Abstract
Reserve refers to the phenomenon of relatively preserved cognition in disproportion to the extent of neuropathology, e.g., in Alzheimer’s disease. A putative functional neural substrate underlying reserve is global functional connectivity of the left lateral frontal cortex (LFC, Brodmann Area 6/44). Resting-state fMRI-assessed global LFC-connectivity is associated with protective factors (education) and better maintenance of memory in mild cognitive impairment (MCI). Since the LFC is a hub of the fronto-parietal control network that regulates the activity of other networks, the question arises whether LFC-connectivity to specific networks rather than the whole-brain may underlie reserve. We assessed resting-state fMRI in 24 MCI and 16 healthy controls (HC) and in an independent validation sample (23 MCI/32 HC). Seed-based LFC-connectivity to seven major resting-state networks (i.e., fronto-parietal, limbic, dorsal-attention, somatomotor, default-mode, ventral-attention, visual) was computed, reserve was quantified as residualized memory performance after accounting for age and hippocampal atrophy. In both samples of MCI, LFC-activity was anti-correlated with the default-mode network (DMN), but positively correlated with the dorsal-attention network (DAN). Greater education predicted stronger LFC-DMN-connectivity (anti-correlation) and LFC-DAN-connectivity. Stronger LFC-DMN and LFC-DAN-connectivity each predicted higher reserve, consistently in both MCI samples. No associations were detected for LFC-connectivity to other networks. These novel results extend our previous findings on global functional connectivity of the LFC, showing that LFC-connectivity specifically to the DAN and DMN, two core memory networks, enhances reserve in the memory domain in MCI.
Highlights
The reserve theory proposes that individuals with favorable cognitive and lifestyle factors such as education, IQ and occupational complexity can transiently maintain relatively high cognitive performance when developing Alzheimer’s disease (AD), the most common cause of dementia in elderly people (Stern, 2012)
Our major findings were that in mild cognitive impairment (MCI) greater LFC-connectivity to the default mode network (DMN) as well as the dorsal-attention network (DAN) was associated with higher memory-related reserve, i.e., relatively high memory performance when accounting for the level of brain pathology
These findings suggest that resting-state connectivity levels of the LFC to particular other networks contributes to memory-related reserve in MCI
Summary
The reserve theory proposes that individuals with favorable cognitive and lifestyle factors such as education, IQ and occupational complexity can transiently maintain relatively high cognitive performance when developing Alzheimer’s disease (AD), the most common cause of dementia in elderly people (Stern, 2012). The LFC hub shows strong positive connectivity to fronto-parietal and dorsal attention subnetworks of the control network among other networks, but negative connectivity (anticorrelated) to the default mode network (DMN) (Cole et al, 2012). Since these networks have previously been implicated in episodic memory (Chai et al, 2014; Franzmeier et al, 2017a), it is possible that the global LFC connectivity to those networks is of particular importance for supporting reserve of memory abilities in AD. Rather than assessing global LFC-connectivity at the whole-brain level as done previously (Cole et al, 2012; Franzmeier et al, 2017b), we assessed here systematically the global connectivity of LFC to other resting-state networks as a predictor of higher memory reserve in MCI
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