Arto Nordlund Gerald P Novak George P Paraskevas Gayan Perera Oliver Peters Inez H G B Ramakers Lorena Rami Eloy Rodríguez-Rodríguez Catherine M Roe Uros Rot Eckart Rüther Isabel Santana Johannes Schröder Sang W Seo Hilkka Soininen Luiza Spiru Erik Stomrud Hanne Struyfs Charlotte E Teunissen Stephanie J B Vos Linda J C van Waalwijk van Doorn Gunhild Waldemar Åsa K Wallin Jens Wiltfang Henrik Zetterberg

JAMA Psychiatry 2018 01;75(1):84-95

Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.

Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.

Design, Setting, And Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.

Main Outcomes And Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.

Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.

Conclusions And Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.3391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786156PMC
January 2018

The Cerebrospinal Fluid Aβ1-42/Aβ1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting.

J Alzheimers Dis 2017 ;60(2):561-576

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, UAntwerp, Antwerp, Belgium.

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone.

Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting.

Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181).

Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.
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http://dx.doi.org/10.3233/JAD-170327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611891PMC
April 2018

Multicenter Analytical Validation of Aβ40 Immunoassays.

Front Neurol 2017 3;8:310. Epub 2017 Jul 3.

Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, VU University Medical Center, Neurocampus, Amsterdam, Netherlands.

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.
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http://dx.doi.org/10.3389/fneur.2017.00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497061PMC
July 2017

No added diagnostic value of non-phosphorylated tau fraction (p-tau) in CSF as a biomarker for differential dementia diagnosis.

Alzheimers Res Ther 2017 Jul 14;9(1):49. Epub 2017 Jul 14.

Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

Background: The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ, t-tau, and p-tau overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-tau), may improve differential dementia diagnosis. The goal of this study is to investigate if p-tau can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis.

Methods: The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ, t-tau, p-tau, and p-tau were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests.

Results: The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-tau to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-tau increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-tau when differentiating between AD or non-AD dementias and controls.

Conclusions: The addition of p-tau to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.
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http://dx.doi.org/10.1186/s13195-017-0275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513364PMC
July 2017

Consensus guidelines for lumbar puncture in patients with neurological diseases.

Alzheimers Dement (Amst) 2017 18;8:111-126. Epub 2017 May 18.

Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

Introduction: Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain.

Methods: We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III).

Results: Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications.

Discussion: When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.
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http://dx.doi.org/10.1016/j.dadm.2017.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454085PMC
May 2017

Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment.

Alzheimers Dement 2017 Mar 27;13(3):285-295. Epub 2016 Oct 27.

Danish Dementia Research Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Electronic address:

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.
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http://dx.doi.org/10.1016/j.jalz.2016.09.009DOI Listing
March 2017

Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia.

Alzheimers Dement 2017 Mar 27;13(3):274-284. Epub 2016 Oct 27.

Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.
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http://dx.doi.org/10.1016/j.jalz.2016.09.008DOI Listing
March 2017

Validation of the Semiquantitative Static SUVR Method for F-AV45 PET by Pharmacokinetic Modeling with an Arterial Input Function.

J Nucl Med 2017 09 23;58(9):1483-1489. Epub 2017 Mar 23.

Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium

Increased brain uptake of F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (V) to assess cross-sectional differences in plaque load. Dynamic 60-min F-AV45 (291 ± 67 MBq) and 1-min O-HO (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). F-AV45 V was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min after injection, using either cerebellar gray matter (SUVR) or whole subcortical white matter (SUVR) as the reference. Additionally, whole cerebellum, pons, centrum semiovale, and a composite region were examined as alternative references. Blood flow was quantified by O-HO SUV. Data are presented as mean ± SEM. There was rapid metabolization of F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with V, differences in cortical Aβ load between aMCI and AD were overestimated by SUVR (+4% ± 2%) and underestimated by SUVR (-10% ± 2%). V correlated better with SUVR (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, < 0.0001) than with SUVR (Pearson r: from 0.51 for temporal lobe [ = 0.002] to 0.82 for precuneus [ < 0.0001]) in all tested regions. Correlation results for the alternative references were in between those for CB and WM. O-HO data showed that blood flow was decreased in AD compared with aMCI in cortical regions (-5% ± 1%) and in the reference regions (CB, -9% ± 8%; WM, -8% ± 8%). Increased brain uptake of F-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVR is better correlated with V and more closely reflects V differences between aMCI and AD than SUVR.
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http://dx.doi.org/10.2967/jnumed.116.184481DOI Listing
September 2017

EEG Dominant Frequency Peak Differentiates Between Alzheimer's Disease and Frontotemporal Lobar Degeneration.

J Alzheimers Dis 2017 ;55(1):53-58

Center for Neurosciences, Vrije Universiteit Brussel, Brussel, Belgium.

We investigated the power of EEG as biomarker in differential diagnosis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). EEG was recorded from 106 patients with AD or FTLD, of which 37 had a definite diagnosis, and 40 controls. Dominant frequency peaks were extracted for all 19 channels, for each subject. The average frequency of the largest dominant frequency peaks (maxpeak) was significantly lower in AD than FTLD patients and controls. Based on ROC analysis, classification could be made with diagnostic accuracy of 78.9%. Our findings show that quantitative analysis of EEG maxpeak frequency is an easy and useful measure for differential dementia diagnosis.
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http://dx.doi.org/10.3233/JAD-160188DOI Listing
February 2018

A Decade of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Belgium.

J Alzheimers Dis 2016 08;54(1):383-95

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer's disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.
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http://dx.doi.org/10.3233/JAD-151097DOI Listing
August 2016

The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer's Disease.

J Alzheimers Dis 2016 07;53(4):1523-38

ADx NeuroSciences NV, Technologiepark Zwijnaarde 4, 9052 Gent, Belgium.

Background: In diagnosing Alzheimer's disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42/tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers.

Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42, Aβ1-40, and Aβ1-38. All six analytes were considered as single parameters as well as ratios.

Methods: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinical and neuropsychological (MMSE) examinations for at least one year.

Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio.

Conclusion: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline.
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http://dx.doi.org/10.3233/JAD-160227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981899PMC
July 2016

Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study.

J Alzheimers Dis 2016 04;52(4):1321-33

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.

MicroRNAs (miRNAs) regulate translational inhibition of proteins, but are also detected in body fluids, including cerebrospinal fluid (CSF), where they may serve as disease-specific biomarkers. Previously, we showed differential expression of miR-146a, miR-29a, and miR-125b in the CSF of Alzheimer's disease (AD) patients versus controls. In this study, we aim to confirm these findings by using larger, independent sample cohorts of AD patients and controls from three different centers. Furthermore, we aim to identify confounding factors that possibly arise using such a multicenter approach. The study was extended by including patients diagnosed with mild cognitive impairment due to AD, frontotemporal dementia and dementia with Lewy bodies. Previous results of decreased miR-146a levels in AD patients compared to controls were confirmed in one center. When samples from all three centers were combined, several confounding factors were identified. After controlling for these factors, we did not identify differences in miRNA levels between the different groups. However, we provide suggestions to circumvent various pitfalls when measuring miRNAs in CSF to improve future studies.
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http://dx.doi.org/10.3233/JAD-160038DOI Listing
April 2016

sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers.

EMBO Mol Med 2016 05 2;8(5):466-76. Epub 2016 May 2.

BioMedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss-of-function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type-1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross-sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non-AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho-tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.
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http://dx.doi.org/10.15252/emmm.201506123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120370PMC
May 2016

Diagnostic Impact of Cerebrospinal Fluid Biomarker (Pre-)Analytical Variability in Alzheimer's Disease.

J Alzheimers Dis 2016 ;51(1):97-106

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer's disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau(181P) >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between -20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.
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http://dx.doi.org/10.3233/JAD-150953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927863PMC
December 2016

Validation of soluble amyloid-β precursor protein assays as diagnostic CSF biomarkers for neurodegenerative diseases.

J Neurochem 2016 Apr 24;137(1):112-21. Epub 2016 Jan 24.

Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.

Analytical validation of a biomarker assay is essential before implementation in clinical practice can occur. In this study, we analytically validated the performance of assays detecting soluble amyloid-β precursor protein (sAPP) α and β in CSF in two laboratories according to previously standard operating procedures serving this goal. sAPPα and sAPPβ ELISA assays from two vendors (IBL-international, Meso Scale Diagnostics) were validated. The performance parameters included precision, sensitivity, dilutional linearity, recovery, and parallelism. Inter-laboratory variation, biomarker comparison (sAPPα vs. sAPPβ) and clinical performance was determined in three laboratories using 60 samples of patients with subjective memory complaints, Alzheimer's disease, or frontotemporal dementia. All performance parameters of the assays were similar between labs and within predefined acceptance criteria. The only exceptions were minor out-of-range results for recovery at low concentrations and, despite being within predefined acceptance criteria, non-comparability of the results for evaluation of the dilutional linearity and hook-effect. Based on the inter-laboratory correlation between Lab #1 and Lab #2, the IBL-international assays were more robust (sAPPα: r(2) = 0.92, sAPPβ: r(2) = 0.94) than the Meso Scale Diagnostics (MSD) assay (sAPPα: r(2) = 0.70, sAPPβ: r(2) = 0.80). Specificity of assays was confirmed using assay-specific peptide competitors. Clinical validation showed consistent results across the clinical groups in the different laboratories for all assays. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, the study shows that the newly developed standard operating procedures provide highly useful tools for the validation of new biomarker assays. A recommendation was made for renewed instructions to evaluate the dilutional linearity and hook-effect. We analytically validated the performance of assays detecting soluble amyloid-β precursor protein (sAPP) α and β in CSF according to SOPs in agreement with ISO15189 guidelines. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, this study proofs that the newly developed SOPs, with a minor modification, provide highly useful tools for the validation of new biomarker assays.
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http://dx.doi.org/10.1111/jnc.13527DOI Listing
April 2016

Diffusion Kurtosis Imaging: A Possible MRI Biomarker for AD Diagnosis?

J Alzheimers Dis 2015 ;48(4):937-48

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

The purpose of this explorative study was to investigate whether diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) parameter changes are reliable measures of white matter integrity changes in Alzheimer's disease (AD) patients using a whole brain voxel-based analysis (VBA). Therefore, age- and gender-matched patients with mild cognitive impairment (MCI) due to AD (n = 18), dementia due to AD (n = 19), and age-matched cognitively healthy controls (n = 14) were prospectively included. The magnetic resonance imaging protocol included routine structural brain imaging and DKI. Datasets were transformed to a population-specific atlas space. Groups were compared using VBA. Differences in diffusion and mean kurtosis measures between MCI and AD patients and controls were shown, and were mainly found in the splenium of the corpus callosum and the corona radiata. Hence, DTI and DKI parameter changes are suggestive of white matter changes in AD.
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http://dx.doi.org/10.3233/JAD-150253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927852PMC
August 2016

Performance and complications of lumbar puncture in memory clinics: Results of the multicenter lumbar puncture feasibility study.

Alzheimers Dement 2016 Feb 11;12(2):154-163. Epub 2015 Sep 11.

Department of Clinical Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal Sweden.

Introduction: Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations.

Methods: We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain.

Results: A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect.

Discussions: The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
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http://dx.doi.org/10.1016/j.jalz.2015.08.003DOI Listing
February 2016

Cerebrospinal Fluid P-Tau181P: Biomarker for Improved Differential Dementia Diagnosis.

Front Neurol 2015 17;6:138. Epub 2015 Jun 17.

Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp , Antwerp , Belgium ; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken , Antwerp , Belgium.

The goal of this study is to investigate the value of tau phosphorylated at threonine 181 (P-tau181P) in the Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker panel for differential dementia diagnosis in autopsy confirmed AD and non-AD patients. The study population consisted of 140 autopsy confirmed AD and 77 autopsy confirmed non-AD dementia patients. CSF concentrations of amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and P-tau181P were determined with single analyte ELISA-kits (INNOTEST(®), Fujirebio, Ghent, Belgium). Diagnostic accuracy was assessed through receiver operating characteristic (ROC) curve analyses to obtain area under the curve (AUC) values and to define optimal cutoff values to discriminate AD from pooled and individual non-AD groups. ROC curve analyses were only performed on biomarkers and ratios that differed significantly between the groups. Pairwise comparison of AUC values was performed by means of DeLong tests. The Aβ1-42/P-tau181P ratio (AUC = 0.770) performed significantly better than Aβ1-42 (AUC = 0.677, P = 0.004), T-tau (AUC = 0.592, P < 0.001), and Aβ1-42/T-tau (AUC = 0.678, P = 0.001), while P-tau181P (AUC = 0.720) performed significantly better than T-tau (AUC = 0.592, P < 0.001) to discriminate between AD and the pooled non-AD group. When comparing AD and the individual non-AD diagnoses, Aβ1-42/P-tau181P (AUC = 0.894) discriminated AD from frontotemporal dementia significantly better than Aβ1-42 (AUC = 0.776, P = 0.020) and T-tau (AUC = 0.746, P = 0.004), while P-tau181P/T-tau (AUC = 0.958) significantly improved the differentiation between AD and Creutzfeldt-Jakob disease as compared to Aβ1-42 (AUC = 0.688, P = 0.004), T-tau (AUC = 0.874, P = 0.040), and Aβ1-42/P-tau181P (AUC = 0.760, P = 0.003). In conclusion, this study demonstrates P-tau181P is an essential component of the AD CSF biomarker panel, and combined assessment of Aβ1-42, T-tau, and P-tau181P renders, to present date, the highest diagnostic power to discriminate between AD and non-AD dementias.
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http://dx.doi.org/10.3389/fneur.2015.00138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470274PMC
July 2015

Validation of a quantitative cerebrospinal fluid alpha-synuclein assay in a European-wide interlaboratory study.

Neurobiol Aging 2015 Sep 15;36(9):2587-96. Epub 2015 May 15.

Department of Neuropathology, University Medical Center, Göttingen, Germany; Paracelsus-Elena-Klinik, Kassel, Germany; Department of Neurosurgery, University Medical Center, Göttingen, Germany.

Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program - Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.05.003DOI Listing
September 2015

C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer's disease.

Alzheimers Dement 2015 Dec 16;11(12):1461-1469. Epub 2015 Jun 16.

Department of Research, ADx NeuroSciences, Ghent, Belgium. Electronic address:

Introduction: Biomarkers monitoring synaptic degeneration/loss would be valuable for Alzheimer's disease (AD) diagnosis. Postsynaptic protein neurogranin may be a promising cerebrospinal fluid (CSF) biomarker but has not yet been evaluated as a plasma biomarker.

Methods: Using an in-house designed prototype enzyme-linked immunosorbent assay (ELISA) targeting neurogranin C-terminally, we studied neurogranin in paired CSF/plasma samples of controls (n = 29) versus patients experiencing MCI, or dementia, due to AD (in total n = 59).

Results: CSF neurogranin was increased in AD and positively correlated with CSF tau, whereas there was a negative relationship between CSF neurogranin (and tau) and CSF Aβ1-42/Aβ1-40. No differences were detected in plasma neurogranin between controls and AD. Also, there was no correlation between CSF and plasma neurogranin, excluding confounding effects of the latter.

Discussion: This study strengthens the potential of neurogranin as an AD CSF biomarker, which now needs validation in larger studies. As tools, straightforward immunoassays can be used, as demonstrated by the described ELISA.
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http://dx.doi.org/10.1016/j.jalz.2015.05.012DOI Listing
December 2015

A 22-single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ42.

Alzheimers Dement 2015 Dec 15;11(12):1452-1460. Epub 2015 Jun 15.

Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

Introduction: The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making.

Methods: We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci for AD in 1162 Flanders-Belgian AD patients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (Aβ1-42, T-Tau, P-Tau181P).

Results: A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE ε4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08-2.58 per unit; P < 1.0e(-15)). Onset age and CSF Aβ1-42 decreased with increasing GRS (Ponset_age = 9.0e(-11); PAβ = 8.9e(-7)).

Discussion: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility.
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http://dx.doi.org/10.1016/j.jalz.2015.02.013DOI Listing
December 2015

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

Authors:
Willemijn J Jansen Rik Ossenkoppele Dirk L Knol Betty M Tijms Philip Scheltens Frans R J Verhey Pieter Jelle Visser Pauline Aalten Dag Aarsland Daniel Alcolea Myriam Alexander Ina S Almdahl Steven E Arnold Inês Baldeiras Henryk Barthel Bart N M van Berckel Kristen Bibeau Kaj Blennow David J Brooks Mark A van Buchem Vincent Camus Enrica Cavedo Kewei Chen Gael Chetelat Ann D Cohen Alexander Drzezga Sebastiaan Engelborghs Anne M Fagan Tormod Fladby Adam S Fleisher Wiesje M van der Flier Lisa Ford Stefan Förster Juan Fortea Nadia Foskett Kristian S Frederiksen Yvonne Freund-Levi Giovanni B Frisoni Lutz Froelich Tomasz Gabryelewicz Kiran Dip Gill Olymbia Gkatzima Estrella Gómez-Tortosa Mark Forrest Gordon Timo Grimmer Harald Hampel Lucrezia Hausner Sabine Hellwig Sanna-Kaisa Herukka Helmut Hildebrandt Lianna Ishihara Adrian Ivanoiu William J Jagust Peter Johannsen Ramesh Kandimalla Elisabeth Kapaki Aleksandra Klimkowicz-Mrowiec William E Klunk Sebastian Köhler Norman Koglin Johannes Kornhuber Milica G Kramberger Koen Van Laere Susan M Landau Dong Young Lee Mony de Leon Viviana Lisetti Alberto Lleó Karine Madsen Wolfgang Maier Jan Marcusson Niklas Mattsson Alexandre de Mendonça Olga Meulenbroek Philipp T Meyer Mark A Mintun Vincent Mok José Luis Molinuevo Hanne M Møllergård John C Morris Barbara Mroczko Stefan Van der Mussele Duk L Na Andrew Newberg Agneta Nordberg Arto Nordlund Gerald P Novak George P Paraskevas Lucilla Parnetti Gayan Perera Oliver Peters Julius Popp Sudesh Prabhakar Gil D Rabinovici Inez H G B Ramakers Lorena Rami Catarina Resende de Oliveira Juha O Rinne Karen M Rodrigue Eloy Rodríguez-Rodríguez Catherine M Roe Uros Rot Christopher C Rowe Eckart Rüther Osama Sabri Páscual Sanchez-Juan Isabel Santana Marie Sarazin Johannes Schröder Christin Schütte Sang W Seo Femke Soetewey Hilkka Soininen Luiza Spiru Hanne Struyfs Charlotte E Teunissen Magda Tsolaki Rik Vandenberghe Marcel M Verbeek Victor L Villemagne Stephanie J B Vos Linda J C van Waalwijk van Doorn Gunhild Waldemar Anders Wallin Åsa K Wallin Jens Wiltfang David A Wolk Marzena Zboch Henrik Zetterberg

JAMA 2015 May;313(19):1924-38

Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden87UCL Institute of Neurology, Queen Square, London, United Kingdom.

Importance: Cerebral amyloid-β 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-ε4 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 ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 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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http://dx.doi.org/10.1001/jama.2015.4668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486209PMC
May 2015

Diagnostic Accuracy of Cerebrospinal Fluid Amyloid-β Isoforms for Early and Differential Dementia Diagnosis.

J Alzheimers Dis 2015 ;45(3):813-22

Reference Center for Biological Markers of Dementia (BIODEM), and Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.

Background: Overlapping cerebrospinal fluid biomarkers (CSF) levels between Alzheimer's disease (AD) and non-AD patients decrease differential diagnostic accuracy of the AD core CSF biomarkers. Amyloid-β (Aβ) isoforms might improve the AD versus non-AD differential diagnosis.

Objective: To determine the added diagnostic value of Aβ isoforms, Aβ(1-37), Aβ(1-38), and Aβ(1-40), as compared to the AD CSF biomarkers Aβ(1-42), T-tau, and P-tau(181P).

Methods: CSF from patients with dementia due to AD (n = 50), non-AD dementias (n = 50), mild cognitive impairment due to AD (n = 50) and non-demented controls (n = 50) was analyzed with a prototype multiplex assay using MSD detection technology. The non-AD group consisted of frontotemporal dementia (FTD; n = 17), dementia with Lewy bodies (DLB; n = 17), and vascular dementia (n = 16).

Results: Aβ(1-37) and Aβ(1-38) increased accuracy to differentiate AD from FTD or DLB. Aβ(1-37), Aβ(1-38), and Aβ(1-40) levels correlated with Mini-Mental State Examination scores and disease duration in dementia due to AD. The Aβ(1-42)/Aβ(1-40) ratio improved diagnostic performance of Aβ(1-42) in most differential diagnostic situations. Aβ(1-42) levels were lower in APOE ε4 carriers compared to non-carriers.

Conclusions: Aβ isoforms help to differentiate AD from FTD and DLB. Aβ isoforms increase diagnostic performance of Aβ(1-42). In contrast to Aβ1-42, Aβ isoforms seem to be correlated with disease severity in AD. Adding the Aβ isoforms to the current biomarker panel could enhance diagnostic accuracy.
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http://dx.doi.org/10.3233/JAD-141986DOI Listing
January 2016

Association of cerebrospinal fluid prion protein levels and the distinction between Alzheimer disease and Creutzfeldt-Jakob disease.

JAMA Neurol 2015 Mar;72(3):267-75

Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Biochemistry, Neurochemistry Unit, Lyon, France6Lyon 1 University, Lyon Neuroscience Research Center, Bron Cedex, France.

Importance: Although typical forms of Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are clinically distinguishable, atypical AD phenotypes may pose a diagnostic challenge. The major biological diagnostic biomarker for identifying CJD, 14-3-3 protein in cerebrospinal fluid (CSF), unfortunately lacks specificity when confronting a rapid dementia presentation.

Objective: To assess the relevance of total CSF prion protein (t-PrP) levels in the differential biological diagnosis between atypical AD phenotypes and CJD.

Design, Setting, And Participants: A retrospective study in an autopsy-confirmed cohort of 82 patients was performed to evaluate the relevance of CSF t-PrP to distinguish 30 definite cases of AD from 52 definite cases of CJD. Next, CSF t-PrP concentration was measured in a cohort of 104 patients including 55 patients with probable AD, 26 with probable sporadic CJD, and 23 control patients for whom 14-3-3 protein, total tau, phosphorylated tau 181 (P-tau181), and Aβ1-42 were available. We investigated 46 patients diagnosed as having probable AD who presented atypical phenotypes. A diagnosis strategy was proposed to classify atypical AD phenotypes with suspicion of CJD based on a decision tree combining CSF biomarkers.

Main Outcomes And Measures: We determined CSF t-PrP levels for all patients. We calculated the ratio of total tau and P-tau181 and determined the diagnostic accuracy of each biomarker alone or in combination. We calculated the misclassification rate for each biomarker that corresponded to the percentage of patients within the group of atypical AD phenotypes wrongly classified as CJD.

Results: In patients with CJD, CSF t-PrP concentrations were decreased compared with control participants and patients with AD. When considering the differential diagnosis of CJD compared with atypical AD phenotypes, CSF t-PrP determination reached 82.1% sensitivity and 91.3% specificity. The misclassification rate of atypical AD phenotypes decreased from 43.5%, obtained when using the CSF 14-3-3 protein determination alone, to only 4.3% when calculating the ratio total tau/(P-tau181 × t-PrP). The proposed classification tree permitted correct classification of 98.4% of the patients.

Conclusions And Relevance: For unusual phenotypes of AD, especially cases presenting with a biological ambiguity suggesting CJD, determination of CSF t-PrP levels increased diagnostic accuracy. The use of CSF t-PrP levels may be beneficial in clinical practice in addition to the current classic biomarkers.
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http://dx.doi.org/10.1001/jamaneurol.2014.4068DOI Listing
March 2015