Metabolic Correlates of Reserve and Resilience in MCI due to Alzheimer's Disease (AD)

Background: We explored the presence of both reserve and resilience in late-converter MCI due to AD and in slowly-progressing amyloid-positive MCI by assessing topography and extent of neurodegeneration i) with respect to both "aggressive" and typically progressing phenotypes; ii) in the whole group of MCI grounding the stratification on educational levels. Methods: We analyzed 94 MCI-AD patients followed until conversion to dementia and 39 MCI patients with brain amyloidosis (AMY+MCI) with available baseline FDG PET. Using a data-driven approach based on conversion time, MCI-AD were divided into 'typical AD' and 'late-converter' subgroup. Similarly, based on the annual rate of MMSE reduction, AMY+MCI group was divided, obtaining smoldering (first tertile) and aggressive (third tertile) subgroups. Finally, we divided the whole group (MCI-AD and AMY+ MCI) according to years of schooling, obtaining four subgroups: poorly-educated (Low-EDUC, first quartile), patients with average education (Average-EDUC, second quartile), highly-educated (High-EDUC, third quartile) and exceptionally educated (Except-EDUC; fourth quartile). FDG-PET of typical-AD, late converters, aggressive and smoldering AMY+MCI subgroups as well as education-based subgroups were compared to controls and between each other using two-sample t-test design (SPM8; p<0.05 family-wise-error-corrected). Results: Late converters were characterized by relatively preserved metabolism in the right middle temporal gyrus (BA 21) and in the left orbitofrontal cortex (BA 47) with respect to typical-AD. When compared to CTR, High-EDUC subgroup demonstrated a more extended bilateral hypometabolism in posterior parietal cortex, posterior cingulate and precuneus than Low- and Average-EDUC expressing the same level of cognitive impairment. By contrast, Except-EDUC patients showed less extended cluster of hypometabolism and a post-hoc analysis demonstrated that metabolism in middle and inferior temporal gyri (BA 20 and 21) was relatively spared in this subgroup with respect to the other MCI patients. Conclusions: Middle and inferior temporal gyri may represent sites of resilience (when relatively preserved) rather than a hallmark of a more aggressive pattern (when hypometabolic). These regions may constitute a relatively homogeneous AD progression-related pattern of hypometabolism despite the interference of cognitive reserve. Further studies are needed to explore the existence of a non-linear relationship between education and brain metabolism and to better disclose education-related resilience mechanisms