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Alzheimers Dement. 2018 Jan;14(1):43-53. doi: 10.1016/j.jalz.2017.06.2268. Epub 2017 Jul 22.

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

Author information

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.

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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