20-year depressive symptoms, dementia, and structural neuropathology in older women.

INTRODUCTION: The course of depressive symptoms and dementia risk is unclear, as are potential structural neuropathological common causes. METHODS: Utilizing joint latent class mixture models, we identified longitudinal trajectories of annually assessed depressive symptoms and dementia risk over 21 years in 957 older women (baseline age 72.7 years old) from the Women's Health Initiative Memory Study. In a subsample of 569 women who underwent structural magnetic resonance imaging, we examined whether estimates of cerebrovascular disease and Alzheimer's disease (AD)-related neurodegeneration were associated with identified trajectories. RESULTS: Five trajectories of depressive symptoms and dementia risk were identified. Compared to women with minimal symptoms, women who reported mild and stable and emerging depressive symptoms were at the highest risk of developing dementia and had more cerebrovascular disease and AD-related neurodegeneration. DISCUSSION: There are heterogeneous profiles of depressive symptoms and dementia risk. Common neuropathological factors may contribute to both depression and dementia. Highlights The progression of depressive symptoms and concurrent dementia risk is heterogeneous. Emerging depressive symptoms may be a prodromal symptom of dementia. Cerebrovascular disease and AD are potentially shared neuropathological factors.

Loneliness, social isolation, and cardiovascular disease among nonveteran and veteran women.

We examined the prospective associations of social isolation and loneliness with incident cardiovascular disease (CVD) among aging nonveteran and veteran women, and effect modification by veteran status. Participants with no history of myocardial infarction (MI), stroke, coronary heart disease (CHD), or coronary heart failure from the Women's Health Initiative Extension Study II self-reported social isolation, loneliness, health behaviors, health status, and veteran status. CVD and CVD subevents were physician adjudicated. Hazard ratios (HR) and 95% confidence intervals (CI) for the Interquartile Range (IQR) in social isolation (IQR = 1) and loneliness (IQR=.33) were calculated using Cox proportional hazard models adjusting for sociodemographic, health behavior, and health status characteristics. Veteran status was tested as an effect modifier. Among 52,442 women (Mean age = 79 ± 6.1; veterans n = 1023; 89.2% non-Hispanic White), 3579 major CVD events occurred over an average 5.8 follow-up years. Compared to nonveterans, veteran women reported higher levels of social isolation (p < .01) and loneliness (p < .01). The CVD HR was 1.07 (95% CI, 1.04-1.10) for the IQR in social isolation and 1.03 (95% CI, 1.10-1.06) for the IQR in loneliness. The HR for the IQR in both social isolation and loneliness was 1.10 (95% CI, 1.05-1.15). Social isolation was associated with CHD (HR = 1.12; 95% CI, 1.03-1.21). The CHD HR for the IQR in social isolation was 1.12 (95% CI, 1.03-1.21). Associations did not differ by veteran status (all p-interactions > 0.08). Findings suggest that the adverse associations of social isolation and loneliness with CVD are similar among veteran and nonveteran women.

Neuropsychological correlates of early grief in bereaved older adults.

Prolonged grief disorder (PGD) is associated with impairments in cognitive functioning, but the neuropsychological correlates of early grief in older adults are poorly understood. This preliminary study cross-sectionally examined neuropsychological functioning in bereaved adults with high and low grief symptoms and a non-bereaved comparison sample and further explored the relationship between multidomain cognitive measures and grief severity. A total of ninety-three nondemented older adults (high grief: n = 44; low grief: n = 49) within 12 months post-bereavement and non-bereaved comparison participants (n = 43) completed neuropsychological battery including global and multiple domain-specific cognitive functioning. Linear regression models were used to analyze differences in multidomain cognitive measures between the groups and specifically examine the associations between cognitive performance and grief severity in the bereaved, after covariate adjustment, including depressive symptoms. Bereaved older adults with higher grief symptoms performed worse than those with lower symptoms and non-bereaved participants on executive functioning and attention and processing speed measures. In the bereaved, poorer executive functioning, attention and processing speed correlated with higher grief severity. Attention/processing speed-grief severity correlation was seen in those with time since loss ≤ 6 months, but not > 6 months. Intense early grief is characterised by poorer executive functioning, attention, and processing speed, resembling findings in PGD. The putative role of poorer cognitive functioning during early grief on the transition to integrated grief or the development of PGD remains to be elucidated.

The relationship between depressive symptoms and subtypes of mild cognitive impairment in post-menopausal women: Results from the Women's Health Initiative Memory Study.

BACKGROUND: Depressive symptoms are associated with age-related cognitive impairment, but the relative risk of specific subtypes of mild cognitive impairment (MCI) conferred by depressive symptoms is unclear. The purpose of this exploratory study was to determine the longitudinal association between baseline depressive symptoms and incident cases of MCI subtypes (amnestic vs. non-amnestic) and probable dementia (PD) (Alzheimer's disease, vascular, mixed) among postmenopausal women. METHODS: Depressive symptoms were assessed at study baseline using an 8-item Burnam algorithm in 7043 postmenopausal women who participated in the Women's Health Initiative Memory Study (WHIMS) and the WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) extension study. During the median 9.4-year follow-up interval, the presence of MCI and PD was classified by a central adjudication committee. Classification of participants by MCI subtype (amnestic single and multi-domain, non-amnestic single and multi-domain) was done algorithmically based on established criteria using data from annual cognitive testing. RESULTS: At baseline, 557 women (7.9%) had clinically significant depressive symptoms based on Burnam algorithm cut-point of 0.06. Depressive symptoms at baseline were associated with an increased risk of incident amnestic MCI (hazard ratio [HR] = 1.91, 95% confidence interval [CI] 1.32-2.78, p < 0.0001), but not non-amnestic MCI (HR = 1.39, 95% CI 0.91-2.14, p = 0.13) after controlling for demographic factors. This relationship between depressive symptoms and amnestic MCI remained consistent after controlling for lifestyle variables, cardiovascular risk factors, antidepressant use, and history of hormone therapy. There were no significant associations between depressive symptoms and incidence of PD. CONCLUSION: Depressive symptoms at baseline among postmenopausal older women are associated with higher incidence of amnestic MCI, suggesting that they may be an independent risk factor or part of the early prodrome of dementia.

Ventral striatal subregional dysfunction in late-life grief: Relationships with yearning and depressive symptoms.

Bereaved older adults experiencing high grief in the first year after an attachment loss is at increased risk for prolonged grief disorder (PGD) via unknown mechanisms. Yearning, a core grief symptom, is linked to the ventral striatal (VS) brain function, but the role of this neuronal system in late-life grief is poorly understood. As a first step, we examined the VS subregional abnormalities associated with multidimensional symptoms in bereaved elders during the first year post-loss. Sixty-five bereaved elders completed clinical assessments within 13 months post-loss. Ventral caudate (VCau) and nucleus accumbens (NAcc) functional connectivity (FC) was assessed using seed-based resting-state functional MRI. VCau and NAcc FC differences between high (inventory of complicated grief [ICG] score≥30; n = 35) and low (ICG score<30; n = 30) grief, and the relationships between ventral striatal subregional FC and clinical measures (yearning and depressive symptoms) were assessed after covariate adjustments (α < 0.05; 3dClustSim corrected). Relative to low grief participants, those with high grief showed higher FC between VCau and the medial prefrontal, orbitofrontal, and subgenual cingulate cortices. VCau FC abnormalities positively correlated with yearning (r2 = 0.24, p < 0.001). In contrast, FC between VCau and temporoparietal junction negatively correlated with depressive symptoms, a commonly co-occurring symptom (r2 = 0.37, p < 0.001). The FC between NAcc and insula/striatum positively correlated with yearning (r2 = 0.35, p < 0.001); no other NAcc FC findings were seen in the full sample. In women, higher FC between the NAcc and bilateral posterior cingulate, precuneus, and visual areas were found in those with high, relative to low grief symptoms. Distinct VS subregional abnormalities associate with yearning and depressive symptoms in bereaved elders. Whether ventral striatal dysfunction correlates with PGD development and/or worsening depression remains to be elucidated.

Association of Global Cognitive Function With Psychological Distress and Adherence to Public Health Recommendations During the Coronavirus Disease 2019 Pandemic: The Women's Health Initiative.

BACKGROUND: The association of cognitive function with symptoms of psychological distress during the coronavirus disease 2019 (COVID-19) pandemic or adherence to COVID-19 protective health behaviors is not well-understood. METHODS: We examined 2 890 older women from the Women's Health Initiative cohort. Prepandemic (ie, within 12 months prior to pandemic onset) and peripandemic global cognitive function scores were assessed with the modified Telephone Interview for Cognitive Status (TICS-m). Anxiety, stress, and depressive symptom severity during the pandemic were assessed using validated questionnaires. We examined adherence to protective behaviors that included safe hygiene, social distancing, mask wearing, and staying home. Multivariable models were adjusted for age, race, ethnicity, education, region of residence, alcohol intake, and comorbidities. RESULTS: Every 5-point lower prepandemic TICS-m score was associated with 0.33-point mean higher (95% confidence interval [CI], 0.20, 0.45) perceived stress and 0.20-point mean higher (95% CI, 0.07, 0.32) depressive symptom severity during the pandemic. Higher depressive symptom severity, but not anxiety or perceived stress, was associated with a 0.69-point (95% CI, -1.13, -0.25) mean decline in TICS-m from the prepandemic to peripandemic period. Every 5-point lower peripandemic TICS-m score was associated with 12% lower odds ratio (OR, 0.88; 95% CI, 0.80, 0.97) of practicing safe hygiene. CONCLUSIONS: Among older women, we observed that: (a) lower prepandemic global cognitive function was associated with higher stress and depressive symptom severity during the pandemic; (b) higher depressive symptom severity during the pandemic was associated with cognitive decline; and (c) lower global cognitive function during the pandemic was associated with lower odds of practicing safe hygiene.

Associations Between Changes in Loneliness and Social Connections, and Mental Health During the COVID-19 Pandemic: The Women's Health Initiative.

BACKGROUND: Older women have faced significant disruptions in social connections during the coronavirus disease 2019 pandemic. Whether loneliness increased or whether a change in loneliness from pre- to intrapandemic period was associated with mental health during the pandemic is unknown. METHODS: Older women (n = 27 479; mean age 83.2 [SD: 5.4] years) completed surveys in mid-2020, including questions about loneliness, living arrangements, changes in social connections, and mental health. Loneliness was also previously assessed in 2014-2016. We examined whether loneliness changed from the pre- to intrapandemic period and explored factors associated with this change. In multivariable models, we investigated the association of changes in loneliness and social connections with mental health. RESULTS: Loneliness increased from pre- to intrapandemic levels. Factors associated with worsening loneliness included older age, experiencing stressful life events, bereavement, histories of vascular disease and depression, and social connection disruptions. Factors associated with a decrease in loneliness included identifying as Black, engaging in more frequent physical activity, being optimistic, and having a higher purpose in life. A 3-point increase in loneliness scores was associated with higher perceived stress, higher depressive, and higher anxiety symptoms. Social connection disruptions showed modest or no associations with mental health. CONCLUSIONS: Loneliness increased during the pandemic in older women and was associated with higher stress, depressive, and anxiety symptoms. Our findings point to opportunities for interventions targeting lifestyle behaviors, well-being, disrupted social connections, and paying closer attention to those with specific medical and mental health histories that may reduce loneliness and improve mental health.

Loneliness, Circulating Endocannabinoid Concentrations, and Grief Trajectories in Bereaved Older Adults: A Longitudinal Study.

Background: Loneliness is one of the most distressing grief symptoms and is associated with adverse mental health in bereaved older adults. The endocannabinoid signaling (ECS) system is stress-responsive and circulating endocannabinoid (eCB) concentrations are elevated following bereavement. This study examined the association between loneliness and circulating eCB concentrations in grieving older adults and explored the role of eCBs on the association between baseline loneliness and grief symptom trajectories. Methods: A total of 64 adults [grief with high loneliness: n = 18; grief with low loneliness: n = 26; and healthy comparison (HC): n = 20] completed baseline clinical assessments for the UCLA loneliness scale. In grief participants, longitudinal clinical assessments, including the Inventory of Complicated Grief and 17-item Hamilton Depression Rating scales, were collected over 6 months. Baseline circulating eCB [N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)] concentrations were quantified in the serum using isotope dilution, liquid chromatography-mass spectrometry; cortisol concentrations were measured in the same samples using radioimmunoassay. Results: Circulating AEA concentrations were higher in severely lonely grieving elders than in HC group; cortisol concentrations were not different among the groups. Cross-sectionally, loneliness scores were positively associated with AEA concentrations in grievers; this finding was not significant after accounting for depressive symptom severity. Grieving individuals who endorsed high loneliness and had higher 2-AG concentrations at baseline showed faster grief symptom resolution. Conclusions: These novel findings suggest that in lonely, bereaved elders, increased circulating eCBs, a reflection of an efficient ECS system, are associated with better adaptation to bereavement. Circulating eCBs as potential moderators and mediators of the loneliness-grief trajectory associations should be investigated.

Grief and the COVID-19 Pandemic in Older Adults.

(Appeared originally in Am J Geriatr Psychiatry 2020; 28:10 1119-1125).

The influence of depression on the relationship between loneliness and grief trajectories in bereaved older adults.

Loneliness is associated with adverse mental health outcomes in older adults. Bereavement triggers intense feelings of loneliness. This pilot study explored the association between baseline loneliness and grief symptom trajectories in bereaved elders and explored if this association is moderated by depressive symptom changes. 56 individuals aged 50 years and older, within 13-months following bereavement, completed assessments. Loneliness was measured at baseline using the UCLA loneliness scale-version 3. Grief and depressive symptoms were measured over 26 weeks using the inventory of complicated grief (ICG) and the 17-item Hamilton Depressive Rating (HAM-D) scales, respectively. Linear regression explored the cross-sectional association between loneliness and grief symptoms, after adjusting for covariates including depressive symptoms. A mixed-effects linear model tested whether baseline loneliness was related to grief symptom trajectory over 26 weeks, after accounting for depressive symptom changes. Loneliness was associated with grief symptom severity at baseline; however, this cross-sectional association was not significant after adjusting for depressive symptoms. Longitudinally, baseline loneliness was positively associated with grief symptom trajectories; however, depressive symptom changes moderated this association. Depressive symptom alterations appear to weaken the loneliness-grief symptom change association. These exploratory findings point to opportunities for interventions targeting loneliness and depression that may reduce grief intensity over time in bereaved elders.

Circulating endocannabinoid concentrations in grieving adults.

Bereavement is one of the most intense, distressing, and traumatic events an elderly person will experience. The symptom responses to bereavement vary, particularly during the first year. However, the neurobiology underlying the symptom variance in grief is poorly understood. The endocannabinoid signaling (ECS) system is stress-responsive; mounting evidence implicates the central ECS in psychopathology. The current study aimed to investigate the hypothesis that the ECS is abnormal in grief, using circulating eCB concentrations as a biomarker of central ECS. A predominantly older sample of grief participants, within 13 months following the death of a loved one, and healthy comparison (HC) participants were studied. Associations of circulating eCBs with symptom variance in grievers were also examined. A total of 61 (grief: n = 44; HC: n = 17) adults completed cross-sectional clinical assessments and a fasting blood draw. Assessments included the Inventory of Complicated Grief scale; the 17-item Hamilton Depression Rating Scale; and the Hamilton Anxiety scale. Serum eCB concentrations (i.e., N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]) were quantified using isotope dilution, liquid chromatography-mass spectrometry. Relative to HC participants, grievers had significantly elevated serum AEA but similar 2-AG concentrations. In grievers, serum AEA concentrations were positively associated with depressive and anxiety symptoms, but only in those with low grief symptoms. These novel findings indicate that elevated circulating eCB concentrations are found following bereavement. The eCB signaling response varies based on the degree of grief severity. Circulating eCB measures may have the potential to serve as biomarkers of prolonged grief disorder.

Grief and the COVID-19 Pandemic in Older Adults.

In few periods in human history have bereavement and grief been on so many people's minds as they are today. As the coronavirus disease 2019 (COVID-19) ravages the world, we have seen many perish in a short time. Many have died alone because of requirements for physical distancing. Even more will succumb as COVID-19 continues to spread. Moreover, deaths from other causes, numbering over 50 million annually, are also happening amid physical distancing and other COVID-19-related challenges. The pandemic is affecting the way terminally ill patients are being cared for, when and how people are dying of other causes, and how bodies are being handled and bereavement rituals performed. The bereaved are required to grieve without the support of usual social and cultural rituals. Grieving is further encumbered by cascading life stressors deriving from policies needed to mitigate the pandemic. Though we are often heartened by human resilience in response to death and other hardships, for some, the burden of this pandemic will be too much. Among other mental health problems, we will likely see an increase in prolonged grief disorder. In this commentary, we review the new diagnosis of prolonged grief disorder and outline why we might anticipate increased rates of this condition on the heels of COVID-19, especially among older persons. The authors suggest ways that might mitigate this emerging problem.

Amygdala Functional Connectivity Features in Grief: A Pilot Longitudinal Study.

OBJECTIVE: Acute grief, in an important minority of older adults, can become protracted, intense, and debilitating, leading to the development of complicated grief (CG). However, the neurobiologic mechanisms underlying a maladaptive grief response after an attachment loss are unknown. The current study aimed to examine the amygdala brain network features that cross-sectionally explain the symptom variance and longitudinally relate to grief symptom trajectories after an attachment loss. METHODS: Baseline amygdala functional connectivity (Fc) was assessed using a seed-based resting-state functional magnetic resonance imaging method in 35 adults who were within 1-year after death of a loved one and 21 healthy comparison (HC) participants. Magnetic resonance imaging scans were obtained at baseline, and clinical assessments, including the inventory of complicated grief (ICG) were completed at weeks 0, 8, 16, and 26 (endpoint). RESULTS: Relative to HC participants, grief participants showed increased amygdala Fc in the posterior default mode (bilateral medial temporal lobes and left precuneus) and thalamus. Amygdala Fc in the default mode and ventral affective regions positively correlated with ICG scores at baseline. Furthermore, increased baseline amygdala functional connections with the dorsal frontal executive control and salience network regions correlated with worsening ICG scores over time. These longitudinal findings persisted after controlling for covariates, including baseline depressive and anxiety symptoms. CONCLUSION: These results provide novel preliminary evidence suggesting amygdala-based brain network measures to cross-sectionally explain symptom variance and longitudinally correlate with grief symptom trajectories in grievers. Amygdala brain network function measures may have the potential to serve as biomarkers of CG.

General and domain-specific cognitive reserve, mild cognitive impairment, and dementia risk in older women.

INTRODUCTION: In a geographically diverse sample of women, we asked whether cognitive reserve (CR) is best viewed as a general or cognitive domain-specific construct and whether some cognitive reserve domains but not others exert protective effects on risk of developing mild cognitive impairment (MCI) or dementia. METHODS: Estimates of general and domain-specific CR were derived via variance decomposition in 972 cognitively intact women from the Women's Health Initiative Study of Cognitive Aging and Women's Health Memory Study Magnetic Resonance Imaging. Women were then followed up for 13 years. RESULTS: General CR was the strongest predictor of reduced risk for both MCI and dementia, compared to domain-specific CR measures. Verbal memory, figural memory, and spatial CR were independently protective of MCI, but only verbal memory was independently associated with reduced risk for dementia. DISCUSSION: Cognitive reserve is a heterogenous construct with valid quantitative measures identifiable across different neuropsychological processes associated with MCI and dementia.

A candidate gene study of risk for dementia in older, postmenopausal women: Results from the Women's Health Initiative Memory Study.

OBJECTIVE: While a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS). METHODS: We analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non-Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model. RESULTS: One SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with the PD phenotype based on a P value accounting for multiple comparisons. An additional 12 SNPs were associated with the PD phenotype at P ≤ 0.05 (APOE: rs405509, rs439401; TOMM40: rs8106922, and KIBRA: rs4320284, rs11740112, rs10040267, rs13171394, rs6555802, rs2241368, rs244904, rs6555805, and rs10475878). Results of the sensitivity analyes excluding MCI were similar, with addition of COMT rs737865 and BDNF rs1491850 (P ≤ 0.05). CONCLUSIONS: Our results in older women provide supporting evidence that the APOE/TOMM40 genes confer dementia risk and extend these findings to COMT, BDNF, and KIBRA. Our findings may lead to a better understanding of the role these genes play in cognition and cognitive impairment.

Are Optimism and Cynical Hostility Associated with Smoking Cessation in Older Women?

BACKGROUND: Optimism and cynical hostility independently predict morbidity and mortality in Women's Health Initiative (WHI) participants and are associated with current smoking. However, their association with smoking cessation in older women is unknown. PURPOSE: The purpose of this study is to test whether optimism (positive future expectations) or cynical hostility (mistrust of others) predicts smoking cessation in older women. METHODS: Self-reported smoking status was assessed at years 1, 3, and 6 after study entry for WHI baseline smokers who were not missing optimism or cynical hostility scores (n = 10,242). Questionnaires at study entry assessed optimism (Life Orientation Test-Revised) and cynical hostility (Cook-Medley, cynical hostility subscale). Generalized linear mixed models adjusted for sociodemographics, lifestyle factors, and medical and psychosocial characteristics including depressive symptoms. RESULTS: After full covariate adjustment, optimism was not related to smoking cessation. Each 1-point increase in baseline cynical hostility score was associated with 5% lower odds of cessation over 6 years (OR = 0.95, CI = 0.92-0.98, p = 0.0017). CONCLUSIONS: In aging postmenopausal women, greater cynical hostility predicts lower smoking cessation over time. Future studies should examine whether individuals with this trait may benefit from more intensive cessation resources or whether attempting to mitigate cynical hostility itself may aid smoking cessation.