The additive effect of late-life depression and olfactory dysfunction on the risk of dementia was mediated by hypersynchronization of the hippocampus/fusiform gyrus

Abstract

Early detection of patients with late-life depression (LLD) with a high risk of developing dementia contributes to early intervention. Odor identification (OI) dysfunction serves as a marker for predicting dementia, but whether OI dysfunction increases the risk of dementia in LLD patients remains unclear. The present study aimed to explore the interactive effect of LLD and OI dysfunction on the risk of dementia and its underlying neuroimaging changes. One hundred and fifty-seven LLD patients and 101 normal controls were recruited, and data on their OI, cognition, activity of daily living (ADL), and resting-state functional magnetic resonance imaging were collected. Two × two factorial analyses were used to analyze the interactive effects of LLD and OI dysfunction on neuropsychological and neuroimaging abnormalities. Mediation analyses were used to explore whether abnormalities detected by neuroimaging mediated the the associations between OI and cognition/ADL. The results suggested that LLD and OI dysfunction exhibited additive effects on reduced ADL, global cognition and memory scores, as well as neuroimaging variables including (i) increased fractional amplitude of low-frequency fluctuation (fALFF) in the right orbitofrontal cortex and right precentral cortex, and (ii) increased regional homogeneity (ReHo) in the left hippocampus/fusiform gyrus, etc. In addition, these increased fALFF and ReHo values were associated with reduced neuropsychological scores (ADL, global cognition, memory, and language). Moreover, ReHo of the left hippocampus/fusiform gyrus completely mediated the relationship between OI and ADL, and partially mediated the relationship between OI and global cognition. Overall, mediated by the hypersynchronization of the left hippocampus/fusiform gyrus, OI dysfunction may increase the risk of dementia in LLD patients.

Fig. 1. Additive effects of LLD and OI dysfunction on cognitive impairment and ADL disability.

Two × two factorial analyses were used to analyze the influence of the factor “Depression” (LLD and NC) and the factor “Olfaction” (OI dysfunction and intact OI) on neuropsychological scores; control variables included age, sex, and years of education. LLD, late-life depression; NC, normal controls; OI, odor identification.

Fig. 2. Additive effects between LLD and OI dysfunction on fALFF and ReHo.

Two × two factorial analyses were used to analyze the influence of the factor “Depression” (LLD and NC) and factor “Olfaction” (OI dysfunction and intact OI) on fALFF and ReHo, and control variables included age, sex, years of education, and gray matter images. Multiple comparison correction was performed using a false discovery rate (FDR) at P < 0.05. The color scale bar shows the logarithmic scale of p-values (−log10). The closer to yellow, the more significant the difference between groups. fALFF, fractional amplitude of low-frequency fluctuation; ReHo, regional homogeneity.

Fig. 3. Correlations between cognitive function and brain activities in additive regions across all subjects.

ADL, Activities of Daily Living Scale; fALFF, fractional amplitude of low-frequency fluctuation; ReHo, regional homogeneity.

Fig. 4. Associations between OI and global cognition/ADL were mediated by ReHo of the left hippocampus/fusiform gyrus.

The ReHo of the left hippocampus/fusiform gyrus was A a complete mediator of the relationship between OI and ADL, and B a partial mediator of the relationship between OI and global cognition.

Fig. 5. Potential mechanism of how OI dysfunction increases the dementia risk of patients with LLD.

OI dysfunction and LLD exhibited additive effects that resulted in hypersynchronization of the hippocampus/fusiform gyrus, which is a region related to olfaction, depression, and cognition. Persistent hypersynchronization may facilitate neurodegeneration and cause structural abnormalities, leading to cognitive impairment and ADL disability. In addition, the associations between OI dysfunction and cognitive impairment and ADL disability were mediated by hyperactivity of the hippocampus/fusiform area. Overall, OI dysfunction may contribute to the early detection of individuals at high risk of dementia among patients with LLD. The blue box indicates the present analyses and the red box indicates future directions.