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Authors: Förster, Stefan | Buschert, Verena C. | Teipel, Stefan J. | Friese, Uwe | Buchholz, Hans-Georg | Drzezga, Alexander | Hampel, Harald | Bartenstein, Peter | Buerger, Katharina

Article Type: Research Article

Abstract: The effect of cognitive intervention on brain metabolism in AD is largely unexplored. Therefore, we aimed to investigate cognitive parameters and 18 FDG PET to test for effects of a cognitive intervention in patients with aMCI or mild AD. Patients with aMCI (N = 24) or mild AD (N = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches …to determine longitudinal changes, group-by-time interactions and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left anterior temporal pole and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD. Show more

Keywords: FDG PET, cognitive intervention, cognitive training, cognitive stimulation, Alzheimer's disease, mild cognitive impairment

DOI: 10.3233/JAD-2011-0025

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 337-348, 2011

Authors: Förster, Stefan | Buschert, Verena C. | Buchholz, Hans-Georg | Teipel, Stefan J. | Friese, Uwe | Zach, Christian | la Fougere, Christian | Rominger, Axel | Drzezga, Alexander | Hampel, Harald | Bartenstein, Peter | Buerger, Katharina

Article Type: Research Article

Abstract: The effect of cognitive intervention on brain metabolism in Alzheimer's disease (AD) is largely unexplored. Therefore, we aimed to investigate clinical cognitive parameters and 18 FDG PET to test for effects of a cognitive intervention in patients with amnestic mild cognitive impairment (aMCI) or mild AD. Patients with aMCI (n = 24) or mild AD (n = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET …images were analyzed using voxel-based SPM5 approaches to determine longitudinal changes, group-by-time interactions, and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left superior temporal- and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD. Show more

Keywords: Alzheimer's disease, cognitive intervention, cognitive stimulation, cognitive training, FDG PET, mild cognitive impairment

DOI: 10.3233/JAD-2011-100996

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 695-706, 2011

Authors: Ewers, Michael | Cheng, Xin | Zhong, Zhenyu | Nural, Hikmet F. | Walsh, Cathal | Meindl, Thomas | Teipel, Stefan J. | Buerger, Katharina | He, Ping | Shen, Yong | Hampel, Harald

Article Type: Research Article

Abstract: The enzyme β-secretase (BACE1) is essentially involved in the production of cerebral amyloidogenic pathology in Alzheimer's disease (AD). The measurement of BACE1 activity in cerebrospinal fluid (CSF) has been reported, which may render CSF measurement of BACE1 a potential biomarker candidate of AD. In order to investigate whether BACE1 protein activity is correlated with regional brain atrophy in AD, we investigated the association between CSF levels of BACE1 and MRI-assessed hippocampus volume in patients with AD (n = 30). An increase in CSF-BACE1 activity was associated with decreased left and right hippocampus volume corrected for global head volume in the …AD patients. Boot-strapped regression analysis showed that increased CSF levels of BACE1 activity were associated with increased CSF concentration of total tau but not amyloid-β1-42 in AD. White matter hyperintensities did not influence the results. BACE1 activity and protein levels were significantly increased in AD compared to 19 elderly healthy controls. Thus, the CSF biomarker candidate of BACE1 activity was associated with hippocampus atrophy in AD in a robust manner and may reflect neurotoxic amyloid-β-related processes. Show more

Keywords: BACE1, β-secretase, cerebrospinal fluid, hippocampus

DOI: 10.3233/JAD-2011-091153

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 373-381, 2011

Authors: Teipel, Stefan J. | Sabri, Osama | Grothe, Michel | Barthel, Henryk | Prvulovic, David | Buerger, Katharina | Bokde, Arun L.W. | Ewers, Michael | Hoffmann, Wolfgang | Hampel, Harald

Article Type: Review Article

Abstract: The diagnosis of Alzheimer's disease (AD) is presently going through a paradigm shift from disease categories to dimensions and toward the implementation of biomarkers to support identification of predementia and even preclinical asymptomatic stages of the disease. We outline the methodological basis of presently available biomarkers and technological methodologies in AD, including exploratory and hypothesis-based plasma and blood candidates, cerebrospinal fluid markers of amyloid load and axonal destruction, and imaging markers of amyloid deposition, synaptic dysfunction, cortical functional and structural disconnection, and regional atrophy. We integrate biomarker findings into a comprehensive model of AD pathogenesis from healthy aging to cognitive …decline, the resilience to cerebral amyloid load (RECAL) matrix. The RECAL framework integrates factors of risk and resilience to cerebral amyloid load for individual risk prediction. We show the clinical consequences when the RECAL matrix is operationalized into a diagnostic algorithm both for individual counseling of subjects and for the identification of at risk samples for primary and secondary preventive trials. We discuss the implication of biomarkers for the identification of prodromal AD for the primary care system that seems presently not even prepared to cope with the increasing number of subjects afflicted with late stage AD dementia, let alone future cohorts of subjects searching counseling or treatment of predementia and asymptomatic stages of AD. The paradigm shift in AD diagnosis and its operationalization into a diagnostic framework will have major implications for our understanding of disease pathogenesis. Now, for the first time, we have access to in vivo markers of key events in AD pathogenesis integrated into a heuristic framework that makes strong predictions on pattern of multimodal biomarkers in different stages of AD. Critical testing of these predictions will help us to modify or even falsify the currently hold assumptions on the pathogenesis of AD based on in vivo evidence in humans. Show more

Keywords: Alzheimer's disease, amyloid, atrophy, biomarker, blood, cerebrospinal fluid, diagnosis, diffusion tensor imaging, hippocampus, mild cognitive impairment, neurodegeneration, neuroimaging, pathophysiology, positron emission tomography, prognosis, resting state functional magnetic resonance imaging, tau, therapy

DOI: 10.3233/JAD-2012-129030

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S329-S347, 2013

Authors: Buschert, Verena C. | Friese, Uwe | Teipel, Stefan J. | Schneider, Philine | Merensky, Wibke | Rujescu, Dan | Möller, Hans-Jürgen | Hampel, Harald | Buerger, Katharina

Article Type: Research Article

Abstract: Recent studies have shown that patients with Alzheimer's disease (AD) and its possible prodromal stage mild cognitive impairment benefit from cognitive interventions. Few studies so far have used an active control condition and determined effects in different stages of disease. We evaluated a newly developed 6-month group-based multicomponent cognitive intervention in a randomized controlled pilot study on subjects with amnestic mild cognitive impairment (aMCI) and mild AD patients. Forty-three subjects with aMCI and mild AD were recruited. Primary outcome measures were change in global cognitive function as determined by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini Mental …Status Examination (MMSE). Secondary outcomes were specific cognitive and psychopathological ratings. Thirty-nine patients were randomized to intervention groups (IGs: 12 aMCI, 8 AD) and active control groups (CGs: 12 aMCI, 7 AD). At the end of the study, we found significant improvements in the IGMCI compared to the CGMCI in the ADAS-cog (p = 0.02) and for the secondary endpoint Montgomery Asberg Depression Rating Scale (MADRS) (p < 0.01) Effects on the MMSE score showed a non-significant trend (p = 0.07). In AD patients, we found no significant effect of intervention on the primary outcome measures. In conclusion, these results suggest that participation in a 6-month cognitive intervention can improve cognitive and non-cognitive functions in aMCI subjects. In contrast, AD patients showed no significant benefit from intervention. The findings in this small sample support the use of the intervention in larger scales studies with an extended follow-up period to determine long-term effects. Show more

Keywords: Alzheimer's disease, cognitive intervention, cognitive stimulation, cognitive training, mild cognitive impairment, stage-specific

DOI: 10.3233/JAD-2011-100999

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 679-694, 2011

Authors: Franzmeier, Nicolai | Hartmann, Julia C. | Taylor, Alexander N.W. | Araque Caballero, Miguel Á. | Simon-Vermot, Lee | Buerger, Katharina | Kambeitz-Ilankovic, Lana M. | Ertl-Wagner, Birgit | Mueller, Claudia | Catak, Cihan | Janowitz, Daniel | Stahl, Robert | Dichgans, Martin | Duering, Marco | Ewers, Michael

Article Type: Research Article

Abstract: Reserve in aging and Alzheimer’s disease (AD) is defined as maintaining cognition at a relatively high level in the presence of neurodegeneration, an ability often associated with higher education among other life factors. Recent evidence suggests that higher resting-state functional connectivity within the frontoparietal control network, specifically the left frontal cortex (LFC) hub, contributes to higher reserve. Following up these previous resting-state fMRI findings, we probed memory-task related functional connectivity of the LFC hub as a neural substrate of reserve. In elderly controls (CN, n  = 37) and patients with mild cognitive impairment (MCI, n  = 17), we assessed global connectivity of …the LFC hub during successful face-name association learning, using generalized psychophysiological interaction analyses. Reserve was quantified as residualized memory performance, accounted for gender and proxies of neurodegeneration (age, hippocampus atrophy, and APOE genotype). We found that greater education was associated with higher LFC-connectivity in both CN and MCI during successful memory. Furthermore, higher LFC-connectivity predicted higher residualized memory (i.e., reserve). These results suggest that higher LFC-connectivity contributes to reserve in both healthy and pathological aging. Show more

Keywords: Aging, cognitive reserve, education, functional connectivity, memory, mild cognitive impairment, task-fMRI

DOI: 10.3233/JAD-170360

Citation: Journal of Alzheimer's Disease, vol. 59, no. 4, pp. 1381-1392, 2017

Authors: Förster, Stefan | Vaitl, Andreas | Teipel, Stefan J. | Yakushev, Igor | Mustafa, Mona | la Fougère, Christian | Rominger, Axel | Cumming, Paul | Bartenstein, Peter | Hampel, Harald | Hummel, Thomas | Buerger, Katharina | Hundt, Walter | Steinbach, Silke

Article Type: Research Article

Abstract: We used [18 F]fluorodeoxyglucose (FDG) PET analysis to determine performance in different olfactory domains of patients with early AD compared to cognitively healthy subjects, and to map the functional metabolic representation of olfactory impairment in the patient sample. A cohort of patients with early AD (n = 24), consisting of 6 subjects with incipient AD and 18 subjects with mild AD, and a control group of 28 age-matched non-demented individuals were assembled. Patients and controls were tested for olfactory performance using the “Sniffin' Sticks” test battery [odor identification (ID), discrimination (DIS) and threshold (THR)], while patients additionally underwent resting state …FDG-PET. Voxel-wise PET results in the patients were correlated with olfaction scores using the general linear model in SPM5. Patients with early AD showed significantly reduced function in all three olfactory subdomains compared to controls. After controlling for effects due to patients' age, gender, cognitive status, and treating scores in the two other olfactory subdomains as nuisance variables, ID scores correlated with normalized FDG uptake in clusters with peaks in the right superior parietal lobule, fusiform gyrus, inferior frontal gyrus, and precuneus, while DIS scores correlated with a single cluster in the left postcentral cortex, and THR scores correlated with clusters in the right thalamus and cerebellum. The subtests employed in the “Sniffin' Sticks” test battery are complementary indicators of different aspects of olfactory dysfunction in early AD, and support the theory of a parallel organized olfactory system, revealed by FDG-PET correlation analysis. Show more

Keywords: Alzheimer's disease, FDG PET, mild cognitive impairment, olfactory system, smell test

DOI: 10.3233/JAD-2010-091549

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 581-591, 2010

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: Wolfsgruber, Steffen | Kleineidam, Luca | Weyrauch, Anne-Sophie | Barkhoff, Miriam | Röske, Sandra | Peters, Oliver | Preis, Lukas | Gref, Daria | Spruth, Eike Jakob | Altenstein, Slawek | Priller, Josef | Fließbach, Klaus | Schneider, Anja | Wiltfang, Jens | Bartels, Claudia | Jessen, Frank | Maier, Franziska | Düzel, Emrah | Metzger, Coraline | Glanz, Wenzel | Buerger, Katharina | Janowitz, Daniel | Perneczky, Robert | Rauchmann, Boris-Stephan | Kilimann, Ingo | Teipel, Stefan | Laske, Christoph | Munk, Matthias H. | Roy, Nina | Spottke, Annika | Ramirez, Alfredo | Heneka, Michael T. | Brosseron, Frederic | Wagner, Michael | on behalf of the DELCODE study group

Article Type: Research Article

Abstract: Background: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer’s disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD). Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD. Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n  = 82 “AD relatives”; mean age: 65.7 years (SD = 4.47); 59% female) and a similar group of n  =  236 healthy controls without FHAD from the DELCODE study. We …measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD (“SCD-plus score”). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group. Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group. Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, family history, subjective cognitive decline

DOI: 10.3233/JAD-215416

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 545-555, 2022