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4. Predicting Alzheimer's disease progression: Results from the TADPOLE Challenge

Author

Polina Golland, Esther E. Bron, Razvan V. Marinescu, Daniel C. Alexander, Frederik Barkhof, Michael W. Weiner, Nick C. Fox, Alexandra L. Young, Stefan Klein, Arthur W. Toga, and Neil P. Oxtoby

Subjects
Epidemiology, business.industry, Health Policy, Disease progression, Tadpole (physics), Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, Medicine, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, business, Neuroscience
Published
2020
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5. Accounting for systematic spatiotemporal variation improves connectome‐based models of tau spreading in human Alzheimer’s disease

Author

Michel J. Grothe, Daniel C. Alexander, Neil P. Oxtoby, Leon M Aksman, Olof Strandberg, Oskar Hansson, Ruben Smith, Gil D. Rabinovici, Alexandra L. Young, Rik Ossenkoppele, Jacob W. Vogel, Alan C. Evans, and Renaud La Joie

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Variation (linguistics), Developmental Neuroscience, Epidemiology, Health Policy, Connectome, Person centered, Neurology (clinical), Disease, Geriatrics and Gerontology, Psychology, Neuroscience
Published
2020
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6. Characterising the spatiotemporal heterogeneity of neurodegenerative diseases using subtype and stage inference

Author

Martina Bocchetta, James H. Cole, Steven Williams, Daniel C. Alexander, Jonathan D. Rohrer, and Alexandra L. Young

Subjects
Epidemiology, Computer science, business.industry, Health Policy, Big data, Inference, Disease, Computational biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Multi omics, Neurology (clinical), Stage (hydrology), Geriatrics and Gerontology, business
Published
2020
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7. Multimodal modelling of the heterogeneity of Alzheimer’s disease

Author

Daniel C. Alexander, Jonathan M. Schott, Alexandra L. Young, and Mar Estarellas Garcia

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Neurology (clinical), Disease, Geriatrics and Gerontology, business, Neuroscience
Published
2020
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9. Subtype and stage inference identifies distinct atrophy patterns in genetic frontotemporal dementia that MAP onto specific MAPT mutations

Author

Sandro Sorbi, James B. Rowe, Matthis Synofzik, A. Danek, Martina Bocchetta, Johannes Levin, Markus Otto, Rhian S Convery, Fabrizio Tagliavini, Steven Williams, Daniel C. Alexander, Barbara Borroni, Mollie Neason, David L. Thomas, Jonathan D. Rohrer, Carmela Tartaglia, Alexandre de Mendonça, Giovanni B. Frisoni, David M. Cash, Katrina M. Moore, Roberta Ghidoni, Alexander Gerhard, Elizabeth Finger, Alexandra L. Young, Isabel Santana, Christopher C Butler, Fermin Moreno, Caroline Graff, John C. van Swieten, Mario Masellis, Raquel Sánchez-Valle, Robert Laforce, Simon Ducharme, Daniela Galimberti, and Rik Vandenberghe

Subjects
Epidemiology, Health Policy, Neurodegeneration, Inference, Biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Atrophy, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Stage (cooking), Neuroscience, Frontotemporal dementia
Published
2020
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10. Tau‐first subtype of Alzheimer’s disease progression consistently identified through PET and CSF

Author

Andre Altmann, Neil P. Oxtoby, Daniel C. Alexander, P. A. Wijeratne, Isadora Lopes Alves, Marzia Antonella Scelsi, Frederik Barkhof, Leon M Aksman, and Alexandra L. Young

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease progression, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2020
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11. Spatiotemporal imaging phenotypes of tau pathology in Alzheimer’s disease

Author

Ruben Smith, Oskar Hansson, Daniel C. Alexander, Yasser Iturria Medina, Alan C. Evans, Gil D. Rabinovici, Alexandra L. Young, Olof Strandberg, Leon M Aksman, Michel J. Grothe, Neil P. Oxtoby, Jacob W. Vogel, Renaud La Joie, and Rik Ossenkoppele

Subjects
Pathology, medicine.medical_specialty, Tau pathology, Epidemiology, business.industry, Health Policy, Disease, Phenotype, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2020
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12. Sequences of cognitive decline in typical Alzheimer's disease and posterior cortical atrophy estimated using a novel event-based model of disease progression

Author

Nicholas C. Firth, Alexandra L. Young, Emilie V. Brotherhood, Sebastian J. Crutch, Silvia Primativo, Neil P. Oxtoby, Keir X.X. Yong, and Daniel C. Alexander

Subjects
Epidemiology, posterior cortical atrophy, Disease, kernel density estimate, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Alzheimer Disease, medicine, Dementia, Humans, Cognitive Dysfunction, Cognitive decline, disease progression model, floor, 030304 developmental biology, Event (probability theory), 0303 health sciences, Featured Articles, effect, Health Policy, Disease progression, Posterior cortical atrophy, Brain, Cognition, nonparametric mixture model, Models, Theoretical, Featured Article, Alzheimer's disease, medicine.disease, cognitive decline, Magnetic Resonance Imaging, Cognitive test, non‐Gaussian, Psychiatry and Mental health, Disease Progression, Neurology (clinical), ceiling, Geriatrics and Gerontology, Atrophy, Psychology, Neuroscience, 030217 neurology & neurosurgery, dementia
Abstract

Introduction This work aims to characterize the sequence in which cognitive deficits appear in two dementia syndromes. Methods Event-based modeling estimated fine-grained sequences of cognitive decline in clinically-diagnosed posterior cortical atrophy (PCA) ( n = 94 ) and typical Alzheimer's disease (tAD) ( n = 61 ) at the UCL Dementia Research Centre. Our neuropsychological battery assessed memory, vision, arithmetic, and general cognition. We adapted the event-based model to handle highly non-Gaussian data such as cognitive test scores where ceiling/floor effects are common. Results Experiments revealed differences and similarities in the fine-grained ordering of cognitive decline in PCA (vision first) and tAD (memory first). Simulation experiments reveal that our new model equals or exceeds performance of the classic event-based model, especially for highly non-Gaussian data. Discussion Our model recovered realistic, phenotypical progression signatures that may be applied in dementia clinical trials for enrichment, and as a data-driven composite cognitive end-point.

Published
2019

13. IC‐P‐076: GENOMEWIDE ASSOCIATION STUDY OF DATA‐DRIVEN ALZHEIMER'S DISEASE SUBTYPES

Author

Sebastien Ourselin, Daniel C. Alexander, Razvan V. Marinescu, Andre Altmann, Marzia Antonella Scelsi, Alexandra L. Young, and Jonathan M. Schott

Subjects
0301 basic medicine, Genetics, Epidemiology, business.industry, Health Policy, Disease, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Developmental Neuroscience, Genomewide association, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Published
2018
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14. P1‐372: SUBTYPES OF NEURODEGENERATION IN ALZHEIMER DISEASE: A HEAD‐TO‐HEAD COMPARISON OF FOUR BRAIN ATROPHY SUBTYPE ALGORITHMS IN ADNI

Author

Alexandra L. Young, Sergey Shcherbinin, Shannon L. Risacher, Arnaud Charil, Andrew J. Saykin, Daniel C. Alexander, Adam J. Schwarz, and Neil P. Oxtoby

Subjects
Pathology, medicine.medical_specialty, Epidemiology, business.industry, Head to head, Health Policy, Neurodegeneration, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Atrophy, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business
Published
2018
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16. [IC‐P‐079]: MULTIPLE DISTINCT ATROPHY PATTERNS FOUND IN GENETIC FRONTOTEMPORAL DEMENTIA USING SUBTYPE AND STAGE INFERENCE (SUSTAIN)

Author

Robert Laforce, John C. van Swieten, Alexandre de Mendonça, Katrina M. Dick, Razvan V. Marinescu, Daniela Galimberti, Daniel C. Alexander, Fabrizio Tagliavini, Mario Masellis, Barbara Borroni, Sandro Sorbi, Neil P. Oxtoby, James B. Rowe, Maria Carmela Tartaglia, Jonathan M. Schott, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Giovanni B. Frisoni, Elizabeth Finger, Sebastien Ourselin, Alexandra L. Young, David M. Cash, Martina Bocchetta, Caroline Graff, and M. Jorge Cardoso

Subjects
Epidemiology, Health Policy, Inference, Biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Atrophy, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Stage (cooking), Neuroscience, Frontotemporal dementia
Published
2017
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17. [IC‐P‐154]: CHARACTERISING THE PROGRESSION OF ALZHEIMER's DISEASE SUBTYPES USING SUBTYPE AND STAGE INFERENCE (SUSTAIN)

Author

Sebastian J. Crutch, Razvan V. Marinescu, Nick C. Fox, Nicholas C. Firth, Jonathan D. Rohrer, Daniel C. Alexander, Keir X.X. Yong, Alexandra L. Young, David M. Cash, Neil P. Oxtoby, and Jonathan M. Schott

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, 05 social sciences, Inference, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, 050501 criminology, medicine, Neurology (clinical), Geriatrics and Gerontology, Stage (cooking), business, 0505 law
Published
2017
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18. [P4–164]: DATA‐DRIVEN MODELS OF DISEASE PROGRESSION AND APPLICATIONS TO ALZHEIMER's DISEASE: EVENT‐BASED MODEL AND DIFFERENTIAL EQUATION MODELS OF BIOMARKER CHANGES IN ADNI

Author

Daniel C. Alexander, Razvan V. Marinescu, Neil P. Oxtoby, and Alexandra L. Young

Subjects
Epidemiology, business.industry, Health Policy, Event based, Disease progression, Disease, Computational biology, Differential equation models, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Biomarker (medicine), Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2017
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19. [IC‐P‐141]: ANALYSIS OF THE HETEROGENEITY OF POSTERIOR CORTICAL ATROPHY: DATA‐DRIVEN MODEL PREDICTS DISTINCT ATROPHY PATTERNS FOR THREE DIFFERENT COGNITIVE SUBGROUPS

Author

Sara Garbarino, Daniel C. Alexander, Razvan V. Marinescu, Jorge Cardoso, Silvia Primativo, Arman Eshaghi, Manja Lehmann, Sebastian J. Crutch, Nick C. Fox, Neil P. Oxtoby, Alexandra L. Young, Timothy J. Shakespeare, Nicholas C. Firth, and Keir Yong

Subjects
Epidemiology, Health Policy, Posterior cortical atrophy, Cognition, Biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Atrophy, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Neuroscience
Published
2017
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20. [P4–257]: ANALYSIS OF THE HETEROGENEITY OF POSTERIOR CORTICAL ATROPHY: DATA‐DRIVEN MODEL PREDICTS DISTINCT ATROPHY PATTERNS FOR THREE DIFFERENT COGNITIVE SUBGROUPS

Author

Razvan Valentin Marinescu, Silvia Primativo, Alexandra L. Young, Neil P. Oxtoby, Nicholas C. Firth, Arman Eshaghi, Sara Garbarino, Jorge M. Cardoso, Keir Yong, Nick C. Fox, Manja Lehmann, Timothy J. Shakespeare, Sebastian J. Crutch, and Daniel C. Alexander

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2017
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21. P2‐144: Model‐Based Comparison of Autosomal‐Dominant and Late‐Onset Alzheimer's Disease Progression in the Dian and ADNI Studies

Author

Marco Lorenzi, Neil P. Oxtoby, Philip S.J. Weston, Jon M. Schott, David M. Cash, Sebastien Ourselin, Alexandra L. Young, Nick C. Fox, and Daniel C. Alexander

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Health Policy, Disease progression, Late onset, Biology, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery
Published
2016
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22. P1‐009: A Data‐Driven Comparison of the Progression of Brain Atrophy in Posterior Cortical Atrophy and Alzheimer's Disease

Author

Sebastian J. Crutch, Timothy J. Shakespeare, Viktor Wottschel, Marco Lorenzi, Nick C. Fox, Daniel C. Alexander, Manja Lehmann, Silvia Primativo, Keir Yong, Razvan V. Marinescu, Marc Modat, Arman Eshaghi, Neil P. Oxtoby, Nicholas C. Firth, M. Jorge Cardoso, and Alexandra L. Young

Subjects
0303 health sciences, Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Posterior cortical atrophy, Disease, medicine.disease, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 0302 clinical medicine, Atrophy, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published
2016
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23. P3‐314: Data‐Driven Disease Progression Modelling Using Neuropsychological Tests: Posterior Cortical Atrophy Vs Alzheimer's Disease

Author

Sebastian J. Crutch, Alexandra L. Young, Emilie V. Brotherhood, Silvia Primativo, Neil P. Oxtoby, Razvan V. Marinescu, Nicholas C. Firth, and Daniel C. Alexander

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease progression, Neuropsychology, Posterior cortical atrophy, Disease, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2016
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24. IC‐P‐106: Cross‐Sectional Modeling of Regional Perfusion and Gray Matter Volume in Alzheimer's Disease

Author

Alle Meije Wink, Wiro J. Niessen, John C. van Swieten, Wiesje M. van der Flier, Alexandra L. Young, Xavier Golay, Stefan Klein, Marion Smits, Frederik Barkhof, Neil P. Oxtoby, Esther E. Bron, and Daniel C. Alexander

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Regional perfusion, Neurology (clinical), Geriatrics and Gerontology, business, Nuclear medicine, Gray (unit)
Published
2016
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25. P1‐327: Cross‐Sectional Modeling of Regional Perfusion and Gray Matter Volume in Alzheimer's Disease

Author

Esther E. Bron, Alexandra L. Young, Neil P. Oxtoby, Marion Smits, John C. Swieten, Alle Meije Wink, Wiesje M. van der Flier, Frederik Barkhof, Xavier Golay, Wiro J. Niessen, Stefan Klein, and Daniel C. Alexander

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2016
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26. O2‐05‐01: A DATA‐DRIVEN MODEL OF BIOMARKER CHANGES IN SPORADIC ALZHEIMER'S DISEASE

Author

Daniel C. Alexander, Nick C. Fox, Pankaj Daga, Alexandra L. Young, Sebastien Ourselin, Jonathan M. Schott, David M. Cash, and Neil P. Oxtoby

Subjects
Oncology, medicine.medical_specialty, education.field_of_study, Epidemiology, Proportional hazards model, Health Policy, Population, Disease, medicine.disease, Cognitive test, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Atrophy, Developmental Neuroscience, Neuroimaging, Internal medicine, medicine, Biomarker (medicine), Neurology (clinical), Geriatrics and Gerontology, Abnormality, education
Abstract

We demonstrate the use of a probabilistic generative model to explore the biomarker changes occurring as Alzheimer's disease develops and progresses. We enhanced the recently introduced event-based model for use with a multi-modal sporadic disease data set. This allows us to determine the sequence in which Alzheimer's disease biomarkers become abnormal without reliance on a priori clinical diagnostic information or explicit biomarker cut points. The model also characterizes the uncertainty in the ordering and provides a natural patient staging system. Two hundred and eighty-five subjects (92 cognitively normal, 129 mild cognitive impairment, 64 Alzheimer's disease) were selected from the Alzheimer's Disease Neuroimaging Initiative with measurements of 14 Alzheimer's disease-related biomarkers including cerebrospinal fluid proteins, regional magnetic resonance imaging brain volume and rates of atrophy measures, and cognitive test scores. We used the event-based model to determine the sequence of biomarker abnormality and its uncertainty in various population subgroups. We used patient stages assigned by the event-based model to discriminate cognitively normal subjects from those with Alzheimer's disease, and predict conversion from mild cognitive impairment to Alzheimer's disease and cognitively normal to mild cognitive impairment. The model predicts that cerebrospinal fluid levels become abnormal first, followed by rates of atrophy, then cognitive test scores, and finally regional brain volumes. In amyloid-positive (cerebrospinal fluid amyloid-β1-42 < 192 pg/ml) or APOE-positive (one or more APOE4 alleles) subjects, the model predicts with high confidence that the cerebrospinal fluid biomarkers become abnormal in a distinct sequence: amyloid-β1-42, phosphorylated tau, total tau. However, in the broader population total tau and phosphorylated tau are found to be earlier cerebrospinal fluid markers than amyloid-β1-42, albeit with more uncertainty. The model's staging system strongly separates cognitively normal and Alzheimer's disease subjects (maximum classification accuracy of 99%), and predicts conversion from mild cognitive impairment to Alzheimer's disease (maximum balanced accuracy of 77% over 3 years), and from cognitively normal to mild cognitive impairment (maximum balanced accuracy of 76% over 5 years). By fitting Cox proportional hazards models, we find that baseline model stage is a significant risk factor for conversion from both mild cognitive impairment to Alzheimer's disease (P = 2.06 × 10(-7)) and cognitively normal to mild cognitive impairment (P = 0.033). The data-driven model we describe supports hypothetical models of biomarker ordering in amyloid-positive and APOE-positive subjects, but suggests that biomarker ordering in the wider population may diverge from this sequence. The model provides useful disease staging information across the full spectrum of disease progression, from cognitively normal to mild cognitive impairment to Alzheimer's disease. This approach has broad application across neurodegenerative disease, providing insights into disease biology, as well as staging and prognostication.

Published
2014
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