- Email: [email protected]
DIAGNOSTIC AND PROGNOSTIC POWER OF FLUID AND NEUROIMAGING MARKERS OF PATHOLOGY AND NEURODEGENERATION: THE ALZHEIMER'S IMAGING, BIOMARKERS, AND LIFESTYLE (AIBL) STUDY OF AGEING EXPERIENCE
P174
Podium Presentations: Sunday, July 16, 2017
SUNDAY, JULY 16, 2017 FEATURED RESEARCH SESSION F1-02 COMBINATORIAL BIOMARKERS FOR ALZHEIMER’S DISEASE – HUGE, BUT CHALLENGING, OPPORTUNITY F1-02-01
DIAGNOSTIC AND PROGNOSTIC POWER OF FLUID AND NEUROIMAGING MARKERS OF PATHOLOGY AND NEURODEGENERATION: THE ALZHEIMER’S IMAGING, BIOMARKERS, AND LIFESTYLE (AIBL) STUDY OF AGEING EXPERIENCE
Victor L. L. Villemagne1,2, Samantha Burnham3, James D. Doecke4, Pierrick Bourgeat5, Vincent Dore2,3, Simon M. Laws6, Steven Collins1, Qiao-Xin Li7, Stephanie R. Rainey-Smith8, Alan Rembach1, Yen Ying Lim9, Paul Maruff10, Veer Bala Gupta11, Greg Savage12, Olivier Salvado13, David Ames14, Christopher C. Rowe2, Ralph N. Martins15, Colin L. Masters7, 1The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 2Austin Health, Melbourne, Australia; 3CSIRO, Melbourne, Australia; 4CSIRO Computational Informatics/Australian e-Health Research Centre, Brisbane, Australia; 5CSIRO, Brisbane, Australia; 6Edith Cowan University and Cooperative Research Centre (CRC) for Mental Health, Perth, Australia; 7 The Florey Institute of Neuroscience and Mental Health, Parkville, Australia; 8Australian Alzheimer’s Research Foundation, Perth, Australia; 9 Florey Institute of Neuroscience and Mental Health, Parkville, Australia; 10 Cogstate Ltd., Melbourne, Australia; 11Edith Cowan University, Perth, Australia; 12Macquarie University, Sydney, Australia; 13Commonwealth Scientific and Industrial Research Organisation, Brisbane, Australia; 14The University of Melbourne, Melbourne, Australia; 15Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Australia. Contact e-mail: [email protected] Background: Neuroimaging and fluid biomarkers are being increasingly used for the diagnosis, prognosis, as well as recruitment and outcome measures in disease-specific therapeutic trials of Alzheimer’s disease (AD). Methods: We examined different neuroimaging markers in the context of predicting disease progression and cognitive trajectories, alone and in combination with fluid and genetic biomarkers (f.e. APOE or BDNF). We assessed the predictive power of cross-sectional and longitudinal approaches of neuroimaging measures of Ab-pathology, brain volumetrics, and what predictive information can be derived from the combination of these markers. With the advent of tau imaging, we also tested the performance of neuroimaging and fluid biomarkers against the new proposed categorical classification that combines measures of Ab, tau, and neuronal injury. Finally, we tested the performance of blood surrogate markers as predictors of pathology and disease progression. Results: When assessed alone, baseline measures of Ab burden were a much stronger predictor of disease progression (OR 11.3) than rates of Ab accumulation established over 4.5 years (OR 5.1). Furthermore, the predictive value of Ab imaging increases with increasing Ab burden (from PPV 46% to PPV 84% in MCI). While BDNF polymorphism had no effect on Ab accumulation, APOE4 carriers showed faster rates of Ab deposition at the early stages of the accumulation process. Individuals with high Ab burden carrying APOE4 or BDNF polymorphism declined faster than non-carriers. Cognitively unimpaired individuals who presented only with signs of neurodegeneration but no Ab-pathology, did not show cognitive decline nor cortical grey matter atrophy over 6 years. The combination of markers of Ab-pathology and markers of neuronal injury seem to be a stronger predictor of cognitive decline than the combination of markers of tau pathology and
markers of neuronal injury. Blood markers, validated against similar cohorts (ADNI), showed high accuracy in predicting brain Ab pathology and cognitive decline. Conclusions: Markers of Abpathology are highly predictive of cognitive decline and disease progression. Combination with neuroimaging markers of neurodegeneration and/or genetic markers refines the predictive power of markers of AD pathology. Improvement in blood biomarkers are allowing accurately prediction of Ab-pathology, providing a platform for developing a population-based screens.
F1-02-02
DISCOVERY AND VALIDATION OF MULTIMODAL BIOMARKER SIGNATURES RELATING TO ALZHEIMER’S DISEASE PATHOLOGY AND PROGRESSION
Sarah Westwood1,2, Abdul Hye3, Alberto Lleo4, Alejo J. NevadoHolgado2, Alison L. Baird2, Anders Wallin5, Anoushka Leslie3, Beatriz Jimenez6, Benjamine Young Liu2, Cristina Legido-Quigley3, Danai Dima3, David Ruvolo2, Elaine Holmes6, Ellie D’Hondt7, Eric Westman8, Frederik Barkhof9, Giovanni B. Frisoni10, Henrik Zetterberg11,12, Isabelle Bos13, Jake Pearce6, Johannes Streffer14, Jose Luis Molinuevo15, Julius Popp16, Lars Bertram17, Luke Whiley6, Lynn Maslen6, Maria Gomez-Romero6, Mark David6, Matthew Lewis6, Natalja Kurbatova18, Nicholas J. Ashton3, Nicola Voyle3, Olivia Kowalczyk3, Pablo Martinez-Lage19, Petroula Proitsi3,12, Philip Scheltens20, Pieter Jelle Visser9,13, Richard JB. Dobson3, Rik Vandenberghe21, Sebastiaan Engelborghs22,23, Stephanie J. B. Vos24, Stuart G. Snowden3, Toby Athersuch6, Tom Ashby7, Torben Kimhofer6, Wilfried Verachtert7, Simon Lovestone25, 1University of Oxford, Department of Psychiatry, Oxford, United Kingdom; 2University of Oxford, Oxford, United Kingdom; 3King’s College London, London, United Kingdom; 4 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 5Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Moelndal, Sweden; 6Imperial College London, London, United Kingdom; 7IMEC International, Leuven, Belgium; 8Karolinska Institute, Stockholm, Sweden; 9VU University Medical Center, Amsterdam, Netherlands; 10University of Geneva, Geneva, Switzerland; 11University of Gothenburg, Gothenburg, Sweden; 12University College London, London, United Kingdom; 13Maastricht University, Maastricht, Netherlands; 14 Janssen Research & Development, Beerse, Belgium; 15Alzheimer’s Disease Unit and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, Barcelona, Spain; 16University Hospital Lausanne, Lausanne, Switzerland; 17 University of L€ubeck, L€ubeck, Germany; 18European Bioinformatics Institute, Hinxton, United Kingdom; 19Fundacion CITA-Alzheimer Fundazioa, San Sebastian, Spain; 20Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands; 21University Hospital Leuven, Leuven, Belgium; 22University of Antwerp, Antwerp, Belgium; 23Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; 24Maastricht University Medical Center, Maastricht, Netherlands; 25King’s College London, Institute of Psychiatry and National Institute of Health Research (NIHR) Biomedical Research Centre for Mental Health, Oxford, United Kingdom. Contact e-mail: [email protected] Background: Biomarkers of Alzheimer’s disease (AD) pathology and progression have now been identified across various modalities. The aims of the two studies presented (ANM-MMB and EMIF-AD biomarker discovery) are to discover and replicate previously identified biomarkers of disease pathology and progression, and moreover to determine whether a multimodal biomarker signature may add value in comparison to a biomarker of a single modality. Methods: The ANM-MMB cohort is comprised of 718 AD, MCI converters and non-converters, and control subjects selected from the AddNeuroMed, Alzheimer’s research trust and Dementia case register cohorts. Cognitive measures, serum and urine
Podium Presentations: Sunday, July 16, 2017
SUNDAY, JULY 16, 2017 FEATURED RESEARCH SESSION F1-02 COMBINATORIAL BIOMARKERS FOR ALZHEIMER’S DISEASE – HUGE, BUT CHALLENGING, OPPORTUNITY F1-02-01
DIAGNOSTIC AND PROGNOSTIC POWER OF FLUID AND NEUROIMAGING MARKERS OF PATHOLOGY AND NEURODEGENERATION: THE ALZHEIMER’S IMAGING, BIOMARKERS, AND LIFESTYLE (AIBL) STUDY OF AGEING EXPERIENCE
Victor L. L. Villemagne1,2, Samantha Burnham3, James D. Doecke4, Pierrick Bourgeat5, Vincent Dore2,3, Simon M. Laws6, Steven Collins1, Qiao-Xin Li7, Stephanie R. Rainey-Smith8, Alan Rembach1, Yen Ying Lim9, Paul Maruff10, Veer Bala Gupta11, Greg Savage12, Olivier Salvado13, David Ames14, Christopher C. Rowe2, Ralph N. Martins15, Colin L. Masters7, 1The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; 2Austin Health, Melbourne, Australia; 3CSIRO, Melbourne, Australia; 4CSIRO Computational Informatics/Australian e-Health Research Centre, Brisbane, Australia; 5CSIRO, Brisbane, Australia; 6Edith Cowan University and Cooperative Research Centre (CRC) for Mental Health, Perth, Australia; 7 The Florey Institute of Neuroscience and Mental Health, Parkville, Australia; 8Australian Alzheimer’s Research Foundation, Perth, Australia; 9 Florey Institute of Neuroscience and Mental Health, Parkville, Australia; 10 Cogstate Ltd., Melbourne, Australia; 11Edith Cowan University, Perth, Australia; 12Macquarie University, Sydney, Australia; 13Commonwealth Scientific and Industrial Research Organisation, Brisbane, Australia; 14The University of Melbourne, Melbourne, Australia; 15Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Australia. Contact e-mail: [email protected] Background: Neuroimaging and fluid biomarkers are being increasingly used for the diagnosis, prognosis, as well as recruitment and outcome measures in disease-specific therapeutic trials of Alzheimer’s disease (AD). Methods: We examined different neuroimaging markers in the context of predicting disease progression and cognitive trajectories, alone and in combination with fluid and genetic biomarkers (f.e. APOE or BDNF). We assessed the predictive power of cross-sectional and longitudinal approaches of neuroimaging measures of Ab-pathology, brain volumetrics, and what predictive information can be derived from the combination of these markers. With the advent of tau imaging, we also tested the performance of neuroimaging and fluid biomarkers against the new proposed categorical classification that combines measures of Ab, tau, and neuronal injury. Finally, we tested the performance of blood surrogate markers as predictors of pathology and disease progression. Results: When assessed alone, baseline measures of Ab burden were a much stronger predictor of disease progression (OR 11.3) than rates of Ab accumulation established over 4.5 years (OR 5.1). Furthermore, the predictive value of Ab imaging increases with increasing Ab burden (from PPV 46% to PPV 84% in MCI). While BDNF polymorphism had no effect on Ab accumulation, APOE4 carriers showed faster rates of Ab deposition at the early stages of the accumulation process. Individuals with high Ab burden carrying APOE4 or BDNF polymorphism declined faster than non-carriers. Cognitively unimpaired individuals who presented only with signs of neurodegeneration but no Ab-pathology, did not show cognitive decline nor cortical grey matter atrophy over 6 years. The combination of markers of Ab-pathology and markers of neuronal injury seem to be a stronger predictor of cognitive decline than the combination of markers of tau pathology and
markers of neuronal injury. Blood markers, validated against similar cohorts (ADNI), showed high accuracy in predicting brain Ab pathology and cognitive decline. Conclusions: Markers of Abpathology are highly predictive of cognitive decline and disease progression. Combination with neuroimaging markers of neurodegeneration and/or genetic markers refines the predictive power of markers of AD pathology. Improvement in blood biomarkers are allowing accurately prediction of Ab-pathology, providing a platform for developing a population-based screens.
F1-02-02
DISCOVERY AND VALIDATION OF MULTIMODAL BIOMARKER SIGNATURES RELATING TO ALZHEIMER’S DISEASE PATHOLOGY AND PROGRESSION
Sarah Westwood1,2, Abdul Hye3, Alberto Lleo4, Alejo J. NevadoHolgado2, Alison L. Baird2, Anders Wallin5, Anoushka Leslie3, Beatriz Jimenez6, Benjamine Young Liu2, Cristina Legido-Quigley3, Danai Dima3, David Ruvolo2, Elaine Holmes6, Ellie D’Hondt7, Eric Westman8, Frederik Barkhof9, Giovanni B. Frisoni10, Henrik Zetterberg11,12, Isabelle Bos13, Jake Pearce6, Johannes Streffer14, Jose Luis Molinuevo15, Julius Popp16, Lars Bertram17, Luke Whiley6, Lynn Maslen6, Maria Gomez-Romero6, Mark David6, Matthew Lewis6, Natalja Kurbatova18, Nicholas J. Ashton3, Nicola Voyle3, Olivia Kowalczyk3, Pablo Martinez-Lage19, Petroula Proitsi3,12, Philip Scheltens20, Pieter Jelle Visser9,13, Richard JB. Dobson3, Rik Vandenberghe21, Sebastiaan Engelborghs22,23, Stephanie J. B. Vos24, Stuart G. Snowden3, Toby Athersuch6, Tom Ashby7, Torben Kimhofer6, Wilfried Verachtert7, Simon Lovestone25, 1University of Oxford, Department of Psychiatry, Oxford, United Kingdom; 2University of Oxford, Oxford, United Kingdom; 3King’s College London, London, United Kingdom; 4 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 5Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Moelndal, Sweden; 6Imperial College London, London, United Kingdom; 7IMEC International, Leuven, Belgium; 8Karolinska Institute, Stockholm, Sweden; 9VU University Medical Center, Amsterdam, Netherlands; 10University of Geneva, Geneva, Switzerland; 11University of Gothenburg, Gothenburg, Sweden; 12University College London, London, United Kingdom; 13Maastricht University, Maastricht, Netherlands; 14 Janssen Research & Development, Beerse, Belgium; 15Alzheimer’s Disease Unit and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, Barcelona, Spain; 16University Hospital Lausanne, Lausanne, Switzerland; 17 University of L€ubeck, L€ubeck, Germany; 18European Bioinformatics Institute, Hinxton, United Kingdom; 19Fundacion CITA-Alzheimer Fundazioa, San Sebastian, Spain; 20Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands; 21University Hospital Leuven, Leuven, Belgium; 22University of Antwerp, Antwerp, Belgium; 23Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; 24Maastricht University Medical Center, Maastricht, Netherlands; 25King’s College London, Institute of Psychiatry and National Institute of Health Research (NIHR) Biomedical Research Centre for Mental Health, Oxford, United Kingdom. Contact e-mail: [email protected] Background: Biomarkers of Alzheimer’s disease (AD) pathology and progression have now been identified across various modalities. The aims of the two studies presented (ANM-MMB and EMIF-AD biomarker discovery) are to discover and replicate previously identified biomarkers of disease pathology and progression, and moreover to determine whether a multimodal biomarker signature may add value in comparison to a biomarker of a single modality. Methods: The ANM-MMB cohort is comprised of 718 AD, MCI converters and non-converters, and control subjects selected from the AddNeuroMed, Alzheimer’s research trust and Dementia case register cohorts. Cognitive measures, serum and urine