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2. Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients

Author

de Boni, Laura, Wallis, Amber, Hays Watson, Aurelia, Ruiz-Riquelme, Alejandro, Leyland, Louise-Ann, Bourinaris, Thomas, Hannaway, Naomi, Wüllner, Ullrich, Peters, Oliver, Priller, Josef, Falkenburger, Björn H, Wiltfang, Jens, Bähr, Mathias, Zerr, Inga, Bürger, Katharina, Perneczky, Robert, Teipel, Stefan, Löhle, Matthias, Hermann, Wiebke, Schott, Björn-Hendrik, Brockmann, Kathrin, Spottke, Annika, Haustein, Katrin, Breuer, Peter, Houlden, Henry, Weil, Rimona S, and Bartels, Tim

Published
2024
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3. Effect of Spatial Disorientation in a Virtual Environment on Gait and Vital Features in Patients with Dementia: Pilot Single-Blind Randomized Control Trial

Author

Amaefule, Chimezie O, Lüdtke, Stefan, Kirste, Thomas, and Teipel, Stefan J

Subjects
Information technology, T58.5-58.64, Public aspects of medicine, RA1-1270
Abstract

BackgroundOrientation deficits are among the most devastating consequences of early dementia. Digital navigation devices could overcome these deficits if adaptable to the user’s needs (ie, provide situation-aware, proactive navigation assistance). To fulfill this task, systems need to automatically detect spatial disorientation from sensors in real time. Ideally, this would require field studies consisting of real-world navigation. However, such field studies can be challenging and are not guaranteed to cover sufficient instances of disorientation due to the large variability of real-world settings and a lack of control over the environment. ObjectiveExtending a foregoing field study, we aim to evaluate the feasibility of using a sophisticated virtual reality (VR) setup, which allows a more controlled observation of disorientation states and accompanying behavioral and physiological parameters in cognitively healthy older people and people with dementia. MethodsIn this feasibility study, we described the experimental design and pilot outcomes of an ongoing study aimed at investigating the effect of disorientation on gait and selected physiological features in a virtual laboratory. We transferred a real-world navigation task to a treadmill-based virtual system for gait analysis. Disorientation was induced by deliberately manipulating landmarks in the VR projection. Associated responses in motion behavior and physiological parameters were recorded by sensors. Primary outcomes were variations in motion and physiological parameters, frequency of disorientation, and questionnaire-derived usability estimates (immersion and perceived control of the gait system) for our population of interest. At this time, the included participants were 9 cognitively healthy older participants [5/9 women, 4/9 men; mean age 70 years, SD 4.40; Mini–Mental State Examination (MMSE) mean 29, SD 0.70) and 4 participants with dementia (2/4 women, 2/4 men; mean age 78 years, SD 2.30 years; MMSE mean 20.50, SD 7.54). Recruitment is ongoing, with the aim of including 30 cognitively healthy older participants and 20 participants with dementia. ResultsAll 13 participants completed the experiment. Patients’ route was adapted by shortening it relative to the original route. Average instances of disorientation were 21.40, 36.50, and 37.50 for the cognitively healthy older control, cognitively healthy older experimental participants, and participants with dementia, respectively. Questionnaire outcomes indicated that participants experienced adequate usability and immersion; 4.30 for presence, 3.73 for involvement, and 3.85 for realism of 7 possible points, indicating a good overall ability to cope with the experiment. Variations were also observed in motion and physiological parameters during instances of disorientation. ConclusionsThis study presents the first feasibility outcomes of a study investigating the viability of using a sophisticated VR setup, based on an earlier real-world navigation study, to study spatial disorientation among cognitively healthy older people and people with dementia. Preliminary outcomes give confidence to the notion that our setup can be used to assess motion and physiological markers of disorientation, even in people with cognitive decline. Trial RegistrationClinicalTrials.gov; https://clinicaltrials.gov/ct2/show/NCT04134806

Published
2020
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4. Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimers disease.

Author

Martinelli, Filippo, Heinken, Almut, Henning, Ann-Kristin, Ulmer, Maria, Hensen, Tim, González, Antonio, Arnold, Matthias, Asthana, Sanjay, Budde, Kathrin, Engelman, Corinne, Estaki, Mehrbod, Grabe, Hans-Jörgen, Heston, Margo, Johnson, Sterling, Kastenmüller, Gabi, Martino, Cameron, McDonald, Daniel, Rey, Federico, Kilimann, Ingo, Peters, Olive, Wang, Xiao, Spruth, Eike, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Hansen, Niels, Glanz, Wenzel, Buerger, Katharina, Janowitz, Daniel, Laske, Christoph, Munk, Matthias, Spottke, Annika, Roy, Nina, Nauck, Matthias, Teipel, Stefan, Kaddurah-Daouk, Rima, Bendlin, Barbara, Hertel, Johannes, Thiele, Ines, and Knight, Rob

Subjects
Alzheimer’s disease, Co-metabolism, Constraint-based modelling, Formate, Host-microbiome, Metabolic modelling, Metabolomics, Microbiome, Pathways, Humans, Alzheimer Disease, Microbiota, Gastrointestinal Microbiome, Genomics, Formates
Abstract

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimers disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.

Published
2024

5. Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

Author

Chatterjee, Madhurima, Özdemir, Selcuk, Fritz, Christian, Möbius, Wiebke, Kleineidam, Luca, Mandelkow, Eckhard, Biernat, Jacek, Doğdu, Cem, Peters, Oliver, Cosma, Nicoleta Carmen, Wang, Xiao, Schneider, Luisa-Sophia, Priller, Josef, Spruth, Eike, Kühn, Andrea A., Krause, Patricia, Klockgether, Thomas, Vogt, Ina R., Kimmich, Okka, Spottke, Annika, Hoffmann, Daniel C., Fliessbach, Klaus, Miklitz, Carolin, McCormick, Cornelia, Weydt, Patrick, Falkenburger, Björn, Brandt, Moritz, Guenther, René, Dinter, Elisabeth, Wiltfang, Jens, Hansen, Niels, Bähr, Mathias, Zerr, Inga, Flöel, Agnes, Nestor, Peter J., Düzel, Emrah, Glanz, Wenzel, Incesoy, Enise, Bürger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris S., Hopfner, Franziska, Wagemann, Olivia, Levin, Johannes, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Prudlo, Johannes, Gasser, Thomas, Brockmann, Kathrin, Mengel, David, Zimmermann, Milan, Synofzik, Matthis, Wilke, Carlo, Selma-González, Judit, Turon-Sans, Janina, Santos-Santos, Miguel Angel, Alcolea, Daniel, Rubio-Guerra, Sara, Fortea, Juan, Carbayo, Álvaro, Lleó, Alberto, Rojas-García, Ricardo, Illán-Gala, Ignacio, Wagner, Michael, Frommann, Ingo, Roeske, Sandra, Bertram, Lucas, Heneka, Michael T., Brosseron, Frederic, Ramirez, Alfredo, Schmid, Matthias, Beschorner, Rudi, Halle, Annett, Herms, Jochen, Neumann, Manuela, Barthélemy, Nicolas R., Bateman, Randall J., Rizzu, Patrizia, Heutink, Peter, Dols-Icardo, Oriol, Höglinger, Günter, Hermann, Andreas, and Schneider, Anja

Published
2024
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6. The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis

Author

Ye, Lan, Greten, Stephan, Wegner, Florian, Doll-Lee, Johanna, Krey, Lea, Heine, Johanne, Gandor, Florin, Vogel, Annemarie, Berger, Luise, Gruber, Doreen, Levin, Johannes, Katzdobler, Sabrina, Peters, Oliver, Dashti, Eman, Priller, Josef, Spruth, Eike Jakob, Kühn, Andrea A., Krause, Patricia, Spottke, Annika, Schneider, Anja, Beyle, Aline, Kimmich, Okka, Donix, Markus, Haussmann, Robert, Brandt, Moritz, Dinter, Elisabeth, Wiltfang, Jens, Schott, Björn H., Zerr, Inga, Bähr, Mathias, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Weidinger, Endy, Düzel, Emrah, Glanz, Wenzel, Teipel, Stefan, Kilimann, Ingo, Wurster, Isabel, Brockmann, Kathrin, Hoffmann, Daniel C., Klockgether, Thomas, Krause, Olaf, Heck, Johannes, Höglinger, Günter U., and Klietz, Martin

Published
2024
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7. Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition

Author

Hayek, Dayana, Ziegler, Gabriel, Kleineidam, Luca, Brosseron, Frederic, Nemali, Aditya, Vockert, Niklas, Ravichandran, Kishore A., Betts, Matthew J., Peters, Oliver, Schneider, Luisa-Sophie, Wang, Xiao, Priller, Josef, Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Bartels, Claudia, Rostamzadeh, Ayda, Glanz, Wenzel, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Laske, Christoph, Mengel, David, Synofzik, Matthis, Munk, Matthias H., Spottke, Annika, Roy, Nina, Roeske, Sandra, Kuhn, Elizabeth, Ramirez, Alfredo, Dobisch, Laura, Schmid, Matthias, Berger, Moritz, Wolfsgruber, Steffen, Yakupov, Renat, Hetzer, Stefan, Dechent, Peter, Ewers, Michael, Scheffler, Klaus, Schott, Björn H., Schreiber, Stefanie, Orellana, Adelina, de Rojas, Itziar, Marquié, Marta, Boada, Mercè, Sotolongo, Oscar, González, Pablo García, Puerta, Raquel, Düzel, Emrah, Jessen, Frank, Wagner, Michael, Ruiz, Augustín, Heneka, Michael T., and Maass, Anne

Published
2024
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12. A remote digital memory composite to detect cognitive impairment in memory clinic samples in unsupervised settings using mobile devices

Author

Berron, David, Glanz, Wenzel, Clark, Lindsay, Basche, Kristin, Grande, Xenia, Güsten, Jeremie, Billette, Ornella V., Hempen, Ina, Naveed, Muhammad Hashim, Diersch, Nadine, Butryn, Michaela, Spottke, Annika, Buerger, Katharina, Perneczky, Robert, Schneider, Anja, Teipel, Stefan, Wiltfang, Jens, Johnson, Sterling, Wagner, Michael, Jessen, Frank, and Düzel, Emrah

Published
2024
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13. Fronto-striatal alterations correlate with apathy severity in behavioral variant frontotemporal dementia

Author

Upadhyay, Neeraj, Spottke, Annika, Schneider, Anja, Hoffmann, Daniel C., Frommann, Ingo, Ballarini, Tommaso, Fliessbach, Klaus, Bender, Benjamin, Heekeren, Hauke R., Haynes, John Dylan, Ewers, Michael, Düzel, Emrah, Glanz, Wenzel, Dobisch, Laura, Buerger, Katharina, Janowitz, Daniel, Levin, Johannes, Danek, Adrian, Teipel, Stefan, Kilimann, Ingo, Synofzik, Matthis, Wilke, Carlo, Peters, Oliver, Preis, Lukas, Priller, Josef, Spruth, Eike Jakob, Jessen, Frank, and Boecker, Henning

Published
2024
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14. The comorbidity and co-medication profile of patients with progressive supranuclear palsy

Author

Greten, Stephan, Wegner, Florian, Jensen, Ida, Krey, Lea, Rogozinski, Sophia, Fehring, Meret, Heine, Johanne, Doll-Lee, Johanna, Pötter-Nerger, Monika, Zeitzschel, Molly, Hagena, Keno, Pedrosa, David J., Eggers, Carsten, Bürk, Katrin, Trenkwalder, Claudia, Claus, Inga, Warnecke, Tobias, Süß, Patrick, Winkler, Jürgen, Gruber, Doreen, Gandor, Florin, Berg, Daniela, Paschen, Steffen, Classen, Joseph, Pinkhardt, Elmar H., Kassubek, Jan, Jost, Wolfgang H., Tönges, Lars, Kühn, Andrea A., Schwarz, Johannes, Peters, Oliver, Dashti, Eman, Priller, Josef, Spruth, Eike J., Krause, Patricia, Spottke, Annika, Schneider, Anja, Beyle, Aline, Kimmich, Okka, Donix, Markus, Haussmann, Robert, Brandt, Moritz, Dinter, Elisabeth, Wiltfang, Jens, Schott, Björn H., Zerr, Inga, Bähr, Mathias, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Weidinger, Endy, Levin, Johannes, Katzdobler, Sabrina, Düzel, Emrah, Glanz, Wenzel, Teipel, Stefan, Kilimann, Ingo, Prudlo, Johannes, Gasser, Thomas, Brockmann, Kathrin, Hoffmann, Daniel C., Klockgether, Thomas, Krause, Olaf, Heck, Johannes, Höglinger, Günter U., and Klietz, Martin

Published
2024
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15. Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Author

Ehrenberg, Alexander J, Kelberman, Michael A, Liu, Kathy Y, Dahl, Martin J, Weinshenker, David, Falgàs, Neus, Dutt, Shubir, Mather, Mara, Ludwig, Mareike, Betts, Matthew J, Winer, Joseph R, Teipel, Stefan, Weigand, Alexandra J, Eschenko, Oxana, Hämmerer, Dorothea, Leiman, Marina, Counts, Scott E, Shine, James M, Robertson, Ian H, Levey, Allan I, Lancini, Elisa, Son, Gowoon, Schneider, Christoph, Van Egroo, Maxime, Liguori, Claudio, Wang, Qin, Vazey, Elena M, Rodriguez‐Porcel, Federico, Haag, Lena, Bondi, Mark W, Vanneste, Sven, Freeze, Whitney M, Yi, Yeo‐Jin, Maldinov, Mihovil, Gatchel, Jennifer, Satpati, Abhijit, Babiloni, Claudio, Kremen, William S, Howard, Robert, Jacobs, Heidi IL, and Grinberg, Lea T

Subjects
Neurosciences, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Humans, Alzheimer Disease, Brain, Biomarkers, Disease Progression, Clinical Sciences, Geriatrics
Abstract

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Published
2023

16. The association between posterior resting-state EEG alpha rhythms and functional MRI connectivity in older adults with subjective memory complaint

Author

Lopez, Susanna, Hampel, Harald, Chiesa, Patrizia Andrea, Del Percio, Claudio, Noce, Giuseppe, Lizio, Roberta, Teipel, Stefan J., Dyrba, Martin, González-Escamilla, Gabriel, Bakardjian, Hovagim, Cavedo, Enrica, Lista, Simone, Vergallo, Andrea, Lemercier, Pablo, Spinelli, Giuseppe, Grothe, Michel J., Potier, Marie-Claude, Stocchi, Fabrizio, Ferri, Raffaele, Habert, Marie-Odile, Dubois, Bruno, and Babiloni, Claudio

Published
2024
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17. Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia

Author

Ruiz-Rizzo, Adriana L., Finke, Kathrin, Damoiseaux, Jessica S., Bartels, Claudia, Buerger, Katharina, Cosma, Nicoleta Carmen, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Frommann, Ingo, Glanz, Wenzel, Goerss, Doreen, Hetzer, Stefan, Incesoy, Enise I., Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, van Lent, Debora Melo, Munk, Matthias H.J., Peters, Oliver, Priller, Josef, Ramirez, Alfredo, Rostamzadeh, Ayda, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan, Wagner, Michael, Wiltfang, Jens, Yakupov, Renat, Jessen, Frank, Duezel, Emrah, Perneczky, Robert, and Rauchmann, Boris-Stephan

Published
2024
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19. Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer’s disease: results from the DELCODE study

Author

Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, Kolbe, Carl-Christian, Wolfsgruber, Steffen, Santarelli, Francesco, Häsler, Lisa M., McManus, Róisín, Ising, Christina, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Schneider, Luisa-Sophie, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Buerger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Görß, Doreen, Laske, Christoph, Munk, Matthias H., Düzel, Emrah, Yakupow, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Spottke, Annika, Ramirez, Alfredo, Mengel, David, Synofzik, Matthis, Jucker, Mathias, Latz, Eicke, Jessen, Frank, Wagner, Michael, and Heneka, Michael T.

Published
2023
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20. Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: a cross-sectional study

Author

Bernal, Jose, Schreiber, Stefanie, Menze, Inga, Ostendorf, Anna, Pfister, Malte, Geisendörfer, Jonas, Nemali, Aditya, Maass, Anne, Yakupov, Renat, Peters, Oliver, Preis, Lukas, Schneider, Luisa, Herrera, Ana Lucia, Priller, Josef, Spruth, Eike Jakob, Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Rostamzadeh, Ayda, Glanz, Wenzel, Buerger, Katharina, Janowitz, Daniel, Ewers, Michael, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Laske, Christoph, Munk, Matthias H., Spottke, Annika, Roy, Nina, Dobisch, Laura, Dechent, Peter, Scheffler, Klaus, Hetzer, Stefan, Wolfsgruber, Steffen, Kleineidam, Luca, Schmid, Matthias, Berger, Moritz, Jessen, Frank, Wirth, Miranka, Düzel, Emrah, and Ziegler, Gabriel

Published
2023
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21. Exploring the ATN classification system using brain morphology

Author

Heinzinger, Nils, Maass, Anne, Berron, David, Yakupov, Renat, Peters, Oliver, Fiebach, Jochen, Villringer, Kersten, Preis, Lukas, Priller, Josef, Spruth, Eike Jacob, Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Bartels, Claudia, Jessen, Frank, Maier, Franziska, Glanz, Wenzel, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Killimann, Ingo, Göerß, Doreen, Laske, Christoph, Munk, Matthias H., Spottke, Annika, Roy, Nina, Heneka, Michael T., Brosseron, Frederic, Dobisch, Laura, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Wolfsgruber, Steffen, Kleineidam, Luca, Schmid, Matthias, Berger, Moritz, Düzel, Emrah, and Ziegler, Gabriel

Published
2023
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22. Brain reserve contributes to distinguishing preclinical Alzheimer’s stages 1 and 2

Author

Yildirim, Zerrin, Delen, Firuze, Berron, David, Baumeister, Hannah, Ziegler, Gabriel, Schütze, Hartmut, Glanz, Wenzel, Dobisch, Laura, Peters, Oliver, Freiesleben, Silka Dawn, Schneider, Luisa-Sophie, Priller, Josef, Spruth, Eike Jakob, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn-Hendrik, Meiberth, Dix, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Laske, Christoph, Munk, Matthias H., Spottke, Annika, Roy, Nina, Heneka, Michael, Brosseron, Frederic, Wagner, Michael, Roeske, Sandra, Ramirez, Alfredo, Ewers, Michael, Dechent, Peter, Hetzer, Stefan, Scheffler, Klaus, Kleineidam, Luca, Wolfsgruber, Steffen, Yakupov, Renat, Schmid, Matthias, Berger, Moritz, Gurvit, Hakan, Jessen, Frank, and Duzel, Emrah

Published
2023
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24. 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, and Teipel, Stefan J.

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
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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25. Outcomes of clinical utility in amyloid-PET studies: state of art and future perspectives

Author

Cotta Ramusino, Matteo, Perini, Giulia, Altomare, Daniele, Barbarino, Paola, Weidner, Wendy, Salvini Porro, Gabriella, Barkhof, Frederik, Rabinovici, Gil D, van der Flier, Wiesje M, Frisoni, Giovanni B, Garibotto, Valentina, Teipel, Stefan, and Boccardi, Marina

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Aging, Biomedical Imaging, Good Health and Well Being, Alzheimer Disease, Amyloid, Amyloidosis, Humans, Positron-Emission Tomography, Quality of Life, Outcome, Clinical utility, Amyloid-PET, Diagnostic biomarkers, Alzheimer&#8217, s disease, Systematic review, Alzheimer’s disease, Other Physical Sciences, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

PurposeTo review how outcomes of clinical utility are operationalized in current amyloid-PET validation studies, to prepare for formal assessment of clinical utility of amyloid-PET-based diagnosis.MethodsSystematic review of amyloid-PET research studies published up to April 2020 that included outcomes of clinical utility. We extracted and analyzed (a) outcome categories, (b) their definition, and (c) their methods of assessment.ResultsThirty-two studies were eligible. (a) Outcome categories were clinician-centered (found in 25/32 studies, 78%), patient-/caregiver-centered (in 9/32 studies, 28%), and health economics-centered (5/32, 16%). (b) Definition: Outcomes were mainly defined by clinical researchers; only the ABIDE study expressly included stakeholders in group discussions. Clinician-centered outcomes mainly consisted of incremental diagnostic value (25/32, 78%) and change in patient management (17/32, 53%); patient-/caregiver-centered outcomes considered distress after amyloid-pet-based diagnosis disclosure (8/32, 25%), including quantified burden of procedure for patients' outcomes (n = 8) (1/8, 12.5%), impact of disclosure of results (6/8, 75%), and psychological implications of biomarker-based diagnosis (75%); and health economics outcomes focused on costs to achieve a high-confidence etiological diagnosis (5/32, 16%) and impact on quality of life (1/32, 3%). (c) Assessment: all outcome categories were operationalized inconsistently across studies, employing 26 different tools without formal rationale for selection.ConclusionCurrent studies validating amyloid-PET already assessed outcomes for clinical utility, although non-clinician-based outcomes were inconsistent. A wider participation of stakeholders may help produce a more thorough and systematic definition and assessment of outcomes of clinical utility and help collect evidence informing decisions on reimbursement of amyloid-PET.

Published
2021

26. MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints.

Author

Vergallo, Andrea, Lista, Simone, Zhao, Yuhai, Lemercier, Pablo, Teipel, Stefan J, Potier, Marie-Claude, Habert, Marie-Odile, Dubois, Bruno, Lukiw, Walter J, Hampel, Harald, INSIGHT-preAD study group, and Alzheimer Precision Medicine Initiative (APMI)

Subjects
INSIGHT-preAD study group, Alzheimer Precision Medicine Initiative, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer's disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs-miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.

Published
2021

27. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Author

Jansen, Iris E., van der Lee, Sven J., Gomez-Fonseca, Duber, de Rojas, Itziar, Dalmasso, Maria Carolina, Grenier-Boley, Benjamin, Zettergren, Anna, Mishra, Aniket, Ali, Muhammad, Andrade, Victor, Bellenguez, Céline, Kleineidam, Luca, Küçükali, Fahri, Sung, Yun Ju, Tesí, Niccolo, Vromen, Ellen M., Wightman, Douglas P., Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Amouyel, Philippe, Athanasiu, Lavinia, Bahrami, Shahram, Bailly, Henri, Belbin, Olivia, Bergh, Sverre, Bertram, Lars, Biessels, Geert Jan, Blennow, Kaj, Blesa, Rafael, Boada, Mercè, Boland, Anne, Buerger, Katharina, Carracedo, Ángel, Cervera-Carles, Laura, Chene, Geneviève, Claassen, Jurgen A. H. R., Debette, Stephanie, Deleuze, Jean-Francois, de Deyn, Peter Paul, Diehl-Schmid, Janine, Djurovic, Srdjan, Dols-Icardo, Oriol, Dufouil, Carole, Duron, Emmanuelle, Düzel, Emrah, Fladby, Tormod, Fortea, Juan, Frölich, Lutz, García-González, Pablo, Garcia-Martinez, Maria, Giegling, Ina, Goldhardt, Oliver, Gobom, Johan, Grimmer, Timo, Haapasalo, Annakaisa, Hampel, Harald, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernández, Isabel, Herukka, Sanna-Kaisa, Holstege, Henne, Jarholm, Jonas, Kern, Silke, Knapskog, Anne-Brita, Koivisto, Anne M., Kornhuber, Johannes, Kuulasmaa, Teemu, Lage, Carmen, Laske, Christoph, Leinonen, Ville, Lewczuk, Piotr, Lleó, Alberto, de Munain, Adolfo López, Lopez-Garcia, Sara, Maier, Wolfgang, Marquié, Marta, Mol, Merel O., Montrreal, Laura, Moreno, Fermin, Moreno-Grau, Sonia, Nicolas, Gael, Nöthen, Markus M., Orellana, Adelina, Pålhaugen, Lene, Papma, Janne M., Pasquier, Florence, Perneczky, Robert, Peters, Oliver, Pijnenburg, Yolande A. L., Popp, Julius, Posthuma, Danielle, Pozueta, Ana, Priller, Josef, Puerta, Raquel, Quintela, Inés, Ramakers, Inez, Rodriguez-Rodriguez, Eloy, Rujescu, Dan, Saltvedt, Ingvild, Sanchez-Juan, Pascual, Scheltens, Philip, Scherbaum, Norbert, Schmid, Matthias, Schneider, Anja, Selbæk, Geir, Selnes, Per, Shadrin, Alexey, Skoog, Ingmar, Soininen, Hilkka, Tárraga, Lluís, Teipel, Stefan, Tijms, Betty, Tsolaki, Magda, Van Broeckhoven, Christine, Van Dongen, Jasper, van Swieten, John C., Vandenberghe, Rik, Vidal, Jean-Sébastien, Visser, Pieter J., Vogelgsang, Jonathan, Waern, Margda, Wagner, Michael, Wiltfang, Jens, Wittens, Mandy M. J., Zetterberg, Henrik, Zulaica, Miren, van Duijn, Cornelia M., Bjerke, Maria, Engelborghs, Sebastiaan, Jessen, Frank, Teunissen, Charlotte E., Pastor, Pau, Hiltunen, Mikko, Ingelsson, Martin, Andreassen, Ole A., Clarimón, Jordi, Sleegers, Kristel, Ruiz, Agustín, Ramirez, Alfredo, Cruchaga, Carlos, Lambert, Jean-Charles, and van der Flier, Wiesje

Published
2022
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29. Linking early-life bilingualism and cognitive advantage in older adulthood

Author

Ballarini, Tommaso, Kuhn, Elizabeth, Röske, Sandra, Altenstein, Slawek, Bartels, Claudia, Buchholz, Friederike, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Gabelin, Tatjana, Glanz, Wenzel, Görß, Doreen, Haynes, John Dylan, Incesoy, Enise I., Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Kobeleva, Xenia, Laske, Christoph, Lohse, Andrea, Maier, Franziska, Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H., Spottke, Annika, Spruth, Eike Jakob, Teipel, Stefan, Wiltfang, Jens, Wolfsgruber, Steffen, Düzel, Emrah, Jessen, Frank, and Wagner, Michael

Published
2023
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30. Lifelong experiences as a proxy of cognitive reserve moderate the association between connectivity and cognition in Alzheimer's disease

Author

Ersoezlue, Ersin, Rauchmann, Boris-Stephan, Schneider-Axmann, Thomas, Wagner, Michael, Ballarini, Tommaso, Tato, Maia, Utecht, Julia, Kurz, Carolin, Papazov, Boris, Guersel, Selim, Burow, Lena, Koller, Gabriele, Stöcklein, Sophia, Keeser, Daniel, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Cetindag, Arda C., Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Frommann, Ingo, Haynes, John D., Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kleinedam, Luca, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Peters, Oliver, Preis, Lukas, Priller, Josef, Ramirez, Alfredo, Roeske, Sandra, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Spottke, Annika, Spruth, Eike J., Teipel, Stefan, Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Duezel, Emrah, Jessen, Frank, and Perneczky, Robert

Published
2023
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33. Single-value brain activity scores reflect both severity and risk across the Alzheimer’s continuum

Author

Soch, Joram, primary, Richter, Anni, additional, Kizilirmak, Jasmin M, additional, Schütze, Hartmut, additional, Ziegler, Gabriel, additional, Altenstein, Slawek, additional, Brosseron, Frederic, additional, Dechent, Peter, additional, Fliessbach, Klaus, additional, Freiesleben, Silka Dawn, additional, Glanz, Wenzel, additional, Gref, Daria, additional, Heneka, Michael T, additional, Hetzer, Stefan, additional, Incesoy, Enise I, additional, Kilimann, Ingo, additional, Kimmich, Okka, additional, Kleineidam, Luca, additional, Kuhn, Elizabeth, additional, Laske, Christoph, additional, Lohse, Andrea, additional, Lüsebrink, Falk, additional, Munk, Matthias H, additional, Peters, Oliver, additional, Preis, Lukas, additional, Priller, Josef, additional, Ramirez, Alfredo, additional, Roeske, Sandra, additional, Rostamzadeh, Ayda, additional, Roy-Kluth, Nina, additional, Scheffler, Klaus, additional, Schmid, Matthias, additional, Schneider, Anja, additional, Spottke, Annika, additional, Spruth, Eike Jakob, additional, Teipel, Stefan, additional, Wiltfang, Jens, additional, Jessen, Frank, additional, Wagner, Michael, additional, Düzel, Emrah, additional, and Schott, Björn H, additional

Published
2024
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35. Machine Learning–Based Perivascular Space Volumetry in Alzheimer Disease

Author

Deike, Katerina, primary, Decker, Andreas, additional, Scheyhing, Paul, additional, Harten, Julia, additional, Zimmermann, Nadine, additional, Paech, Daniel, additional, Peters, Oliver, additional, Freiesleben, Silka D., additional, Schneider, Luisa-Sophie, additional, Preis, Lukas, additional, Priller, Josef, additional, Spruth, Eike, additional, Altenstein, Slawek, additional, Lohse, Andrea, additional, Fliessbach, Klaus, additional, Kimmich, Okka, additional, Wiltfang, Jens, additional, Bartels, Claudia, additional, Hansen, Niels, additional, Jessen, Frank, additional, Rostamzadeh, Ayda, additional, Düzel, Emrah, additional, Glanz, Wenzel, additional, Incesoy, Enise I., additional, Butryn, Michaela, additional, Buerger, Katharina, additional, Janowitz, Daniel, additional, Ewers, Michael, additional, Perneczky, Robert, additional, Rauchmann, Boris-Stephan, additional, Teipel, Stefan, additional, Kilimann, Ingo, additional, Goerss, Doreen, additional, Laske, Christoph, additional, Munk, Matthias H., additional, Spottke, Annika, additional, Roy, Nina, additional, Wagner, Michael, additional, Roeske, Sandra, additional, Heneka, Michael T., additional, Brosseron, Frederic, additional, Ramirez, Alfredo, additional, Dobisch, Laura, additional, Wolfsgruber, Steffen, additional, Kleineidam, Luca, additional, Yakupov, Renat, additional, Stark, Melina, additional, Schmid, Matthias C., additional, Berger, Moritz, additional, Hetzer, Stefan, additional, Dechent, Peter, additional, Scheffler, Klaus, additional, Petzold, Gabor C., additional, Schneider, Anja, additional, Effland, Alexander, additional, and Radbruch, Alexander, additional

Published
2024
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36. Association of Basal Forebrain Volume with Amyloid, Tau, and Cognition in Alzheimer’s Disease

Author

Yoo, Han Soo, primary, Kim, Han-Kyeol, additional, Lee, Jae-Hoon, additional, Chun, Joong-Hyun, additional, Lee, Hye Sun, additional, Grothe, Michel J., additional, Teipel, Stefan, additional, Cavedo, Enrica, additional, Vergallo, Andrea, additional, Hampel, Harald, additional, Ryu, Young Hoon, additional, Cho, Hanna, additional, and Lyoo, Chul Hyoung, additional

Published
2024
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37. Aβ oligomers peak in early stages of Alzheimer's disease preceding tau pathology

Author

Blömeke, Lara, primary, Rehn, Fabian, additional, Kraemer‐Schulien, Victoria, additional, Kutzsche, Janine, additional, Pils, Marlene, additional, Bujnicki, Tuyen, additional, Lewczuk, Piotr, additional, Kornhuber, Johannes, additional, Freiesleben, Silka D., additional, Schneider, Luisa‐Sophie, additional, Preis, Lukas, additional, Priller, Josef, additional, Spruth, Eike J., additional, Altenstein, Slawek, additional, Lohse, Andrea, additional, Schneider, Anja, additional, Fliessbach, Klaus, additional, Wiltfang, Jens, additional, Hansen, Niels, additional, Rostamzadeh, Ayda, additional, Düzel, Emrah, additional, Glanz, Wenzel, additional, Incesoy, Enise I., additional, Butryn, Michaela, additional, Buerger, Katharina, additional, Janowitz, Daniel, additional, Ewers, Michael, additional, Perneczky, Robert, additional, Rauchmann, Boris‐Stephan, additional, Teipel, Stefan, additional, Kilimann, Ingo, additional, Goerss, Doreen, additional, Laske, Christoph, additional, Munk, Matthias H., additional, Sanzenbacher, Carolin, additional, Spottke, Annika, additional, Roy‐Kluth, Nina, additional, Heneka, Michael T., additional, Brosseron, Frederic, additional, Wagner, Michael, additional, Wolfsgruber, Steffen, additional, Kleineidam, Luca, additional, Stark, Melina, additional, Schmid, Matthias, additional, Jessen, Frank, additional, Bannach, Oliver, additional, Willbold, Dieter, additional, and Peters, Oliver, additional

Published
2024
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38. Don’t forget about tau: the effects of ApoE4 genotype on Alzheimer’s disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment—data from the Dementia Competence Network

Author

Benson, Gloria S., Bauer, Chris, Hausner, Lucrezia, Couturier, Samuel, Lewczuk, Piotr, Peters, Oliver, Hüll, Michael, Jahn, Holger, Jessen, Frank, Pantel, Johannes, Teipel, Stefan J., Wagner, Michael, Schuchhardt, Johannes, Wiltfang, Jens, Kornhuber, Johannes, and Frölich, Lutz

Published
2022
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40. Gaussian graphical models reveal inter-modal and inter-regional conditional dependencies of brain alterations in Alzheimer's disease

Author

Dyrba, Martin, Mohammadi, Reza, Grothe, Michel J., Kirste, Thomas, and Teipel, Stefan J.

Subjects
Quantitative Biology - Neurons and Cognition, Statistics - Applications
Abstract

Alzheimer's disease (AD) is characterized by a sequence of pathological changes, which are commonly assessed in vivo using MRI and PET. Currently, the most approaches to analyze statistical associations between brain regions rely on Pearson correlation. However, these are prone to spurious correlations arising from uninformative shared variance. Notably, there are no appropriate multivariate statistical models available that can easily integrate dozens of variables derived from such data, being able to use the additional information provided from the combination of data sources. Gaussian graphical models (GGMs) can estimate the conditional dependency from given data, which is expected to reflect the underlying causal relationships. We applied GGMs to assess multimodal regional brain alterations in AD. We obtained data from N=972 subjects from the Alzheimer's Disease Neuroimaging Initiative. The mean amyloid load (AV45-PET), glucose metabolism (FDG-PET), and gray matter volume (MRI) were calculated. GGMs were estimated using a Bayesian framework for the combined multimodal data to obtain conditional dependency networks. Conditional dependency matrices were much sparser (10% density) than Pearson correlation matrices (50% density). Within modalities, conditional dependency networks yielded clusters connecting anatomically adjacent regions. For associations between different modalities, only few region-specific connections remained. Graph-theoretical network statistics were significantly altered between groups, with a biphasic u-shape trajectory. GGMs removed shared variance among multimodal measures of regional brain alterations in MCI and AD, and yielded sparser matrices compared to Pearson correlation networks. Therefore, GGMs may be used as alternative to thresholding-approaches typically applied to correlation networks to obtain the most informative relations between variables., Comment: 24 pages, 9 figures, 2 tables, supporting material

Published
2018
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41. Applicability of in vivo staging of regional amyloid burden in a cognitively normal cohort with subjective memory complaints: the INSIGHT-preAD study.

Author

Sakr, Fatemah, Grothe, Michel, Cavedo, Enrica, Jelistratova, Irina, Habert, Marie-Odile, Dyrba, Martin, Gonzalez-Escamilla, Gabriel, Bertin, Hugo, Locatelli, Maxime, Lehericy, Stephane, Teipel, Stefan, Dubois, Bruno, and Hampel, Harald

Subjects
Amyloid PET, In vivo staging, Subjective memory complaint, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Cognition, Cognitive Dysfunction, Cohort Studies, Diagnostic Self Evaluation, Female, Follow-Up Studies, Humans, Male, Memory, Mental Status and Dementia Tests
Abstract

BACKGROUND: Current methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimers disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individuals amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimers disease (AD). METHODS: The monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models. RESULTS: In total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVRCereb = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort. CONCLUSIONS: The proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD.

Published
2019

42. Performance evaluation of automated white matter hyperintensity segmentation algorithms in a multicenter cohort on cognitive impairment and dementia

Author

Malo Gaubert, Andrea Dell’Orco, Catharina Lange, Antoine Garnier-Crussard, Isabella Zimmermann, Martin Dyrba, Marco Duering, Gabriel Ziegler, Oliver Peters, Lukas Preis, Josef Priller, Eike Jakob Spruth, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Björn H. Schott, Franziska Maier, Wenzel Glanz, Katharina Buerger, Daniel Janowitz, Robert Perneczky, Boris-Stephan Rauchmann, Stefan Teipel, Ingo Kilimann, Christoph Laske, Matthias H. Munk, Annika Spottke, Nina Roy, Laura Dobisch, Michael Ewers, Peter Dechent, John Dylan Haynes, Klaus Scheffler, Emrah Düzel, Frank Jessen, Miranka Wirth, for the DELCODE study group, Amthauer Holger, Cetindag Arda Can, Cosma Nicoleta Carmen, Diesing Dominik, Ehrlich Marie, Fenski Frederike, Freiesleben Silka Dawn, Fuentes Manuel, Hauser Dietmar, Hujer Nicole, Incesoy Enise Irem, Kainz Christian, Lange Catharina, Lindner Katja, Megges Herlind, Peters Oliver, Preis Lukas, Altenstein Slawek, Lohse Andrea, Franke Christiana, Priller Josef, Spruth Eike, Villar Munoz Irene, Barkhoff Miriam, Boecker Henning, Brosseron Frederic, Daamen Marcel, Engels Tanja, Faber Jennifer, Fließbach Klaus, Frommann Ingo, Grobe-Einsler Marcus, Hennes Guido, Herrmann Gabi, Jost Lorraine, Kalbhen Pascal, Kimmich Okka, Kobeleva Xenia, Kofler Barbara, McCormick Cornelia, Miebach Lisa, Miklitz Carolin, Müller Anna, Oender Demet, Polcher Alexandra, Purrer Veronika, Röske Sandra, Schneider Christine, Schneider Anja, Spottke Annika, Vogt Ina, Wagner Michael, wolfsgruber Steffen, Yilmaz Sagik, Bartels Claudia, Dechent Peter, Hansen Niels, Hassoun Lina, Hirschel Sina, Nuhn Sabine, Pfahlert Ilona, Rausch Lena, Schott Björn, Timäus Charles, Werner Christine, Wiltfang Jens, Zabel Lioba, Zech Heike, Bader Abdelmajid, Baldermann Juan Carlos, Dölle Britta, Drzezga Alexander, Escher Claus, Ghiasi Nasim Roshan, Hardenacke Katja, Jessen Frank, Lützerath Hannah, Maier Franziska, Marquardt Benjamin, Martikke Anja, Meiberth Dix, Petzler Snjezana, Rostamzadeh Ayda, Sannemann Lena, Schild Ann-Katrin, Sorgalla Susanne, Stockter Simone, Thelen Manuela, Tscheuschler Maike, Uhle Franziska, Zeyen Philip, Bittner Daniel, Cardenas-Blanco Arturo, Dobisch Laura, Düzel Emrah, Grieger-Klose Doreen, Hartmann Deike, Metzger Coraline, Nestor Peter, Ruß Christin, Schulze Franziska, Speck Oliver, Yakupov Renat, Ziegler Gabriel, Brauneis Christine, Bürger Katharina, Catak Cihan, Coloma Andrews Lisa, Dichgans Martin, Dörr Angelika, Ertl-Wagner Birgit, Frimmer Daniela, Huber Brigitte, Janowitz Daniel, Kreuzer Max, Markov Eva, Müller Claudia, Rominger Axel, Schmid (ehemals Spreider) Jennifer, Seegerer Anna, Stephan Julia, Zollver Adelgunde, Burow Lena, de Jonge Sylvia, Falkai Peter, Garcia Angarita Natalie, Görlitz Thomas, Gürsel Selim Üstün, Horvath Ildiko, Kurz Carolin, Meisenzahl-Lechner Eva, Perneczky Robert, Utecht Julia, Dyrba Martin, Janecek-Meyer Heike, Kilimann Ingo, Lappe Chris, Lau Esther, Pfaff Henrike, Raum Heike, Sabik Petr, Schmidt Monika, Schulz Heike, Schwarzenboeck Sarah, Teipel Stefan, Weber Marc-Andre, Buchmann Martina, Heger Tanja, Hinderer Petra, Kuder-Buletta Elke, Laske Christoph, Munk Matthias, Mychajliw Christian, Soekadar Surjo, sulzer Patricia, and Trunk Theresia

Subjects
white matter hyperintensities segmentation, evaluation, FLAIR, deep learning, aging, Alzheimer’s disease, Psychiatry, RC435-571
Abstract

BackgroundWhite matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimer’s disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research.MethodsWe used a pseudo-randomly selected dataset (n = 50) from the DZNE-multicenter observational Longitudinal Cognitive Impairment and Dementia Study (DELCODE) that included 3D fluid-attenuated inversion recovery (FLAIR) images from participants across the cognitive continuum. Performances of top-rated algorithms for automated WMH segmentation [Brain Intensity Abnormality Classification Algorithm (BIANCA), lesion segmentation toolbox (LST), lesion growth algorithm (LGA), LST lesion prediction algorithm (LPA), pgs, and sysu_media] were compared to manual reference segmentation (RS).ResultsAcross tools, segmentation performance was moderate for global WMH volume and number of detected lesions. After retraining on a DELCODE subset, the deep learning algorithm sysu_media showed the highest performances with an average Dice’s coefficient of 0.702 (±0.109 SD) for volume and a mean F1-score of 0.642 (±0.109 SD) for the number of lesions. The intra-class correlation was excellent for all algorithms (>0.9) but BIANCA (0.835). Performance improved with high WMH burden and varied across brain regions.ConclusionTo conclude, the deep learning algorithm, when retrained, performed well in the multicenter context. Nevertheless, the performance was close to traditional methods. We provide methodological recommendations for future studies using automated WMH segmentation to quantify and assess WMH along the continuum of cognitive impairment and AD dementia.

Published
2023
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45. Ethics, design, and implementation criteria of digital assistive technologies for people with dementia from a multiple stakeholder perspective: a qualitative study.

Author

Köhler, Stefanie, Perry, Julia, Biernetzky, Olga A., Kirste, Thomas, and Teipel, Stefan J.

Subjects
ASSISTIVE technology, DEMENTIA, DIGITAL technology, MEDICAL personnel, CORE competencies, ARTIFICIAL implants
Abstract

Background: Dementia impairs the ability of people with dementia to be autonomous and independent. They need support from third parties, who should ideally respect their autonomy and independence as much as possible. Supporting people with dementia can be very burdensome for caregivers and numbers of patients increase while numbers of potential caregivers decline. Digital assistive technologies (DATs) that directly support patients or their caregivers may help bridging the increasing gap between need of support and available resources. DATs have the potential to preserve the autonomy and independence of people with dementia and promote their abilities, if they are properly designed in close interaction with future users. In our study, we focused on ethical concerns, technological requirements, and implementation criteria for DAT in general and specifically to support outdoor mobility of people with dementia. Methods: We applied a qualitative approach and conducted a World Café (2 tables, n = 7) and an online focus group (n = 6) with people with dementia, relatives, healthcare professionals, scientists, ethics experts, and experts for digitally-assisted medical care. We descriptively analyzed the data using a content analysis approach. Results: The participants reported technological (e.g., lack of Wi-Fi), financial (e.g., expensive devices or lack of budget for DATs), political (e.g., legal hurdles such as the European Medical Device Law or data protection regulations) as well as user-related hurdles (e.g., lack of digital competence) for the implementation of DAT in dementia care. Among the issues discussed were the importance of autonomy, independence, safety, privacy, and questions of decision making capacity in DAT's use. Participants identified opportunities and benefits in self-learning, situation-aware DATs and wished for dementia-friendly communities. They emphasized the value of personal interaction that should not be replaced, but rather supported by DAT. Conclusion: The results revealed multiple hurdles and ethical concerns for DAT use and provided recommendations for designing and implementing DATs. Further investigations are needed on the impact of DAT on personal interactions in caregiving and the role of DAT in dementia-friendly communities. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease

Author

Franzmeier, Nicolai, Düzel, Emrah, Jessen, Frank, Buerger, Katharina, Levin, Johannes, Duering, Marco, Dichgans, Martin, Haass, Christian, Suárez-Calvet, Marc, Fagan, Anne M, Paumier, Katrina, Benzinger, Tammie, Masters, Colin L, Morris, John C, Perneczky, Robert, Janowitz, Daniel, Catak, Cihan, Wolfsgruber, Steffen, Wagner, Michael, Teipel, Stefan, Kilimann, Ingo, Ramirez, Alfredo, Rossor, Martin, Jucker, Mathias, Chhatwal, Jasmeer, Spottke, Annika, Boecker, Henning, Brosseron, Frederic, Falkai, Peter, Fliessbach, Klaus, Heneka, Michael T, Laske, Christoph, Nestor, Peter, Peters, Oliver, Fuentes, Manuel, Menne, Felix, Priller, Josef, Spruth, Eike J, Franke, Christiana, Schneider, Anja, Kofler, Barbara, Westerteicher, Christine, Speck, Oliver, Wiltfang, Jens, Bartels, Claudia, Caballero, Miguel Ángel Araque, Metzger, Coraline, Bittner, Daniel, Weiner, Michael, Lee, Jae-Hong, Salloway, Stephen, Danek, Adrian, Goate, Alison, Schofield, Peter R, Bateman, Randall J, and Ewers, Michael

Subjects
Clinical Trials and Supportive Activities, Brain Disorders, Aging, Basic Behavioral and Social Science, Dementia, Neurosciences, Behavioral and Social Science, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease, Neurodegenerative, Biomedical Imaging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Alzheimer Disease, Amyloid beta-Protein Precursor, Brain Mapping, Cognitive Dysfunction, Female, Frontal Lobe, Functional Laterality, Humans, Imaging, Three-Dimensional, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Nerve Net, Presenilin-1, Presenilin-2, Alzheimer's disease, cognitive reserve, resting state connectivity, memory, dementia biomarkers, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Published
2018

47. Basal Forebrain Volume, but Not Hippocampal Volume, Is a Predictor of Global Cognitive Decline in Patients With Alzheimer's Disease Treated With Cholinesterase Inhibitors

Author

Teipel, Stefan J, Cavedo, Enrica, Hampel, Harald, Grothe, Michel J, Initiative, Alzheimer's Disease Neuroimaging, Initiative, Alzheimer Precision Medicine, Aguilar, Lisi Flores, Babiloni, Claudio, Baldacci, Filippo, Benda, Norbert, Black, Keith L, Bokde, Arun LW, Bonuccelli, Ubaldo, Broich, Karl, Bun, René S, Cacciola, Francesco, Castrillo, Juan, Ceravolo, Roberto, chiesa, Patrizia A, Colliot, Olivier, Coman, Cristina-Maria, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L, Depypere, Herman, Dubois, Bruno, Duggento, Andrea, Durrleman, Stanley, Escott-price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A, Garaci, Francesco, Genthon, Remy, George, Nathalie, Giorgi, Filippo S, Graziani, Manuela, Haberkamp, Marion, Habert, Marie-Odile, Herholz, Karl, Karran, Eric, Seung, H KIM, Koronyo, Yosef, Koronyo-Hamaoui, Maya, Lamari, Foudil, Langevin, Todd, Lehéricy, Stéphane, Lista, Simone, Lorenceau, Jean, Mapstone, Mark, Neri, Christian, Nisticò, Robert, Nyasse-Messene, Francis, O'Bryant, Sid E, Perry, George, Ritchie, Craig, Rojkova, Katrine, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S, Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R, Vergallo, Andrea, Villain, Nicolas, Welikovitch, Lindsay A, Woodcock, Janet, and Younesi, Erfan

Subjects
Biological Psychology, Psychology, Neurosciences, Brain Disorders, Dementia, Neurodegenerative, Clinical Research, Acquired Cognitive Impairment, Behavioral and Social Science, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Neurological, Alzheimer's Disease Neuroimaging Initiative, Alzheimer Precision Medicine Initiative, MRI, basal forebrain, cholinergic treatment, executive function, hippocampus, memory, prediction, Clinical Sciences, Clinical sciences, Biological psychology
Abstract

Background: Predicting the progression of cognitive decline in Alzheimer's disease (AD) is important for treatment selection and patient counseling. Structural MRI markers such as hippocampus or basal forebrain volumes might represent useful instruments for the prediction of cognitive decline. The primary objective was to determine the predictive value of hippocampus and basal forebrain volumes for global and domain specific cognitive decline in AD dementia during cholinergic treatment. Methods: We used MRI and cognitive data from 124 patients with the clinical diagnosis of AD dementia, derived from the ADNI-1 cohort, who were on standard of care cholinesterase inhibitor treatment during a follow-up period between 0.4 and 3.1 years. We used linear mixed effects models with cognitive function as outcome to assess the main effects as well as two-way interactions between baseline volumes and time controlling for age, sex, and total intracranial volume. This model accounts for individual variation in follow-up times. Results: Basal forebrain volume, but not hippocampus volume, was a significant predictor of rates of global cognitive decline. Larger volumes were associated with smaller rates of cognitive decline. Left hippocampus volume had a modest association with rates of episodic memory decline. Baseline performance in global cognition and memory was significantly associated with hippocampus and basal forebrain volumes; in addition, basal forebrain volume was associated with baseline performance in executive function. Conclusions: Our findings indicate that in AD dementia patients, basal forebrain volume may be a useful marker to predict subsequent cognitive decline during cholinergic treatment.

Published
2018

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