The Dynamics of Cortical and Hippocampal Atrophy in Alzheimer Disease

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.