44 results on '"Peters Oliver"'
Search Results
2. Symptomatic Clusters Related to Amyloid Positivity in Cognitively Unimpaired Individuals.
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Sannemann, Lena, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Lammerding, Dominik, Laske, Christoph, Munk, Matthias H.J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, and Rostamzadeh, Ayda
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AMYLOID ,ALZHEIMER'S disease ,COGNITIVE interviewing ,CEREBROSPINAL fluid ,COGNITION disorders - Abstract
Background: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ
42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42 /ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology. [ABSTRACT FROM AUTHOR]- Published
- 2024
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3. Respectful Caring for the Agitated Elderly (ReCAGE): A Multicentre, Prospective, Observational Study to Evaluate the Effectiveness of Special Care Units for People with Dementia
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Mendes, Aline, primary, Bergh, Sverre, additional, Cesana, Bruno Mario, additional, Handels, Ron, additional, Ciccone, Alfonso, additional, Cognat, Emmanuel, additional, Fabbo, Andrea, additional, Fascendini, Sara, additional, Frisoni, Giovanni B., additional, Froelich, Lutz, additional, Jori, Maria Cristina, additional, Mecocci, Patrizia, additional, Merlo, Paola, additional, Peters, Oliver, additional, Tsolaki, Magdalini, additional, and Defanti, Carlo Alberto, additional
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- 2023
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4. Individualized Summary Assessment of Detailed Neuropsychological Testing for the Etiological Diagnosis of Newly Detected Cognitive Impairment in Hospitalized Geriatric Patients
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Mäurer, Anja, primary, Himmel, Gudrun, additional, Lange, Catharina, additional, Mathies, Franziska, additional, Apostolova, Ivayla, additional, Peters, Oliver, additional, and Buchert, Ralph, additional
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- 2023
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5. A 6-items Questionnaire (6-QMD) captures a Mediterranean like dietary pattern and is associated with memory performance and hippocampal volume in elderly and persons at risk for Alzheimer’s disease
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Rauchmann, Boris-Stephan, primary, Gross, Patrizia, additional, Ersoezlue, Ersin, additional, Wagner, Michael, additional, Tommaso, Ballarini, additional, Kurz, Carolin, additional, Tatò, Maia, additional, Utecht, Julia, additional, Papazov, Boris, additional, Guersel, Selim, additional, Totzke, Marie, additional, Trappmann, Lena, additional, Burow, Lena, additional, Koller, Gabriele, additional, Stöcklein, Sophia, additional, Keeser, Daniel, additional, Altenstein, Slawek, additional, Bartels, Claudia, additional, Buerger, Katharina, additional, Dechent, Peter, additional, Dobisch, Laura, additional, Ewers, Michael, additional, Fliessbach, Klaus, additional, Freiesleben, Silka Dawn, additional, Glanz, Wenzel, additional, Goeerss, Doreen, additional, Gref, Daria, additional, Haynes, John Dylan, additional, Janowitz, Daniel, additional, Kilimann, Ingo, additional, Kimmich, Okka, additional, Kleineidam, Luca, additional, Laske, Christoph, additional, Lohse, Andrea, additional, Maier, Franziska, additional, Metzger, Coraline D., additional, Munk, Matthias H., additional, Peters, Oliver, additional, Preis, Lukas, additional, Priller, Josef, additional, Roeske, Sandra, additional, Roy, Nina, additional, Sanzenbacher, Carolin, additional, Scheffler, Klaus, additional, Schneider, Anja, additional, Schott, Björn Hendrik, additional, Spottke, Annika, additional, Spruth, Eike Jakob, additional, Teipel, Stefan, additional, van Lent, Debora Melo, additional, Wiltfang, Jens, additional, Wolfsgruber, Steffen, additional, Yakupov, Renat, additional, Düzel, Emrah, additional, Jessen, Frank, additional, and Perneczky, Robert, additional
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- 2023
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6. Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline
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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 Meléndez, Ana Lucía, Hetzer, Stefan, Janowitz, Daniel, Kilimann, Ingo, Krause, Bernd Joachim, Lange, Catharina, Laske, Christoph, Munk, Matthias H., Peters, Oliver, Priller, Josef, Ramírez, 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, DELCODE Study Group, 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 Meléndez, Ana Lucía, Hetzer, Stefan, Janowitz, Daniel, Kilimann, Ingo, Krause, Bernd Joachim, Lange, Catharina, Laske, Christoph, Munk, Matthias H., Peters, Oliver, Priller, Josef, Ramírez, 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, and DELCODE Study Group
- 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.
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- 2023
7. A Residual Marker of Cognitive Reserve Is Associated with Resting-State Intrinsic Functional Connectivity Along the Alzheimer's Disease Continuum
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Ersoezlue, Ersin, Perneczky, Robert, Keeser, Daniel, Papazov, Boris, Totzke, Marie, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Tato, Maia, Glanz, Wenzel, Haynes, John Dylan, Heneka, Michael T, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Munk, Matthias H, Peters, Oliver, Utecht, Julia, Priller, Josef, Ramirez, Alfredo, Roeske, Sandra, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H, Spottke, Annika, Spruth, Eike J, Teipel, Stefan, Kurz, Carolin, Unterfeld, Chantal, Wagner, Michael, Wang, Xiao, Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Duezel, Emrah, Jessen, Frank, Rauchmann, Boris-Stephan, group, DELCODE study, Häckert, Jan, Guersel, Selim, Burow, Lena, Koller, Gabriele, and Stoecklein, Sophia
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cognition ,General Neuroscience ,resting-state functional connectivity ,General Medicine ,cognitive reserve ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Clinical Psychology ,pathology [Alzheimer Disease] ,intrinsic network connectivity ,Neural Pathways ,Humans ,functional MRI ,ddc:610 ,Geriatrics and Gerontology ,Nerve Net ,diagnostic imaging [Brain] ,Alzheimer’s disease - 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.
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- 2023
8. A Comparison of Operational Definitions for Mild Cognitive Impairment
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Polcher, Alexandra, primary, Wolfsgruber, Steffen, additional, Peters, Oliver, additional, Frölich, Lutz, additional, Wiltfang, Jens, additional, Kornhuber, Johannes, additional, Hüll, Michael, additional, Rüther, Eckart, additional, Lewczuk, Piotr, additional, Maier, Wolfgang, additional, Jessen, Frank, additional, and Wagner, Michael, additional
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- 2022
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9. Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer's Disease Spectrum
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Teipel, Stefan J., Dyrba, Martin, Ballarini, Tommaso, Brosseron, Frederic, Bruno, Davide, Buerger, Katharina, Cosma, Nicoleta-Carmen, Dechent, Peter, Dobisch, Laura, Duezel, 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, Ramirez, Alfredo, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Bjoern H., Spottke, Annika, Spruth, Eike J., Wagner, Michael, Wiltfang, Jens, Jessen, Frank, Heneka, Michael T., Teipel, Stefan J., Dyrba, Martin, Ballarini, Tommaso, Brosseron, Frederic, Bruno, Davide, Buerger, Katharina, Cosma, Nicoleta-Carmen, Dechent, Peter, Dobisch, Laura, Duezel, 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, Ramirez, Alfredo, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Bjoern H., Spottke, Annika, Spruth, Eike J., Wagner, Michael, Wiltfang, Jens, Jessen, Frank, and Heneka, Michael T.
- 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 DELCODEcohort, 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 A beta(42)/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 A beta(42) and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.
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- 2022
10. Relevance of Subjective Cognitive Decline in Older Adults with a First-Degree Family History of Alzheimer's Disease
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Wolfsgruber, Steffen, Kleineidam, Luca, Weyrauch, Anne-Sophie, Barkhoff, Miriam, Roeske, 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, Duezel, 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, Wolfsgruber, Steffen, Kleineidam, Luca, Weyrauch, Anne-Sophie, Barkhoff, Miriam, Roeske, 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, Duezel, 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, and Wagner, Michael
- 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.
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- 2022
11. A Comparison of Operational Definitions for Mild Cognitive Impairment
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Polcher, Alexandra, Wolfsgruber, Steffen, Peters, Oliver, Froelich, Lutz, Wiltfang, Jens, Kornhuber, Johannes, Huell, Michael, Ruether, Eckart, Lewczuk, Piotr, Maier, Wolfgang, Jessen, Frank, Wagner, Michael, Polcher, Alexandra, Wolfsgruber, Steffen, Peters, Oliver, Froelich, Lutz, Wiltfang, Jens, Kornhuber, Johannes, Huell, Michael, Ruether, Eckart, Lewczuk, Piotr, Maier, Wolfgang, Jessen, Frank, and Wagner, Michael
- Abstract
Background: Consideration of many tests from different cognitive domains in defining mild cognitive impairment (MCI) is clinical routine, but guidelines for a neuropsychological operationalization of MCI are lacking. Objective: Among different operational MCI criteria, to identify those which are best in predicting either conversion to dementia, or a biomarker profile indicative for Alzheimer's disease (AD). Methods: Memory clinic patients without dementia (N= 558; mean age = 66; up to 3 years of follow-up; n = 360 with baseline CSF biomarkers) were included in an observational study using most liberal criteria of cognitive impairment. Four operational definitions of MCI were retrospectively applied: 1) amnestic MCI (CERAD word list delayed recall), 2) CERAD total score, 3) comprehensive criteria and 4) base rate corrected CERAD. We compared their accuracy in predicting incident all-cause dementia or AD dementia within three years, or a concurrent CSF A beta(42)/tau-ratio indicative of AD. Results: The four definitions overlapped considerably, classified 35-58% of the original sample as impaired and were associated with markedly increased PPVs regarding incident all-cause dementia (39-46% versus 26% of the original sample), AD dementia and AD biomarker positivity. The base rate corrected MCI definition had the highest prognostic accuracy. Conclusion: The operational criteria examined seem suitable to specify MCI in memory clinic settings, as they identify subjects at high risk of clinical progression. Depending on the neuropsychological battery in use, one or several of these criteria could help to calibrate the clinical judgment of test results, reduce false-positive decisions, and define risk-enriched groups for clinical trials.
- Published
- 2022
12. Association Between Ginkgo Biloba Extract Prescriptions and Dementia Incidence in Outpatients with Mild Cognitive Impairment in Germany: A Retrospective Cohort Study
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Bohlken, Jens, primary, Peters, Oliver, additional, and Kostev, Karel, additional
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- 2022
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13. Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer’s Disease Spectrum
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Teipel, Stefan J., primary, Dyrba, Martin, additional, Ballarini, Tommaso, additional, Brosseron, Frederic, additional, Bruno, Davide, additional, Buerger, Katharina, additional, Cosma, Nicoleta-Carmen, additional, Dechent, Peter, additional, Dobisch, Laura, additional, Düzel, Emrah, additional, Ewers, Michael, additional, Fliessbach, Klaus, additional, Haynes, John D., additional, Janowitz, Daniel, additional, Kilimann, Ingo, additional, Laske, Christoph, additional, Maier, Franziska, additional, Metzger, Coraline D., additional, Munk, Matthias H., additional, Peters, Oliver, additional, Pomara, Nunzio, additional, Preis, Lukas, additional, Priller, Josef, additional, Ramírez, Alfredo, additional, Roy, Nina, additional, Scheffler, Klaus, additional, Schneider, Anja, additional, Schott, Björn H., additional, Spottke, Annika, additional, Spruth, Eike J., additional, Wagner, Michael, additional, Wiltfang, Jens, additional, Jessen, Frank, additional, and Heneka, Michael T., additional
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- 2022
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14. Rationale, Design, and Methodology of a Prospective Cohort Study for Coping with Behavioral and Psychological Symptoms of Dementia: The RECage Project
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Poptsi, Eleni, primary, Tsolaki, Magda, additional, Bergh, Sverre, additional, Cesana, Bruno Mario, additional, Ciceone, Alfonso, additional, Fabbo, Andrea, additional, Frisoni, Giovanni B., additional, Frölich, Lutz, additional, Guazzarini, Anna Giulia, additional, Hugon, Jacques, additional, Fascendini, Sara, additional, Lavolpe, Sara, additional, Mecocci, Patrizia, additional, Peters, Oliver, additional, and Defanti, Carlo Alberto, additional
- Published
- 2021
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15. Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status
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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, Duzel, Emrah, Jessen, Frank, Peters, Oliver, Boecker, Henning, 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, Duzel, Emrah, Jessen, Frank, Peters, Oliver, and Boecker, Henning
- Abstract
Background: Amyloid-beta 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 (SCDA beta+) and amyloidnegative SCD (SCDA beta-) 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 (SUVRFBB). Results: ReHo was significantly higher (voxel-wise p < 0.01, cluster-level p < 0.05) in the bilateral precuneus for SCDA beta+ patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDA beta+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDA beta+) and precuneus SUVRFBB (both groups). Conclusion: While partial confounding influences due to a higher APOE epsilon 4 carrier ratio among SCDA beta+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-beta load, highlighting incipient pathology in stage 2 of the AD continuum.
- Published
- 2021
16. Identification of a Cascade of Changes in Activities of Daily Living Preceding Short-Term Clinical Deterioration in Mild Alzheimer's Disease Dementia via Lead-Lag Analysis
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Fuentes, Manuel, Klostermann, Arne, Kleineidam, Luca, Bauer, Chris, Schuchhardt, Johannes, Maier, Wolfgang, Jessen, Frank, Froelich, Lutz, Wiltfang, Jens, Kornhuber, Johannes, Kloeppel, Stefan, Schieting, Vera, Teipel, Stefan J., Wagner, Michael, Peters, Oliver, Fuentes, Manuel, Klostermann, Arne, Kleineidam, Luca, Bauer, Chris, Schuchhardt, Johannes, Maier, Wolfgang, Jessen, Frank, Froelich, Lutz, Wiltfang, Jens, Kornhuber, Johannes, Kloeppel, Stefan, Schieting, Vera, Teipel, Stefan J., Wagner, Michael, and Peters, Oliver
- Abstract
Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer's disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer's dementia (AD; MMSE= 23.9 +/- 2.88) were followed at 12 and 24 months. Leadlag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 neuropsychological subtest scores from the CERAD+ test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (Delta MMSE 5.8 +/- 8.64; Delta CDR-SOB 4.32 +/- 4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures.
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- 2020
17. Prominent Non-Memory Deficits in Alzheimer’s Disease Are Associated with Faster Disease Progression
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Scheltens, Nienke ME, Tijms, Betty M, Heymans, Martijn W, Rabinovici, Gil D, Cohn-Sheehy, Brendan I, Miller, Bruce L, Kramer, Joel H, Wolfsgruber, Steffen, Wagner, Michael, Kornhuber, Johannes, Peters, Oliver, Scheltens, Philip, van der Flier, Wiesje M, Amsterdam Dementia Cohort, Alzheimer’s Disease Neuroimaging Initiative, German Dementia Competence Network, University of San Francisco Memory and Aging Center, Neurology, Amsterdam Neuroscience - Neurodegeneration, Epidemiology and Data Science, APH - Personalized Medicine, and APH - Methodology
- Subjects
Male ,cognition ,0301 basic medicine ,Aging ,psychology [Alzheimer Disease] ,Time Factors ,Kaplan-Meier Estimate ,Disease ,Neuropsychological Tests ,Neurodegenerative ,Alzheimer's Disease ,0302 clinical medicine ,Risk of mortality ,2.1 Biological and endogenous factors ,Aetiology ,mortality [Memory Disorders] ,medicine.diagnostic_test ,subtypes ,General Neuroscience ,phenotypes ,General Medicine ,Neuropsychological test ,Psychiatry and Mental health ,Clinical Psychology ,University of San Francisco Memory and Aging Center ,Phenotype ,Neurological ,Cohort ,Disease Progression ,Female ,Mental health ,Cognitive Sciences ,Superior Sagittal Sinus ,Alzheimer’s disease ,clustering ,Alzheimer's Disease Neuroimaging Initiative ,medicine.medical_specialty ,Clinical Dementia Rating ,Clinical Sciences ,Amsterdam Dementia Cohort ,German Dementia Competence Network ,Article ,03 medical and health sciences ,disease progression ,Alzheimer Disease ,Clinical Research ,Internal medicine ,mental disorders ,Acquired Cognitive Impairment ,medicine ,Humans ,Dementia ,Memory impairment ,ddc:610 ,Aged ,Memory Disorders ,Neurology & Neurosurgery ,business.industry ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer’s Disease Neuroimaging Initiative ,medicine.disease ,mortality ,Brain Disorders ,Cross-Sectional Studies ,Good Health and Well Being ,030104 developmental biology ,mortality [Alzheimer Disease] ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Background: Alzheimer's disease (AD) is a heterogeneous disorder. Objective: To investigate whether cognitive AD subtypes are associated with different rates of disease progression. Methods: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. Results: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; p interaction
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- 2018
18. Value of Neuropsychological Tests to Identify Patients with Depressive Symptoms on the Alzheimer’s Disease Continuum
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Menne, Felix, primary, Schipke, Carola Gertrud, additional, Klostermann, Arne, additional, Fuentes-Casañ, Manuel, additional, Freiesleben, Silka Dawn, additional, Bauer, Chris, additional, and Peters, Oliver, additional
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- 2020
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19. Identification of a Cascade of Changes in Activities of Daily Living Preceding Short-Term Clinical Deterioration in Mild Alzheimer’s Disease Dementia via Lead-Lag Analysis
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Fuentes, Manuel, primary, Klostermann, Arne, additional, Kleineidam, Luca, additional, Bauer, Chris, additional, Schuchhardt, Johannes, additional, Maier, Wolfgang, additional, Jessen, Frank, additional, Frölich, Lutz, additional, Wiltfang, Jens, additional, Kornhuber, Johannes, additional, Klöppel, Stefan, additional, Schieting, Vera, additional, Teipel, Stefan J., additional, Wagner, Michael, additional, and Peters, Oliver, additional
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- 2020
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20. Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls
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Feinkohl, Insa, primary, Schipke, Carola G., additional, Kruppa, Jochen, additional, Menne, Felix, additional, Winterer, Georg, additional, Pischon, Tobias, additional, and Peters, Oliver, additional
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- 2020
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21. Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease
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Teipel, Stefan J., Metzger, Coraline D., Brosseron, Frederic, Buerger, Katharina, Brueggen, Katharina, Catak, Cihan, Diesing, Dominik, Dobisch, Laura, Fliessbach, 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, Rene J., Wagner, Michael, Duezel, Emrah, Jessen, Frank, Dyrba, Martin, Teipel, Stefan J., Metzger, Coraline D., Brosseron, Frederic, Buerger, Katharina, Brueggen, Katharina, Catak, Cihan, Diesing, Dominik, Dobisch, Laura, Fliessbach, 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, Rene J., Wagner, Michael, Duezel, Emrah, Jessen, Frank, and Dyrba, Martin
- 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.
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- 2018
22. Cerebrospinal Fluid Biomarkers and Clinical Progression in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment
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Wolfsgruber, Steffen, Polcher, Alexandra, Koppara, Alexander, Kleineidam, Luca, Froelich, Lutz, Peters, Oliver, Huell, Michael, Ruether, Eckart, Wiltfang, Jens, Maier, Wolfgang, Kornhuber, Johannes, Lewczuk, Piotr, Jessen, Frank, Wagner, Michael, Wolfsgruber, Steffen, Polcher, Alexandra, Koppara, Alexander, Kleineidam, Luca, Froelich, Lutz, Peters, Oliver, Huell, Michael, Ruether, Eckart, Wiltfang, Jens, Maier, Wolfgang, Kornhuber, Johannes, Lewczuk, Piotr, Jessen, Frank, and Wagner, Michael
- Abstract
Background: There is very limited data on the prevalence of abnormal cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and their predictive value for clinical progression in memory clinic patients with subjective cognitive decline (SCD). Objective: To assess the frequency of abnormal CSF biomarkers of AD and their predictive value for clinical progression in memory clinic patients with SCD in comparison to patients with mild cognitive impairment (MCI) from the same cohort. Methods: We analyzed prospective data from memory clinic patients of the German Competence Network Dementia cohort with a baseline diagnosis of SCD (n = 82) or MCI (n = 134), distinguished by actuarial neuropsychological MCI criteria ( Jak-Bondi criteria). Risk of clinical progression during 3-year follow-up was evaluated with Cox-Proportional-Hazard models. Results: Prevalence of abnormal values in CSF markers of tau-mediated neurodegeneration (67.8% versus 46.3%) but not of amyloid deposition (40.3% versus 35.4%) was significantly higher in MCI compared to SCD. The rate of incident AD dementia (26.1% versus 12.2%) was also significantly higher in MCI. In SCD, additional 22% progressed to MCI during follow-up. Combined amyloid/tau abnormality was the strongest predictor of clinical progression in both groups. Conclusion: High prevalence of biomarker abnormality and clinical progression, together with the predictive value of CSF biomarkers, in memory clinic patients with SCD support the validity and usefulness of this condition as a pre-MCI at risk stage of AD.
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- 2017
23. Cerebrospinal Fluid Biomarkers and Clinical Progression in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment
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Wolfsgruber, Steffen, primary, Polcher, Alexandra, additional, Koppara, Alexander, additional, Kleineidam, Luca, additional, Frölich, Lutz, additional, Peters, Oliver, additional, Hüll, Michael, additional, Rüther, Eckart, additional, Wiltfang, Jens, additional, Maier, Wolfgang, additional, Kornhuber, Johannes, additional, Lewczuk, Piotr, additional, Jessen, Frank, additional, and Wagner, Michael, additional
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- 2017
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24. Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer’s Disease
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Sabbagh, Marwan N., primary, Schäuble, Barbara, additional, Anand, Keshav, additional, Richards, Danielle, additional, Murayama, Shigeo, additional, Akatsu, Hiroyasu, additional, Takao, Masaki, additional, Rowe, Christopher C., additional, Masters, Colin L., additional, Barthel, Henryk, additional, Gertz, Hermann-Josef, additional, Peters, Oliver, additional, Rasgon, Natalie, additional, Jovalekic, Aleksandar, additional, Sabri, Osama, additional, Schulz-Schaeffer, Walter J., additional, and Seibyl, John, additional
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- 2017
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25. The Latent Dementia Phenotype delta is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment
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Koppara, Alexander, Wolfsgruber, Steffen, Kleineidam, Luca, Schmidtke, Klaus, Froelich, Lutz, Kurz, Alexander, Schulz, Stefanie, Hampel, Harald, Heuser, Isabella, Peters, Oliver, Reischies, Friedel M., Jahn, Holger, Luckhaus, Christian, Huell, Michael, Gertz, Hermann-Josef, Schroeder, Johannes, Pantel, Johannes, Rienhoff, Otto, Ruether, Eckart, Henn, Fritz, Wiltfang, Jens, Maier, Wolfgang, Jessen, Frank, Kornhuber, Johannes, Wagner, Michael, Koppara, Alexander, Wolfsgruber, Steffen, Kleineidam, Luca, Schmidtke, Klaus, Froelich, Lutz, Kurz, Alexander, Schulz, Stefanie, Hampel, Harald, Heuser, Isabella, Peters, Oliver, Reischies, Friedel M., Jahn, Holger, Luckhaus, Christian, Huell, Michael, Gertz, Hermann-Josef, Schroeder, Johannes, Pantel, Johannes, Rienhoff, Otto, Ruether, Eckart, Henn, Fritz, Wiltfang, Jens, Maier, Wolfgang, Jessen, Frank, Kornhuber, Johannes, and Wagner, Michael
- Abstract
Background: The recently proposed latent variable delta is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. Objective: To investigate the association of delta with AD biomarkers and to compare the prediction of d with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). Methods: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable delta and compared delta with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. Results: In patients with MCI, delta based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF A beta(42)/tau ratio indicative of AD (n = 340, AUC = 0.78, p < 0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC= 0.84, p < 0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of d based on reduced test batteries yielded somewhat lower effects. Conclusion: These findings support the interpretation of d as a construct capturing the disease-related essence of cognitive and functional impairments in patients with MCI and dementia, and suggest that d might become an analytical tool for dementia research.
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- 2016
26. Combination of Structural MRI and FDG-PET of the Brain Improves Diagnostic Accuracy in Newly Manifested Cognitive Impairment in Geriatric Inpatients
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Ritter, Kerstin, primary, Lange, Catharina, additional, Weygandt, Martin, additional, Mäurer, Anja, additional, Roberts, Anna, additional, Estrella, Melanie, additional, Suppa, Per, additional, Spies, Lothar, additional, Prasad, Vikas, additional, Steffen, Ingo, additional, Apostolova, Ivayla, additional, Bittner, Daniel, additional, Gövercin, Mehmet, additional, Brenner, Winfried, additional, Mende, Christine, additional, Peters, Oliver, additional, Seybold, Joachim, additional, Fiebach, Jochen B., additional, Steinhagen-Thiessen, Elisabeth, additional, Hampel, Harald, additional, Haynes, John-Dylan, additional, and Buchert, Ralph, additional
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- 2016
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27. The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment
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Koppara, Alexander, primary, Wolfsgruber, Steffen, additional, Kleineidam, Luca, additional, Schmidtke, Klaus, additional, Frölich, Lutz, additional, Kurz, Alexander, additional, Schulz, Stefanie, additional, Hampel, Harald, additional, Heuser, Isabella, additional, Peters, Oliver, additional, Reischies, Friedel M., additional, Jahn, Holger, additional, Luckhaus, Christian, additional, Hüll, Michael, additional, Gertz, Hermann-Josef, additional, Schröder, Johannes, additional, Pantel, Johannes, additional, Rienhoff, Otto, additional, Rüther, Eckart, additional, Henn, Fritz, additional, Wiltfang, Jens, additional, Maier, Wolfgang, additional, Jessen, Frank, additional, Kornhuber, Johannes, additional, and Wagner, Michael, additional
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- 2015
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28. Prediction of Alzheimer's Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status.
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Lange, Catharina, Suppa, Per, Pietrzyk, Uwe, Makowski, Marcus R., Spies, Lothar, Peters, Oliver, Buchert, Ralph, and Alzheimer’s Disease Neuroimaging Initiative
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ALZHEIMER'S disease ,MILD cognitive impairment ,MAGNETIC resonance imaging ,BIOMARKERS ,NEURODEGENERATION ,DIAGNOSIS of dementia ,ALZHEIMER'S disease diagnosis ,BRAIN metabolism ,AMYLOIDOSIS ,BRAIN ,DEOXY sugars ,LONGITUDINAL method ,NEUROPSYCHOLOGICAL tests ,NERVE tissue proteins ,RADIOPHARMACEUTICALS ,SURVIVAL analysis (Biometry) ,POSITRON emission tomography ,THREE-dimensional imaging ,DISEASE complications - Abstract
The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients. [ABSTRACT FROM AUTHOR]
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- 2018
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29. Alzheimer Amyloid Peptide Aβ42 Regulates Gene Expression of Transcription and Growth Factors
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Barucker, Christian, primary, Sommer, Anette, additional, Beckmann, Georg, additional, Eravci, Murat, additional, Harmeier, Anja, additional, Schipke, Carola G., additional, Brockschnieder, Damian, additional, Dyrks, Thomas, additional, Althoff, Veit, additional, Fraser, Paul E., additional, Hazrati, Lili-Naz, additional, George-Hyslop, Peter St, additional, Breitner, John C.S., additional, Peters, Oliver, additional, and Multhaup, Gerhard, additional
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- 2015
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30. APOE-Dependent Phenotypes in Subjects with Mild Cognitive Impairment Converting to Alzheimer's Disease
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Morgen, Katrin, primary, Frölich, Lutz, additional, Tost, Heike, additional, Plichta, Michael M., additional, Kölsch, Heike, additional, Rakebrandt, Fabian, additional, Rienhoff, Otto, additional, Jessen, Frank, additional, Peters, Oliver, additional, Jahn, Holger, additional, Luckhaus, Christian, additional, Hüll, Michael, additional, Gertz, Hermann-Josef, additional, Schröder, Johannes, additional, Hampel, Harald, additional, Teipel, Stefan J., additional, Pantel, Johannes, additional, Heuser, Isabella, additional, Wiltfang, Jens, additional, Rüther, Eckart, additional, Kornhuber, Johannes, additional, Maier, Wolfgang, additional, and Meyer-Lindenberg, Andreas, additional
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- 2013
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31. The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment.
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Koppara, Alexander, Wolfsgruber, Steffen, Kleineidam, Luca, Schmidtke, Klaus, Frölich, Lutz, Kurz, Alexander, Schulz, Stefanie, Hampel, Harald, Heuser, Isabella, Peters, Oliver, Reischies, Friedel M., Jahn, Holger, Luckhaus, Christian, Hüll, Michael, Gertz, Hermann-Josef, Schröder, Johannes, Pantel, Johannes, Rienhoff, Otto, Rütherg, Eckart, and Henn, Fritz
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DEMENTIA ,CEREBROSPINAL fluid ,BIOMARKERS ,ALZHEIMER'S disease ,MILD cognitive impairment ,PHENOTYPES ,GENETICS ,DIAGNOSIS of dementia ,COGNITION disorders ,LONGITUDINAL method ,NEUROPSYCHOLOGICAL tests ,NERVE tissue proteins ,PEPTIDES ,PSYCHOLOGICAL tests ,LOGISTIC regression analysis ,ACTIVITIES of daily living ,PREDICTIVE tests ,RETROSPECTIVE studies ,DISEASE progression ,PSYCHOLOGICAL factors ,PSYCHOLOGY - Abstract
Background: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials.Objective: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI).Methods: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences.Results: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p < 0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p < 0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects.Conclusion: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research. [ABSTRACT FROM AUTHOR]- Published
- 2016
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- View/download PDF
32. Validation of the Erlangen Score Algorithm for the Prediction of the Development of Dementia due to Alzheimer's Disease in Pre-Dementia Subjects.
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Lewczuk, Piotr, Kornhuber, Johannes, Toledo, Jon B., Trojanowski, John Q., Knapik-Czajka, Malgorzata, Peters, Oliver, Wiltfang, Jens, Shaw, Leslie M., German Dementia Competence Network, and US-ADNI
- Subjects
ALZHEIMER'S disease research ,DEMENTIA research ,BIOMARKERS ,CEREBROSPINAL fluid ,BLOOD-brain barrier - Abstract
Background: In previous studies, a dichotomous stratification of subjects into "cerebrospinal fluid (CSF) normal" and "CSF pathologic" was used to investigate the role of biomarkers in the prediction of progression to dementia in pre-dementia/mild cognitive impairment subjects. With the previously published Erlangen Score Algorithm, we suggested a division of CSF patterns into five groups, covering all possible CSF result combinations based on the presence of pathologic tau and/or amyloid-β CSF values.Objective: This study aimed to validate the Erlangen Score diagnostic algorithm based on the results of biomarkers analyses obtained in different patients cohorts, with different pre-analytical protocols, and with different laboratory analytical platforms.Methods: We evaluated the algorithm in two cohorts of pre-dementia subjects: the US-Alzheimer's Disease Neuroimaging Initiative and the German Dementia Competence Network.Results: In both cohorts, the Erlangen scores were strongly associated with progression to Alzheimer's disease. Neither the scores of the progressors nor the scores of the non-progressors differed significantly between the two projects, in spite of significant differences in the cohorts, laboratory methods, and the samples treatment.Conclusions: Our findings confirm the utility of the Erlangen Score algorithm as a useful tool in the early neurochemical diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]- Published
- 2015
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33. Association of N-Acetylaspartate and Cerebrospinal Fluid Aβ42 in Dementia
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Jessen, Frank, primary, Lewczuk, Piotr, additional, Gür, Okan, additional, Block, Wolfgang, additional, Ende, Gabriele, additional, Frölich, Lutz, additional, Hammen, Thilo, additional, Arlt, Sönke, additional, Kornhuber, Johannes, additional, Kucinski, Thomas, additional, Popp, Julius, additional, Peters, Oliver, additional, Maier, Wolfgang, additional, Träber, Frank, additional, and Wiltfang, Jens, additional
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- 2011
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34. Long-Term Stability of Alzheimer's Disease Biomarker Proteins in Cerebrospinal Fluid
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Schipke, Carola G., primary, Jessen, Frank, additional, Teipel, Stefan, additional, Luckhaus, Christian, additional, Wiltfang, Jens, additional, Esselmann, Hermann, additional, Frölich, Lutz, additional, Maier, Wolfgang, additional, Rüther, Eckart, additional, Heppner, Frank L., additional, Prokop, Stefan, additional, Heuser, Isabella, additional, and Peters, Oliver, additional
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- 2011
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35. Measurement of ERK 1/2 in CSF from Patients with Neuropsychiatric Disorders and Evidence for the Presence of the Activated Form
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Klafki, Hans-Wolfgang, primary, Lewczuk, Piotr, additional, Kamrowski-Kruck, Heike, additional, Maler, Juan Manuel, additional, Müller, Katharina, additional, Peters, Oliver, additional, Heuser, Isabella, additional, Jessen, Frank, additional, Popp, Julius, additional, Frölich, Lutz, additional, Wolf, Stefanie, additional, Prinz, Berit, additional, Luckhaus, Christian, additional, Schröder, Johannes, additional, Pantel, Johannes, additional, Gertz, Hermann-Josef, additional, Kölsch, Heike, additional, Müller, Bernhard W., additional, Esselmann, Hermann, additional, Bibl, Mirko, additional, Kornhuber, Johannes, additional, and Wiltfang, Jens, additional
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- 2009
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36. Astrocyte Function is Modified by Alzheimer's Disease-like Pathology in Aged Mice
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Peters, Oliver, primary, Schipke, Carola G., additional, Philipps, Andreas, additional, Haas, Brigitte, additional, Pannasch, Ulrike, additional, Wang, Li Ping, additional, Benedetti, Bruno, additional, Kingston, Ann E., additional, and Kettenmann, Helmut, additional
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- 2009
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37. Association of N-Acetylaspartate and Cerebrospinal Fluid Aβ42 in Dementia.
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Jessen, Frank, Lewczuk, Piotr, Gür, Okan, Block, Wolfgang, Ende, Gabriele, Frölich, Lutz, Hammen, Thilo, Arlt, Sönke, Kornhuber, Johannes, Kucinski, Thomas, Popp, Julius, Peters, Oliver, Maier, Wolfgang, Träber, Frank, and Wiltfang, Jens
- Subjects
AMYLOID ,MITOCHONDRIA ,ALZHEIMER'S disease research ,MILD cognitive impairment ,TEMPORAL lobe - Abstract
The interplay of amyloid and mitochondrial function is considered crucial in the pathophysiology of Alzheimer's disease (AD). We tested the association of the putative marker of mitochondrial function N-acetylaspartate (NAA) as measured by proton magnetic resonance spectroscopy within the medial temporal lobe and cerebrospinal fluid amyoid-β
42 (Aβ42 ), total Tau and pTau181. 109 patients were recruited in a multicenter study (40 mild AD patients, 14 non-AD dementia patients, 29 mild cognitive impairment (MCI) AD-type patients, 26 MCI of non-AD type patients). NAA correlated with Aβ42 within the AD group. Since the NAA concentration is coupled to neuronal mitochondrial function, the correlation between NAA and Aβ42 may reflect the interaction between disrupted mitochondrial pathways and amyloid production. [ABSTRACT FROM AUTHOR]- Published
- 2011
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38. Validation of the Erlangen Score Algorithm for the Prediction of the Development of Dementia due to Alzheimer's Disease in Pre-Dementia Subjects.
- Author
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Lewczuk, Piotr, Kornhuber, Johannes, Toledo, Jon B, Trojanowski, John Q, Knapik-Czajka, Malgorzata, Peters, Oliver, Wiltfang, Jens, Shaw, Leslie M, and US-ADNI
- Subjects
NEUROBEHAVIORAL disorders ,DEMENTIA - Abstract
A correction to the article "Validation of the Erlangen Score Algorithm for the Prediction of the Development of Dementia due to Alzheimer's Disease in Pre-Dementia Subjects" that was published in the 2015 issue is presented.
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- 2016
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39. Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy: A Bayesian Approach.
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Teipel SJ, Dyrba M, Levin F, Altenstein S, Berger M, Beyle A, Brosseron F, Buerger K, Burow L, Dobisch L, Ewers M, Fliessbach K, Frommann I, Glanz W, Goerss D, Gref D, Hansen N, Heneka MT, Incesoy EI, Janowitz D, Keles D, Kilimann I, Laske C, Lohse A, Munk MH, Perneczky R, Peters O, Preis L, Priller J, Rostamzadeh A, Roy N, Schmid M, Schneider A, Spottke A, Spruth EJ, Wiltfang J, Düzel E, Jessen F, Kleineidam L, and Wagner M
- 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., Competing Interests: SJT participated in scientific advisory boards of Roche Pharma AG, Biogen, Grifols, and Eisai and is member of the independent data safety and monitoring board of the Study ENVISION (Biogen)., (© 2023 – The authors. Published by IOS Press.)
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- 2023
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40. Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline.
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Daamen M, Scheef L, Li S, Grothe MJ, Gaertner FC, Buchert R, Buerger K, Dobisch L, Drzezga A, Essler M, Ewers M, Fliessbach K, Herrera Melendez AL, Hetzer S, Janowitz D, Kilimann I, Krause BJ, Lange C, Laske C, Munk MH, Peters O, Priller J, Ramirez A, Reimold M, Rominger A, Rostamzadeh A, Roeske S, Roy N, Scheffler K, Schneider A, Spottke A, Spruth EJ, Teipel SJ, Wagner M, Düzel E, Jessen F, and Boecker H
- Subjects
- Humans, Amyloid metabolism, Magnetic Resonance Imaging methods, Positron-Emission Tomography, Amyloidogenic Proteins, Amyloid beta-Peptides metabolism, Basal Forebrain diagnostic imaging, Alzheimer Disease diagnostic imaging, Alzheimer Disease pathology, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction pathology
- 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.
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- 2023
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41. A Residual Marker of Cognitive Reserve Is Associated with Resting-State Intrinsic Functional Connectivity Along the Alzheimer's Disease Continuum.
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Ersoezlue E, Perneczky R, Tato M, Utecht J, Kurz C, Häckert J, Guersel S, Burow L, Koller G, Stoecklein S, Keeser D, Papazov B, Totzke M, Ballarini T, Brosseron F, Buerger K, Dechent P, Dobisch L, Ewers M, Fliessbach K, Glanz W, Haynes JD, Heneka MT, Janowitz D, Kilimann I, Kleineidam L, Laske C, Maier F, Munk MH, Peters O, Priller J, Ramirez A, Roeske S, Roy N, Scheffler K, Schneider A, Schott BH, Spottke A, Spruth EJ, Teipel S, Unterfeld C, Wagner M, Wang X, Wiltfang J, Wolfsgruber S, Yakupov R, Duezel E, Jessen F, and Rauchmann BS
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- Humans, Cognition, Neural Pathways, Nerve Net, Magnetic Resonance Imaging, Brain diagnostic imaging, Alzheimer Disease pathology, Cognitive Reserve
- 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.
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- 2023
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42. Relevance of Subjective Cognitive Decline in Older Adults with a First-Degree Family History of Alzheimer's Disease.
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Wolfsgruber S, Kleineidam L, Weyrauch AS, Barkhoff M, Röske S, Peters O, Preis L, Gref D, Spruth EJ, Altenstein S, Priller J, Fließbach K, Schneider A, Wiltfang J, Bartels C, Jessen F, Maier F, Düzel E, Metzger C, Glanz W, Buerger K, Janowitz D, Perneczky R, Rauchmann BS, Kilimann I, Teipel S, Laske C, Munk MH, Roy N, Spottke A, Ramirez A, Heneka MT, Brosseron F, and Wagner M
- Subjects
- Aged, Biomarkers cerebrospinal fluid, Cross-Sectional Studies, Female, Humans, Male, Neuropsychological Tests, Alzheimer Disease pathology, Cognitive Dysfunction psychology
- 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.
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- 2022
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43. Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status.
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Li S, Daamen M, Scheef L, Gaertner FC, Buchert R, Buchmann M, Buerger K, Catak C, Dobisch L, Drzezga A, Ertl-Wagner B, Essler M, Fliessbach K, Haynes JD, Incesoy EI, Kilimann I, Krause BJ, Lange C, Laske C, Priller J, Ramirez A, Reimold M, Rominger A, Roy N, Scheffler K, Maurer A, Schneider A, Spottke A, Spruth EJ, Teipel SJ, Tscheuschler M, Wagner M, Wolfsgruber S, Düzel E, Jessen F, Peters O, and Boecker H
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- Aged, Aniline Compounds, Cohort Studies, Female, Humans, Male, Parietal Lobe pathology, Stilbenes, Amyloid beta-Peptides metabolism, Cognitive Dysfunction diagnostic imaging, Magnetic Resonance Imaging
- 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.
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- 2021
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44. Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease.
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Teipel SJ, Metzger CD, Brosseron F, Buerger K, Brueggen K, Catak C, Diesing D, Dobisch L, Fliebach K, Franke C, Heneka MT, Kilimann I, Kofler B, Menne F, Peters O, Polcher A, Priller J, Schneider A, Spottke A, Spruth EJ, Thelen M, Thyrian RJ, Wagner M, Düzel E, Jessen F, and Dyrba M
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- Aged, Alzheimer Disease cerebrospinal fluid, Amyloid beta-Peptides cerebrospinal fluid, Female, Germany, Humans, Image Processing, Computer-Assisted, Male, Oxygen blood, Peptide Fragments cerebrospinal fluid, Alzheimer Disease diagnostic imaging, Alzheimer Disease physiopathology, Brain diagnostic imaging, Dementia diagnostic imaging, Magnetic Resonance Imaging, Prodromal Symptoms, Rest
- 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.
- Published
- 2018
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