Sex matters: acute functional connectivity changes as markers of remission in late-life depression differ by sex.

The efficacy of antidepressant treatment in late-life is modest, a problem magnified by an aging population and increased prevalence of depression. Understanding the neurobiological mechanisms of treatment response in late-life depression (LLD) is imperative. Despite established sex differences in depression and neural circuits, sex differences associated with fMRI markers of antidepressant treatment response are underexplored. In this analysis, we assess the role of sex on the relationship of acute functional connectivity changes with treatment response in LLD. Resting state fMRI scans were collected at baseline and day one of SSRI/SNRI treatment for 80 LLD participants. One-day changes in functional connectivity (differential connectivity) were related to remission status after 12 weeks. Sex differences in differential connectivity profiles that distinguished remitters from non-remitters were assessed. A random forest classifier was used to predict the remission status with models containing various combinations of demographic, clinical, symptomatological, and connectivity measures. Model performance was assessed with area under the curve, and variable importance was assessed with permutation importance. The differential connectivity profile associated with remission status differed significantly by sex. We observed evidence for a difference in one-day connectivity changes between remitters and non-remitters in males but not females. Additionally, prediction of remission was significantly improved in male-only and female-only models over pooled models. Predictions of treatment outcome based on early changes in functional connectivity show marked differences between sexes and should be considered in future MR-based treatment decision-making algorithms.

White Noise-Is Anxiety in Late-Life Associated With White Matter Hyperintensity Burden?

OBJECTIVE: We investigated the relationship between anxiety phenotypes (global anxiety, worry, and rumination) and white matter hyperintensities (WMH), with special consideration for the roles of age and executive function (EF). Our hypotheses were 1) anxiety phenotypes would be associated with WMH and 2) EF would moderate this relationship. DESIGN: Cross-sectional. SETTING: Participants were recruited from the local community (Pittsburgh, PA). PARTICIPANTS: We recruited 110 older adults (age ≥ 50) with varying worry severity and clinical comorbidity. INTERVENTIONS: Not applicable. MEASUREMENTS: Demographics (age, sex, race, education), clinical measures (cumulative illness burden, global anxiety, worry, and rumination), EF, and WMH quantified with magnetic resonance imaging. RESULTS: Lower global anxiety and worry severity were significantly correlated with higher WMH volume, though the global anxiety relationship was not significant after controlling for age. Rumination as not associated with WMH burden. EF was not correlated with either global anxiety, worry, rumination, or WMH. However, in those with advanced age and/or greater WMH burden, there was an association between worry and EF as well as EF and WMH. CONCLUSION: Longitudinal studies are needed in order to clarify the complex interactions between anxiety phenotypes, WMH, and EF.

Independent replication of advanced brain age in mild cognitive impairment and dementia: detection of future cognitive dysfunction.

We previously developed a novel machine-learning-based brain age model that was sensitive to amyloid. We aimed to independently validate it and to demonstrate its utility using independent clinical data. We recruited 650 participants from South Korean memory clinics to undergo magnetic resonance imaging and clinical assessments. We employed a pretrained brain age model that used data from an independent set of largely Caucasian individuals (n = 757) who had no or relatively low levels of amyloid as confirmed by positron emission tomography (PET). We investigated the association between brain age residual and cognitive decline. We found that our pretrained brain age model was able to reliably estimate brain age (mean absolute error = 5.68 years, r(650) = 0.47, age range = 49-89 year) in the sample with 71 participants with subjective cognitive decline (SCD), 375 with mild cognitive impairment (MCI), and 204 with dementia. Greater brain age was associated with greater amyloid and worse cognitive function [Odds Ratio, (95% Confidence Interval {CI}): 1.28 (1.06-1.55), p = 0.030 for amyloid PET positivity; 2.52 (1.76-3.61), p < 0.001 for dementia]. Baseline brain age residual was predictive of future cognitive worsening even after adjusting for apolipoprotein E e4 and amyloid status [Hazard Ratio, (95% CI): 1.94 (1.33-2.81), p = 0.001 for total 336 follow-up sample; 2.31 (1.44-3.71), p = 0.001 for 284 subsample with baseline Clinical Dementia Rating ≤ 0.5; 2.40 (1.43-4.03), p = 0.001 for 240 subsample with baseline SCD or MCI]. In independent data set, these results replicate our previous findings using this model, which was able to delineate significant differences in brain age according to the diagnostic stages of dementia as well as amyloid deposition status. Brain age models may offer benefits in discriminating and tracking cognitive impairment in older adults.

It goes both ways: The relationship between anxiety and mild cognitive impairment.

OBJECTIVE: To investigate the relationship between anxiety and mild cognitive impairment (MCI), and whether it is mediated by perceived stress, at the population level. METHOD AND DESIGN: In a longitudinal study of 368 adults aged 65+ from a population-based cohort, we annually assessed anxiety symptoms (GAD-7), perceived stress (PSS-4), and ratings on the Clinical Dementia Rating (CDR®), where CDR = 0.5 was operationalized as MCI. Examining data from three consecutive assessment waves, we first determined the associations between anxiety at the first wave with MCI at the third wave, and vice versa. We then used mediation analyses to determine whether the pathways in both directions were mediated by perceived stress at the second wave, adjusting for demographics and other relevant covariates. RESULTS: We confirmed significant bidirectional longitudinal associations between anxiety and MCI. Perceived stress was detected as a significant mediator for both pathways between anxiety and MCI, explaining 37.1% of the total effect (TE) of anxiety on incident MCI while conversely explaining 27.1% of the TE of MCI on anxiety. CONCLUSIONS: A bidirectional relationship with a 2-year lag between anxiety and MCI was mediated through perceived stress. Clinicians should be sensitive both to potential consequent anxiety when patients present with cognitive impairment, and to potential incipient MCI when the presenting complaint is anxiety. Managing stress may help mitigate adverse outcomes.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Are All Anxieties Created Equal? Stress-related Networks and Anxiety Phenotypes in Old Age.

OBJECTIVE: The dysregulation of stress-related networks due to chronic symptoms such as severe worry and/or rumination is one of the putative pathways linking anxiety in late-life with cognitive decline and increased cardiovascular burden. Symptoms such as severe worry or rumination respond poorly to standard treatment and drive the morbidity associated with anxiety in older adults. We assessed if any of the neural networks anchored in the stress-related regions of interest (ROIs) are associated with distinct anxiety phenotypes (worry, rumination and global anxiety). METHODS: We recruited older participants (over 50 years of age) with varying levels of worry (N = 91) to undergo resting state fMRI. We computed seed-based connectivity for each ROI: the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus, habenula, and amygdala. We limited our connectivity analyses to extracted regions for each seeded ROI-based network based on their canonical networks in 1,000 participants (Neurosynth). Using connectivity and clinical factors, we fit cross-validated elastic net models to predict scores on Penn State Worry Questionnaire, Rumination Subscale Questionnaire, Hamilton Anxiety Rating Scale, and Perceived Stress Scale. RESULTS: We identified several distinct connectivity patterns that predict anxiety phenotypes' severity. Greater worry was associated with greater paraventricular nucleus of the hypothalamus -subgenual anterior cingulate cortex, parahippocampal, and olfactory and amygdala-PHC connectivity. Greater global anxiety was associated with lower amygdala-superior temporal gyrus connectivity. Greater perceived stress was associated with lower amygdala-inferior temporal gyrus and amygdala-fusiform gyrus connectivity. CONCLUSION: Our study suggests that various late-life anxiety phenotypes (worry, global anxiety, rumination) may be associated with varying functional connectivity related to stress and emotion regulation. This may aid in the development of future targeted interventions.

Relationships Between Early Maternal Warmth and Social Connection: A Randomized Clinical Trial With Naltrexone.

OBJECTIVE: Early experiences of having received maternal warmth predict responses to opportunities to connect with others later in life. However, the understanding of neurochemical mechanisms by which such relationships emerge remains incomplete. Endogenous opioids, involved in social connection in both animals and humans, may contribute to this link. Therefore, the current study examined a) relationships between early maternal warmth and brain and self-report responses to novel social targets (i.e., outcomes that may promote social connection) and b) the effect of the opioid antagonist, naltrexone, on such relationships. METHODS: Eighty-two adult participants completed a retrospective report of early maternal warmth. On a second visit, participants were randomized to 50 mg of oral naltrexone (n = 42) or placebo (n = 40), followed by a magnetic resonance imaging scan where functional brain activity in response to images of novel social targets (strangers) was assessed. Approximately 24 hours later, participants reported on their feelings of social connection since leaving the scanner. RESULTS: In the placebo condition, greater early maternal warmth was associated with less dorsal anterior cingulate cortex, anterior insula, ventral striatum, and amygdala activity in response to images of novel social targets (r values ≥ -0.360, p values ≤ .031), and greater feelings of social connection (r = 0.524, p < .001) outside of the laboratory. The same relationships, however, were not present in the naltrexone condition. CONCLUSIONS: Results highlight relationships between early maternal warmth and responses to the social world at large and suggest that opioids might contribute to social connection by supporting the buffering effects of warm early life experiences on social connection later in life.Trial Registration: Clinical Trials NCT02818036.

Depression Symptoms Declining Among Older Adults: Birth Cohort Analyses From the Rust Belt.

OBJECTIVES: To investigate potential birth cohort effects in depression symptoms in older adults. DESIGN: Population-based prospective cohort. SETTING: Small-town communities in Pennsylvania. PARTICIPANTS: Three thousand two hundred and twenty seven older adults (average baseline age = 71.6) born between 1902 and 1941. MEASUREMENTS: Four decade-long birth cohorts were the primary predictors in this study: 1902-1911, 1912-1921, 1922-1931, and 1932-1941. The outcome was symptoms of depression assessed at baseline and follow-up study visits using a modified Center for Epidemiologic Studies Depression Scale (mCES-D). The depression outcome was operationalized as: 1). A binary outcome of having greater than equal to 5 depression symptoms on the total mCES-D at any study visit, and 2). A continuous outcome of four factor-analyzed component scores of the mCES-D including depressed mood, anergia/hopelessness, withdrawal, and poor self-esteem. All analyses were jointly modeled with attrition and adjusted for age, sex, education, Mini Mental State Examination score, antidepressant medications, and total prescription medications. RESULTS: Participants from more recently born cohorts were significantly less likely to have a study visit in which they reported greater than or equal to 5 depression symptoms, controlling for attrition. Specifically, in comparison to the 1902-1911 referent cohort, the 1912-1921 birth cohort was 43% less likely (odds ratio [OR] = 0.566, 95% confidence interval [CI]: 0.341-0.939), the 1922-1931 birth cohort was 63% less likely (OR = 0.0369, 95% CI: 0.215-0.632), and the 1932-1941 cohort was 79% less likely (OR = 0.205, 95% CI: 0.106-0.399). The cohort effect was most evident in the depressed mood and anergia/hopelessness symptom composites. CONCLUSION: Reduced rates of depression symptoms observed in successive birth cohorts of older adults may reflect compression of morbidity or other secular trends.

Risk of Mortality in Elderly Coronavirus Disease 2019 Patients With Mental Health Disorders: A Nationwide Retrospective Study in South Korea.

OBJECTIVE: This study aimed to investigate the different clinical characteristics among elderly coronavirus disease 2019 (COVID-19) patients with and without mental disorders in South Korea and determine if these characteristics have an association with underlying mental disorders causing mortality. METHOD: A population-based comparative cohort study was conducted using the national claims database. Individuals aged ≥65 years with confirmed COVID-19 between January 1, 2020 and April 10, 2020 were assessed. The endpoints for evaluating mortality for all participants were death, 21 days after diagnosis, or April 10, 2020. The risk of mortality associated with mental disorders was estimated using Cox hazards regression. RESULTS: We identified 814 elderly COVID-19 patients (255 [31.3%] with mental disorder and 559 [68.7%] with nonmental disorder). Individuals with mental disorders were found more likely to be older, taking antithrombotic agents, and had diabetes, hypertension, chronic obstructive lung disease, and urinary tract infections than those without mental disorders. After propensity score stratification, our study included 781 patients in each group (236 [30.2%] with mental disorder and 545 [69.8%] with nonmental disorder). The mental disorder group showed higher mortality rates than the nonmental disorder group (12.7% [30/236] versus 6.8% [37/545]). However, compared to patients without mental disorders, the hazard ratio (HR) for mortality in elderly COVID-19 patients with mental disorders was not statistically significant (HR: 1.57, 95%CI: 0.95-2.56). CONCLUSION: Although the association between mental disorders in elderly individuals and mortality in COVID-19 is unclear, this study suggests that elderly patients with comorbid conditions and those taking psychiatric medications might be at a higher risk of COVID-19.

Anxiety Disorders in the Elderly.

Recent data has linked anxiety and its disorders in late life to increased morbidity and mortality, especially related to a higher cardiovascular burden and an increased cognitive decline. Clinically, anxiety symptoms may be more difficult to elicit in older adults who are less accurate in identifying anxiety symptoms and tend to minimize symptoms and to attribute symptoms to physical illness. Although SSRIs have proven more effective than psychotherapy in late-life anxiety, many elderly anxious subjects prefer psychotherapeutic interventions. These interventions appear to work best when tailored for the needs, expectations, and cultural background of older anxious subjects.

Disruption of Neural Homeostasis as a Model of Relapse and Recurrence in Late-Life Depression.

The significant public health burden associated with late-life depression (LLD) is magnified by the high rates of recurrence. In this manuscript, we review what is known about recurrence risk factors, conceptualize recurrence within a model of homeostatic disequilibrium, and discuss the potential significance and challenges of new research into LLD recurrence. The proposed model is anchored in the allostatic load theory of stress. We review the allostatic response characterized by neural changes in network function and connectivity and physiologic changes in the hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system, and circadian rhythm. We discuss the role of neural networks' instability following treatment response as a source of downstream disequilibrium, triggering and/or amplifying abnormal stress response, cognitive dysfunction and behavioral changes, ultimately precipitating a full-blown recurrent episode of depression. We propose strategies to identify and capture early change points that signal recurrence risk through mobile technology to collect ecologically measured symptoms, accompanied by automated algorithms that monitor for state shifts (persistent worsening) and variance shifts (increased variability) relative to a patient's baseline. Identifying such change points in relevant sensor data could potentially provide an automated tool that could alert clinicians to at-risk individuals or relevant symptom changes even in a large practice.

Advances and Barriers for Clinical Neuroimaging in Late-Life Mood and Anxiety Disorders.

PURPOSE OF REVIEW: Mood and anxiety disorders are very commonly experienced by older adults and are becoming a growing concern due to the rapidly aging global population. Recent advances in neuroimaging may help in improving outcomes in late-life mood and anxiety disorders. The elucidation of mechanisms contributing to late-life mental health disorders may ultimately lead to the identification of novel therapeutic interventions. Alternatively, clinically validated imaging biomarkers may allow for the prediction of treatment response and identification of better therapeutic approaches in late-life mood and anxiety disorders. RECENT FINDINGS: In community samples, late-life depression and late-life generalized anxiety disorder occur up to 38 and 15%, respectively, while late-life bipolar disorder is less common and occur in approximately 0.5% of the population. There are significant challenges in treating and improving outcome in late-life mood and anxiety disorders. Time to treatment response and treatment resistance are increased in older adults. Novel neuroimaging techniques have the potential to improve diagnostic and therapeutic outcome in late-life mood and anxiety disorders either through "personalized pharmacotherapy" or through identifying dysfunction regions/networks to be subsequently used for direct interventions such as transcranial magnetic stimulation. This review will provide an overview of recent literature that substantiates the potential role of neuroimaging in clinical practice, as well as the barriers that must be overcome prior to clinical translation.

Emotion Reactivity and Cerebrovascular Burden in Late-Life GAD: A Neuroimaging Study.

OBJECTIVE: Generalized anxiety disorder (GAD) in older adults is associated with persistent deficits in emotion reactivity (ER) and regulation, yet the neural basis of these deficits has not been explored. This study focuses on the neural basis of ER deficits in late-life GAD and the association with cerebrovascular burden. METHODS: Twenty elderly nonanxious participants and 17 late-life GAD participants were included. The faces-shapes functional magnetic resonance imaging task was used to assess ER; the Hamilton Anxiety Rating Scale and the Penn State Worry Questionnaire to measure global anxiety and worry, respectively; linear regression models to examine the association between ER and global anxiety severity and between ER and worry severity; and mediation analysis to explore the effect of ER on the relationship between global anxiety/worry severity and cerebrovascular burden. RESULTS: A positive association was found between ER and global anxiety in the left parahippocampus, left and right precuneus, and right superior occipital gyrus. A negative association was found between ER and worry severity in the left and right precuneus. The association between cerebrovascular burden and anxiety/worry severity was indirectly mediated by increased ER in limbic and paralimbic areas and by decreased ER in prefrontal regulatory regions. CONCLUSION: These results indicate that ER is associated with different neural activation patterns for worry and global anxiety and that ER-related functional connectivity indirectly mediates the relationship between cerebrovascular burden and late-life GAD. This latter result supports a yet-unexplored cerebrovascular pathway involved in the pathophysiology of late-life anxiety.

Altered Functional Magnetic Resonance Imaging Markers of Affective Processing During Treatment of Late-Life Depression.

OBJECTIVE: This study investigated neural substrate changes in affective processing among late-life depression (LLD) patients undergoing antidepressant treatment and determined if these changes correlated with remission status. METHODS: Thirty-three LLD patients were enrolled in a 12-week venlafaxine treatment course. During treatment functional magnetic resonance imaging (fMRI) scans, paired with an affective task that assessed emotional reactivity and regulation, were performed on days 1, 2, 3, and 7 and at week 12. Following treatment patients were classified as remitters or non-remitters. A voxel-wise two-way repeated-measures ANOVA was performed to assess the fMRI data at a significance level of α = 0.05, corrected. RESULTS: The emotional reactivity contrast demonstrated a significant interaction between remission status and scan time in the right middle temporal gyrus (MTG) (F = 24.1, df = 1,112, k = 102). Further analysis showed increased emotional reactivity-induced activity among non-remitters, and decreased activity among remitters, which significantly differed from baseline at day 7 (95% CI: 0.027, 0.540; Cohen's d = -1.35) and week 12 (95% CI: -0.171, -0.052; Cohen's d = 0.68), respectively. No significant interaction was observed with the emotional regulation contrast, but multiple regions had significant main effects of scan time, including the cuneus, occipital lobe, insula, lingual gyrus, posterior cingulate cortex, and MTG. CONCLUSIONS: During treatment of LLD patients, affective processing-induced activity in the right MTG shows changes based on remission status. This alteration becomes evident early during the course of treatment, suggesting that antidepressant pharmacotherapy may acutely affect the neural basis of emotional reactivity in a differential manner that is relevant to illness remission.

Emotion reactivity and regulation in late-life generalized anxiety disorder: functional connectivity at baseline and post-treatment.

OBJECTIVES: Generalized anxiety disorder (GAD) is one of the most prevalent mental disorders in the elderly, but its functional neuroanatomy is not well understood. Given the role of emotion dysregulation in GAD, we sought to describe the neural bases of emotion regulation in late-life GAD by analyzing the functional connectivity (FC) in the Salience Network and the Executive Control Network during worry induction and worry reappraisal. METHODS: The study included 28 elderly GAD and 31 non-anxious comparison participants. Twelve elderly GAD completed a 12-week pharmacotherapy trial. We used an in-scanner worry script that alternates blocks of worry induction and reappraisal. We assessed network FC, using the following seeds: anterior insula (AI), dorsolateral prefrontal cortex (dlPFC), the bed nucleus of stria terminalis (BNST), and the paraventricular nucleus (PVN). RESULTS: GAD participants exhibited greater FC during worry induction between the left AI and the right orbitofrontal cortex, and between the BNST and the subgenual cingulate. During worry reappraisal, the non-anxious participants had greater FC between the left dlPFC and the medial PFC, as well as between the left AI and the medial PFC, and elderly GAD patients had greater FC between the PVN and the amygdala. Following 12 weeks of pharmacotherapy, GAD participants had greater connectivity between the dlPFC and several prefrontal regions during worry reappraisal. CONCLUSION: FC during worry induction and reappraisal points toward abnormalities in both worry generation and worry reappraisal. Following successful pharmacologic treatment, we observed greater connectivity in the prefrontal nodes of the Executive Control Network during reappraisal of worry.