Distinct Neural Correlates of Executive Function by Amyloid Positivity and Associations with Clinical Progression in Mild Cognitive Impairment

Abstract

Purpose: This study aimed to identify the neural basis of executive function (EF) in amnestic mild cognitive impairment (aMCI) according to beta-amyloid (Aβ) positivity. Furthermore, we explored if the identified brain areas could serve as predictors for clinical progression.

Materials and methods: We included individuals with aMCI using data from [¹⁸F]-florbetapir-positron emission tomography (PET), fluorodeoxyglucose-PET, and EF scores, as well as follow-up clinical severity scores at 1 and 5 years from baseline from the Alzheimer's Disease Neuroimaging Initiative database. The correlations between EF score and regional cerebral glucose metabolism (rCMglc) were analyzed separately for aMCI with low Aβ burden (aMCI Aβ-, n=230) and aMCI with high Aβ burden (aMCI Aβ+, n=268). Multiple linear regression analysis was conducted to investigate the associations between rCMglc and clinical progression.

Results: Longitudinal courses differed between aMCI Aβ- and aMCI Aβ+ groups. On average, aMCI Aβ- subjects maintained their level of clinical severity, whereas aMCI Aβ+ subjects showed progression. EF impairment in aMCI Aβ- was related to the anterior cingulate cortex (ACC), whereas that in aMCI Aβ+ was related to Alzheimer's Disease-vulnerable brain regions. ACC and the posterior cingulate cortex were associated with clinical progression in aMCI Aβ- and aMCI Aβ+, respectively.

Conclusion: Our findings suggest that although MCI subjects showed similar behavioral phenotypes at the time of diagnosis, EF and further progression were associated with different brain regions according to Aβ burden. Clarification of the etiologies and nature of EF impairment in aMCI are critical for disease prognosis and management.

Keywords: Mild cognitive impairment; amyloid; anterior cingulate cortex; cognitive function; positron emission tomography; posterior cingulate cortex.