Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV

Saloner, Rowan; Paolillo, Emily W; Heaton, Robert K.; Grelotti, David J.; Stein, Murray B.; Miller, Andrew H.; Atkinson, J. Hampton; Letendre, Scott; Ellis, Ronald J.; Grant, Igor; Iudicello, Jennifer E.; Moore, David J.

doi:10.1007/s13365-020-00925-1

Cited by 17 publications

(15 citation statements)

References 43 publications

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“…Our multivariable analyses of the TS cohort also confirmed that a level of depressive symptoms consistent with at least mild depression (BDI-II > 13), was also significantly associated with NC performance, supporting the contribution of depression to worse NC outcomes in PWH, which that has been recently reported in the CHARTER cohort 100; 101 . These results also implicate a potential interaction between the rs13045 A allele and depression, which is currently under investigation.…”

Section: Discussionsupporting

confidence: 86%

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

Akay

Bond

Dombroski

et al. 2022

Preprint

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Coding and noncoding single-nucleotide variants (SNVs) of EIF2AK3, which encodes an integrated stress response (ISR) kinase, may play a role in neurodegenerative disorders. We used a candidate gene approach to determine the correlation of EIF2AK3 SNVs with neurocognitive (NC) impairment (NCI), which can persist with viral suppression from antiretroviral therapy (ART) in people with HIV (PWH). This retrospective study of prospectively collected data included participants of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, after excluding participants with severe neuropsychiatric comorbidities. Genome-wide data previously obtained in the CHARTER cohort participants (n=1,047) were analyzed to interrogate the association of three noncoding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global NCI (GDS≥0.5). Targeted sequencing (TS) was performed in 992 participants with available genomic DNA to determine the association of three coding EIF2AK3 SNVs with GDS and NCI. Analyses included univariable and multivariable methods such as analysis of variance and regression. Multivariable models covaried demographic, disease-associated, and treatment characteristics. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4+ T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA ≤ 200 copies/mL. A minority of participants had at least one risk allele for rs6739095 (T,41.7%), rs1913671 (C,41.4%), and rs11684404 (C,39.4%). All three noncoding EIF2AK3 SNVs were associated with significantly worse GDS and more NCI (all p<0.05). By TS, fewer participants had at least one risk allele for rs1805165 (G,30.9%), rs867529 (G,30.9%), and rs13045 (A,41.2%). Homozygosity for all three coding SNVs was associated with significantly worse GDS and more NCI (all p<0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II (BDI) > 13 were independently associated with GDS and NCI (p<0.001). The other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were specifically associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but were present in multivariable analyses. Specific SNVs in EIF2AK3 may be an important component of genetic vulnerability to NC complications in PWH. Identification of host factors that predict NCI could allow for earlier interventions, including those directly modulating the ISR, to improve NC outcomes.

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Section: Discussionsupporting

confidence: 86%

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

Akay

Bond

Dombroski

et al. 2022

Preprint

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“…Future studies should also examine HIV-associated biotypes that could potentially modify the observed associations between cardiac IA and depressive symptom severity. Given that PWH treated with ARTs in advantaged countries are often able to achieve undetectable viral load status and CD4+ cell recovery, there has been a shift in attention to other HIV biotypes such as humoral and cellular inflammation status also shown to be predictive of HIV-associated mood disturbance and neurocognitive impairment (100)(101)(102)(103). Functional imaging studies reveal that both cognitive and interoceptive task performance and corresponding activity in mid-insula and anterior-insula do vary as a function of change in levels of peripheral inflammation (104,105).…”

Section: Discussionmentioning

confidence: 99%

Anterior Insula Activation during Cardiac Interoception Relates to Depressive Symptom Severity in HIV-positive and HIV-negative Post-Menopausal Women

et al. 2022

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ObjectiveThis study aimed to determine whether subclinical symptoms of depression in postmenopausal women are associated with blood oxygen level–dependent (BOLD) activity within the anterior insula during cardiac interoceptive awareness and whether this association differs for persons living with the human immunodeficiency virus (PWH).MethodTwenty-three postmenopausal (mean [standard deviation] age = 56.5 [4.8] years) and 27 HIV-negative women (mean [standard deviation] age = 56.4 [8.0]) underwent functional magnetic resonance imaging while performing a heartbeat detection task. BOLD activation within the bilateral anterior insula based on the contrast of a heartbeat detection condition with and without a distracting tone was entered along with age, HIV status, and psychological stress into two multivariate regression models with self-reported depressive symptom severity as the outcome.ResultsDepressive symptoms did not vary by HIV status, nor was there a main effect or interaction for PWH on insula BOLD activation. Depressive symptoms were positively associated with psychological stress for the left (β = 0.310, t(49) = 2.352, p = .023) and right brain models (β = 0.296, t(49) = 2.265, p = .028) as well as the magnitude of BOLD activation in the left insula (β = 0.290, t(49) = 2.218, p = .032) and right insula (β = 0.318, t(49) = 2.453, p = .018), respectively. Exploratory analyses revealed that greater magnitude of BOLD activation attributed to exteroceptive noise (tone) was also correlated with self-reported distrust and preoccupation with interoceptive sensations.ConclusionsResults support an active interference model for interoceptive awareness wherein greater BOLD signal in the anterior insula in the presence of distracting exteroceptive stimuli may reflect greater prediction error, a feature of depression.

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“…This report is unique in evaluating the joint contributions of systemic inflammation and depression to long-term neurocognitive decline. Numerous reports link depression ( Watkins and Treisman, 2015 ; Namagga et al., 2021 ; Kohn et al., 2021 ) and both systemic and neuroinflammation ( Tedaldi et al., 2015 ; Hong and Banks, 2015 ; Gannon et al., 2011 ; Saloner et al., 2021 ) to neurocognitive impairment in HIV. Our work complements and extends these prior observations.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive reports have delineated the contributions of depression ( Pinheiro et al., 2016 ; Rubin and Maki, 2019 ), inflammation ( Alakkas et al., 2019 ; McGuire et al., 2015 ; Burdo et al., 2013 ) and neurodegeneration ( Mackiewicz et al., 2019 ; Wenzel et al., 2019 ; Pulliam et al., 2019 ; Bryant et al., 2015 ) separately to neurocognition. For example, we examined the joint effects of depression (Beck Depression Inventory-II; BDI-II) and systemic inflammation (plasma CRP) on longitudinal profiles of neurocognition over and average of 33 months of follow-up in 143 PWH on ART ( Saloner et al., 2020 ). Global cognition, processing speed, motor function, and attention/working memory all decreased as CRP increased, but only among PWH who exhibited moderate to severe depressive symptoms (BDI-II>22).…”

Section: Introductionmentioning

confidence: 99%

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years

Tang

Collier

Morgello

et al. 2022

Brain, Behavior, & Immunity - Health

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Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV

Cited by 17 publications

References 43 publications

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

Anterior Insula Activation during Cardiac Interoception Relates to Depressive Symptom Severity in HIV-positive and HIV-negative Post-Menopausal Women

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years

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