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1. Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer's disease.

Author

Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, González, Pablo García, McManus, Róisín M., Ising, Christina, Santarelli, Francesco, Kolbe, Carl-Christian, Häsler, Lisa M., Wolfsgruber, Steffen, Marquié, Marta, Boada, Mercè, Orellana, Adelina, de Rojas, Itziar, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Cetindag, Arda, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Bürger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Laske, Christoph, Munk, Matthias H., Düzel, Emrah, Yakupov, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Teunissen, Charlotte E., Marchant, Natalie L., Spottke, Annika, Jucker, Mathias, Latz, Eicke, Wagner, Michael, Mengel, David, Synofzik, Matthis, Jessen, Frank, Ramirez, Alfredo, Ruiz, Agustín, Heneka, Michael, Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, González, Pablo García, McManus, Róisín M., Ising, Christina, Santarelli, Francesco, Kolbe, Carl-Christian, Häsler, Lisa M., Wolfsgruber, Steffen, Marquié, Marta, Boada, Mercè, Orellana, Adelina, de Rojas, Itziar, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Cetindag, Arda, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Bürger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Laske, Christoph, Munk, Matthias H., Düzel, Emrah, Yakupov, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Teunissen, Charlotte E., Marchant, Natalie L., Spottke, Annika, Jucker, Mathias, Latz, Eicke, Wagner, Michael, Mengel, David, Synofzik, Matthis, Jessen, Frank, Ramirez, Alfredo, Ruiz, Agustín, and Heneka, Michael

Abstract

There is an urgent need to improve the understanding of neuroinflammation in Alzheimer's disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile.

Published
2022

2. Musical Activity During Life Is Associated With Multi-Domain Cognitive and Brain Benefits in Older Adults

Author

Böttcher, Adriana, Zarucha, Alexis, Köbe, Theresa, Gaubert, Malo, Höppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Düzel, Emrah, Jessen, Frank, Röske, Sandra, Wagner, Michael, Kempermann, Gerd, Wirth, Miranka, Böttcher, Adriana, Zarucha, Alexis, Köbe, Theresa, Gaubert, Malo, Höppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Düzel, Emrah, Jessen, Frank, Röske, Sandra, Wagner, Michael, Kempermann, Gerd, and Wirth, Miranka

Abstract

Regular musical activity as a complex multimodal lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer’s disease. This cross-sectional study investigated the association and interplay between musical instrument playing during life, multi-domain cognitive abilities and brain morphology in older adults (OA) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Participants reporting having played a musical instrument across three life periods (n = 70) were compared to controls without a history of musical instrument playing (n = 70), well-matched for reserve proxies of education, intelligence, socioeconomic status and physical activity. Participants with musical activity outperformed controls in global cognition, working memory, executive functions, language, and visuospatial abilities, with no effects seen for learning and memory. The musically active group had greater gray matter volume in the somatosensory area, but did not differ from controls in higher-order frontal, temporal, or hippocampal volumes. However, the association between gray matter volume in distributed frontal-to-temporal regions and cognitive abilities was enhanced in participants with musical activity compared to controls. We show that playing a musical instrument during life relates to better late-life cognitive abilities and greater brain capacities in OA. Musical activity may serve as a multimodal enrichment strategy that could help preserve cognitive and brain health in late life. Longitudinal and interventional studies are needed to support this notion.

Published
2022

3. Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer’s disease

Author

Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, González, Pablo García, McManus, Róisín M., Ising, Christina, Santarelli, Francesco, Kolbe, Carl-Christian, Häsler, Lisa M., Wolfsgruber, Steffen, Marquie, Marta, Boada, Merce, Orellana, Adelina, de Rojas, Itziar, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Cetindag, Arda, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Bürger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan J., Kilimann, Ingo, Görß, Doreen, Laske, Christoph, Munk, Matthias H., Duzel, Emrah, Yakupov, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Teunissen, Charlotte E., Marchant, Natalie L., Spottke, Annika, Jucker, Mathias, Latz, Eicke, Wagner, Michael, Mengel, David, Synofzik, Matthis, Jessen, Frank, Ramirez, Alfredo, Ruiz, Agustin, Heneka, Michael T., Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, González, Pablo García, McManus, Róisín M., Ising, Christina, Santarelli, Francesco, Kolbe, Carl-Christian, Häsler, Lisa M., Wolfsgruber, Steffen, Marquie, Marta, Boada, Merce, Orellana, Adelina, de Rojas, Itziar, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Cetindag, Arda, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Bürger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan J., Kilimann, Ingo, Görß, Doreen, Laske, Christoph, Munk, Matthias H., Duzel, Emrah, Yakupov, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Teunissen, Charlotte E., Marchant, Natalie L., Spottke, Annika, Jucker, Mathias, Latz, Eicke, Wagner, Michael, Mengel, David, Synofzik, Matthis, Jessen, Frank, Ramirez, Alfredo, Ruiz, Agustin, and Heneka, Michael T.

Published
2022

4. Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve

Author

Kleineidam, Luca, Wolfsgruber, Steffen, Weyrauch, Anne-Sophie, Zulka, Linn E., Forstmeier, Simon, Roeske, Sandra, van den Bussche, Hendrik, Kaduszkiewicz, Hanna, Wiese, Birgitt, Weyerer, Siegfried, Werle, Jochen, Fuchs, Angela, Pentzek, Michael, Brettschneider, Christian, Konig, Hans-Helmut, Weeg, Dagmar, Bickel, Horst, Luppa, Melanie, Rodriguez, Francisca S., Freiesleben, Silka Dawn, Erdogan, Selin, Unterfeld, Chantal, Peters, Oliver, Spruth, Eike J., Altenstein, Slawek, Lohse, Andrea, Priller, Josef, Fliessbach, Klaus, Kobeleva, Xenia, Schneider, Anja, Bartels, Claudia, Schott, Bjoern H., Wiltfang, Jens, Maier, Franziska, Glanz, Wenzel, Incesoy, Enise I., Butryn, Michaela, Duezel, Emrah, Buerger, Katharina, Janowitz, Daniel, Ewers, Michael, Rauchmann, Boris-Stephan, Perneczky, Robert, Kilimann, Ingo, Goerss, Doreen, Teipel, Stefan, Laske, Christoph, Munk, Matthias H. J., Spottke, Annika, Roy, Nina, Brosseron, Frederic, Heneka, Michael T., Ramirez, Alfredo, Yakupov, Renat, Scherer, Martin, Maier, Wolfgang, Jessen, Frank, Riedel-Heller, Steffi G., Wagner, Michael, Kleineidam, Luca, Wolfsgruber, Steffen, Weyrauch, Anne-Sophie, Zulka, Linn E., Forstmeier, Simon, Roeske, Sandra, van den Bussche, Hendrik, Kaduszkiewicz, Hanna, Wiese, Birgitt, Weyerer, Siegfried, Werle, Jochen, Fuchs, Angela, Pentzek, Michael, Brettschneider, Christian, Konig, Hans-Helmut, Weeg, Dagmar, Bickel, Horst, Luppa, Melanie, Rodriguez, Francisca S., Freiesleben, Silka Dawn, Erdogan, Selin, Unterfeld, Chantal, Peters, Oliver, Spruth, Eike J., Altenstein, Slawek, Lohse, Andrea, Priller, Josef, Fliessbach, Klaus, Kobeleva, Xenia, Schneider, Anja, Bartels, Claudia, Schott, Bjoern H., Wiltfang, Jens, Maier, Franziska, Glanz, Wenzel, Incesoy, Enise I., Butryn, Michaela, Duezel, Emrah, Buerger, Katharina, Janowitz, Daniel, Ewers, Michael, Rauchmann, Boris-Stephan, Perneczky, Robert, Kilimann, Ingo, Goerss, Doreen, Teipel, Stefan, Laske, Christoph, Munk, Matthias H. J., Spottke, Annika, Roy, Nina, Brosseron, Frederic, Heneka, Michael T., Ramirez, Alfredo, Yakupov, Renat, Scherer, Martin, Maier, Wolfgang, Jessen, Frank, Riedel-Heller, Steffi G., and Wagner, Michael

Abstract

IntroductionSeveral lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them. MethodsWe systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-epsilon 4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE). ResultsRegarding (1), higher OCRS was associated with a reduced association of APOE-epsilon 4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF A beta 42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR wa

Published
2022

5. Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer's disease

Author

Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, Gonzalez, Pablo Garcia, McManus, Roisin M., Ising, Christina, Santarelli, Francesco, Kolbe, Carl-Christian, Haesler, Lisa M., Wolfsgruber, Steffen, Marquie, Marta, Boada, Merce, Orellana, Adelina, de Rojas, Itziar, Roeske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Cetindag, Arda, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Bjorn H., Buerger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Laske, Christoph, Munk, Matthias H., Duzel, Emrah, Yakupov, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Teunissen, Charlotte E., Marchant, Natalie L., Spottke, Annika, Jucker, Mathias, Latz, Eicke, Wagner, Michael, Mengel, David, Synofzik, Matthis, Jessen, Frank, Ramirez, Alfredo, Ruiz, Agustin, Heneka, Michael T., Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, Gonzalez, Pablo Garcia, McManus, Roisin M., Ising, Christina, Santarelli, Francesco, Kolbe, Carl-Christian, Haesler, Lisa M., Wolfsgruber, Steffen, Marquie, Marta, Boada, Merce, Orellana, Adelina, de Rojas, Itziar, Roeske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Cetindag, Arda, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Bjorn H., Buerger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Laske, Christoph, Munk, Matthias H., Duzel, Emrah, Yakupov, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Teunissen, Charlotte E., Marchant, Natalie L., Spottke, Annika, Jucker, Mathias, Latz, Eicke, Wagner, Michael, Mengel, David, Synofzik, Matthis, Jessen, Frank, Ramirez, Alfredo, Ruiz, Agustin, and Heneka, Michael T.

Abstract

There is an urgent need to improve the understanding of neuroinflammation in Alzheimer's disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile.

Published
2022

6. Musical Activity During Life Is Associated With Multi-Domain Cognitive and Brain Benefits in Older Adults

Author

Boettcher, Adriana, Zarucha, Alexis, Koebe, Theresa, Gaubert, Malo, Hoeppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Duezel, Emrah, Jessen, Frank, Roeske, Sandra, Wagner, Michael, Kempermann, Gerd, Wirth, Miranka, Boettcher, Adriana, Zarucha, Alexis, Koebe, Theresa, Gaubert, Malo, Hoeppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Duezel, Emrah, Jessen, Frank, Roeske, Sandra, Wagner, Michael, Kempermann, Gerd, and Wirth, Miranka

Abstract

Regular musical activity as a complex multimodal lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer's disease. This cross-sectional study investigated the association and interplay between musical instrument playing during life, multi-domain cognitive abilities and brain morphology in older adults (OA) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Participants reporting having played a musical instrument across three life periods (n = 70) were compared to controls without a history of musical instrument playing (n = 70), well-matched for reserve proxies of education, intelligence, socioeconomic status and physical activity. Participants with musical activity outperformed controls in global cognition, working memory, executive functions, language, and visuospatial abilities, with no effects seen for learning and memory. The musically active group had greater gray matter volume in the somatosensory area, but did not differ from controls in higher-order frontal, temporal, or hippocampal volumes. However, the association between gray matter volume in distributed frontal-to-temporal regions and cognitive abilities was enhanced in participants with musical activity compared to controls. We show that playing a musical instrument during life relates to better late-life cognitive abilities and greater brain capacities in OA. Musical activity may serve as a multimodal enrichment strategy that could help preserve cognitive and brain health in late life. Longitudinal and interventional studies are needed to support this notion.

Published
2022

7. Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease

Author

Billette, Ornella, V, Ziegler, Gabriel, Aruci, Merita, Schuetze, Hartmut, Kizilirmak, Jasmin M., Richter, Anni, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Cardenas-Blanco, Arturo, Dahmen, Philip, Dechent, Peter, Dobisch, Laura, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Goeerss, Doreen, Haynes, John Dylan, Heneka, Michael T., Kilimann, Ingo, Kimmich, Okka, Kleineidam, Luca, Laske, Christoph, Lohse, Andrea, Rostamzadeh, Ayda, Metzger, Coraline, Munk, Matthias H., Peters, Oliver, Preis, Lukas, Priller, Josef, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Ramirez, Alfredo, Roeske, Sandra, Roy, Nina, Teipel, Stefan, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Zeidman, Peter, Jessen, Frank, Schott, Bjorn H., Duezel, Emrah, Maass, Anne, Billette, Ornella, V, Ziegler, Gabriel, Aruci, Merita, Schuetze, Hartmut, Kizilirmak, Jasmin M., Richter, Anni, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Cardenas-Blanco, Arturo, Dahmen, Philip, Dechent, Peter, Dobisch, Laura, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Goeerss, Doreen, Haynes, John Dylan, Heneka, Michael T., Kilimann, Ingo, Kimmich, Okka, Kleineidam, Luca, Laske, Christoph, Lohse, Andrea, Rostamzadeh, Ayda, Metzger, Coraline, Munk, Matthias H., Peters, Oliver, Preis, Lukas, Priller, Josef, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Ramirez, Alfredo, Roeske, Sandra, Roy, Nina, Teipel, Stefan, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Zeidman, Peter, Jessen, Frank, Schott, Bjorn H., Duezel, Emrah, and Maass, Anne

Abstract

Background and Objectives We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy. Methods We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of beta-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education. Results In the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the pre

Published
2022

8. Relevance of Subjective Cognitive Decline in Older Adults with a First-Degree Family History of Alzheimer's Disease

Author

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.

Published
2022

9. Musical Activity During Life Is Associated With Multi-Domain Cognitive and Brain Benefits in Older Adults

Author

Böttcher, Adriana, Zarucha, Alexis, Köbe, Theresa, Gaubert, Malo, Höppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Düzel, Emrah, Jessen, Frank, Röske, Sandra, Wagner, Michael, Kempermann, Gerd, Wirth, Miranka, Böttcher, Adriana, Zarucha, Alexis, Köbe, Theresa, Gaubert, Malo, Höppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Düzel, Emrah, Jessen, Frank, Röske, Sandra, Wagner, Michael, Kempermann, Gerd, and Wirth, Miranka

Abstract

Regular musical activity as a complex multimodal lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer’s disease. This cross-sectional study investigated the association and interplay between musical instrument playing during life, multi-domain cognitive abilities and brain morphology in older adults (OA) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Participants reporting having played a musical instrument across three life periods (n = 70) were compared to controls without a history of musical instrument playing (n = 70), well-matched for reserve proxies of education, intelligence, socioeconomic status and physical activity. Participants with musical activity outperformed controls in global cognition, working memory, executive functions, language, and visuospatial abilities, with no effects seen for learning and memory. The musically active group had greater gray matter volume in the somatosensory area, but did not differ from controls in higher-order frontal, temporal, or hippocampal volumes. However, the association between gray matter volume in distributed frontal-to-temporal regions and cognitive abilities was enhanced in participants with musical activity compared to controls. We show that playing a musical instrument during life relates to better late-life cognitive abilities and greater brain capacities in OA. Musical activity may serve as a multimodal enrichment strategy that could help preserve cognitive and brain health in late life. Longitudinal and interventional studies are needed to support this notion.

Published
2022

10. Musical Activity During Life Is Associated With Multi-Domain Cognitive and Brain Benefits in Older Adults

Author

Böttcher, Adriana, Zarucha, Alexis, Köbe, Theresa, Gaubert, Malo, Höppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Düzel, Emrah, Jessen, Frank, Röske, Sandra, Wagner, Michael, Kempermann, Gerd, Wirth, Miranka, Böttcher, Adriana, Zarucha, Alexis, Köbe, Theresa, Gaubert, Malo, Höppner, Angela, Altenstein, Slawek, Bartels, Claudia, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Haynes, John Dylan, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline, Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Teipel, Stefan J., Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Düzel, Emrah, Jessen, Frank, Röske, Sandra, Wagner, Michael, Kempermann, Gerd, and Wirth, Miranka

Abstract

Regular musical activity as a complex multimodal lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer’s disease. This cross-sectional study investigated the association and interplay between musical instrument playing during life, multi-domain cognitive abilities and brain morphology in older adults (OA) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Participants reporting having played a musical instrument across three life periods (n = 70) were compared to controls without a history of musical instrument playing (n = 70), well-matched for reserve proxies of education, intelligence, socioeconomic status and physical activity. Participants with musical activity outperformed controls in global cognition, working memory, executive functions, language, and visuospatial abilities, with no effects seen for learning and memory. The musically active group had greater gray matter volume in the somatosensory area, but did not differ from controls in higher-order frontal, temporal, or hippocampal volumes. However, the association between gray matter volume in distributed frontal-to-temporal regions and cognitive abilities was enhanced in participants with musical activity compared to controls. We show that playing a musical instrument during life relates to better late-life cognitive abilities and greater brain capacities in OA. Musical activity may serve as a multimodal enrichment strategy that could help preserve cognitive and brain health in late life. Longitudinal and interventional studies are needed to support this notion.

Published
2022

11. Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer's disease spectrum

Author

Amaefule, Chimezie O., Dyrba, Martin, Wolfsgruber, Steffen, Polcher, Alexandra, Schneider, Anja, Fliessbach, Klaus, Spottke, Annika, Meiberth, Dix, Preis, Lukas, Peters, Oliver, Incesoy, Enise I., Spruth, Eike J., Priller, Josef, Altenstein, Slawek, Bartels, Claudia, Wiltfang, Jens, Janowitz, Daniel, Buerger, Katharina, Laske, Christoph, Munk, Matthias, Rudolph, Janna, Glanz, Wenzel, Dobisch, Laura, Haynes, John D., Dechent, Peter, Ertl-Wagner, Birgit, Scheffler, Klaus, Kilimann, Ingo, Duezel, Emrah, Metzger, Coraline D., Wagner, Michael, Jessen, Frank, Teipel, Stefan J., Amaefule, Chimezie O., Dyrba, Martin, Wolfsgruber, Steffen, Polcher, Alexandra, Schneider, Anja, Fliessbach, Klaus, Spottke, Annika, Meiberth, Dix, Preis, Lukas, Peters, Oliver, Incesoy, Enise I., Spruth, Eike J., Priller, Josef, Altenstein, Slawek, Bartels, Claudia, Wiltfang, Jens, Janowitz, Daniel, Buerger, Katharina, Laske, Christoph, Munk, Matthias, Rudolph, Janna, Glanz, Wenzel, Dobisch, Laura, Haynes, John D., Dechent, Peter, Ertl-Wagner, Birgit, Scheffler, Klaus, Kilimann, Ingo, Duezel, Emrah, Metzger, Coraline D., Wagner, Michael, Jessen, Frank, and Teipel, Stefan J.

Abstract

Background: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer's disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. Method: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. Result: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. Conclusion: Consistent associations between cognitive domain score

Published
2021

12. Improving 3D convolutional neural network comprehensibility via interactive visualization of relevance maps: evaluation in Alzheimer's disease

Author

Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantre, Daniel, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Bjoern H., Spottke, Annika, Spruth, Eike J., Weber, Marc-Andre, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, Teipel, Stefan J., Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantre, Daniel, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Bjoern H., Spottke, Annika, Spruth, Eike J., Weber, Marc-Andre, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, and Teipel, Stefan J.

Abstract

Background Although convolutional neural networks (CNNs) achieve high diagnostic accuracy for detecting Alzheimer's disease (AD) dementia based on magnetic resonance imaging (MRI) scans, they are not yet applied in clinical routine. One important reason for this is a lack of model comprehensibility. Recently developed visualization methods for deriving CNN relevance maps may help to fill this gap as they allow the visualization of key input image features that drive the decision of the model. We investigated whether models with higher accuracy also rely more on discriminative brain regions predefined by prior knowledge. Methods We trained a CNN for the detection of AD in N = 663 T1-weighted MRI scans of patients with dementia and amnestic mild cognitive impairment (MCI) and verified the accuracy of the models via cross-validation and in three independent samples including in total N = 1655 cases. We evaluated the association of relevance scores and hippocampus volume to validate the clinical utility of this approach. To improve model comprehensibility, we implemented an interactive visualization of 3D CNN relevance maps, thereby allowing intuitive model inspection. Results Across the three independent datasets, group separation showed high accuracy for AD dementia versus controls (AUC >= 0.91) and moderate accuracy for amnestic MCI versus controls (AUC approximate to 0.74). Relevance maps indicated that hippocampal atrophy was considered the most informative factor for AD detection, with additional contributions from atrophy in other cortical and subcortical regions. Relevance scores within the hippocampus were highly correlated with hippocampal volumes (Pearson's r approximate to -0.86, p < 0.001). Conclusion The relevance maps highlighted atrophy in regions that we had hypothesized a priori. This strengthens the comprehensibility of the CNN models, which were trained in a purely data-driven manner based on the scans and diagnosis labels. The high hippocampus relev

Published
2021

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

Author

Ballarini, Tommaso, van Lent, Debora Melo, Brunner, Julia, Schroeder, Alina, Wolfsgruber, Steffen, Altenstein, Slawek, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Hauser, Dietmar, Haynes, John Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline Danielle, Munk, Matthias, Perneczky, Robert, Peters, Oliver, Priller, Josef, Ramirez, Alfredo, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, Wagner, Michael, Ballarini, Tommaso, van Lent, Debora Melo, Brunner, Julia, Schroeder, Alina, Wolfsgruber, Steffen, Altenstein, Slawek, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Hauser, Dietmar, Haynes, John Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline Danielle, Munk, Matthias, Perneczky, Robert, Peters, Oliver, Priller, Josef, Ramirez, Alfredo, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, and Wagner, Michael

Abstract

Objective To determine whether following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer disease (AD), we analyzed cross-sectional data from the German DZNE-Longitudinal Cognitive Impairment and Dementia Study. Method The sample (n = 512, mean age 69.5 +/- 5.9 years) included 169 cognitively normal participants and individuals at higher AD risk (53 with relatives with AD, 209 with subjective cognitive decline, and 81 with mild cognitive impairment). We defined MeDi adherence according to the food frequency questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI, and cognitive performance was assessed with an extensive neuropsychological battery. AD-related biomarkers (beta-amyloid(42/40) [A beta(42/40)] ratio, phosphorylated tau 181 [pTau181]) in CSF were assessed in n = 226 individuals. We analyzed the associations between MeDi and outcomes with linear regression models controlling for several covariates. In addition, we applied hypothesis-driven mediation and moderation analysis. Results Higher MeDi adherence related to larger mediotemporal gray matter volume (p < 0.05 family-wise error corrected), better memory (beta +/- SE = 0.03 +/- 0.02; p = 0.038), and less amyloid (A beta(42/40) ratio, beta +/- SE = 0.003 +/- 0.001; p = 0.008) and pTau181 (beta +/- SE = -1.96 +/- 0.68; p = 0.004) pathology. Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations among A beta(42/40) ratio, pTau181, and mediotemporal atrophy. Results were consistent correcting for APOE-epsilon 4 status. Conclusion Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. They suggest that these associations might be explained by a decrease of amyloidosis and tau pathology. Longitudinal and dietary intervention studies should further examine this conjecture and it

Published
2021

14. Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer’s disease

Author

Wesselman, L. M. P., van Lent, D. Melo, Schröder, A., van de Rest, O., Peters, Oliver, Menne, Felix, Fuentes, M., Priller, Josef, Spruth, E. J., Altenstein, Slawek, Schneider, Anja, Fließbach, K., Roeske, Sandra, Wolfsgruber, S., Kleineidam, L., Spottke, A., Pross, V., Wiltfang, Jens, Vukovich, R., Schild, A. K., Duzel, Emrah, Metzger, C. D., Glanz, Wenzel, Buerger, K., Janowitz, D., Perneczky, Robert, Tato, M., Teipel, Stefan J., Kilimann, Ingo, Laske, C., Buchmann, M., Ramirez, Alfredo, Sikkes, S. A. M., Jessen, Frank, van der Flier, Wiesje M., Wagner, Michael, Wesselman, L. M. P., van Lent, D. Melo, Schröder, A., van de Rest, O., Peters, Oliver, Menne, Felix, Fuentes, M., Priller, Josef, Spruth, E. J., Altenstein, Slawek, Schneider, Anja, Fließbach, K., Roeske, Sandra, Wolfsgruber, S., Kleineidam, L., Spottke, A., Pross, V., Wiltfang, Jens, Vukovich, R., Schild, A. K., Duzel, Emrah, Metzger, C. D., Glanz, Wenzel, Buerger, K., Janowitz, D., Perneczky, Robert, Tato, M., Teipel, Stefan J., Kilimann, Ingo, Laske, C., Buchmann, M., Ramirez, Alfredo, Sikkes, S. A. M., Jessen, Frank, van der Flier, Wiesje M., and Wagner, Michael

Published
2021

15. Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer’s disease spectrum

Author

Amaefule, Chimezie O., Dyrba, Martin, Wolfsgruber, Steffen, Polcher, Alexandra, Schneider, Anja, Fliessbach, Klaus, Spottke, Annika, Meiberth, Dix, Preis, Lukas, Peters, Oliver, Incesoy, Enise I., Spruth, Eike J., Priller, Josef, Altenstein, Slawek, Bartels, Claudia, Wiltfang, Jens, Janowitz, Daniel, Bürger, Katharina, Laske, Christoph, Munk, Matthias H., Rudolph, Janna, Glanz, Wenzel, Dobisch, Laura, Haynes, John-Dylan, Dechent, Peter, Ertl-Wagner, Birgit, Scheffler, Klaus, Kilimann, Ingo, Duzel, Emrah, Metzger, Coraline D., Wagner, Michael, Jessen, Frank, Teipel, Stefan J., Amaefule, Chimezie O., Dyrba, Martin, Wolfsgruber, Steffen, Polcher, Alexandra, Schneider, Anja, Fliessbach, Klaus, Spottke, Annika, Meiberth, Dix, Preis, Lukas, Peters, Oliver, Incesoy, Enise I., Spruth, Eike J., Priller, Josef, Altenstein, Slawek, Bartels, Claudia, Wiltfang, Jens, Janowitz, Daniel, Bürger, Katharina, Laske, Christoph, Munk, Matthias H., Rudolph, Janna, Glanz, Wenzel, Dobisch, Laura, Haynes, John-Dylan, Dechent, Peter, Ertl-Wagner, Birgit, Scheffler, Klaus, Kilimann, Ingo, Duzel, Emrah, Metzger, Coraline D., Wagner, Michael, Jessen, Frank, and Teipel, Stefan J.

Published
2021

16. Improving 3D convolutional neural network comprehensibility via interactive visualization of relevance maps: evaluation in Alzheimer’s disease

Author

Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantré, Daniel, Dechent, Peter, Dobisch, Laura, Duzel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H., Spottke, Annika, Spruth, Eike J., Weber, Marc-André, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, Teipel, Stefan J., Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantré, Daniel, Dechent, Peter, Dobisch, Laura, Duzel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H., Spottke, Annika, Spruth, Eike J., Weber, Marc-André, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, and Teipel, Stefan J.

Published
2021

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

Author

Ballarini, Tommaso, Melo van Lent, Debora, Brunner, Julia, Schröder, Alina, Wolfsgruber, Steffen, Altenstein, Slawek, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Duzel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Hauser, Dietmar, Haynes, John Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline Danielle, Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Priller, Josef, Ramirez, Alfredo, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, Wagner, Michael, Ballarini, Tommaso, Melo van Lent, Debora, Brunner, Julia, Schröder, Alina, Wolfsgruber, Steffen, Altenstein, Slawek, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Duzel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Hauser, Dietmar, Haynes, John Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline Danielle, Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Priller, Josef, Ramirez, Alfredo, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, and Wagner, Michael

Published
2021

18. Improving 3D convolutional neural network comprehensibility via interactive visualization of relevance maps: evaluation in Alzheimer's disease

Author

Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantre, Daniel, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Bjoern H., Spottke, Annika, Spruth, Eike J., Weber, Marc-Andre, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, Teipel, Stefan J., Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantre, Daniel, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Bjoern H., Spottke, Annika, Spruth, Eike J., Weber, Marc-Andre, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, and Teipel, Stefan J.

Abstract

Background Although convolutional neural networks (CNNs) achieve high diagnostic accuracy for detecting Alzheimer's disease (AD) dementia based on magnetic resonance imaging (MRI) scans, they are not yet applied in clinical routine. One important reason for this is a lack of model comprehensibility. Recently developed visualization methods for deriving CNN relevance maps may help to fill this gap as they allow the visualization of key input image features that drive the decision of the model. We investigated whether models with higher accuracy also rely more on discriminative brain regions predefined by prior knowledge. Methods We trained a CNN for the detection of AD in N = 663 T1-weighted MRI scans of patients with dementia and amnestic mild cognitive impairment (MCI) and verified the accuracy of the models via cross-validation and in three independent samples including in total N = 1655 cases. We evaluated the association of relevance scores and hippocampus volume to validate the clinical utility of this approach. To improve model comprehensibility, we implemented an interactive visualization of 3D CNN relevance maps, thereby allowing intuitive model inspection. Results Across the three independent datasets, group separation showed high accuracy for AD dementia versus controls (AUC >= 0.91) and moderate accuracy for amnestic MCI versus controls (AUC approximate to 0.74). Relevance maps indicated that hippocampal atrophy was considered the most informative factor for AD detection, with additional contributions from atrophy in other cortical and subcortical regions. Relevance scores within the hippocampus were highly correlated with hippocampal volumes (Pearson's r approximate to -0.86, p < 0.001). Conclusion The relevance maps highlighted atrophy in regions that we had hypothesized a priori. This strengthens the comprehensibility of the CNN models, which were trained in a purely data-driven manner based on the scans and diagnosis labels. The high hippocampus relev

Published
2021

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

Author

Ballarini, Tommaso, van Lent, Debora Melo, Brunner, Julia, Schroeder, Alina, Wolfsgruber, Steffen, Altenstein, Slawek, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Hauser, Dietmar, Haynes, John Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline Danielle, Munk, Matthias, Perneczky, Robert, Peters, Oliver, Priller, Josef, Ramirez, Alfredo, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, Wagner, Michael, Ballarini, Tommaso, van Lent, Debora Melo, Brunner, Julia, Schroeder, Alina, Wolfsgruber, Steffen, Altenstein, Slawek, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Hauser, Dietmar, Haynes, John Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline Danielle, Munk, Matthias, Perneczky, Robert, Peters, Oliver, Priller, Josef, Ramirez, Alfredo, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, and Wagner, Michael

Abstract

Objective To determine whether following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer disease (AD), we analyzed cross-sectional data from the German DZNE-Longitudinal Cognitive Impairment and Dementia Study. Method The sample (n = 512, mean age 69.5 +/- 5.9 years) included 169 cognitively normal participants and individuals at higher AD risk (53 with relatives with AD, 209 with subjective cognitive decline, and 81 with mild cognitive impairment). We defined MeDi adherence according to the food frequency questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI, and cognitive performance was assessed with an extensive neuropsychological battery. AD-related biomarkers (beta-amyloid(42/40) [A beta(42/40)] ratio, phosphorylated tau 181 [pTau181]) in CSF were assessed in n = 226 individuals. We analyzed the associations between MeDi and outcomes with linear regression models controlling for several covariates. In addition, we applied hypothesis-driven mediation and moderation analysis. Results Higher MeDi adherence related to larger mediotemporal gray matter volume (p < 0.05 family-wise error corrected), better memory (beta +/- SE = 0.03 +/- 0.02; p = 0.038), and less amyloid (A beta(42/40) ratio, beta +/- SE = 0.003 +/- 0.001; p = 0.008) and pTau181 (beta +/- SE = -1.96 +/- 0.68; p = 0.004) pathology. Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations among A beta(42/40) ratio, pTau181, and mediotemporal atrophy. Results were consistent correcting for APOE-epsilon 4 status. Conclusion Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. They suggest that these associations might be explained by a decrease of amyloidosis and tau pathology. Longitudinal and dietary intervention studies should further examine this conjecture and it

Published
2021

20. Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer's disease spectrum

Author

Amaefule, Chimezie O., Dyrba, Martin, Wolfsgruber, Steffen, Polcher, Alexandra, Schneider, Anja, Fliessbach, Klaus, Spottke, Annika, Meiberth, Dix, Preis, Lukas, Peters, Oliver, Incesoy, Enise I., Spruth, Eike J., Priller, Josef, Altenstein, Slawek, Bartels, Claudia, Wiltfang, Jens, Janowitz, Daniel, Buerger, Katharina, Laske, Christoph, Munk, Matthias, Rudolph, Janna, Glanz, Wenzel, Dobisch, Laura, Haynes, John D., Dechent, Peter, Ertl-Wagner, Birgit, Scheffler, Klaus, Kilimann, Ingo, Duezel, Emrah, Metzger, Coraline D., Wagner, Michael, Jessen, Frank, Teipel, Stefan J., Amaefule, Chimezie O., Dyrba, Martin, Wolfsgruber, Steffen, Polcher, Alexandra, Schneider, Anja, Fliessbach, Klaus, Spottke, Annika, Meiberth, Dix, Preis, Lukas, Peters, Oliver, Incesoy, Enise I., Spruth, Eike J., Priller, Josef, Altenstein, Slawek, Bartels, Claudia, Wiltfang, Jens, Janowitz, Daniel, Buerger, Katharina, Laske, Christoph, Munk, Matthias, Rudolph, Janna, Glanz, Wenzel, Dobisch, Laura, Haynes, John D., Dechent, Peter, Ertl-Wagner, Birgit, Scheffler, Klaus, Kilimann, Ingo, Duezel, Emrah, Metzger, Coraline D., Wagner, Michael, Jessen, Frank, and Teipel, Stefan J.

Abstract

Background: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer's disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. Method: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. Result: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. Conclusion: Consistent associations between cognitive domain score

Published
2021

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

Author

Sannemann, Lena, Schild, Ann-Katrin, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Cosma, Nicoleta Carmen, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Polcher, Alexandra, Priller, Josef, Rauchmann, Boris, Roesch, Christina, Rudolph, Janna, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan, Vukovich, Ruth, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Duezel, Emrah, Jessen, Frank, Sannemann, Lena, Schild, Ann-Katrin, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Cosma, Nicoleta Carmen, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Polcher, Alexandra, Priller, Josef, Rauchmann, Boris, Roesch, Christina, Rudolph, Janna, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan, Vukovich, Ruth, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Duezel, Emrah, and Jessen, Frank

Abstract

BackgroundEarly identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries.MethodsWe analyzed data of n=687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n=242), mild cognitive impairment (MCI, n=115), AD (n=77), CO (n=209), and first-degree relatives of AD patients (REL, n=44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries.ResultsThe numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low A ss 42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p<.05).ConclusionThese findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated wit

Published
2020

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

Author

Sannemann, Lena, Schild, Ann-Katrin, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Cosma, Nicoleta-Carmen, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Polcher, Alexandra, Priller, Josef, Rauchmann, Boris-Stephan, Rösch, Christina, Rudolph, Janna, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Duezel, Emrah, Jessen, Frank, Sannemann, Lena, Schild, Ann-Katrin, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Cosma, Nicoleta-Carmen, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Polcher, Alexandra, Priller, Josef, Rauchmann, Boris-Stephan, Rösch, Christina, Rudolph, Janna, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan J., Vukovich, Ruth, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Duezel, Emrah, and Jessen, Frank

Published
2020

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

Author

Herdick, Meret, Dyrba, Martin, Fritz, Hans-Christian J., Altenstein, Slawek, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cetindag, Arda Can, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H., Peters, Oliver, Priller, Josef, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Tscheuschler, Maike, Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, Teipel, Stefan J., Grothe, Michel J., Herdick, Meret, Dyrba, Martin, Fritz, Hans-Christian J., Altenstein, Slawek, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cetindag, Arda Can, Dechent, Peter, Dobisch, Laura, Duezel, Emrah, Ertl-Wagner, Birgit, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H., Peters, Oliver, Priller, Josef, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Tscheuschler, Maike, Vukovich, Ruth, Wiltfang, Jens, Jessen, Frank, Teipel, Stefan J., and Grothe, Michel J.

Published
2020

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

Author

Sannemann, Lena, Schild, Ann-Katrin, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Cosma, Nicoleta Carmen, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Polcher, Alexandra, Priller, Josef, Rauchmann, Boris, Roesch, Christina, Rudolph, Janna, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan, Vukovich, Ruth, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Duezel, Emrah, Jessen, Frank, Sannemann, Lena, Schild, Ann-Katrin, Altenstein, Slawek, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Cosma, Nicoleta Carmen, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Laske, Christoph, Metzger, Coraline D., Munk, Matthias H. J., Perneczky, Robert, Peters, Oliver, Polcher, Alexandra, Priller, Josef, Rauchmann, Boris, Roesch, Christina, Rudolph, Janna, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan, Vukovich, Ruth, Wagner, Michael, Wiltfang, Jens, Wolfsgruber, Steffen, Duezel, Emrah, and Jessen, Frank

Abstract

BackgroundEarly identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries.MethodsWe analyzed data of n=687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n=242), mild cognitive impairment (MCI, n=115), AD (n=77), CO (n=209), and first-degree relatives of AD patients (REL, n=44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries.ResultsThe numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low A ss 42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p<.05).ConclusionThese findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated wit

Published
2020

25. Improving 3D convolutional neural network comprehensibility via interactive visualization of relevance maps: Evaluation in Alzheimer's disease

Author

Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantré, Daniel, Dechent, Peter, Dobisch, Laura, Düzel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H., Spottke, Annika, Spruth, Eike J., Weber, Marc-André, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, Teipel, Stefan J., Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantré, Daniel, Dechent, Peter, Dobisch, Laura, Düzel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H., Spottke, Annika, Spruth, Eike J., Weber, Marc-André, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, and Teipel, Stefan J.

Abstract

Background: Although convolutional neural networks (CNN) achieve high diagnostic accuracy for detecting Alzheimer's disease (AD) dementia based on magnetic resonance imaging (MRI) scans, they are not yet applied in clinical routine. One important reason for this is a lack of model comprehensibility. Recently developed visualization methods for deriving CNN relevance maps may help to fill this gap. We investigated whether models with higher accuracy also rely more on discriminative brain regions predefined by prior knowledge. Methods: We trained a CNN for the detection of AD in N=663 T1-weighted MRI scans of patients with dementia and amnestic mild cognitive impairment (MCI) and verified the accuracy of the models via cross-validation and in three independent samples including N=1655 cases. We evaluated the association of relevance scores and hippocampus volume to validate the clinical utility of this approach. To improve model comprehensibility, we implemented an interactive visualization of 3D CNN relevance maps. Results: Across three independent datasets, group separation showed high accuracy for AD dementia vs. controls (AUC$\geq$0.92) and moderate accuracy for MCI vs. controls (AUC$\approx$0.75). Relevance maps indicated that hippocampal atrophy was considered as the most informative factor for AD detection, with additional contributions from atrophy in other cortical and subcortical regions. Relevance scores within the hippocampus were highly correlated with hippocampal volumes (Pearson's r$\approx$-0.86, p<0.001). Conclusion: The relevance maps highlighted atrophy in regions that we had hypothesized a priori. This strengthens the comprehensibility of the CNN models, which were trained in a purely data-driven manner based on the scans and diagnosis labels., Comment: 24 pages, 9 figures/tables, supplementary material, source code available on GitHub

Published
2020
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26. Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study

Author

Miebach, Lisa, Wolfsgruber, Steffen, Polcher, Alexandra, Peters, Oliver, Menne, Felix, Luther, Katja, Incesoy, Enise, Priller, Josef, Spruth, Eike, Altenstein, Slawek, Buerger, Katharina, Catak, Cihan, Janowitz, Daniel, Perneczky, Robert, Utecht, Julia, Laske, Christoph, Buchmann, Martina, Schneider, Anja, Fliessbach, Klaus, Kalbhen, Pascal, Heneka, Michael T., Brosseron, Frederic, Spottke, Annika, Roy, Nina, Teipel, Stefan J., Kilimann, Ingo, Wiltfang, Jens, Bartels, Claudia, Duezel, Emrah, Dobisch, Laura, Metzger, Coraline, Meiberth, Dix, Ramirez, Alfredo, Jessen, Frank, Wagner, Michael, Miebach, Lisa, Wolfsgruber, Steffen, Polcher, Alexandra, Peters, Oliver, Menne, Felix, Luther, Katja, Incesoy, Enise, Priller, Josef, Spruth, Eike, Altenstein, Slawek, Buerger, Katharina, Catak, Cihan, Janowitz, Daniel, Perneczky, Robert, Utecht, Julia, Laske, Christoph, Buchmann, Martina, Schneider, Anja, Fliessbach, Klaus, Kalbhen, Pascal, Heneka, Michael T., Brosseron, Frederic, Spottke, Annika, Roy, Nina, Teipel, Stefan J., Kilimann, Ingo, Wiltfang, Jens, Bartels, Claudia, Duezel, Emrah, Dobisch, Laura, Metzger, Coraline, Meiberth, Dix, Ramirez, Alfredo, Jessen, Frank, and Wagner, Michael

Abstract

BackgroundSubjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers.MethodsWe analyzed data of 205 cognitively normal participants of the DELCODE study (mean age=68.9years; 52% female) with available CSF AD biomarkers (A beta-42, p-Tau181, A beta-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers.ResultsLower A beta-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower A beta 42 and lower A beta 42/Tau ratio, but not with total Tau or p-Tau181.ConclusionsFindings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely assoc

Published
2019

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

Author

Miebach, Lisa, Wolfsgruber, Steffen, Polcher, Alexandra, Peters, Oliver, Menne, Felix, Luther, Katja, Incesoy, Enise, Priller, Josef, Spruth, Eike, Altenstein, Slawek, Buerger, Katharina, Catak, Cihan, Janowitz, Daniel, Perneczky, Robert, Utecht, Julia, Laske, Christoph, Buchmann, Martina, Schneider, Anja, Fliessbach, Klaus, Kalbhen, Pascal, Heneka, Michael T., Brosseron, Frederic, Spottke, Annika, Roy, Nina, Teipel, Stefan J., Kilimann, Ingo, Wiltfang, Jens, Bartels, Claudia, Duezel, Emrah, Dobisch, Laura, Metzger, Coraline, Meiberth, Dix, Ramirez, Alfredo, Jessen, Frank, Wagner, Michael, Miebach, Lisa, Wolfsgruber, Steffen, Polcher, Alexandra, Peters, Oliver, Menne, Felix, Luther, Katja, Incesoy, Enise, Priller, Josef, Spruth, Eike, Altenstein, Slawek, Buerger, Katharina, Catak, Cihan, Janowitz, Daniel, Perneczky, Robert, Utecht, Julia, Laske, Christoph, Buchmann, Martina, Schneider, Anja, Fliessbach, Klaus, Kalbhen, Pascal, Heneka, Michael T., Brosseron, Frederic, Spottke, Annika, Roy, Nina, Teipel, Stefan J., Kilimann, Ingo, Wiltfang, Jens, Bartels, Claudia, Duezel, Emrah, Dobisch, Laura, Metzger, Coraline, Meiberth, Dix, Ramirez, Alfredo, Jessen, Frank, and Wagner, Michael

Abstract

BackgroundSubjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers.MethodsWe analyzed data of 205 cognitively normal participants of the DELCODE study (mean age=68.9years; 52% female) with available CSF AD biomarkers (A beta-42, p-Tau181, A beta-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers.ResultsLower A beta-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower A beta 42 and lower A beta 42/Tau ratio, but not with total Tau or p-Tau181.ConclusionsFindings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely assoc

Published
2019

28. Subjective cognitive decline and stage 2 of Alzheimer disease in patients from memory centers

Author

Jessen, Frank, Wolfsgruber, Steffen, Kleineindam, Luca, Spottke, Annika, Altenstein, Slawek, Bartels, Claudia, Berger, Moritz, Brosseron, Frederic, Daamen, Marcel, Dichgans, Martin, Dobisch, Laura, Ewers, Michael, Fenski, Friederike, Fliessbach, Klaus, Freiesleben, Silka D., Glanz, Wenzel, Goerss, Doreen, Guersel, Selim, Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Lohse, Andrea, Maier, Franziska, Metzger, Coraline, Munk, Matthias, Preis, Lukas, Sanzenbacher, Carolin, Spruth, Eike, Rauchmann, Boris, Vukovich, Ruth, Yakupov, Renat, Weyrauch, Anne-Sophie, Ziegler, Gabriel, Schmid, Matthias, Laske, Christoph, Perneczky, Robert, Schneider, Anja, Wiltfang, Jens, Teipel, Stefan, Buerger, Katharina, Priller, Josef, Peters, Oliver, Ramirez, Alfredo, Boecker, Henning, Heneka, Michael T., Wagner, Michael, Duezel, Emrah, Jessen, Frank, Wolfsgruber, Steffen, Kleineindam, Luca, Spottke, Annika, Altenstein, Slawek, Bartels, Claudia, Berger, Moritz, Brosseron, Frederic, Daamen, Marcel, Dichgans, Martin, Dobisch, Laura, Ewers, Michael, Fenski, Friederike, Fliessbach, Klaus, Freiesleben, Silka D., Glanz, Wenzel, Goerss, Doreen, Guersel, Selim, Janowitz, Daniel, Kilimann, Ingo, Kobeleva, Xenia, Lohse, Andrea, Maier, Franziska, Metzger, Coraline, Munk, Matthias, Preis, Lukas, Sanzenbacher, Carolin, Spruth, Eike, Rauchmann, Boris, Vukovich, Ruth, Yakupov, Renat, Weyrauch, Anne-Sophie, Ziegler, Gabriel, Schmid, Matthias, Laske, Christoph, Perneczky, Robert, Schneider, Anja, Wiltfang, Jens, Teipel, Stefan, Buerger, Katharina, Priller, Josef, Peters, Oliver, Ramirez, Alfredo, Boecker, Henning, Heneka, Michael T., Wagner, Michael, and Duezel, Emrah

Abstract

Introduction It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum. Methods Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study. Results The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD-A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO-A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group. Discussion Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD-A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression.

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