%0 Journal Article %J J Alzheimers Dis %D 2022 %T Improved Alzheimer's Disease versus Frontotemporal Lobar Degeneration Differential Diagnosis Combining EEG and Neurochemical Biomarkers: A Pilot Study. %A Laton, Jorne %A Van Schependom, Jeroen %A Goossens, Joery %A Wiels, Wietse %A Sieben, Anne %A De Deyn, Peter Paul %A Goeman, Johan %A Streffer, Johannes %A van der Zee, Julie %A Martin, Jean-Jacques %A Van Broeckhoven, Christine %A De Vos, Maarten %A Bjerke, Maria %A Nagels, Guy %A Engelborghs, Sebastiaan %X

BACKGROUND: Distinguishing between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy.

OBJECTIVE: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis.

METHODS: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42, T-tau, P-tau181, and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG).

RESULTS: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95% . Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD.

CONCLUSION: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools.

%B J Alzheimers Dis %V 90 %P 1739-1747 %8 2022 Dec 06 %G eng %N 4 %R 10.3233/JAD-220693 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus. %A Lukkarinen, Heikki %A Tesseur, Ina %A Pemberton, Darrel %A van der Ark, Peter %A Timmers, Maarten %A Slemmon, Randy %A Janssens, Luc %A Streffer, Johannes %A Van Nueten, Luc %A Bottelbergs, Astrid %A Rauramaa, Tuomas %A Koivisto, Anne M %A Herukka, Sanna-Kaisa %A Korhonen, Ville E %A Junkkari, Antti %A Hiltunen, Mikko %A Engelborghs, Sebastiaan %A Blennow, Kaj %A Zetterberg, Henrik %A Kolb, Hartmuth C %A Leinonen, Ville %X

BACKGROUND: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.

OBJECTIVE: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.

METHODS: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.

RESULTS: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p <  0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.

CONCLUSION: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

%B J Alzheimers Dis %V 80 %P 1629-1642 %8 2021 Apr 20 %G eng %N 4 %R 10.3233/JAD-201361 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology. %A Shi, Liu %A Winchester, Laura M %A Liu, Benjamine Y %A Killick, Richard %A Ribe, Elena M %A Westwood, Sarah %A Baird, Alison L %A Buckley, Noel J %A Hong, Shengjun %A Dobricic, Valerija %A Kilpert, Fabian %A Franke, Andre %A Kiddle, Steven %A Sattlecker, Martina %A Dobson, Richard %A Cuadrado, Antonio %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Ten Kate, Mara %A Scheltens, Philip %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Alcolea, Daniel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Teunissen, Charlotte E %A Freund-Levi, Yvonne %A Frölich, Lutz %A Legido-Quigley, Cristina %A Barkhof, Frederik %A Blennow, Kaj %A Rasmussen, Katrine Laura %A Nordestgaard, Børge Grønne %A Frikke-Schmidt, Ruth %A Nielsen, Sune Fallgaard %A Soininen, Hilkka %A Vellas, Bruno %A Kloszewska, Iwona %A Mecocci, Patrizia %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Bertram, Lars %A Nevado-Holgado, Alejo J %A Lovestone, Simon %X

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.

OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.

METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).

RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.

CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

%B J Alzheimers Dis %V 77 %P 1353-1368 %8 2020 Sep 29 %G eng %N 3 %R 10.3233/JAD-200208 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort. %A Westwood, Sarah %A Baird, Alison L %A Anand, Sneha N %A Nevado-Holgado, Alejo J %A Kormilitzin, Andrey %A Shi, Liu %A Hye, Abdul %A Ashton, Nicholas J %A Morgan, Angharad R %A Bos, Isabelle %A Vos, Stephanie J B %A Baker, Susan %A Buckley, Noel J %A Ten Kate, Mara %A Scheltens, Philip %A Teunissen, Charlotte E %A Vandenberghe, Rik %A Gabel, Silvy %A Meersmans, Karen %A Engelborghs, Sebastiaan %A De Roeck, Ellen E %A Sleegers, Kristel %A Frisoni, Giovanni B %A Blin, Olivier %A Richardson, Jill C %A Bordet, Régis %A Molinuevo, José L %A Rami, Lorena %A Wallin, Anders %A Kettunen, Petronella %A Tsolaki, Magda %A Verhey, Frans %A Lleo, Alberto %A Sala, Isabel %A Popp, Julius %A Peyratout, Gwendoline %A Martínez-Lage, Pablo %A Tainta, Mikel %A Johannsen, Peter %A Freund-Levi, Yvonne %A Frölich, Lutz %A Dobricic, Valerija %A Legido-Quigley, Cristina %A Bertram, Lars %A Barkhof, Frederik %A Zetterberg, Henrik %A Morgan, B Paul %A Streffer, Johannes %A Visser, Pieter Jelle %A Lovestone, Simon %X

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

%B J Alzheimers Dis %V 74 %P 213-225 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985466?dopt=Abstract %R 10.3233/JAD-190434 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Added Diagnostic Value of Cerebrospinal Fluid Biomarkers for Differential Dementia Diagnosis in an Autopsy-Confirmed Cohort. %A Niemantsverdriet, Ellis %A Feyen, Bart F E %A Le Bastard, Nathalie %A Martin, Jean-Jacques %A Goeman, Johan %A De Deyn, Peter Paul %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

BACKGROUND: Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt.

OBJECTIVE: Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis.

METHODS: Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42, T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses.

RESULTS: Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively.

CONCLUSION: AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses.

%B J Alzheimers Dis %V 63 %P 373-381 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614653?dopt=Abstract %R 10.3233/JAD-170927 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid Biomarkers for Early and Differential Alzheimer's Disease Diagnosis. %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

An accurate and early diagnosis of Alzheimer's disease (AD) is important to select optimal patient care and is critical in current clinical trials targeting core AD neuropathological features. The past decades, much progress has been made in the development and validation of cerebrospinal fluid (CSF) biomarkers for the biochemical diagnosis of AD, including standardization and harmonization of (pre-) analytical procedures. This has resulted in three core CSF biomarkers for AD diagnostics, namely the 42 amino acid long amyloid-beta peptide (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181). These biomarkers have been incorporated into research diagnostic criteria for AD and have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnoses. The implementation of the CSF Aβ1-42/Aβ1-40 ratio in the core biomarker panel will improve the biomarker analytical variability, and will also improve early and differential AD diagnosis through a more accurate reflection of pathology. Numerous biomarkers are being investigated for their added value to the core AD biomarkers, aiming at the AD core pathological features like the amyloid mismetabolism, tau pathology, or synaptic or neuronal degeneration. Others aim at non-AD neurodegenerative, vascular or inflammatory hallmarks. Biomarkers are essential for an accurate identification of preclinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, a biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future.

%B J Alzheimers Dis %V 62 %P 1199-1209 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562530?dopt=Abstract %R 10.3233/JAD-170680 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER). %A Niemantsverdriet, Ellis %A Ribbens, Annemie %A Bastin, Christine %A Benoit, Florence %A Bergmans, Bruno %A Bier, Jean-Christophe %A Bladt, Roxanne %A Claes, Lene %A De Deyn, Peter Paul %A Deryck, Olivier %A Hanseeuw, Bernard %A Ivanoiu, Adrian %A Lemper, Jean-Claude %A Mormont, Eric %A Picard, Gaëtane %A Salmon, Eric %A Segers, Kurt %A Sieben, Anne %A Smeets, Dirk %A Struyfs, Hanne %A Thiery, Evert %A Tournoy, Jos %A Triau, Eric %A Vanbinst, Anne-Marie %A Versijpt, Jan %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

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.

%B J Alzheimers Dis %V 63 %P 1509-1522 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29782314?dopt=Abstract %R 10.3233/JAD-171140 %0 Journal Article %J J Alzheimers Dis %D 2017 %T BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants. %A Timmers, Maarten %A Barão, Soraia %A Van Broeck, Bianca %A Tesseur, Ina %A Slemmon, John %A de Waepenaert, Katja %A Bogert, Jennifer %A Shaw, Leslie M %A Engelborghs, Sebastiaan %A Moechars, Dieder %A Mercken, Marc %A Van Nueten, Luc %A Tritsmans, Luc %A De Strooper, Bart %A Streffer, Johannes Rolf %X

The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aβ1 - 42. As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials.

%B J Alzheimers Dis %V 56 %P 1437-1449 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28157093?dopt=Abstract %R 10.3233/JAD-160829 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Cerebrospinal Fluid Aβ1-42/Aβ1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting. %A Niemantsverdriet, Ellis %A Ottoy, Julie %A Somers, Charisse %A De Roeck, Ellen %A Struyfs, Hanne %A Soetewey, Femke %A Verhaeghe, Jeroen %A Van den Bossche, Tobi %A Van Mossevelde, Sara %A Goeman, Johan %A De Deyn, Peter Paul %A Mariën, Peter %A Versijpt, Jan %A Sleegers, Kristel %A Van Broeckhoven, Christine %A Wyffels, Leonie %A Albert, Adrien %A Ceyssens, Sarah %A Stroobants, Sigrid %A Staelens, Steven %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

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.

%B J Alzheimers Dis %V 60 %P 561-576 %8 2017 %G eng %N 2 %R 10.3233/JAD-170327 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team. %A Arnerić, Stephen P %A Batrla-Utermann, Richard %A Beckett, Laurel %A Bittner, Tobias %A Blennow, Kaj %A Carter, Leslie %A Dean, Robert %A Engelborghs, Sebastiaan %A Genius, Just %A Gordon, Mark Forrest %A Hitchcock, Janice %A Kaplow, June %A Luthman, Johan %A Meibach, Richard %A Raunig, David %A Romero, Klaus %A Samtani, Mahesh N %A Savage, Mary %A Shaw, Leslie %A Stephenson, Diane %A Umek, Robert M %A Vanderstichele, Hugo %A Willis, Brian %A Yule, Susan %X

Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

%B J Alzheimers Dis %V 55 %P 19-35 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662307?dopt=Abstract %R 10.3233/JAD-160573 %0 Journal Article %J J Alzheimers Dis %D 2017 %T EEG Dominant Frequency Peak Differentiates Between Alzheimer's Disease and Frontotemporal Lobar Degeneration. %A Goossens, Joery %A Laton, Jorne %A Van Schependom, Jeroen %A Gielen, Jeroen %A Struyfs, Hanne %A Van Mossevelde, Sara %A Van den Bossche, Tobi %A Goeman, Johan %A De Deyn, Peter Paul %A Sieben, Anne %A Martin, Jean-Jacques %A Van Broeckhoven, Christine %A van der Zee, Julie %A Engelborghs, Sebastiaan %A Nagels, Guy %X

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.

%B J Alzheimers Dis %V 55 %P 53-58 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636837?dopt=Abstract %R 10.3233/JAD-160188 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Neutrophil Gelatinase-Associated Lipocalin and its Receptors in Alzheimer's Disease (AD) Brain Regions: Differential Findings in AD with and without Depression. %A Dekens, Doortje W %A Naudé, Petrus J W %A Engelborghs, Sebastiaan %A Vermeiren, Yannick %A Van Dam, Debby %A Oude Voshaar, Richard C %A Eisel, Ulrich L M %A De Deyn, Peter P %X

Co-existing depression worsens Alzheimer's disease (AD) pathology. Neutrophil gelatinase-associated lipocalin (NGAL) is a newly identified (neuro)inflammatory mediator in the pathophysiologies of both AD and depression. This study aimed to compare NGAL levels in healthy controls, AD without depression (AD-D), and AD with co-existing depression (AD+D) patients. Protein levels of NGAL and its receptors, 24p3R and megalin, were assessed in nine brain regions from healthy controls (n = 19), AD-D (n = 19), and AD+D (n = 21) patients. NGAL levels in AD-D patients were significantly increased in brain regions commonly associated with AD. In the hippocampus, NGAL levels were even further increased in AD+D subjects. Unexpectedly, NGAL levels in the prefrontal cortex of AD+D patients were comparable to those in controls. Megalin levels were increased in BA11 and amygdala of AD+D patients, while no changes in 24p3R were detected. These findings indicate significant differences in neuroimmunological regulation between AD patients with and without co-existing depression. Considering its known effects, elevated NGAL levels might actively promote neuropathological processes in AD with and without depression.

%B J Alzheimers Dis %V 55 %P 763-776 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716662?dopt=Abstract %R 10.3233/JAD-160330 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization. %A Lewczuk, Piotr %A Lelental, Natalia %A Lachmann, Ingolf %A Holzer, Max %A Flach, Katharina %A Brandner, Sebastian %A Engelborghs, Sebastiaan %A Teunissen, Charlotte E %A Zetterberg, Henrik %A Molinuevo, José Luis %A Mroczko, Barbara %A Blennow, Kaj %A Popp, Julius %A Parnetti, Lucilla %A Chiasserini, Davide %A Perret-Liaudet, Armand %A Spitzer, Philipp %A Maler, Juan Manuel %A Kornhuber, Johannes %X

BACKGROUND: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF).

OBJECTIVE: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF.

METHODS: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method.

RESULTS: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively.

CONCLUSION: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.

%B J Alzheimers Dis %V 55 %P 159-170 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662295?dopt=Abstract %R 10.3233/JAD-160448 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer's Disease. %A De Vos, Ann %A Struyfs, Hanne %A Jacobs, Dirk %A Fransen, Erik %A Klewansky, Tom %A De Roeck, Ellen %A Robberecht, Caroline %A Van Broeckhoven, Christine %A Duyckaerts, Charles %A Engelborghs, Sebastiaan %A Vanmechelen, Eugeen %X

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.

%B J Alzheimers Dis %V 53 %P 1523-38 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392859?dopt=Abstract %R 10.3233/JAD-160227 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics. %A Lelental, Natalia %A Brandner, Sebastian %A Kofanova, Olga %A Blennow, Kaj %A Zetterberg, Henrik %A Andreasson, Ulf %A Engelborghs, Sebastiaan %A Mroczko, Barbara %A Gabryelewicz, Tomasz %A Teunissen, Charlotte %A Mollenhauer, Brit %A Parnetti, Lucilla %A Chiasserini, Davide %A Molinuevo, José Luis %A Perret-Liaudet, Armand %A Verbeek, Marcel M %A Andreasen, Niels %A Brosseron, Frederic %A Bahl, Justyna M C %A Herukka, Sanna-Kaisa %A Hausner, Lucrezia %A Frölich, Lutz %A Labonte, Anne %A Poirier, Judes %A Miller, Anne-Marie %A Zilka, Norbert %A Kovacech, Branislav %A Urbani, Andrea %A Suardi, Silvia %A Oliveira, Catarina %A Baldeiras, Ines %A Dubois, Bruno %A Rot, Uros %A Lehmann, Sylvain %A Skinningsrud, Anders %A Betsou, Fay %A Wiltfang, Jens %A Gkatzima, Olymbia %A Winblad, Bengt %A Buchfelder, Michael %A Kornhuber, Johannes %A Lewczuk, Piotr %K Amyloid beta-Peptides %K Animals %K Anti-Bacterial Agents %K Biomarkers %K Cattle %K Clinical Chemistry Tests %K Dementia %K Humans %K Peptide Fragments %K Quality Control %K Reference Standards %K Serum Albumin, Bovine %K Sodium Azide %K tau Proteins %K Time Factors %K Tissue Preservation %X

BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers.

METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study.

RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects.

CONCLUSION: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

%B J Alzheimers Dis %V 52 %P 51-64 %8 2016 03 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967210?dopt=Abstract %R 10.3233/JAD-150883 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Decade of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Belgium. %A Somers, Charisse %A Struyfs, Hanne %A Goossens, Joery %A Niemantsverdriet, Ellis %A Luyckx, Jill %A De Roeck, Naomi %A De Roeck, Ellen %A De Vil, Bart %A Cras, Patrick %A Martin, Jean-Jacques %A De Deyn, Peter-Paul %A Bjerke, Maria %A Engelborghs, Sebastiaan %X

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.

%B J Alzheimers Dis %V 54 %P 383-95 %8 2016 Aug 10 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567807?dopt=Abstract %R 10.3233/JAD-151097 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Impact of Cerebrospinal Fluid Biomarker (Pre-)Analytical Variability in Alzheimer's Disease. %A Niemantsverdriet, Ellis %A Goossens, Joery %A Struyfs, Hanne %A Martin, Jean-Jacques %A Goeman, Johan %A De Deyn, Peter Paul %A Vanderstichele, Hugo %A Engelborghs, Sebastiaan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Autopsy %K Cognitive Dysfunction %K Enzyme-Linked Immunosorbent Assay %K Exercise %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Peptide Fragments %K Psychiatric Status Rating Scales %K Retrospective Studies %K Statistics, Nonparametric %K tau Proteins %X

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.

%B J Alzheimers Dis %V 51 %P 97-106 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836187?dopt=Abstract %R 10.3233/JAD-150953 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of microRNAs in Cerebrospinal Fluid as Biomarkers for Different Forms of Dementia in a Multicenter Study. %A Müller, Mareike %A Kuiperij, H Bea %A Versleijen, Alexandra A M %A Chiasserini, Davide %A Farotti, Lucia %A Baschieri, Francesca %A Parnetti, Lucilla %A Struyfs, Hanne %A De Roeck, Naomi %A Luyckx, Jill %A Engelborghs, Sebastiaan %A Claassen, Jurgen A %A Verbeek, Marcel M %X

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.

%B J Alzheimers Dis %V 52 %P 1321-33 %8 2016 Apr 16 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104900?dopt=Abstract %R 10.3233/JAD-160038 %0 Journal Article %J Lancet Neurol %D 2014 %T Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. %A Dubois, Bruno %A Feldman, Howard H %A Jacova, Claudia %A Hampel, Harald %A Molinuevo, José Luis %A Blennow, Kaj %A DeKosky, Steven T %A Gauthier, Serge %A Selkoe, Dennis %A Bateman, Randall %A Cappa, Stefano %A Crutch, Sebastian %A Engelborghs, Sebastiaan %A Frisoni, Giovanni B %A Fox, Nick C %A Galasko, Douglas %A Habert, Marie-Odile %A Jicha, Gregory A %A Nordberg, Agneta %A Pasquier, Florence %A Rabinovici, Gil %A Robert, Philippe %A Rowe, Christopher %A Salloway, Stephen %A Sarazin, Marie %A Epelbaum, Stéphane %A de Souza, Leonardo C %A Vellas, Bruno %A Visser, Pieter J %A Schneider, Lon %A Stern, Yaakov %A Scheltens, Philip %A Cummings, Jeffrey L %K Alzheimer Disease %K Biomarkers %K Humans %K International Cooperation %K Phenotype %K Practice Guidelines as Topic %K Societies, Medical %X

In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

%B Lancet Neurol %V 13 %P 614-29 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24849862?dopt=Abstract %R 10.1016/S1474-4422(14)70090-0