Publications by authors named "Frederic Brosseron"

40 Publications

Multi-cohort profiling reveals elevated CSF levels of brain-enriched proteins in Alzheimer's disease.

Ann Clin Transl Neurol 2021 Jul 15;8(7):1456-1470. Epub 2021 Jun 15.

Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden.

Objective: Decreased amyloid beta (Aβ) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer's disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages.

Methods: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification.

Results: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Aβ42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations.

Interpretation: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.
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http://dx.doi.org/10.1002/acn3.51402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283172PMC
July 2021

Resting-State Network Alterations Differ between Alzheimer's Disease Atrophy Subtypes.

Cereb Cortex 2021 Jun 3. Epub 2021 Jun 3.

Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen 37075, Germany.

Several Alzheimer's disease (AD) atrophy subtypes were identified, but their brain network properties are unclear. We analyzed data from two independent datasets, including 166 participants (103 AD/63 controls) from the DZNE-longitudinal cognitive impairment and dementia study and 151 participants (121 AD/30 controls) from the AD neuroimaging initiative cohorts, aiming to identify differences between AD atrophy subtypes in resting-state functional magnetic resonance imaging intra-network connectivity (INC) and global and nodal network properties. Using a data-driven clustering approach, we identified four AD atrophy subtypes with differences in functional connectivity, accompanied by clinical and biomarker alterations, including a medio-temporal-predominant (S-MT), a limbic-predominant (S-L), a diffuse (S-D), and a mild-atrophy (S-MA) subtype. S-MT and S-D showed INC reduction in the default mode, dorsal attention, visual and limbic network, and a pronounced reduction of "global efficiency" and decrease of the "clustering coefficient" in parietal and temporal lobes. Despite severe atrophy in limbic areas, the S-L exhibited only marginal global network but substantial nodal network failure. S-MA, in contrast, showed limited impairment in clinical and cognitive scores but pronounced global network failure. Our results contribute toward a better understanding of heterogeneity in AD with the detection of distinct differences in functional connectivity networks accompanied by CSF biomarker and cognitive differences in AD subtypes.
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http://dx.doi.org/10.1093/cercor/bhab130DOI Listing
June 2021

Hippocampal and Hippocampal-Subfield Volumes From Early-Onset Major Depression and Bipolar Disorder to Cognitive Decline.

Front Aging Neurosci 2021 21;13:626974. Epub 2021 Apr 21.

Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany.

The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases. We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups. Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode. HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups.
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http://dx.doi.org/10.3389/fnagi.2021.626974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097178PMC
April 2021

Mediterranean Diet, Alzheimer Disease Biomarkers and Brain Atrophy in Old Age.

Neurology 2021 May 5. Epub 2021 May 5.

Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.

Objective: To determine if following a Mediterranean-like diet (MeDi) relates to cognitive functions and biomarkers for Alzheimer's disease (AD), we analyzed cross-sectional data from the German Longitudinal Cognitive Impairment and Dementia Study METHOD: The sample (n=512, mean age: 69.5±5.9 years) included 169 cognitively normal participants and subjects at higher AD risk (53 AD relatives, 209 SCD and 81 MCI). We defined MeDi adherence based on the Food Frequency Questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI and cognitive performance with an extensive neuropsychological battery. AD-related biomarkers (Aβ42/40 ratio, pTau181) in cerebrospinal fluid were assessed in n=226 individuals. We analyzed the associations between MeDi and the outcomes with linear regression models controlling for several covariates. Additionally, we applied hypothesis-driven mediation and moderation analysis.

Results: Higher MeDi adherence related to larger mediotemporal gray matter volume (p<0.05 FWE corrected), better memory (β±SE = 0.03 ± 0.02; p=0.038), and less amyloid (Aβ42/40 ratio, β±SE = 0.003 ± 0.001; p=0.008) and pTau181 pathology (β±SE = -1.96±0.68; p=0.004). Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations between Aβ42/40 ratio, pTau181 and mediotemporal atrophy. Results were consistent correcting for ApoE-ε4 status.

Conclusion: Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. Importantly, they suggest that these associations might be explained by a decrease of amyloidosis and tau-pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications.
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http://dx.doi.org/10.1212/WNL.0000000000012067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253566PMC
May 2021

Differential Proteome Analysis Using 2D-DIGE.

Methods Mol Biol 2021 ;2228:77-84

Medizinisches Proteom-Center (MPC), Medical Faculty, Ruhr-University Bochum, Bochum, Germany.

Classical 2D-PAGE allows comparison and quantitation of proteomes by visualization of protein patterns using gel stains and comparative image analysis. The introduction of fluorescent reagents for protein labeling (difference in-gel electrophoresis or DIGE) has brought substantial improvement in this field. It provides multiplexing of up to three samples in one gel, higher sensitivity compared to normal protein staining methods, and a higher linear range for quantitation. This article gives detailed protocols for 2D-DIGE, including both minimal and saturation labeling.
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http://dx.doi.org/10.1007/978-1-0716-1024-4_7DOI Listing
June 2021

Proteome Analysis with Classical 2D-PAGE.

Methods Mol Biol 2021 ;2228:53-62

Medizinisches Proteom-Center (MPC), Medical Faculty, Ruhr-University Bochum, Bochum, Germany.

Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) is based on the combination of two orthogonal separation techniques. In the first dimension, proteins are separated by their isoelectric point, a technique known as isoelectric focusing (IEF). There are two important variants of IEF, which are carrier-ampholine (CA)-based IEF and immobilized pH-gradient (IPG)-based IEF. In the second dimension, proteins are further separated by their electrophoretic mobility using SDS-PAGE. Finally, proteins can be visualized and quantified by different staining procedures such as Coomassie, silver staining, or fluorescence labeling. This article gives detailed protocols for 2D-PAGE, using both CA- and IPG-based separation in the first dimension.
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http://dx.doi.org/10.1007/978-1-0716-1024-4_5DOI Listing
June 2021

Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer's disease spectrum.

Neuroimage Clin 2020 11;28:102495. Epub 2020 Nov 11.

German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117 Berlin, Germany.

Background: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer's disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes.

Methods: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aβ42/40 biomarker data, which was available in a subset of participants.

Results: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aβ42/40 stratified analyses largely matched these results.

Conclusions: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry.
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http://dx.doi.org/10.1016/j.nicl.2020.102495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689403PMC
June 2021

Major Surgery Affects Memory in Individuals with Cerebral Amyloid-β Pathology.

J Alzheimers Dis 2021 ;79(2):863-874

Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 'Marqués de Valdecilla' University Hospital, University of Cantabria, Institute for Research 'Marqués de Valdecilla' (IDIVAL), Santander, Spain.

Background: Major surgery has been associated with perioperative neurocognitive disorders (PND), but the contributing factors and long-term prognosis are uncertain. We hypothesize that preclinical Alzheimer's disease (AD) might predispose to cognitive deterioration after surgery.

Objective: To analyze the effect of amyloid-β on the cognitive trajectory after orthopedic surgery in a sample of non-demented subjects.

Methods: Non-demented individuals older than 65 years that were on the waiting list for orthopedic surgery with spinal anesthesia underwent a neuropsychological assessment before and after surgery. During surgery, cerebrospinal fluid samples were obtained to determine AD biomarkers.

Results: Cumulative incidence of PND was 55.2%during a mean follow-up of nine months. The most affected cognitive domains were executive function and constructional praxis. The presence of abnormal levels of amyloid-β was associated to a postoperative impairment in verbal and visual memory tests. According to their AD biomarker profile, participants were categorized as either Amyloid Positive (A+) or Amyloid Negative (A-). The incidence of PND did not differ between both groups. The A- group showed a tendency similar to the global sample, worsening in executive function tests and improving on memory scales due to practice effects. In contrast, the A + group showed a notable worsening on memory performance.

Conclusion: Our findings support the hypothesis that surgery may promote or accelerate memory decline in cognitively asymptomatic subjects with brain amyloid-β deposits.
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http://dx.doi.org/10.3233/JAD-191229DOI Listing
January 2021

Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers-results from the DELCODE study.

Alzheimers Res Ther 2020 10 16;12(1):131. Epub 2020 Oct 16.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Background: Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries.

Methods: We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries.

Results: The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p < .05).

Conclusion: These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline.

Trial Registration: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.
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http://dx.doi.org/10.1186/s13195-020-00701-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566134PMC
October 2020

Interrelations of Alzheimer´s disease candidate biomarkers neurogranin, fatty acid-binding protein 3 and ferritin to neurodegeneration and neuroinflammation.

J Neurochem 2021 Jun 18;157(6):2210-2224. Epub 2020 Sep 18.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) and other neurodegenerative diseases correlate strongest to levels of tau or neurofilament, indicating an inflammatory response to neuronal damage or death. To test this hypothesis, we investigated three AD candidate markers (ferritin, fatty acid binding protein 3 (FABP-3), and neurogranin) in interrelation to established AD and inflammatory protein markers. We further aimed to determine if such interrelations would be evident in pathological subjects only or also under non-pathological circumstances. Cerebrospinal fluid levels of the three proteins were quantified in samples from the University Clinic of Bonn (UKB) Department of Neurodegenerative Diseases & Geriatric Psychiatry, Germany. Data were analyzed based on clinical or biomarker-defined stratification of subjects with adjustment for covariates age, sex, and APOE status. Levels of ferritin, FABP-3 and neurogranin were elevated in subjects with pathological levels of t-tau independent of beta-amyloid status. The three markers correlated with each other, tau isoforms, age, and those inflammatory markers previously described as related to neurodegeneration, predominantly sTREM2, macrophage migration inhibitory factor, soluble vascular endothelial growth factor receptor, soluble vascular cell adhesion molecule 1 (sVCAM-1), and C1q. These interrelations existed in subjects with pathological and sub-pathological tau levels, in particular for FABP-3 and neurogranin. Relations to ferritin were independent of absolute levels of tau, too, but showed differing trajectories between pathological and non-pathological subjects. A specific set of inflammatory markers is highly related to markers of neuronal damage such as tau, neurogranin, or FABP-3. These proteins could be used as readouts of the inflammatory response during the neurodegeneration phase of AD.
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http://dx.doi.org/10.1111/jnc.15175DOI Listing
June 2021

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients.

Alzheimers Dement 2020 11 18;16(11):1504-1514. Epub 2020 Aug 18.

German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.

Introduction: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations.

Methods: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures.

Results: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant.

Discussion: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.
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http://dx.doi.org/10.1002/alz.12150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102202PMC
November 2020

Minor neuropsychological deficits in patients with subjective cognitive decline.

Neurology 2020 09 7;95(9):e1134-e1143. Epub 2020 Jul 7.

From the German Center for Neurodegenerative Diseases (S.W., L.K., J.G., A.P., I.F., S.R., M.T., A. Spottke, A.R., B.K., K.F., A. Schneider, M.H., F.B., D.M., F.J., M.W.); Department of Neurodegenerative Diseases and Geriatric Psychiatry (S.W., L.K., J.G., A.P., I.F., A.R., B.K., K.F., A. Schneider, M.T.H., F.B., M.W.), University of Bonn; German Center for Neurodegenerative Diseases (E.J.S., J.P., O.P., F.M., M.F.C.); Department of Psychiatry and Psychotherapy (E.J.S., C.F., J.P.), Charité-Universitätsmedizin Berlin; German Center for Neurodegenerative Diseases (I.K., S.T.); Department of Psychosomatic Medicine (I.K., S.T.), Rostock University Medical Center; German Center for Neurodegenerative Diseases (K.B.); Institute for Stroke and Dementia Research (K.B., D.J.), University Hospital, LMU Munich; German Center for Neurodegenerative Diseases (C.L., M.B.); Section for Dementia Research (C.L., M.B.), Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen; Charité-Universitätsmedizin Berlin (O.P., F.M., M.F.C.), corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin; (O.P., F.M., M.F.C.), Berlin Institute of Health, Institute of Psychiatry and Psychotherapy; German Center for Neurodegenerative Diseases (J.W., C.B.); Department of Psychiatry and Psychotherapy (J.W., C.B.), University Medical Center Goettingen, University of Goettingen; German Center for Neurodegenerative Diseases (E.D., C.M.); Institute of Cognitive Neurology and Dementia Research (E.D., C.M., W.G.) and Department of Psychiatry and Psychotherapy (C.M.), Otto-von-Guericke University, Magdeburg; Department of Neurology (A. Spottke), University Hospital Bonn; and Division of Neurogenetics and Molecular Psychiatry (A.R.) and Department of Psychiatry (M.T., D.M., F.J.), Medical Faculty University of Cologne, Germany.

Objective: To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD).

Method: We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology.

Results: We observed worse performance (Cohen d = ≈0.25-0.5, adjusted for age, sex differences with analysis of covariance) in global performance, memory, executive functions, and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately ( = ≈0.3) associated with lower CSF β-amyloid and CSF β-amyloid/phosphorylated tau181 in the whole sample and specifically in the SCD subgroup.

Conclusions: Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD.
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http://dx.doi.org/10.1212/WNL.0000000000010142DOI Listing
September 2020

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

Acta Neuropathol 2020 06 12;139(6):1025-1044. Epub 2020 Mar 12.

Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau, total tau, and Aβ was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.
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http://dx.doi.org/10.1007/s00401-020-02138-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244617PMC
June 2020

Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia.

J Neurochem 2020 12 30;155(6):650-661. Epub 2020 Jan 30.

Department of Neurodegenerative Disease and Geriatric Psychiatry, Bonn, Germany.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder causing memory loss, language problems and behavioural disturbances. AD is associated with the accumulation of fibrillar amyloid-β (Aβ) and the formation of neurofibrillary tau tangles. Fibrillar Aβ itself represents a danger-associated molecular pattern, which is recognized by specific microglial receptors. One of the key players is formation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, whose activation has been demonstrated in AD patient brains and transgenic animal models of AD. Here, we investigated whether Aβ oligomers or protofibrils that represent lower molecular aggregates prior to Aβ deposition are able to activate the NLRP3 inflammasome and subsequent interleukin-1 beta (IL-1β) release by microglia. In our study, we used Aβ preparations of different sizes: small oligomers and protofibrils of which the structure was confirmed by atomic force microscopy. Primary microglial cells from C57BL/6 mice were treated with the respective Aβ preparations and NLRP3 inflammasome activation, represented by caspase-1 cleavage, IL-1β production, and apoptosis-associated speck-like protein containing a CARD speck formation was analysed. Both protofibrils and low molecular weight Aβ aggregates induced a significant increase in IL-1β release. Inflammasome activation was confirmed by apoptosis-associated speck-like protein containing a CARD speck formation and detection of active caspase-1. The NLRP3 inflammasome inhibitor MCC950 completely inhibited the Aβ-induced immune response. Our results show that the NLRP3 inflammasome is activated not only by fibrillar Aβ aggregates as reported before, but also by lower molecular weight Aβ oligomers and protofibrils, highlighting the possibility that microglial activation by these Aβ species may initiate innate immune responses in the central nervous system prior to the onset of Aβ deposition. Cover Image for this issue: https://doi.org/10.1111/jnc.14773.
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http://dx.doi.org/10.1111/jnc.14945DOI Listing
December 2020

NLRP3 inflammasome activation drives tau pathology.

Nature 2019 11 20;575(7784):669-673. Epub 2019 Nov 20.

Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany.

Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.
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http://dx.doi.org/10.1038/s41586-019-1769-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324015PMC
November 2019

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study.

Alzheimers Dement 2020 02 6;16(2):292-304. Epub 2020 Jan 6.

Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany.

Introduction: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY.

Methods: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published.

Results: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors.

Discussion: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.
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http://dx.doi.org/10.1016/j.jalz.2019.07.018DOI Listing
February 2020

Multicenter Tract-Based Analysis of Microstructural Lesions within the Alzheimer's Disease Spectrum: Association with Amyloid Pathology and Diagnostic Usefulness.

J Alzheimers Dis 2019 ;72(2):455-465

German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.

Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer's disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis (p < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases.
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http://dx.doi.org/10.3233/JAD-190446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918918PMC
November 2020

Quantitative proteomics of synaptosome S-nitrosylation in Alzheimer's disease.

J Neurochem 2020 03 21;152(6):710-726. Epub 2019 Oct 21.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Increasing evidence suggests that both synaptic loss and neuroinflammation constitute early pathologic hallmarks of Alzheimer's disease. A downstream event during inflammatory activation of microglia and astrocytes is the induction of nitric oxide synthase type 2, resulting in an increased release of nitric oxide and the post-translational S-nitrosylation of protein cysteine residues. Both early events, inflammation and synaptic dysfunction, could be connected if this excess nitrosylation occurs on synaptic proteins. In the long term, such changes could provide new insight into patho-mechanisms as well as biomarker candidates from the early stages of disease progression. This study investigated S-nitrosylation in synaptosomal proteins isolated from APP/PS1 model mice in comparison to wild type and NOS2 mice, as well as human control, mild cognitive impairment and Alzheimer's disease brain tissues. Proteomics data were obtained using an established protocol utilizing an isobaric mass tag method, followed by nanocapillary high performance liquid chromatography tandem mass spectrometry. Statistical analysis identified the S-nitrosylation sites most likely derived from an increase in nitric oxide (NO) in dependence of presence of AD pathology, age and the key enzyme NOS2. The resulting list of candidate proteins is discussed considering function, previous findings in the context of neurodegeneration, and the potential for further validation studies.
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http://dx.doi.org/10.1111/jnc.14870DOI Listing
March 2020

Memorability of photographs in subjective cognitive decline and mild cognitive impairment: Implications for cognitive assessment.

Alzheimers Dement (Amst) 2019 Dec 5;11:610-618. Epub 2019 Sep 5.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Introduction: Impaired long-term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable.

Methods: We conducted item-based analyses of long-term visual recognition memory. Three hundred ninety-four participants (healthy controls, subjective cognitive decline [SCD], and MCI) in the multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs.

Results: We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set.

Discussion: Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.
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http://dx.doi.org/10.1016/j.dadm.2019.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732671PMC
December 2019

Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study.

Alzheimers Res Ther 2019 07 31;11(1):66. Epub 2019 Jul 31.

German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.

Background: Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers.

Methods: We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers.

Results: Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181.

Conclusions: Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.
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http://dx.doi.org/10.1186/s13195-019-0515-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668160PMC
July 2019

The BDNF SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease.

Mol Psychiatry 2021 02 21;26(2):614-628. Epub 2019 Mar 21.

Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain.

In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNF an important modulating factor of cognitive impairment in AD. However, the effect of BDNF on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNF on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNF carriers compared to BDNF homozogytes. BDNF was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNF could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNF was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNF is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.
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http://dx.doi.org/10.1038/s41380-019-0404-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754794PMC
February 2021

Dysregulation of TLR5 and TAM Ligands in the Alzheimer's Brain as Contributors to Disease Progression.

Mol Neurobiol 2019 Sep 9;56(9):6539-6550. Epub 2019 Mar 9.

Department of Neurodegenerative Disease and Gerontopsychiatry / Neurology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

The hypothesis that accumulation of beta-amyloid (Aβ) species in the brain represents a major event in Alzheimer's disease (AD) pathogenesis still prevails; nevertheless, an array of additional pathological processes contributes to clinical presentation and disease progression. We sought to identify novel targets for AD within genes related to amyloid precursor protein (APP) processing, innate immune responses, and the catecholamine system. Through a series of bioinformatics analyses, we identified TLR5 and other genes involved in toll-like receptor (TLR) signaling as potential AD targets. It is believed that Aβ species induce activation of microglia and astrocytes in AD, with a negative impact on disease progression. The TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases plays pivotal roles in limiting inflammatory responses upon TLR stimulation, for which we further studied their implication in the TLR5 alterations observed in AD. We validated the up-regulation of TLR5 in the frontal cortex of moderate AD cases. In addition, we observed up-regulation of the TAM ligands protein S (PROS1), galectin-3 (LGALS3), and Tulp-1. Furthermore, we identified an association of the TAM ligand GAS6 with AD progression. In THP-1 cells, co-stimulation with Aβ and flagellin for 24 h induced up-regulation of TYRO3 and GAS6, which could be prevented by neutralization of TLR5. Our results underscore the role of TLR dysregulations in AD, suggesting the presence of an immunosuppressive response during moderate disease stages, and implicate TAM signaling in AD immune dysregulation.
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http://dx.doi.org/10.1007/s12035-019-1540-3DOI Listing
September 2019

CSF total tau levels are associated with hippocampal novelty irrespective of hippocampal volume.

Alzheimers Dement (Amst) 2018 2;10:782-790. Epub 2018 Nov 2.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Introduction: We examined the association between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, neural novelty responses, and brain volume in predementia old age.

Methods: We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Seventy-six participants completed task functional magnetic resonance imaging and provided CSF (40 cognitively unimpaired, 21 experiencing subjective cognitive decline, and 15 with mild cognitive impairment). We assessed the correlation between CSF biomarkers and whole-brain functional magnetic resonance imaging novelty responses to scene images.

Results: Total tau levels were specifically and negatively associated with novelty responses in the right amygdala and right hippocampus. Mediation analyses showed no evidence that these associations were dependent on the volume of hippocampus/amygdala. No relationship was found between phosphorylated-tau or Aβ levels and novelty responses.

Discussion: Our data show that CSF levels of total tau are associated with anatomically specific reductions in novelty processing, which cannot be fully explained by atrophy.
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http://dx.doi.org/10.1016/j.dadm.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280588PMC
November 2018

Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease.

J Alzheimers Dis 2018 ;64(3):801-813

German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.

Background: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD).

Objective: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD.

Methods: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors.

Results: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume.

Conclusion: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.
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http://dx.doi.org/10.3233/JAD-180106DOI Listing
July 2019

Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer's disease.

Alzheimers Res Ther 2018 02 26;10(1):25. Epub 2018 Feb 26.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Background: Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this study, we sought to clarify the utility of inflammatory biomarkers in diagnostic procedures of AD in three steps: (1) to screen for proteins that are robustly detectable in cerebrospinal fluid; (2) based on this analysis, to explore any associations between the analytically robust markers and salient pathological features of AD; and (3) to determine the discriminative power of these markers in the clinical diagnosis of AD.

Methods: From a total of 46 proteins, 15 that were robustly detectable in cerebrospinal fluid were identified. A subsequent analysis of these markers in a cohort of 399 patients (nondemented subjects, patients with mild cognitive impairment [MCI], and patients with AD, supplemented by smaller cohorts of other diseases) was conducted. Fluid biomarker data were related to AD pathology and neuropsychological markers and adjusted for confounders such as age, sex, apolipoprotein E genotype, and biobank storage time.

Results: Cerebrospinal fluid levels of C-reactive protein and soluble TREM2 differed between nondemented subjects, patients with MCI, or patients with AD and were associated with amyloid and tau pathology. Several markers were associated with tau pathology only or with other neurodegenerative diseases. Correlations between neuropsychological performance and inflammatory markers were weak, but they were most prominent in AD and for the most challenging cognitive tests. All investigated covariates had significant influence, with varying effects across the markers. Still, none of the markers achieved discriminative power of more than 70% to distinguish between patient groups defined by clinical or neuropathological categories.

Conclusions: Basic analytical considerations proved indispensable for this type of study because only one-third of the tested markers were robustly detectable in cerebrospinal fluid. Detectable inflammatory protein markers were associated in multiple ways with AD pathology. Yet, even significantly associated markers were not powerful enough in terms of effect strength, sensitivity, and specificity, and hence they were not suited for direct use in clinical diagnostic practice. Targets other than those most commonly considered in this field of research might provide results with better clinical applicability.
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http://dx.doi.org/10.1186/s13195-018-0353-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828084PMC
February 2018

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease.

Brain 2018 04;141(4):1186-1200

German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany.

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.
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http://dx.doi.org/10.1093/brain/awy008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888938PMC
April 2018

Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer's disease (DELCODE).

Alzheimers Res Ther 2018 02 7;10(1):15. Epub 2018 Feb 7.

German Center for Neurodegenerative Diseases (DZNE), Leipziger Straße 44, 39120, Magdeburg, Germany.

Background: Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention.

Methods: The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer's dementia patients, first-degree relatives of patients with Alzheimer's dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets.

Results: In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer's Disease Assessment Scale-cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Aβ42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected.

Conclusions: The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Aβ42 concentration.

Trial Registration: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.
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http://dx.doi.org/10.1186/s13195-017-0314-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802096PMC
February 2018

Tau plasma levels in subjective cognitive decline: Results from the DELCODE study.

Sci Rep 2017 08 25;7(1):9529. Epub 2017 Aug 25.

Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.

Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = -0.179; p = 0.240), and p-tau181 (r = -0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids.
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http://dx.doi.org/10.1038/s41598-017-08779-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573353PMC
August 2017

Proteome profiling of s-nitrosylated synaptosomal proteins by isobaric mass tags.

J Neurosci Methods 2017 11 5;291:95-100. Epub 2017 Aug 5.

German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurodegenerative Diseases & Gerontopsychiatry, University Hospital Bonn, Bonn, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jneumeth.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625850PMC
November 2017

Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics.

J Alzheimers Dis 2016 03;52(1):51-64

Neurochemistry Laboratory, Faculty of Medicine, CHUC- Coimbra University Hospital, CNC, CNC. IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

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.
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http://dx.doi.org/10.3233/JAD-150883DOI Listing
March 2016