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Original Investigation |

Emerging β-Amyloid Pathology and Accelerated Cortical Atrophy

Niklas Mattsson, MD, PhD1,2,3; Philip S. Insel, MS1,3; Rachel Nosheny, PhD1; Duygu Tosun, PhD1,3; John Q. Trojanowski, MD, PhD4; Leslie M. Shaw, PhD4; Clifford R. Jack Jr, MD5; Michael C. Donohue, PhD6; Michael W. Weiner, MD1,3 ; for the Alzheimer’s Disease Neuroimaging Initiative
[+] Author Affiliations
1Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, California
2Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
3Department of Radiology and Biomedical Imaging, University of California, San Francisco
4Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia
5Department of Radiology, Mayo Clinic, Rochester, Minnesota
6Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla
JAMA Neurol. 2014;71(6):725-734. doi:10.1001/jamaneurol.2014.446.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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Figure 1.
Baseline Volumes in A Priori Defined Gray Matter (GM) Regions

Shown are baseline volumes in the study groups. Volumes are centered and standardized. Baseline volumes are modeled data from linear mixed-effects models (intercepts), adjusted for age, sex, education, APOE ε4 genotype status, and intracranial volume. Horizontal lines are mean values. Significances are indicated for the group effects (pairwise comparisons, comparing every group with the CN Aβ-s group and comparing the AD Aβ+ group with the CN Aβ+ group). When correcting for multiple comparisons (false discovery rate), differences that remained significant were amygdala (CN Aβ+ vs AD Aβ+ [P < .001]), cingulate GM (CN Aβ+ vs AD Aβ+ [P < .05]), overall GM (CN Aβ-s vs AD Aβ+ [P < .05] and CN Aβ+ vs AD Aβ+ [P < .05]), hippocampus (CN Aβ-s vs AD Aβ+ [P < .01] and CN Aβ+ vs AD Aβ+ [P < .001]), temporal lobe GM (CN Aβ-s vs AD Aβ+ [P < .001] and CN Aβ+ vs AD Aβ+ [P < .001]), and parietal lobe GM (CN Aβ-s vs AD Aβ+ [P < .05] and CN Aβ+ vs AD Aβ+ [P < .05]). Aβ indicates β-amyloid; AD, Alzheimer disease; AD Aβ+, Aβ-positive AD group; APOE, apolipoprotein E; CN, cognitively normal; CN Aβ+, Aβ-positive CN group; CN Aβ-d, declining Aβ-negative CN group; and CN Aβ-s, stable Aβ-negative CN group.

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Figure 2.
Atrophy Rates in A Priori Defined Gray Matter (GM) Regions

Shown are atrophy rates in the study groups. Volumes are centered and standardized. Atrophy rates are modeled data from linear mixed-effects models (slopes), adjusted for age, sex, education, APOE ε4 genotype status, and intracranial volume. Horizontal lines are mean values. Significances are indicated for the effects of interaction between time and group (pairwise comparisons, comparing every group with the CN Aβ-s group and comparing the AD Aβ+ group with the CN Aβ+ group). When correcting for multiple comparisons (false discovery rate), differences that remained significant were occipital GM (CN Aβ-s vs AD Aβ+ [P < .05]), hippocampus (CN Aβ-s vs AD Aβ+ [P < .001] and CN Aβ+ vs AD Aβ+ [P < .01]), amygdala (CN Aβ-s vs CN Aβ+ [P < .01] and CN Aβ-s vs AD Aβ+ [P < .05]), frontal GM (CN Aβ-s vs CN Aβ-d [P < .05] and CN Aβ-s vs AD Aβ+ [P < .01]), cingulate GM (CN Aβ-s vs AD Aβ+ [P < .001] and CN Aβ+ vs AD Aβ+ [P < .001]), temporal GM (CN Aβ-s vs CN Aβ+ [P < .05], CN Aβ-s vs AD Aβ+ [P < .001], and CN Aβ+ vs AD Aβ+ [P < .001]), parietal GM (CN Aβ-s vs CN Aβ-d [P < .05], CN Aβ-s vs CN Aβ+ [P < .05], and CN Aβ-s vs AD Aβ+ [P < .01]), and overall GM (CN Aβ-s vs CN Aβ-d [P < .05], CN Aβ-s vs CN Aβ+ [P < .05], CN Aβ-s vs AD Aβ+ [P < .001], and CN Aβ+ vs AD Aβ+ [P < .05]). Aβ indicates β-amyloid; AD, Alzheimer disease; AD Aβ+, Aβ-positive AD group; APOE, apolipoprotein E; CN, cognitively normal; CN Aβ+, Aβ-positive CN group; CN Aβ-d, declining Aβ-negative CN group; and CN Aβ-s, stable Aβ-negative CN group.

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Figure 3.
Comparison of Atrophy Rates Among Groups in All Gray Matter Regions

The top 3 panels show forest plots of differences in atrophy rates for group comparisons. For each region of interest, the effect of group (from linear mixed models, adjusted for age and sex) is indicated. The 95% CIs were generated by bootstrapping (n = 1000) with resampling of participants. The bottom 3 panels show histograms of the group differences. Note that the same individuals are represented multiple times in this figure because each CN Aβ group is included in 2 comparisons. Volumes were centered and standardized. Combinations of regions were defined as described in the Methods section. Aβ indicates β-amyloid; AD, Alzheimer disease; AD Aβ+, Aβ-positive AD group; Bankssts, banks of the superior temporal sulcus; CING, cingulate regions; CN, cognitively normal; CN Aβ+, Aβ-positive CN group; CN Aβ-d, declining Aβ-negative CN group; CN Aβ-s, stable Aβ-negative CN group; FRONT, frontal regions; OCC, occipital regions; OVERALL, all gray matter regions; PARIET, parietal regions; and TEMP, temporal regions.

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