Background: Structural neuroimaging has been applied towards identification of individuals with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, these methods are greatly impacted by age limiting their utility for detection of preclinical pathology. Therefore, careful consideration of age effects in the modeling of AD degenerative patterns could provide more sensitive detection of the earliest stages of brain disease.
Methods: We built linear models for age based on multiple combined structural features (cortical thickness, subcortical structural volumes, ratio of gray to white matter signal intensity, white matter signal abnormalities, total intracranial volume) in 272 healthy adults across a wide age range (D1: age 36-108). These models were then used to create a new support vector machine (SVM) training model with 10-fold cross validation in 136 AD and 268 control participants (D2) based on deviations from the expected age-effects found in the initial sample. Subsequent validation assessed the accuracy of the SVM model to correctly classify AD patients in a new dataset (D3). Finally, we applied the classifier to individuals with MCI to evaluate prediction for early impairment and longitudinal cognitive change.
Results: Optimal cross-validation accuracy was 93.07% in the D2, compared to 91.83% without age detrending in D1. In the validation dataset (D3), the classifier obtained an accuracy of 84.85% (56/66), sensitivity of 85.36% (35/41) and specificity of 84% (21/25). In the MCI dataset, we observed significantly greater longitudinal cognitive decline in MCI who were classified as more ‘AD-like’ (MCI-AD), and this effect was pronounced in individuals who were late MCI. The top five contributive features were volumes of left hippocampus, right hippocampus, left amygdala, the thickness of left and right medial temporal & parahippocampus gyrus.
Conclusions: Linear detrending for age in SVM for combined structural features resulted in good performance for classification of AD and generalization of MCI prediction. Such procedures should be employed in future work.