Neuronal Injury Biomarkers for Assessment of Cognitive Reserve in Alzheimer’s Disease

Introduction: The model of cognitive reserve has been extensively investigated in patients with Alzheimer’s Disease (AD). Many factors could be identified as being influencing or predictive for a higher cognitive reserve. Neuronal injury correlates with cognitive decline in AD with [18F]-fluordesoxyglucose positron-emission-tomography (FDG-PET), structural MRI and total tau in cerebrospinal fluid (CSFt-tau) as the most important biomarkers of neuronal injury according to the A/T/N-classification. The aim of this study was to compare neuronal injury biomarkers with the cognitive performance and further cognitive development to evaluate their potential to predict the individual cognitive reserve. Subjects & Methods: In 110 mild cognitive impaired and demented subjects (age 71 ± 8 years) with a final diagnosis of AD dementia were assessed at baseline by mini-mental-state-examination (MMSE), FDG-PET, MRI and CSFt-tau. Using partial correlation, we tested first for each neuronal injury marker the correlation with MMSE, controlled for age, gender and leukoencephalopathy. Next using multiple regression analysis, we calculated the expected MMSE score based on neuronal injury markers and covariates (MMSENI). The residuals of the partial correlation for each biomarker and the difference between MMSENI and MMSECLI were correlated with the cognitive outcome of patients at clinical follow-up (27 ± 13 months). Results: FDG-PET correlated highly with MMSECLI (R = -0.49, p < 0.01), whereas hippocampal atrophy in MRI (R = -0.15, p = 0.14) and CSFt-tau (R = -0.12, p = 0.22) showed only weak correlations. High neuronal injury relative to cognitive performance was associated with more pronounced cognitive deterioration at follow-up for the residuals of FDG-PET (R = -0.40, p = 0.005) and the combined model (R = -0.43, p = 0.04). Conclusions: The residuals in the correlation of neuronal injury in FDG-PET and cognitive performance represent the individual cognitive reserve in patients with AD and may allow a prediction of an individual’s clinical course. Thus, the individual cognitive reserve should be considered as a covariate in therapeutic trials