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 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.