Emerging β-amyloid pathology and accelerated cortical atrophy.
OBJECTIVE
The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood.


OBJECTIVE
To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons.


METHODS
Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive.


METHODS
Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models.


RESULTS
Baseline gray matter volumes were similar among the CN Aβ groups, but atrophy rates were increased in frontoparietal regions in the declining Aβ-negative and Aβ-positive groups and in amygdala and temporal regions in the Aβ-positive group. Aβ-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions.


CONCLUSIONS
Emerging Aβ pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage Aβ pathology may have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD.
Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, California2Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Möl.
Niklas
N
Mattsson
Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, California3Department of Radiology and Biomedical Imaging, University of California, San Francisco.
Philip S
PS
Insel
Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, California.
Rachel
R
Nosheny
Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, California3Department of Radiology and Biomedical Imaging, University of California, San Francisco.
Duygu
D
Tosun
Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
John Q
JQ
Trojanowski
Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Leslie M
LM
Shaw
Department of Radiology, Mayo Clinic, Rochester, Minnesota.
Clifford R
CR
Jack
Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla.
Michael C
MC
Donohue
Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, California3Department of Radiology and Biomedical Imaging, University of California, San Francisco.
Michael W
MW
Weiner
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001284:Atrophy; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments