Authors: Ochmann, Sina | Dyrba, Martin | Grothe, Michel J. | Kasper, Elisabeth | Webel, Steffi | Hauenstein, Karlheinz | Teipel, Stefan J.
Article Type: Research Article
Abstract: Background: Cognitive rehabilitation (CR) is a cognitive intervention for patients with Alzheimer’s disease (AD) that aims to maintain everyday competences. The analysis of functional connectivity (FC) in resting-state functional MRI has been used to investigate the effects of cognitive interventions. Objectives: We evaluated the effect of CR on the default mode network FC in a group of patients with mild AD, compared to an active control group. Methods: We performed a three-month interventional study including 16 patients with a diagnosis of AD. The intervention group (IG) consisted of eight patients, performing twelve sessions of CR. The active control group (CG) …performed a standardized cognitive training. We used a seed region placed in the posterior cingulate cortex (PCC) for FC analysis, comparing scans acquired before and after the intervention. Effects were thresholded at a significance of p < 0.001 (uncorrected) and a minimal cluster size of 50 voxels. Results: The interaction of group by time showed a higher increase of PCC connectivity in IG compared to CG in the bilateral cerebellar cortex. CG revealed widespread, smaller clusters of higher FC increase compared with IG. Across all participants, an increase in quality of life was associated with connectivity increase over time in the bilateral precuneus. Conclusions: CR showed an effect on the FC of the DMN in the IG. These effects need further study in larger samples to confirm if FC analysis may suit as a surrogate marker for the effect of cognitive interventions in AD. Show more
Keywords: Alzheimer’s disease, cognitive rehabilitation, default mode network, dementia, functional connectivity, functional MRI
DOI: 10.3233/JAD-160773
Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1303-1313, 2017
Authors: Sakr, Fatemah | Dyrba, Martin | Bräuer, Anja | Teipel, Stefan | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Background: Lipidomics may provide insight into biochemical processes driving Alzheimer’s disease (AD) pathogenesis and ensuing clinical trajectories. Objective: To identify a peripheral lipidomics signature associated with AD pathology and investigate its potential to predict clinical progression. Methods: We used Bayesian elastic net regression to select plasma lipid classes associated with the CSF pTau/Aβ42 ratio as a biomarker of AD pathology in preclinical and prodromal AD cases from the ADNI cohort. Consensus clustering of the selected lipid classes was used to identify lipidomic endophenotypes and study their association with clinical progression. Results: In the APOE4 -adjusted model, ether-glycerophospholipids, lyso-glycerophospholipids, free-fatty acids, …cholesterol esters, and complex sphingolipids were found to be associated with the CSF pTau/Aβ42 ratio. We found an optimal number of five lipidomic endophenotypes in the prodromal and preclinical cases, respectively. In the prodromal cases, these clusters differed with respect to the risk of clinical progression as measured by clinical dementia rating score conversion. Conclusion: Lipid alterations can be captured at the earliest phases of AD. A lipidomic signature in blood may provide a dynamic overview of an individual’s metabolic status and may support identifying different risks of clinical progression. Show more
Keywords: Alzheimer’s disease, heterogeneity, lipidomics, risk assessment
DOI: 10.3233/JAD-201504
Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1115-1127, 2022
Authors: Dyrba, Martin | Grothe, Michel J. | Mohammadi, Abdolreza | Binder, Harald | Kirste, Thomas | Teipel, Stefan J. | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Alzheimer’s disease (AD) is characterized by a cascade of pathological processes that can be assessed in vivo using different neuroimaging methods. Recent research suggests a systematic sequence of pathogenic events on a global biomarker level, but little is known about the associations and dependencies of distinct lesion patterns on a regional level. Markov random fields are a probabilistic graphical modeling approach that represent the interaction between individual random variables by an undirected graph. We propose the novel application of this approach to study the interregional associations and dependencies between multimodal imaging markers of AD pathology and to compare different hypotheses …regarding the spread of the disease. We retrieved multimodal imaging data from 577 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative. Mean amyloid load (AV45-PET), glucose metabolism (FDG-PET), and gray matter volume (MRI) were calculated for the six principle nodes of the default mode network— a functional network of brain regions that appears to be preferentially targeted by AD. Multimodal Markov random field models were developed for three different hypotheses regarding the spread of the disease: the “intraregional evolution model”, the “trans-neuronal spread” hypothesis, and the “wear-and-tear” hypothesis. The model likelihood to reflect the given data was evaluated using tenfold cross-validation with 1,000 repetitions. The most likely graph structure contained the posterior cingulate cortex as main hub region with edges to various other regions, in accordance with the “wear-and-tear” hypothesis of disease vulnerability. Probabilistic graphical models facilitate the analysis of interactions between several variables in a network model and therefore afford great potential to complement traditional multiple regression analyses in multimodal neuroimaging research. Show more
Keywords: Alzheimer’s disease, AV45-PET, FDG-PET, Markov random field, mild cognitive impairment, multimodal imaging, probabilistic graphical model
DOI: 10.3233/JAD-161197
Citation: Journal of Alzheimer's Disease, vol. 65, no. 3, pp. 731-746, 2018
Authors: Teipel, Stefan J. | Temp, Anna Gesine Marie | Levin, Fedor | Dyrba, Martin | Grothe, Michel J. | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Background: TAR DNA-binding protein 43 (TDP-43) has been recognized as a frequent co-pathology of Alzheimer’s disease (AD). The effect of the presence of TDP-43 pathology on in vivo measures of AD-related amyloid pathology using amyloid sensitive PET is still unresolved. Objective: To study the association of TDP-43 pathology with antemortem amyloid PET signal. Methods: We studied 30 cases from the ADNI autopsy sample with available ratings of presence of TDP-43 and antemortem amyloid sensitive 18 F-FlorbetapirPET. We used Bayesian regression to determine the effect of TDP-43 on global and regional amyloid PET signal. In a post-hoc analysis, we assessed the …association of TDP-43 pathology with antemortem memory performance. Results: We found substantial to strong evidence for a negative effect of TDP-43 (Bayes factor against the null model (BF10 ) = 9.0) and hippocampal sclerosis (BF10 = 6.4) on partial volume corrected hippocampal 18 F-Florbetapir uptake. This effect was only partly mediated by the negative effect of TDP-43 on hippocampal volume. In contrast, Bayesian regression supported that there is no effect of TDP-43 on global cortical PET-signal (BF10 = 0.65). We found an anecdotal level of evidence for a negative effect of TDP-43 pathology on antemortem memory performance after accounting for global amyloid PET signal (BF10 = 1.6). Conclusion: Presence of TDP-43 pathology does not confound the global amyloid PET-signal but has a selective effect on hippocampal PET-signal that appears only partially dependent on TDP-43 mediated atrophy. Show more
Keywords: Amyloid pathology, florbetapir PET, hippocampal sclerosis, hippocampal volume, memory, TAR DNA-binding protein 43
DOI: 10.3233/JAD-201032
Citation: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 663-670, 2021
Authors: Brueggen, Katharina | Dyrba, Martin | Barkhof, Frederik | Hausner, Lucrezia | Filippi, Massimo | Nestor, Peter J. | Hauenstein, Karlheinz | Klöppel, Stefan | Grothe, Michel J. | Kasper, Elisabeth | Teipel, Stefan J. | and the EDSD study group
Article Type: Research Article
Abstract: Background: Hippocampal grey matter (GM) atrophy predicts conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Pilot data suggests that mean diffusivity (MD) in the hippocampus, as measured with diffusion tensor imaging (DTI), may be a more accurate predictor of conversion than hippocampus volume. In addition, previous studies suggest that volume of the cholinergic basal forebrain may reach a diagnostic accuracy superior to hippocampal volume in MCI. Objective: The present study investigated whether increased MD and decreased volume of the hippocampus, the basal forebrain and other AD-typical regions predicted time to conversion from MCI to AD dementia. Methods: 79 …MCI patients with DTI and T1 -weighted magnetic resonance imaging (MRI) were retrospectively included from the European DTI Study in Dementia (EDSD) dataset. Of these participants, 35 converted to AD dementia after 6–46 months (mean: 21 months). We used Cox regression to estimate the relative conversion risk predicted by MD values and GM volumes, controlling for age, gender, education and center. Results: Decreased GM volume in all investigated regions predicted an increased risk for conversion. Additionally, increased MD in the right basal forebrain predicted increased conversion risk. Reduced volume of the right hippocampus was the only significant predictor in a stepwise model combining all predictor variables. Conclusion: Volume reduction of the hippocampus, the basal forebrain and other AD-related regions was predictive of increased risk for conversion from MCI to AD. In this study, volume was superior to MD in predicting conversion. Show more
Keywords: Diffusion tensor imaging, magnetic resonance imaging, Mild Cognitive Impairment, Alzheimer’s disease, atrophy, basal forebrain, cholinergic, early diagnosis
DOI: 10.3233/JAD-150063
Citation: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 197-204, 2015
Authors: Teipel, Stefan J. | Grothe, Michel J. | Filippi, Massimo | Fellgiebel, Andreas | Dyrba, Martin | Frisoni, Giovanni B. | Meindl, Thomas | Bokde, Arun L.W. | Hampel, Harald | Klöppel, Stefan | Hauenstein, Karlheinz | the EDSD study group
Article Type: Research Article
Abstract: Diffusion tensor imaging (DTI) allows the simultaneous measurement of several diffusion indices that provide complementary information on the substrate of white matter alterations in neurodegenerative diseases. These indices include fractional anisotropy (FA) as measure of fiber tract integrity, and the mode of anisotropy (Mode) reflecting differences in the shape of the diffusion tensor. We used a multivariate approach based on joint independent component analysis of FA and Mode in a large sample of 138 subjects with Alzheimer's disease (AD) dementia, 37 subjects with cerebrospinal fluid biomarker positive mild cognitive impairment (MCI-AD), and 153 healthy elderly controls from the European DTI …Study on Dementia to comprehensively study alterations of microstructural white matter integrity in AD dementia and predementia AD. We found a parallel decrease of FA and Mode in intracortically projecting fiber tracts, and a parallel increase of FA and Mode in the corticospinal tract in AD patients compared to controls. Subjects with MCI-AD showed a similar, but spatially more restricted pattern of diffusion changes. Our findings suggest an early axonal degeneration in intracortical projecting fiber tracts in dementia and predementia stages of AD. An increase of Mode, parallel to an increase of FA, in the corticospinal tract suggests a more linear shape of diffusion due to loss of crossing fibers along relatively preserved cortico-petal and cortico-fugal fiber tracts in AD. Supporting this interpretation, we found three populations of fiber tracts, namely cortico-petal and cortico-fugal, commissural, and intrahemispherically projecting fiber tracts, in the peak area of parallel FA and Mode increase. Show more
Keywords: Crossing fibers, diffusion spectrum imaging, diffusion tensor imaging, early diagnosis, fractional anisotropy, mode of anisotropy, predementia Alzheimer's disease
DOI: 10.3233/JAD-131829
Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 69-83, 2014
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: 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
