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Brain microRNAs associated with late-life depressive symptoms are also associated with cognitive trajectory and dementia.

ABSTRACT: Late-life depression is associated with an increased risk for dementia but we have limited knowledge of the molecular mechanisms underlying this association. Here we investigated whether brain microRNAs, important posttranscriptional regulators of gene expression, contribute to this association. Late-life depressive symptoms were assessed annually in 300 participants of the Religious Orders Study and Rush Memory and Aging Project for a mean of 7 years. Participants underwent annual cognitive testing, clinical assessment of cognitive status, and uniform neuropathologic examination after death. microRNAs were profiled from the prefrontal cortex using NanoString platform in the discovery cohort and small RNA sequencing in the replication cohort. A global microRNA association study of late-life depressive symptoms was performed using linear mixed model adjusting for the potential confounding factors. Four brain microRNAs were associated with late-life depressive symptoms at adjusted p < 0.05: miR-484, miR-26b-5p, miR-30d-5p, and miR-197-3p. Lower expression levels of these miRNAs were associated having greater depressive symptoms. Furthermore, lower levels of miR-484 and miR-197-3p were associated with faster decline of cognition over time. Moreover, lower miR-484 level was associated with higher probability of having Alzheimer's dementia. Importantly, the associations between miR-484 and depressive symptoms and Alzheimer's dementia, respectively, were replicated in an independent cohort. Lastly, the predicted targets of miR-484 were enriched in a brain protein co-expression module involving synaptic transmission and regulation of synaptic plasticity. This study identified four brain microRNAs associated with late-life depressive symptoms assessed longitudinally. In addition, we found a molecular connection between late-life depression and dementia through miR-484.

SUBMITTER: Wingo TS

PROVIDER: S-EPMC7004995 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceThe neurobiologic basis of late-life depressive symptoms is not well understood.ObjectiveTo test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late-life depressive symptoms. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Longitudinal clinicopathological cohort study at residences of participants in the Chicago, Illinois, metropolitan area. Participants included 124 older persons without dementia in the Rush Memory and Aging Project who had annual evaluations for a mean (SD) of 5.7 (2.8) years, died, and underwent a postmortem neuropathological examination that provided estimates of the densities of Lewy bodies, neurofibrillary tangles, and aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area.Main outcomes and measuresThe number of depressive symptoms (mean [SD], 1.61 [1.48]; range, 0-6; skewness, 0.94) on the Center for Epidemiological Studies Depression Scale averaged across annual evaluations.ResultsBrainstem Lewy bodies were associated with depressive symptoms, and the association was attenuated in those taking antidepressant medication. Brainstem tangles were associated with more depressive symptoms in those without cognitive impairment but with fewer symptoms in those with mild cognitive impairment. Lower density of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was robustly associated with a higher level of depressive symptoms (mean [SE] estimate, -0.014 [0.003]; P < .001; 16.3% increase in adjusted R2). The association was not modified by medication use or cognitive impairment. Neither tyrosine hydroxlyase-immunoreactive neurons in the locus ceruleus nor tryptophan hydroxlyase-immunoreactive neurons in the dorsal raphe nucleus were related to depressive symptoms.Conclusions and relevanceThe results suggest that the mesolimbic dopamine system, especially the ventral tegmental area, has an important role in late-life depressive symptoms.

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Brain microRNAs associated with late-life depressive symptoms are also associated with cognitive trajectory and dementia.

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