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Authors: Teipel, Stefan J. | Metzger, Coraline D. | Brosseron, Frederic | Buerger, Katharina | Brueggen, Katharina | Catak, Cihan | Diesing, Dominik | Dobisch, Laura | Fliebach, Klaus | Franke, Christiana | Heneka, Michael T. | Kilimann, Ingo | Kofler, Barbara | Menne, Felix | Peters, Oliver | Polcher, Alexandra | Priller, Josef | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Thelen, Manuela | Thyrian, René J. | Wagner, Michael | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group

Article Type: Research Article

Abstract: 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. Show more

Keywords: diagnostic accuracy, functional MRI, multicenter, subjective cognitive decline, contstartabstract

DOI: 10.3233/JAD-180106

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 801-813, 2018

Authors: Teipel, Stefan J. | Kuper-Smith, Jan O. | Bartels, Claudia | Brosseron, Frederic | Buchmann, Martina | Buerger, Katharina | Catak, Cihan | Janowitz, Daniel | Dechent, Peter | Dobisch, Laura | Ertl-Wagner, Birgit | Fließbach, Klaus | Haynes, John-Dylan | Heneka, Michael T. | Kilimann, Ingo | Laske, Christoph | Li, Siyao | Menne, Felix | Metzger, Coraline D. | Priller, Josef | Pross, Verena | Ramirez, Alfredo | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Wolfsgruber, Steffen | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group

Article Type: Research Article

Abstract: 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. Show more

Keywords: amyloid, anisotropy, cerebral white matter, cognition, diagnosis, diffusion tensor imaging, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-190446

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 455-465, 2019

Authors: Teipel, Stefan J. | Dyrba, Martin | Ballarini, Tommaso | Brosseron, Frederic | Bruno, Davide | Buerger, Katharina | Cosma, Nicoleta-Carmen | Dechent, Peter | Dobisch, Laura | Düzel, Emrah | Ewers, Michael | Fliessbach, Klaus | Haynes, John D. | Janowitz, Daniel | Kilimann, Ingo | Laske, Christoph | Maier, Franziska | Metzger, Coraline D. | Munk, Matthias H. | Peters, Oliver | Pomara, Nunzio | Preis, Lukas | Priller, Josef | Ramírez, Alfredo | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Schott, Björn H. | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Jessen, Frank | Heneka, Michael T.

Article Type: Research Article

Abstract: Background: Inflammation has been described as a key pathogenic event in Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume …and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42 /ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cholinergic system, neuroinflammation, MRI, plasma, sTREM2

DOI: 10.3233/JAD-215196

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1267-1282, 2022

Authors: Daamen, Marcel | Scheef, Lukas | Li, Shumei | Grothe, Michel J. | Gaertner, Florian C. | Buchert, Ralph | Buerger, Katharina | Dobisch, Laura | Drzezga, Alexander | Essler, Markus | Ewers, Michael | Fliessbach, Klaus | Herrera Melendez, Ana Lucia | Hetzer, Stefan | Janowitz, Daniel | Kilimann, Ingo | Krause, Bernd Joachim | Lange, Catharina | Laske, Christoph | Munk, Matthias H. | Peters, Oliver | Priller, Josef | Ramirez, Alfredo | Reimold, Matthias | Rominger, Axel | Rostamzadeh, Ayda | Roeske, Sandra | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Teipel, Stefan J. | Wagner, Michael | Düzel, Emrah | Jessen, Frank | Boecker, Henning

Article Type: Research Article

Abstract: Background: Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer’s disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. Objective: To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. Methods: The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with …cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Results: Group differences approached significance for BF total volume (p  = 0.061) and the Ch4 subregion (p  = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. Conclusions: The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at “grey zone” levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings. Show more

Keywords: Acetylcholine, Alzheimer’s disease, amyloid, atrophy, basal forebrain, cognitive decline

DOI: 10.3233/JAD-230141

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1013-1028, 2023

Authors: Li, Shumei | Daamen, Marcel | Scheef, Lukas | Gaertner, Florian C. | Buchert, Ralph | Buchmann, Martina | Buerger, Katharina | Catak, Cihan | Dobisch, Laura | Drzezga, Alexander | Ertl-Wagner, Birgit | Essler, Markus | Fliessbach, Klaus | Haynes, John Dylan | Incesoy, Enise Irem | Kilimann, Ingo | Krause, Bernd J. | Lange, Catharina | Laske, Christoph | Priller, Josef | Ramirez, Alfredo | Reimold, Matthias | Rominger, Axel | Roy, Nina | Scheffler, Klaus | Maurer, Angelika | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Teipel, Stefan J. | Tscheuschler, Maike | Wagner, Michael | Wolfsgruber, Steffen | Düzel, Emrah | Jessen, Frank | Peters, Oliver | Boecker, Henning | the DELCODE Study Group

Article Type: Research Article

Abstract: Background: Amyloid-β accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer’s continuum in the 2018 NIA-AA research framework. Objective: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus. Methods: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAβ+) and amyloidnegative SCD (SCDβ−) patients were selected according to visual [18F]-Florbetaben …(FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVR=⫖FBB). Results: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDAβ+patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAβ+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAβ+) and precuneus SUVRFBB (both groups). Conclusion: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAβ+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-β load, highlighting incipient pathology in stage 2 of the AD continuum. Show more

Keywords: Alzheimer’s disease, amyloid, functional magnetic resonance imaging, occipital cortex, PET, precuneus, prodromal symptoms, subjective cognitive decline

DOI: 10.3233/JAD-200472

Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 493-509, 2021

Authors: Ersoezlue, Ersin | Perneczky, Robert | Tato, Maia | Utecht, Julia | Kurz, Carolin | Häckert, Jan | Guersel, Selim | Burow, Lena | Koller, Gabriele | Stoecklein, Sophia | Keeser, Daniel | Papazov, Boris | Totzke, Marie | Ballarini, Tommaso | Brosseron, Frederic | Buerger, Katharina | Dechent, Peter | Dobisch, Laura | Ewers, Michael | Fliessbach, Klaus | Glanz, Wenzel | Haynes, John Dylan | Heneka, Michael T. | Janowitz, Daniel | Kilimann, Ingo | Kleineidam, Luca | Laske, Christoph | Maier, Franziska | Munk, Matthias H. | Peters, Oliver | Priller, Josef | Ramirez, Alfredo | Roeske, Sandra | Roy, Nina | Scheffler, Klaus | Schneider, Anja | Schott, Björn H. | Spottke, Annika | Spruth, Eike J. | Teipel, Stefan | Unterfeld, Chantal | Wagner, Michael | Wang, Xiao | Wiltfang, Jens | Wolfsgruber, Steffen | Yakupov, Renat | Duezel, Emrah | Jessen, Frank | Rauchmann, Boris-Stephan

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) explains inter-individual differences in the impact of the neurodegenerative burden on cognitive functioning. A residual model was proposed to estimate CR more accurately than previous measures. However, associations between residual CR markers (CRM) and functional connectivity (FC) remain unexplored. Objective: To explore the associations between the CRM and intrinsic network connectivity (INC) in resting-state networks along the neuropathological-continuum of Alzheimer’s disease (ADN). Methods: Three hundred eighteen participants from the DELCODE cohort were stratified using cerebrospinal fluid biomarkers according to the A(myloid-β)/T(au)/N(eurodegeneration) classification. CRM was calculated utilizing residuals obtained from a multilinear regression model predicting cognition from …markers of disease burden. Using an independent component analysis in resting-state fMRI data, we measured INC of resting-state networks, i.e., default mode network (DMN), frontoparietal network (FPN), salience network (SAL), and dorsal attention network. The associations of INC with a composite memory score and CRM and the associations of CRM with the seed-to-voxel functional connectivity of memory-related were tested in general linear models. Results: CRM was positively associated with INC in the DMN in the entire cohort. The A+T+N+ group revealed an anti-correlation between the SAL and the DMN. Furthermore, CRM was positively associated with anti-correlation between memory-related regions in FPN and DMN in ADN and A+T/N+. Conclusion: Our results provide evidence that INC is associated with CRM in ADN defined as participants with amyloid pathology with or without cognitive symptoms, suggesting that the neural correlates of CR are mirrored in network FC in resting-state. Show more

Keywords: Alzheimer’s disease, cognition, cognitive reserve, functional MRI, intrinsic network connectivity, resting-state functional connectivity

DOI: 10.3233/JAD-220464

Citation: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 925-940, 2023

Authors: Teipel, Stefan J | Dyrba, Martin | Levin, Fedor | Altenstein, Slawek | Berger, Moritz | Beyle, Aline | Brosseron, Frederic | Buerger, Katharina | Burow, Lena | Dobisch, Laura | Ewers, Michael | Fliessbach, Klaus | Frommann, Ingo | Glanz, Wenzel | Goerss, Doreen | Gref, Daria | Hansen, Niels | Heneka, Michael T. | Incesoy, Enise I. | Janowitz, Daniel | Keles, Deniz | Kilimann, Ingo | Laske, Christoph | Lohse, Andrea | Munk, Matthias H. | Perneczky, Robert | Peters, Oliver | Preis, Lukas | Priller, Josef | Rostamzadeh, Ayda | Roy, Nina | Schmid, Matthias | Schneider, Anja | Spottke, Annika | Spruth, Eike Jakob | Wiltfang, Jens | Düzel, Emrah | Jessen, Frank | Kleineidam, Luca | Wagner, Michael

Article Type: Research Article

Abstract: Background: Cognitive decline is a key outcome of clinical studies in Alzheimer’s disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and …volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid. Show more

Keywords: Alzheimer’s disease, executive function, longitudinal, memory, mild cognitive impairment, non-linear, practice effects, subjective cognitive decline

DOI: 10.3233/ADR-230027

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1055-1076, 2023

Authors: Rauchmann, Boris-Stephan | Gross, Patrizia | Ersoezlue, Ersin | Wagner, Michael | Ballarini, Tommaso | Kurz, Carolin | Tatò, Maia | Utecht, Julia | Papazov, Boris | Guersel, Selim | Totzke, Marie | Trappmann, Lena | Burow, Lena | Koller, Gabriele | Stöcklein, Sophia | Keeser, Daniel | Altenstein, Slawek | Bartels, Claudia | Buerger, Katharina | Dechent, Peter | Dobisch, Laura | Ewers, Michael | Fliessbach, Klaus | Freiesleben, Silka Dawn | Glanz, Wenzel | Goeerss, Doreen | Gref, Daria | Haynes, John Dylan | Janowitz, Daniel | Kilimann, Ingo | Kimmich, Okka | Kleineidam, Luca | Laske, Christoph | Lohse, Andrea | Maier, Franziska | Metzger, Coraline D. | Munk, Matthias H. | Peters, Oliver | Preis, Lukas | Priller, Josef | Roeske, Sandra | Roy, Nina | Sanzenbacher, Carolin | Scheffler, Klaus | Schneider, Anja | Schott, Björn Hendrik | Spottke, Annika | Spruth, Eike Jakob | Teipel, Stefan | van Lent, Debora Melo | Wiltfang, Jens | Wolfsgruber, Steffen | Yakupov, Renat | Düzel, Emrah | Jessen, Frank | Perneczky, Robert

Article Type: Research Article

Abstract: BACKGROUND: There is evidence that adherence to Mediterranean-like diet reduces cognitive decline and brain atrophy in Alzheimer's disease (AD). However, lengthy dietary assessments, such as food frequency questionnaires (FFQs), discourage more frequent use. OBJECTIVE: Here we aimed to validate a 6-items short questionnaire for a Mediterranean-like diet (6-QMD) and explore its associations with memory performance and hippocampal atrophy in healthy elders and individuals at risk for AD. METHODS: We analyzed 938 participants (N = 234 healthy controls and N = 704 participants with an increased AD risk) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). The 6-QMD was validated against the Mediterranean Diet …(MeDi) score and the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) score, both derived from a detailed FFQ. Furthermore, associations between the 6-QMD and memory function as well as hippocampal atrophy were evaluated using linear regressions. RESULTS: The 6-QMD was moderately associated with the FFQ-derived MeDi adherence score (ρ = 0.25, p  < 0.001) and the MIND score (ρ = 0.37, p = < 0.001). Higher fish and olive oil consumption and lower meat and sausage consumption showed significant associations in a linear regression, adjusted for diagnosis, age, sex and education, with memory function (β = 0.1, p  = 0.008) and bilateral hippocampal volumes (left: β = 0.15, p  < 0.001); (right: β = 0.18, p  < 0.001)). CONCLUSIONS: The 6-QMD is a useful and valid brief tool to assess the adherence to MeDi and MIND diets, capturing associations with memory function and brain atrophy in healthy elders and individuals at increased AD dementia risk, making it a valid alternative in settings with time constraints. Show more

DOI: 10.3233/NHA-220190

Citation: Nutrition and Healthy Aging, vol. 8, no. 1, pp. 143-156, 2023