Fine-grained age-matching improves atrophy-based detection of mild cognitive impairment more than amyloid-negative reference subjects

Introduction: In clinical practice, differentiating between age-related gray matter (GM) atrophy and neurodegeneration-related atrophy at early disease stages, such as mild cognitive impairment (MCI), remains challenging. We hypothesized that fined-grained adjustment for age effects and using amyloid-negative reference subjects could increase classification accuracy. Methods: T1-weighted magnetic resonance imaging (MRI) data of 131 cognitively normal (CN) individuals and 91 patients with MCI from the Alzheimer's disease neuroimaging initiative (ADNI) characterized concerning amyloid status, as well as 19 CN individuals and 19 MCI patients from an independent validation sample were segmented, spatially normalized and analyzed in the framework of voxel-based morphometry (VBM). For each participant, statistical maps of GM atrophy were computed as the deviation from the GM of CN reference groups at the voxel level. CN reference groups composed with different degrees of age-matching, and mixed and strictly amyloid-negative CN reference groups were examined regarding their effect on the accuracy in distinguishing between CN and MCI. Furthermore, the effects of spatial smoothing and atrophy threshold were assessed. Results: Approaches with a specific reference group for each age significantly outperformed all other age -adjustment strategies with a maximum area under the curve of 1.0 in the ADNI sample and 0.985 in the validation sample. Accounting for age in a regression-based approach improved classification accuracy over that of a single CN reference group in the age range of the patient sample. Using strictly amyloid-negative reference groups improved classification accuracy only when age was not considered. Conclusion: Our results demonstrate that VBM can differentiate between age-related and MCI-associated atrophy with high accuracy. Crucially, age-specific reference groups significantly increased accuracy, more so than regression-based approaches and using amyloid-negative reference groups.