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Original Contributions |

The Dynamics of Cortical and Hippocampal Atrophy in Alzheimer Disease

Mert R. Sabuncu, PhD; Rahul S. Desikan, MD, PhD; Jorge Sepulcre, MD, PhD; Boon Thye T. Yeo, PhD; Hesheng Liu, PhD; Nicholas J. Schmansky, MSc; Martin Reuter, PhD; Michael W. Weiner, MD; Randy L. Buckner, PhD; Reisa A. Sperling, MD; Bruce Fischl, PhD; for the Alzheimer's Disease Neuroimaging Initiative
Arch Neurol. 2011;68(8):1040-1048. doi:10.1001/archneurol.2011.167.
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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 3 T1-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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Figure 1. Rates of atrophy. A, Hypothetical curve of longitudinal atrophy according to the cumulative diffusion model; B, corresponding rate of atrophy; and C, rate of atrophy as a function of the total amount of Alzheimer disease (AD)–specific atrophy.

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Figure 2. Seven regions of interest generated from the regions demonstrating the greatest magnitude of Alzheimer disease (AD)–specific thinning in the exploratory analysis of the Open Access Series of Imaging Studies data, shown on an inflated surface representation, with dark gray regions representing sulci and light gray regions representing gyri. For illustration purposes, only the right hemisphere is presented. A, Statistical significance values of the difference between healthy control individuals and patients with incipient AD. This exploratory analysis was not corrected for multiple comparisons; therefore, this map is not intended to be an accurate reflection of early AD-specific thinning. However, the overall pattern is in general agreement with reported results. B, The regions of interest.

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Figure 3. Baseline hippocampal volume measurements and the annual rates of Alzheimer disease (AD)–specific cortical thinning and hippocampal volume loss. Shown are mean hippocampal volume (A) and cortical thickness in AD-vulnerable regions of interest (B) across healthy control individuals, presymptomatic individuals, and symptomatic (ie, having amnestic mild cognitive impairment [aMCI] and AD) individuals with an AD-like cerebrospinal fluid molecular profile. Mean rates of hippocampal volume loss (C) and AD-specific cortical thinning (D) are shown for each group. Error bars indicate SEM. Asterisk indicates P < .05 for group differences.

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Figure 4. Best second-order polynomial fit for Alzheimer disease (AD)–specific cortical thinning rates and hippocampal volume loss rates as functions of Mini-Mental State Examination (MMSE) score. Shown are scatterplots of rates of AD-specific hippocampal volume loss (A) and cortical thinning (B) vs MMSE score. Each dot represents an individual with an AD-like cerebrospinal fluid molecular profile. The curves represent best-fit quadratic functions. The curve for the hippocampus is approximately linear (but slightly convex due to a nonsignificant positive coefficient in the quadratic term). The curve for AD-specific cortical thinning is concave, with an optimum at approximately the MMSE score of 21. To examine the sensitivity of the fit to outliers, we reanalyzed these data without the 2 individuals with extreme data, namely, those with MMSE scores of 16 and 15, respectively. All results remained approximately the same. Crucially, the quadratic term for AD-specific thinning was statistically significant, and the optimum score was approximately 21.

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