Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

Kirsi M Kinnunen¹, David M Cash², Teresa Poole³, Chris Frost³, Tammie L S Benzinger⁴, R Laila Ahsan¹, Kelvin K Leung¹, M Jorge Cardoso⁵, Marc Modat⁵, Ian B Malone¹, John C Morris⁶, Randall J Bateman⁶, Daniel S Marcus⁴, Alison Goate⁷, Stephen P Salloway⁸, Stephen Correia⁸, Reisa A Sperling⁹, Jasmeer P Chhatwal⁹, Richard P Mayeux¹⁰, Adam M Brickman¹⁰, Ralph N Martins¹¹, Martin R Farlow¹², Bernardino Ghetti¹³, Andrew J Saykin¹⁴, Clifford R Jack Jr¹⁵, Peter R Schofield¹⁶, Eric McDade⁶, Michael W Weiner¹⁷, John M Ringman¹⁸, Paul M Thompson¹⁹, Colin L Masters²⁰, Christopher C Rowe²¹, Martin N Rossor¹, Sebastien Ourselin⁵, Nick C Fox¹; Dominantly Inherited Alzheimer Network (DIAN)

Affiliations

¹ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
² Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Physics and Bioengineering, Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK. Electronic address: d.cash@ucl.ac.uk.
³ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.
⁴ Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
⁵ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Physics and Bioengineering, Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
⁶ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Neurology, Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
⁹ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Neurology, Columbia University Medical Center, New York, NY, USA.
¹¹ Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
¹² Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴ Department of Radiology and Imaging Sciences, Centre for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
¹⁶ Neuroscience Research Australia, Randwick, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
¹⁷ Department of Radiology, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Department of Neurology, Keck USC School of Medicine, Los Angeles, CA, USA.
¹⁹ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
²⁰ The Florey Institute, University of Melbourne, Parkville, VIC, Australia.
²¹ Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia; Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.

PMID: 28738187
PMCID: PMC5751893
DOI: 10.1016/j.jalz.2017.06.2268

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

Kirsi M Kinnunen et al. Alzheimers Dement. 2018 Jan.

. 2018 Jan;14(1):43-53.

doi: 10.1016/j.jalz.2017.06.2268. Epub 2017 Jul 22.

Authors

Affiliations

¹ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
² Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Physics and Bioengineering, Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK. Electronic address: d.cash@ucl.ac.uk.
³ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.
⁴ Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
⁵ Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK; Department of Medical Physics and Bioengineering, Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
⁶ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Neurology, Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
⁹ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Neurology, Columbia University Medical Center, New York, NY, USA.
¹¹ Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
¹² Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴ Department of Radiology and Imaging Sciences, Centre for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
¹⁶ Neuroscience Research Australia, Randwick, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
¹⁷ Department of Radiology, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹⁸ Department of Neurology, Keck USC School of Medicine, Los Angeles, CA, USA.
¹⁹ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
²⁰ The Florey Institute, University of Melbourne, Parkville, VIC, Australia.
²¹ Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia; Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.

PMID: 28738187
PMCID: PMC5751893
DOI: 10.1016/j.jalz.2017.06.2268

Abstract

Introduction: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials.

Methods: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point.

Results: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point.

Discussion: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

Keywords: Alzheimer's disease; Atrophy; Autosomal dominant; Boundary Shift Integral; Change-point; Dementia; Longitudinal; MRI; Neuroimaging; Nonlinear modeling.

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Figures

**Fig. 1**
Schematic representation of the “step change” (A) and “gradual acceleration” (B) change-point models.

**Fig. 2**
Rates of change estimated from the “step change” and “gradual acceleration” models, as a function of the estimated years from symptom onset (EYO) for the pMut+/qMut+ carriers. The figure shows the relationship between rate of annualized volume change (%) and EYO. 95% confidence intervals are included, computed from the bootstrap samples. Although the schematics in Fig. 1 display the decline in actual volume, these graphs represent the rate of change in volume. A horizontal line indicates the estimated atrophy rate (from the “step change” model) for noncarriers and carriers before the change-point before any deviation from normal rates of change. Vertical dotted lines indicate the change-points for both the “step change” and “gradual acceleration” models. For periods that include the change-point, the estimated rate of atrophy is a weighted combination, representing the transition from the pre-change-point atrophy to the post-change-point atrophy. Top left: whole brain; top right: lateral ventricles; bottom left: left hippocampus; bottom right: right hippocampus.

See this image and copyright information in PMC

References

1. Golde TE, Schneider LS, Koo EH. Anti-aβ therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron. 2011;69:203–13. - PMC - PubMed
1. Ryan NS, Rossor MN. Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomark Med. 2010;4:99–112. - PMC - PubMed
1. Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014;83:253–60. - PMC - PubMed
1. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804. - PMC - PubMed
1. Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12:207–16. - PMC - PubMed

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Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

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Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

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