Resting-state global functional connectivity as a biomarker of cognitive reserve in mild cognitive impairment

Abstract

Cognitive reserve (CR) shows protective effects in Alzheimer's disease (AD) and reduces the risk of dementia. Despite the clinical significance of CR, a clinically useful diagnostic biomarker of brain changes underlying CR in AD is not available yet. Our aim was to develop a fully-automated approach applied to fMRI to produce a biomarker associated with CR in subjects at increased risk of AD. We computed resting-state global functional connectivity (GFC), i.e. the average connectivity strength, for each voxel within the cognitive control network, which may sustain CR due to its central role in higher cognitive function. In a training sample including 43 mild cognitive impairment (MCI) subjects and 24 healthy controls (HC), we found that MCI subjects with high CR (> median of years of education, CR+) showed increased frequency of high GFC values compared to MCI-CR- and HC. A summary index capturing such a surplus frequency of high GFC was computed (called GFC reserve (GFC-R) index). GFC-R discriminated MCI-CR+ vs. MCI-CR-, with the area under the ROC = 0.84. Cross-validation in an independently recruited test sample of 23 MCI subjects showed that higher levels of the GFC-R index predicted higher years of education and an alternative questionnaire-based proxy of CR, controlled for memory performance, gray matter of the cognitive control network, white matter hyperintensities, age, and gender. In conclusion, the GFC-R index that captures GFC changes within the cognitive control network provides a biomarker candidate of functional brain changes of CR in patients at increased risk of AD.

Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

“…Second, the training and the repetition of the cognitive task could lead to a learning effect, increasing the cognitive reserve of these animals and therefore preserving the functional connectivity. Higher functional connectivity has been related with higher cognitive reserve in both healthy elders (Arenaza-Urquijo et al, 2013) and MCI patients (Franzmeier et al, 2017) with respect to subjects with low cognitive reserve. This fact could also be related with the absence of significant differences in the cognitive outcome.…”

Assessment of cognitive reserve using near infrared spectroscopy

“…A recent study by Franzmeier et al (2017) addressed the role of FPN in the development and maintenance of cognitive reserve in Mild Cognitive Impairment (MCI), a clinical precursor of AD. Using fMRI these authors demonstrate that resting-state global functional connectivity of FPN correlates with a proxy measure of cognitive reserve (years of education) in both healthy controls and individuals with MCI and thus can be used as a potential biomarker of changes in cognitive reserve in patients at increased risk of AD (Franzmeier et al, 2017).…”

“…Brain activity was analyzed separately for oxygenated hemoglobin (HbO), deoxygenated (reduced) hemoglobin (HbR) and total hemoglobin (HbT = HbO + HbR). Activity of each prefrontal channel was correlated with all other channels and all positive correlation coefficients were z-transformed (by Fisher's transform) and averaged over all PFC channels (as per Cole et al, 2012 andFranzmeier et al, 2017). For each individual, the resulting GFC numbers (separately for HbO, HbR and HbT) were then correlated with his/her IQ (WASI full score) and two scores of the two PPT subtests namely, the score for the performance with both hands (PP Both Hands) and the score for the assembly subtest (PP Assembly).…”

“…This functional network consists of the lateral prefrontal cortex (LPFC) and the posterior parietal cortex (PPC) making up the so-called frontoparietal network (FPN), and it has been variously termed the cognitive control network or system (Cole et al, 2012), the superordinate cognitive control network (Niendam et al, 2012), the multiple-demand system (Duncan, 2010) and the task-positive network (Fox et al, 2005). The frontoparietal network has received a lot of attention in recent studies (Cole et al, 2012;Cole et al, 2013;Franzmeier et al, 2017).…”

Stemming the Alzheimer tsunami: introduction to the special issue on reserve and resilience in Alzheimer’s disease

“…Franzmeier et al (2016) developed an imaging based metric for capturing inter-individual differences in cognitive reserve in persons at risk for AD. For this, they focused on resting-state global functional connectivity (GFC) within the cognitive control network, because of this network' key role in higher cognitive function and its link to other reserve proxies.…”