Functional Connectivity between the Resting-State Olfactory Network and the Hippocampus in Alzheimer's Disease.

Kanekar Kanekar,Wang Wang,Eslinger Eslinger,Zhang Zhang,Lu Lu,Yang Yang,Karunanayaka Karunanayaka,Elyan Elyan,Jordan Jordan,Testa Testa

doi:10.3390/brainsci9120338

Abstract

Olfactory impairment is associated with prodromal Alzheimer’s disease (AD) and is a risk factor for the development of dementia. AD pathology is known to disrupt brain regions instrumental in olfactory information processing, such as the primary olfactory cortex (POC), the hippocampus, and other temporal lobe structures. This selective vulnerability suggests that the functional connectivity (FC) between the olfactory network (ON), consisting of the POC, insula and orbital frontal cortex (OFC) (Tobia et al., 2016), and the hippocampus may be impaired in early stage AD. Yet, the development trajectory of this potential FC impairment remains unclear. Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to investigate FC changes between the ON and hippocampus in four groups: aged-matched cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. FC was calculated using low frequency fMRI signal fluctuations in the ON and hippocampus (Tobia et al., 2016). We found that the FC between the ON and the right hippocampus became progressively disrupted across disease states, with significant differences between EMCI and LMCI groups. Additionally, there were no significant differences in gray matter hippocampal volumes between EMCI and LMCI groups. Lastly, the FC between the ON and hippocampus was significantly correlated with neuropsychological test scores, suggesting that it is related to cognition in a meaningful way. These findings provide the first in vivo evidence for the involvement of FC between the ON and hippocampus in AD pathology. Results suggest that functional connectivity (FC) between the olfactory network (ON) and hippocampus may be a sensitive marker for Alzheimer’s disease (AD) progression, preceding gray matter volume loss.

Highlights

IntroductionOf particular interest are the well-documented olfactory deficits that often precede cognitive impairment [1,7,8]
Alzheimer’s disease (AD) is marked by the insidious onset of episodic memory loss, but early clinical symptoms include sensory and motor impairments [1,2,3,4,5,6].Of particular interest are the well-documented olfactory deficits that often precede cognitive impairment [1,7,8]
Disease state; second, the olfactory network (ON) functional connectivity (FC) to the hippocampus was significantly different between the early mild cognitive impairment (EMCI) and late mild cognitive impairment (LMCI) groups; third, the ON FC to the hippocampus was a more sensitive indicator of AD progression compared to hippocampal volume in the early stages; and fourth, ON FC was meaningfully related to cognitive functions, based on significant correlation with auditory verbal learning scores (RAVLT)

Summary

Introduction

Of particular interest are the well-documented olfactory deficits that often precede cognitive impairment [1,7,8] These early-stage olfactory deficits often predict the onset of dementia [7,9,10,11,12,13,14]. A post-mortem study demonstrated a significant correlation between patients with impaired odor identification and increased density of tangles in the entorhinal cortex and CA1/subiculum region of the hippocampus [15]. These findings allude to widespread cortical neuronal loss that severely compromises anatomical and functional connections within and between sensory and cognitive networks in AD, namely olfaction and memory [1]. A network approach may clarify if olfactory deficits, such as odor-identification deficits, are to be linked to damage in the primary and secondary olfactory structures, or if they reflect secondary effects of damage in higher-order cortical areas affected by AD

Objectives

Methods

Discussion

Conclusion