Format

Send to

Choose Destination
Lancet Neurol. 2018 Mar;17(3):241-250. doi: 10.1016/S1474-4422(18)30028-0. Epub 2018 Feb 1.

Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study.

Author information

1
Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA; Department of Psychological & Brain Sciences, Washington University, St Louis, MO, USA. Electronic address: bagordon@wustl.edu.
2
Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA; Division of Biology and Biomedical Sciences, Washington University, St Louis, MO, USA.
3
Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.
4
Department of Neurology, Washington University, St Louis, MO, USA.
5
Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA; Department of Biostatistics, Washington University, St Louis, MO, USA.
6
Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA; Department of Neurology, Washington University, St Louis, MO, USA.
7
Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA; Department of Neurology, Washington University, St Louis, MO, USA; Department of Psychological & Brain Sciences, Washington University, St Louis, MO, USA.
8
Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA; Department of Neurology, Washington University, St Louis, MO, USA; The Hope Center for Neurological Disorders, St Louis, MO, USA.
9
Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA.
10
Department of Neurology, Washington University, St Louis, MO, USA; The Hope Center for Neurological Disorders, St Louis, MO, USA.
11
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
12
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, Columbia University, New York, NY, USA.
13
Dementia Research Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK; Translational Imaging Group, Centre for Medical Image Computing, University College London, London, UK.
14
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
15
Department of Psychiatry, Brown University School of Medicine, Providence, RI, USA.
16
Department of Nuclear Medicine, Technische Universität München, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Tübingen, Tübingen, Germany.
17
Dementia Research Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
18
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
19
German Center for Neurodegenerative Diseases (DZNE) Tübingen, Tübingen, Germany; Division of Nuclear Medicine and Clinical Molecular Imaging, University Hospital Tübingen, Tübingen, Germany.
20
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
21
The Florey Institute, University of Melbourne, Parkville, VIC, Australia.
22
Department of Psychiatry, Brown University School of Medicine, Providence, RI, USA; Department of Neurology, Brown University School of Medicine, Providence, RI, USA.
23
Brown University School of Medicine, Providence, RI, USA; Indiana University School of Medicine, Indianapolis, IN, USA.
24
Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney NSW, Australia.
25
Imaging Genetics Center, University of Southern California, Marina del Rey, CA, USA.
26
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
27
Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA; Department of Neurology, Washington University, St Louis, MO, USA; The Hope Center for Neurological Disorders, St Louis, MO, USA.
28
Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.

Abstract

BACKGROUND:

Models of Alzheimer's disease propose a sequence of amyloid β (Aβ) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal.

METHODS:

Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) FINDINGS: 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years [SD 3·3] before expected onset), followed by hypometabolism (14·1 years [5·1] before expected onset), and lastly structural decline (4·7 years [4·2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aβ accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning).

INTERPRETATION:

Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials.

FUNDING:

US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK.

PMID:
29397305
PMCID:
PMC5816717
DOI:
10.1016/S1474-4422(18)30028-0
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center