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1. Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer’s disease

Author

Anna Hofmann, Lisa M. Häsler, Marius Lambert, Stephan A. Kaeser, Susanne Gräber-Sultan, Ulrike Obermüller, Elke Kuder-Buletta, Christian la Fougere, Christoph Laske, Jonathan Vöglein, Johannes Levin, Nick C. Fox, Natalie S. Ryan, Henrik Zetterberg, Jorge J. Llibre-Guerra, Richard J. Perrin, Laura Ibanez, Peter R. Schofield, William S. Brooks, Gregory S. Day, Martin R. Farlow, Ricardo F. Allegri, Patricio Chrem Mendez, Takeshi Ikeuchi, Kensaku Kasuga, Jae-Hong Lee, Jee Hoon Roh, Hiroshi Mori, Francisco Lopera, Randall J. Bateman, Eric McDade, Brian A. Gordon, Jasmeer P. Chhatwal, Mathias Jucker, Stephanie A. Schultz, and Dominantly Inherited Alzheimer Network

Subjects
Science
Abstract

Abstract Disease-modifying therapies for Alzheimer’s disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum. CSF and plasma trajectories were similar at presymptomatic stages, discriminating mutation carriers from non-carrier controls 10-20 years before the estimated onset of clinical symptoms, depending on the statistical model used. However, after symptom onset the rate of change in CSF NfL continued to increase steadily, whereas the rate of change in plasma NfL leveled off. Both plasma and CSF NfL changes were associated with grey-matter atrophy, but not with Aβ-PET changes, supporting a temporal decoupling of Aβ deposition and neurodegeneration. These observations support NfL in both CSF and blood as an early marker of neurodegeneration but suggest that NfL measured in the CSF may be better suited for monitoring clinical trial outcomes in symptomatic AD patients.

Published
2024
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2. Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort

Author

Reddy Peera Kommaddi, Aditi Verma, Graciela Muniz-Terrera, Vivek Tiwari, Keerthana Chithanathan, Latha Diwakar, Ruturaj Gowaikar, Smitha Karunakaran, Palash Kumar Malo, Neill R. Graff-Radford, Gregory S. Day, Christoph Laske, Jonathan Vöglein, Georg Nübling, Takeshi Ikeuchi, Kensaku Kasuga, the Dominantly Inherited Alzheimer Network (DIAN), and Vijayalakshmi Ravindranath

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Women carry a higher burden of Alzheimer’s disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler’s logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.

Published
2023
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3. Symptomatology in 4-repeat tauopathies is associated with data-driven topology of [18F]-PI-2620 tau-PET signal

Author

Sonja Schönecker, Carla Palleis, Nicolai Franzmeier, Sabrina Katzdobler, Christian Ferschmann, Sebastian Schuster, Anika Finze, Maximilian Scheifele, Catharina Prix, Urban Fietzek, Endy Weidinger, Georg Nübling, Jonathan Vöglein, Marianne Patt, Henryk Barthel, Osama Sabri, Adrian Danek, Günter U. Höglinger, Matthias Brendel, and Johannes Levin

Subjects
Progressive supranuclear palsy, Corticobasal syndrome, Parkinsonism, 4-repeat tauopathy, [18F]PI-2620 tau-PET, Data-driven, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [18F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer’s disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression. Therefore, we aimed to investigate the correlation between topology of [18F]PI-2620 uptake and symptomatology in 4-repeat tauopathies.72 patients with possible or probable 4-repeat tauopathy, i.e. 31 patients with PSP-Richardson’s syndrome (PSP-RS), 30 with amyloid-negative CBS and 11 with PSP-non-RS/CBS, underwent [18F]PI-2620-PET. Principal component analysis was performed to identify groups of similar brain regions based on 20–40 min p.i. regional standardized uptake value ratio z-scores. Correlations between component scores and the items of the PSP Rating Scale were explored.Motor signs like gait, arising from chair and postural instability showed a positive correlation with tracer uptake in mesial frontoparietal lobes and the medial superior frontal gyrus and adjacent anterior cingulate cortex. While the signs disorientation and bradyphrenia showed a positive correlation with tracer uptake in the parietooccipital junction, the signs disorientation and arising from chair were negatively correlated with tau-PET signal in the caudate nucleus and thalamus. Total PSP Rating Scale Score showed a trend towards a positive correlation with mesial frontoparietal lobes and a negative correlation with caudate nucleus and thalamus. While in CBS patients, the main finding was a negative correlation of tracer binding in the caudate nucleus and thalamus and a positive correlation of tracer binding in medial frontal cortex with gait and motor signs, in PSP-RS patients various correlations of clinical signs with tracer binding in specific cerebral regions could be detected.Our data reveal [18F]PI-2620 tau-PET topology to correlate with symptomatology in 4-repeat tauopathies. Longitudinal studies will be needed to address whether a deterioration of signs and symptoms over time can be monitored by [18F]PI-2620 in 4-repeat tauopathies and whether [18F]PI-2620 may serve as a marker of disease progression in future therapeutic trials. The detected negative correlation of tracer binding in the caudate nucleus and thalamus with the signs disorientation and arising from chair may be due to an increasing atrophy in these regions leading to partial volume effects and a relative decrease of tracer uptake in the disease course. As cerebral regions correlating with symptomatology differ depending on the clinical phenotype, a precise knowledge of clinical signs and symptoms is necessary when interpreting [18F]PI-2620 PET results.

Published
2023
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4. Covariance-based vs. correlation-based functional connectivity dissociates healthy aging from Alzheimer disease

Author

Jeremy F. Strain, Matthew R. Brier, Aaron Tanenbaum, Brian A. Gordon, John E. McCarthy, Aylin Dincer, Daniel S. Marcus, Jasmeer P. Chhatwal, Neill R. Graff-Radford, Gregory S. Day, Christian la Fougère, Richard J. Perrin, Stephen Salloway, Peter R. Schofield, Igor Yakushev, Takeshi Ikeuchi, Jonathan Vöglein, John C. Morris, Tammie L.S. Benzinger, Randall J. Bateman, Beau M. Ances, and Abraham Z. Snyder

Subjects
Resting-state functional connectivity, Covariance, Aging, Late onset Alzheimer disease, Autosomal dominant Alzheimer disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using either seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating evidence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched controls. Functional connectivity was computed over 222 regions of interest and group differences were evaluated in terms of components projected onto a space of lower dimension. Our principal observations are: (1) Aging is associated with global loss of resting state fMRI signal amplitude that is approximately uniform across resting state networks. (2) Thus, covariance FC measures decrease with age whereas correlation FC is relatively preserved in healthy aging. (3) In contrast, symptomatic ADAD and LOAD both lead to loss of spontaneous activity amplitude as well as severely degraded correlation structure. These results demonstrate a double dissociation between age vs. Alzheimer disease and the amplitude vs. correlation structure of resting state BOLD signals. Modeling results suggest that the AD-associated loss of correlation structure is attributable to a relative increase in the fraction of locally restricted as opposed to widely shared variance.

Published
2022
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5. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Peter R. Millar, Patrick H. Luckett, Brian A. Gordon, Tammie L.S. Benzinger, Suzanne E. Schindler, Anne M. Fagan, Carlos Cruchaga, Randall J. Bateman, Ricardo Allegri, Mathias Jucker, Jae-Hong Lee, Hiroshi Mori, Stephen P Salloway, Igor Yakushev, John C. Morris, Beau M. Ances, Sarah Adams, MS, Ricardo Allegri, PhD, Aki Araki, Nicolas Barthelemy, PhD, Randall Bateman, MD, Jacob Bechara, BS, Tammie Benzinger, MD, PhD, Sarah Berman, MD, PhD, Courtney Bodge, PhD, Susan Brandon, BS, William (Bill) Brooks, MBBS,MPH, Jared Brosch, MD, PhD, Jill Buck, BSN, Virginia Buckles, PhD, Kathleen Carter, PhD, Lisa Cash, BFA, Charlie Chen, BA, Jasmeer Chhatwal, MD,PhD, Patricio Chrem Mendez, MD, Jasmin Chua, BS, Helena Chui, MD, Laura Courtney, BS, Carlos Cruchaga, PhD, Gregory S Day, MD, Chrismary DeLaCruz, BA, Darcy Denner, PhD, Anna Diffenbacher, MS, Aylin Dincer, BS, Tamara Donahue, MS, Jane Douglas, MPh, Duc Duong, BS, Noelia Egido, BS, Bianca Esposito, BS, Anne Fagan, PhD, Marty Farlow, MD, Becca Feldman, BS,BA, Colleen Fitzpatrick, MS, Shaney Flores, BS, Nick Fox, MD, Erin Franklin, MS, Nelly Joseph-Mathurin, PhD, Hisako Fujii, PhD, Samantha Gardener, PhD, Bernardino Ghetti, MD, Alison Goate, PhD, Sarah Goldberg, MS,LPC,NCC, Jill Goldman, MS,MPhil,CGC, Alyssa Gonzalez, BS, Brian Gordon, PhD, Susanne Gräber-Sultan, PhD, Neill Graff-Radford, MD, Morgan Graham, BA, Julia Gray, MS, Emily Gremminger, BA, Miguel Grilo, MD, Alex Groves, Christian Haass, PhD, Lisa Häsler, MSc, Jason Hassenstab, PhD, Cortaiga Hellm, BA, Elizabeth Herries, BA, Laura Hoechst-Swisher, MS, Anna Hofmann, MD, Anna Hofmann, David Holtzman, MD, Russ Hornbeck, MSCS, MPM, Yakushev Igor, MD, Ryoko Ihara, MD, Takeshi Ikeuchi, MD, Snezana Ikonomovic, MD, Kenji Ishii, MD, Clifford Jack, MD, Gina Jerome, MS, Erik Johnson, MD, PHD, Mathias Jucker, PhD, Celeste Karch, PhD, Stephan Käser, PHD, Kensaku Kasuga, MD, Sarah Keefe, BS, William Klunk, MD, PHD, Robert Koeppe, PHD, Deb Koudelis, MHS,RN, Elke Kuder-Buletta, RN, Christoph Laske, PhD, Allan Levey, MD, PHD, Johannes Levin, MD, Yan Li, PHD, Oscar Lopez, MD, MD, Jacob Marsh, BA, Ralph Martins, PhD, Neal Scott Mason, PhD, Colin Masters, MD, Kwasi Mawuenyega, PhD, Austin McCullough, PhD Candidate, Eric McDade, DO, Arlene Mejia, MD, Estrella Morenas-Rodriguez, MD, PhD, John Morris, MD, James Mountz, MD, Cath Mummery, PhD, N eelesh Nadkarni, MD, PhD, Akemi Nagamatsu, RN, Katie Neimeyer, MS, Yoshiki Niimi, MD, James Noble, MD, Joanne Norton, MSN, RN, PMHCNS-BC, Brigitte Nuscher, Ulricke Obermüller, Antoinette O'Connor, MRCPI, Riddhi Patira, MD, Richard Perrin, MD, PhD, Lingyan Ping, PhD, Oliver Preische, MD, Alan Renton, PhD, John Ringman, MD, Stephen Salloway, MD, Peter Schofield, PhD, Michio Senda, MD, PhD, Nicholas T Seyfried, D.Phil, Kristine Shady, BA, BS, Hiroyuki Shimada, MD, PhD, Wendy Sigurdson, RN, Jennifer Smith, PhD, Lori Smith, PA-C, Beth Snitz, PhD, Hamid Sohrabi, PhD, Sochenda Stephens, BS, CCRP, Kevin Taddei, BS, Sarah Thompson, PA-C, Jonathan Vöglein, MD, Peter Wang, PhD, Qing Wang, PhD, Elise Weamer, MPH, Chengjie Xiong, PhD, Jinbin Xu, PhD, and Xiong Xu, BS, MS

Subjects
Brain aging, Alzheimer disease, Resting-state functional connectivity, fMRI, Machine learning, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Published
2022
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6. Hoehn and Yahr Stage and Striatal Dat-SPECT Uptake Are Predictors of Parkinson’s Disease Motor Progression

Author

Holly Jackson, Judith Anzures-Cabrera, Kirsten I. Taylor, Gennaro Pagano, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Guenter Hoeglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Brit Mollenhauer, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Werner Poewe, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Tanya Simuni, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Azad Bonni, Edilio Borroni, Anne Boulay, Markus Britschgi, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Rachelle Doody, Juergen Dukart, Giulia D’Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Paulo Fontoura, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Martin Koller, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Maddalena Marchesi, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Tania Nikolcheva, Susanne Ostrowitzki GP, Benedicte Passmard, Agnes Poirier, Anke Post, Megana Prasad, Nathalie Pross, Tiffany Quock, Benedicte Ricci, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Jeff Sevigny, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Hanno Svoboda KT, Radhika Tripuraneni, Dylan Trundell, Daniel Umbricht, Lynne Verselis, Annamarie Vogt, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
PASADENA, PPMI (Parkinson’s Progression Markers Initiative), Parkinson’s disease, progression predictors, ridge regression, disease stage, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Currently, no treatments available for Parkinson’s disease (PD) can slow PD progression. At the early stage of the disease, only a subset of individuals with PD progress quickly, while the majority have a slowly progressive form of the disease. In developing treatments that aim to slow PD progression, clinical trials aim to include individuals who are likely to progress faster, such that a treatment effect, if one exists, can be identified easier and earlier. The aim of the present study was to identify baseline predictors of clinical progression in early PD. We analyzed 12-month data acquired from the PASADENA trial Part 1 (NCT03100149, n = 76 participants who were allocated to the placebo arm and did not start symptomatic therapy) and the Parkinson’s Progression Markers Initiative (PPMI) study (n = 139 demographically and clinically matched participants). By using ridge regression models including clinical characteristics, imaging, and non-imaging biomarkers, we found that Hoehn and Yahr stage and dopamine transporter single-photon emission computed tomography specific binding ratios (Dat-SPECT SBR) in putamen ipsilateral to the side of motor symptom onset predicted PD progression at the early stage of the disease. Further studies are needed to confirm the validity of these predictors to identify with high accuracy individuals with early PD with a faster progression phenotype.

Published
2021
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7. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data

Author

Gennaro Pagano, Frank G. Boess, Kirsten I. Taylor, Benedicte Ricci, Brit Mollenhauer, Werner Poewe, Anne Boulay, Judith Anzures-Cabrera, Annamarie Vogt, Maddalena Marchesi, Anke Post, Tania Nikolcheva, Gene G. Kinney, Wagner M. Zago, Daniel K. Ness, Hanno Svoboda, Markus Britschgi, Susanne Ostrowitzki, Tanya Simuni, Kenneth Marek, Martin Koller, Jeff Sevigny, Rachelle Doody, Paulo Fontoura, Daniel Umbricht, Azad Bonni, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Günter Höglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Edilio Borroni, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Juergen Dukart, Giulia D'Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Benedicte Passmard, Agnes Poirier, Megana Prasad, Nathalie Pross, Tiffany Quock, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Kirsten Taylor, Radhika Tripuraneni, Dylan Trundell, Lynne Verselis, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
Parkinson's disease, alpha-synuclein (α-syn), prasinezumab, monoclonal antibodies, disease progression, MDS-UPDRS = Movement Disorder Society—Unified Parkinson's Disease Rating Scale, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial Registration: NCT03100149.

Published
2021
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8. Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease

Author

Ophir Keret, Adam M. Staffaroni, John M. Ringman, Yann Cobigo, Sheng‐Yang M. Goh, Amy Wolf, Isabel Elaine Allen, Stephen Salloway, Jasmeer Chhatwal, Adam M. Brickman, Dolly Reyes‐Dumeyer, Randal J. Bateman, Tammie L.S. Benzinger, John C. Morris, Beau M. Ances, Nelly Joseph‐Mathurin, Richard J. Perrin, Brian A. Gordon, Johannes Levin, Jonathan Vöglein, Mathias Jucker, Christian laFougère, Ralph N. Martins, Hamid R. Sohrabi, Kevin Taddei, Victor L. Villemagne, Peter R. Schofield, William S. Brooks, Michael Fulham, Colin L. Masters, Bernardino Ghetti, Andrew J. Saykin, Clifford R. Jack, Neill R. Graff‐Radford, Michael Weiner, David M. Cash, Ricardo F. Allegri, Patricio Chrem, Su Yi, Bruce L. Miller, Gil D. Rabinovici, Howard J. Rosen, and Dominantly Inherited Alzheimer Network

Subjects
autosomal dominant Alzheimer's disease, brain atrophy, Dominantly Inherited Alzheimer Network, preclinical Alzheimer's disease, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD‐MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD‐MC and could help predict risk for dementia during trial enrollment. Methods We created a dementia risk score by entering standardized gray‐matter volumes from 231 DIAD‐MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD‐MC followed longitudinally. Results Our risk score separated asymptomatic versus demented DIAD‐MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%–98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD‐MC participants for prevention trials.

Published
2021
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9. Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease

Author

Stephanie A. Schultz, Jeremy F. Strain, Adedamola Adedokun, Qing Wang, Oliver Preische, Jens Kuhle, Shaney Flores, Sarah Keefe, Aylin Dincer, Beau M. Ances, Sarah B. Berman, Adam M. Brickman, David M. Cash, Jasmeer Chhatwal, Carlos Cruchaga, Michael Ewers, Nick N. Fox, Bernardino Ghetti, Alison Goate, Neill R. Graff-Radford, Jason J. Hassenstab, Russ Hornbeck, Clifford Jack, Jr, Keith Johnson, Nelly Joseph-Mathurin, Celeste M. Karch, Robert A. Koeppe, Athene K.W. Lee, Johannes Levin, Colin Masters, Eric McDade, Richard J. Perrin, Christopher C. Rowe, Stephen Salloway, Andrew J. Saykin, Reisa Sperling, Yi Su, Victor L. Villemagne, Jonathan Vöglein, Michael Weiner, Chengjie Xiong, Anne M. Fagan, John C. Morris, Randall J. Bateman, Tammie L.S. Benzinger, Mathias Jucker, and Brian A. Gordon

Subjects
Neurofilament, Alzheimer's disease, Neurodegeneration, White matter, Blood-based biomarkers, Neuroimaging, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data.In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.

Published
2020
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10. Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimagingResearch in context

Author

Stephanie Doering, Austin McCullough, Brian A. Gordon, Charles D. Chen, Nicole McKay, Diana Hobbs, Sarah Keefe, Shaney Flores, Jalen Scott, Hunter Smith, Stephen Jarman, Kelley Jackson, Russ C. Hornbeck, Beau M. Ances, Chengjie Xiong, Andrew J. Aschenbrenner, Jason Hassenstab, Carlos Cruchaga, Alisha Daniels, Randall J. Bateman, John C. Morris, Tammie L.S. Benzinger, James M. Noble, Gregory S. Day, Neill R. Graff-Radford, Jonathan Voglein, Johannes Levin, Ricardo F. Allegri, Patricio Chrem Mendez, Ezequiel Surace, Sarah B. Berman, Snezana Ikonomovic, Neelesh K. Nadkarni, Francisco Lopera, Laura Ramirez, David Aguillon, Yudy Leon, Claudia Ramos, Diana Alzate, Ana Baena, Natalia Londono, Sonia Moreno, Mathias Jucker, Christoph Laske, Elke Kuder-Buletta, Susanne Graber-Sultan, Oliver Preische, Anna Hofmann, Takeshi Ikeuchi, Kensaku Kasuga, Yoshiki Niimi, Kenji Ishii, Michio Senda, Raquel Sanchez-Valle, Pedro Rosa-Neto, Nick C. Fox, Dave Cash, Jae-Hong Lee, Jee Hoon Roh, Stephen Salloway, Meghan C. Riddle, William Menard, Courtney Bodge, Mustafa Surti, Leonel Tadao Takada, Martin Farlow, Jasmeer P. Chhatwal, V.J. Sanchez-Gonzalez, Maribel Orozco-Barajas, Alison M. Goate, Alan E. Renton, Bianca T. Esposito, Celeste M. Karch, Jacob Marsh, Victoria Fernanadez, Anne M. Fagan, Gina Jerome, Elizabeth Herries, Jorge Llibre-Guerra, Allan I. Levey, Erik C.B. Johnson, Nicholas T. Seyfried, Peter R. Schofield, William S. Brooks, Jacob A. Bechara, Randall Bateman, Eric McDade, Richard J. Perrin, Erin E. Franklin, Tammie Benzinger, Allison Chen, Charles Chen, Nelly Friedrichsen, Brian Gordon, Nancy Hantler, Russ Hornbeck, Steve Jarman, Deborah Koudelis, Parinaz Massoumzadeh, Joyce Nicklaus, Christine Pulizos, Qing Wang, Sheetal Mishall, Edita Sabaredzovic, Emily Deng, Madison Candela, Peter Wang, Xiong Xu, Yan Li, Emily Gremminger, Yinjiao Ma, Ryan Bui, Ruijin Lu, Ralph Martins, Ana Luisa Sosa Ortiz, Laura Courtney, Hiroshi Mori, Charlene Supnet-Bell, Jinbin Xu, John Ringman, Nicolas Barthelemy, John Morris, and Jennifer Smith

Subjects
Alzheimer disease, Positron emission tomography, Tau spread, Tau propagation, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Published
2024
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11. Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

Author

Peter R Millar, Brian A Gordon, Julie K Wisch, Stephanie A Schultz, Tammie LS Benzinger, Carlos Cruchaga, Jason J Hassenstab, Laura Ibanez, Celeste Karch, Jorge J Llibre-Guerra, John C Morris, Richard J Perrin, Charlene Supnet-Bell, Chengjie Xiong, Ricardo F Allegri, Sarah B Berman, Jasmeer P Chhatwal, Patricio A Chrem Mendez, Gregory S Day, Anna Hofmann, Takeshi Ikeuchi, Mathias Jucker, Jae-Hong Lee, Johannes Levin, Francisco Lopera, Yoshiki Niimi, Victor J Sánchez-González, Peter R Schofield, Ana Luisa Sosa-Ortiz, Jonathan Vöglein, for the Dominantly Inherited Alzheimer Network, Randall J Bateman, Beau M Ances, and Eric M McDade

Subjects
Brain aging, Alzheimer disease, Structural MRI, Machine learning, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background “Brain-predicted age” estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. Methods We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education. Results Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. Conclusions We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

Published
2023
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