Cognitive REServe and Clinical ENDOphenotypes – CRESCENDO

Cognitive reserve (CR) has been postulated to mediate the relationship between age- or Alzheimer’s disease (AD)-related pathology and the clinical impact of that pathology. However little is known about the neural implementation that may underlie CR.
Based on the hypothesis that CR can attenuate the effects of age-related neural changes via differential expression of functional MRI (fMRI) identified brain networks, the overall theme of the CRESCENDO (Cognitive REServe and Clinical ENDO phenotype) project is to identify the determinants of heterogeneity in cognitive aging by understanding to what extent CR contributes to explaining this heterogeneity, our approach combines brain imaging biomarkers, neuropsychological assessments, measurements of CR proxies, plasmatic biomarkers of amyloid charge and metabolic disorders.
The CRESCENDO project is an extension in time and scope of an existing epidemiological cohort: the ESPRIT cohort, which is a longitudinal study of cognitive and psychiatric disorders undertaken in France and supported by the ANR LongVie. Its aim is the construction of a comprehensive database incorporating clinical, biological, genetic and environmental risk factors. We plan to organise a new follow-up at 12-year including the 600 younger participants of the ESPRIT cohort.

The first objective of the project will be to investigate the neural implementation of CR by performing a task-related activation during the fMRI acquisition, adopting a strategy using a validated tool - the letter Sternberg cognitive activation task – particularly adapted to identifying patterns of load-related activation that are expressed as a function of CR in cognitive aging. Furthermore, the concept of CR has been proposed to help account for the apparent discrepancy between some determinants of ageing and measurable pathology assessed by structural MRI (sMRI) measurements and between the pathology and its clinical manifestations (e.g., cognition). To investigate this question we plan to carry out a large and detailed sMRI examination including assessments of global and regional atrophy, white matter lesions, microbleeds….
The second objective is to investigate whether the association between CR and cognitive decline is influenced by amyloid charge or lipids profile. To understand the potential impact of amyloid charge on cognitive ageing, we aim to first understand the interrelationships between the 10-year change in plasma Aß40 and Aß42 levels and sMRI and fMRI biomarkers and then to examine the association between measured CR and rate of cognitive decline according to the levels of amyloid charge. Furthermore we will investigate to what extent lipids profile contribute to modify cognitive reserve and to understand whether this relationship is influenced by APOE genotype. In the absence of efficient treatment, this approach could lead to a strategy consisting in developing resilience to the pathological cascade by managing cerebral hypercholesterolemia.
We were able to benefit from the expertise of the extensive research work on CR carried out by our collaborators (Y. Stern : R. Mayeux ; A. Brickman) at the Cognitive Neuroscience Division (the Sergievsky Center and the Taub Institute) of Columbia University, New-York, US. This close partnership between benchmark American and European Centres gives us the unique opportunity to approach the original CR concept by comparing two distinct population-based studies (WHICAP and ESPRIT).
This project will be conducted by both academic and industrial partners who are recognized experts in their fields: INSERM U888 specialized in academic research on brain aging, INTRASENSE, sme specialized in medical imaging solutions, and SysDiag a mixed academic (CNRS)-industrial (BIORAD) group in the field of the biological biomarkers. Moreover, all the partners will benefit from local facilities such as MRI imaging and supercomputing platforms.