Journal
ARCHIVES OF NEUROLOGY
Volume 68, Issue 8, Pages 1040-1048Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/archneurol.2011.167
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Funding
- Foundation for the National Institutes of Health (NIH)
- Avid Radiopharmaceuticals Inc
- GE Healthcare Japan
- Research Association for Biotechnology
- Pfizer Global Research Development
- Forest Laboratories Inc
- Alliance Medicale et Scientifique
- National Multiple Sclerosis Society
- Bayer Healthcare
- Johns Hopkins University
- Alzheimer's Association
- Telemedicine & Advanced Technology Research Center
- University of Pittsburgh
- Neuroscience Early Stage Research Training Program
- Rotman Research Institute
- Wien Center for Alzheimer's Disease and Memory Disorders
- Mount Sinai Medical Center
- Society of Photographic Instrumentation Engineers
- Montreal Neurological Institute and Hospital of McGill University
- Michael J. Fox Foundation for Parkinson's Research
- Elan and Wyeth Alzheimer's Immunotherapy Program (North America)
- University of California
- Tel Aviv University Medical School
- Colloquium Paris
- Ipsen Group
- Wenner-Gren Foundation
- US Social Security Administration
- Korean Neurological Association
- NIH [U01 AG024904]
- Washington University
- Banner Alzheimer's Institute
- Clinical Trials on Alzheimer's Disease
- Veterans Affairs Central Office
- Beijing Institute of Geriatrics
- Innogenetics NV
- New York University
- NeuroVigil Inc
- Centre Hospitalier Regional Universitaire-Hopital Roger Salengro
- Siemens AG
- AstraZeneca AB
- Geneva University Hospitals
- Eli Lilly and Company
- Hopital Pitie-Salpetriere (Assistance Publique-Hopitaux de Paris)
- Institut Catala de Neurocisncies Aplicades
- University of New Mexico School of Medicine
- Merck Co Inc
- US Department of Defense
- US Department of Veterans Affairs
- ADNI
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- National Center for Research Resources [P41-RR14075]
- National Institute for Biomedical Imaging and Bioengineering [R01EB006758]
- National Institute on Aging [AG022381]
- National Institute for Neurological Disorders and Stroke [R01 NS052585-01]
- National Center for Research Resources Biomedical Informatics Research Network [BIRN002, U24 RR021382]
- National Center for Alternative Medicine [RC1 AT005728-01]
- Shared Instrumentation Grants [1S10RR023401, 1S10RR019, 1S10RR023043]
- Ellison Medical Foundation
- Harvard Clinical and Translational Science Center [1KL2RR025757-01]
- Harvard University and its affiliated academic health care centers
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Objective: To characterize rates of regional Alzheimer disease (AD)-specific brain atrophy across the presymptomatic, mild cognitive impairment, and dementia stages. Design: Multicenter case-control study of neuroimaging, cerebrospinal fluid, and cognitive test score data from the Alzheimer's Disease Neuroimaging Initiative. Setting: Research centers across the United States and Canada. Patients: We examined a total of 317 participants with baseline cerebrospinal fluid biomarker measurements and 3T1-weighted magnetic resonance images obtained within 1 year. Main Outcome Measures: We used automated tools to compute annual longitudinal atrophy in the hippocampus and cortical regions targeted in AD. We used Mini-Mental State Examination scores as a measure of cognitive performance. We performed a cross-subject analysis of atrophy rates and acceleration on individuals with an AD-like cerebrospinal fluid molecular profile. Results: In presymptomatic individuals harboring indicators of AD, baseline thickness in AD-vulnerable cortical regions was significantly reduced compared with that of healthy control individuals, but baseline hippocampal volume was not. Across the clinical spectrum, rates of AD-specific cortical thinning increased with decreasing cognitive performance before peaking at approximately the Mini-Mental State Examination score of 21, beyond which rates of thinning started to decline. Annual rates of hippocampal volume loss showed a continuously increasing pattern with decreasing cognitive performance as low as the Mini-Mental State Examination score of 15. Analysis of the second derivative of imaging measurements revealed that AD-specific cortical thinning exhibited early acceleration followed by deceleration. Conversely, hippocampal volume loss exhibited positive acceleration across all study participants. Conclusions: Alzheimer disease-specific cortical thinning and hippocampal volume loss are consistent with a sigmoidal pattern, with an acceleration phase during the early stages of the disease. Clinical trials should carefully consider the nonlinear behavior of these AD biomarkers.
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