Estradiol treatment in young postmenopausal women with self-reported cognitive complaints: Effects on cholinergic-mediated cognitive performance.

OBJECTIVE: Older women are at increased risk of developing Alzheimer's disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17ß-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints. METHODS: Forty postmenopausal women (aged 50-60 years) completed a 3-month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC). RESULTS: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N-back working memory task, regardless of whether they received estradiol treatment. CONCLUSIONS: The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.

Lifetime stress exposure, cognition, and psychiatric wellbeing in women.

Objectives:Although life stress has been associated with worse cognitive and psychiatric functioning, few studies on this topic have examined these associations in older adults and no studies to date have assessed lifetime stress exposure in this context.Method:To address this important issue, we investigated associations between lifetime stress exposure, cognition, and psychiatric wellbeing in 44 women aged 60 and older who completed a comprehensive lifetime stress exposure inventory, two memory tasks, and a complete psychiatric assessment.Results:As hypothesized, greater acute and chronic lifetime stress exposure were both related to poorer psychiatric functioning and more somatic health complaints. Greater lifetime stress exposure was also associated with poorer subjective cognition as indicated by memory and thought problems but not objective indices of memory function.Conclusion:Screening for high life stress exposure may therefore help identify older women at increased risk of experiencing negative psychiatric and cognitive outcomes.

The generalizability of empirically derived syndromes of collateral-reported elder psychopathology across 11 societies.

The purpose of this study was to test whether a syndrome model of elder psychopathology derived from collateral ratings, such as from spouses and adult children, in the United States would be generalizable in 11 other societies. Societies represented South America, Asia, and Europe. The Older Adult Behavior Checklist (OABCL) was completed by collateral informants for 6141 60- to 102-year-olds. The tested model comprised syndromes designated as Anxious/Depressed, Worries, Somatic Complaints, Functional Impairment, Memory/Cognition Problems, Thought Problems, and Irritable/Disinhibited. The model was tested using confirmatory factor analyses in each society separately. The primary model fit index showed a good fit for all societies, while the secondary model fit indices showed acceptable to a good fit for all societies. The items loaded strongly on their respective factors, with a median item loading of 0.69 across the 11 societies. By syndrome, the overall median item loadings ranged from 0.47 for Worries to 0.77 for Functional Impairment. The OABCL syndrome structure was thus generalizable across the tested societies. The OABCL can be used for broad assessment of psychopathology for elders of diverse backgrounds in nursing services and research.

The generalizability of Older Adult Self-Report (OASR) syndromes of psychopathology across 20 societies.

OBJECTIVES: As the world population ages, psychiatrists will increasingly need instruments for measuring constructs of psychopathology that are generalizable to diverse elders. The study tested whether syndromes of co-occurring problems derived from self-ratings of psychopathology by US elders would fit self-ratings by elders in 19 other societies. METHODS/DESIGN: The Older Adult Self-Report (OASR) was completed by 12 826 adults who were 60 to 102 years old in 19 societies from North and South America, Asia, and Eastern, Northern, Southern, and Western Europe, plus the United States. Individual and multigroup confirmatory factor analyses (CFAs) tested the fit of the seven-syndrome OASR model, consisting of the Anxious/Depressed, Worries, Somatic Complaints, Functional Impairment, Memory/Cognition Problems, Thought Problems, and Irritable/Disinhibited syndromes. RESULTS: In individual CFAs, the primary model fit index showed good fit for all societies, while the secondary model fit indices showed acceptable to good fit. The items loaded strongly on their respective factors, with a median item loading of .63 across 20 societies, and 98.7% of the loadings were statistically significant. In multigroup CFAs, 98% of items demonstrated approximate or full metric invariance. Fifteen percent of items demonstrated approximate or full scalar invariance, and another 59% demonstrated scalar invariance across more than half of societies. CONCLUSIONS: The findings supported the generalizability of OASR syndromes across societies. The seven syndromes offer empirically based clinical constructs that are relevant for elders of different backgrounds. They can be used to assess diverse elders and as a taxonomic framework to facilitate communication, services, research, and training in geriatric psychiatry.

Examining the Relationship Between Neurosteroids, Cognition, and Menopause With Neuroimaging Methods.

PURPOSE OF REVIEW: Previous literature has shown inconsistent findings regarding the effects of neurosteroids on the brain in postmenopausal women. The goal of this paper is to examine how and whether advances in neuroimaging have helped elucidate the relationship between the withdrawal of and/or treatment with neurosteroids and cognition at menopause. RECENT FINDINGS: Neuroimaging techniques such as structural and functional MRI have been used in recent studies to examine the relationship between neurosteroids and brain structure and functioning. However, the recent literature shows that different formulations of postmenopausal hormones given at different times, through different routes of administration, and in different combinations with progestins result in a variety of relationships with the brain outcomes. We suggest that still further research is needed to understand how the structural changes resulting from estrogen withdrawal or therapy at menopause can influence cognitive functioning. However, imaging studies are time-, resource-, and expertise-intensive. We believe that this information will help uncover the mechanisms and relationships that can aid in the explanation of the individual differences in the effects of menopause on the brain as well as how this menopause-related hormone change influences risk for pathological aging.

Empirically derived dimensional syndromes of self-reported psychopathology: Cross-cultural comparisons of Portuguese and US elders.

OBJECTIVE: As the world population ages, mental health professionals increasingly need empirically supported assessment instruments for older adult psychopathology. This study tested the degree to which syndromes derived from self-ratings of psychopathology by elders in the US would fit self-ratings by elders in Portugal. METHODS: The Older Adult Self-Report (OASR) was completed by 352 60- to 102-year-olds in Portuguese community and residential settings. RESULTS: Confirmatory factor analyses tested the fit of the 7-syndrome OASR model to self-ratings by Portuguese elders. The primary fit index (Root Mean Square Error of Approximation) showed good fit, while secondary fit indices (the Comparative Fit Index and the Tucker-Lewis Index) showed acceptable fit. Loadings of 95 of the 97 items on their expected syndromes were statistically significant (mean = .63), indicating that the items measured the syndromes well. Correlations between latent factors, ie, between the hypothesized syndrome constructs measured by the items, averaged .66. The correlations between syndromes reflect varying degrees of comorbidity between problems comprising particular pairs of syndromes. CONCLUSIONS: The results support the syndrome structure of the OASR for Portuguese elders, offering Portuguese clinicians and researchers a useful instrument for assessing a broad spectrum of psychopathology. The results also offer a core of empirically supported taxonomic constructs of later life psychopathology as a basis for advancing clinical practice, training, and cross-cultural research.

Strategies for Preventing Cognitive Decline in Healthy Older Adults.

OBJECTIVE: Many advances have been made in the understanding of age-related changes in cognition. As research details the cognitive and neurobiological changes that occur in aging, there is increased interest in developing and understanding methods to prevent, slow, or reverse the cognitive decline that may occur in normal healthy older adults. The Institute of Medicine has recently recognized cognitive aging as having important financial and public health implications for society with the increasing older adult population worldwide. Cognitive aging is not dementia and does not result in the loss of neurons but rather changes in neurotransmission that affect brain functioning. The fact that neurons are structurally intact but may be functionally affected by increased age implies that there is potential for remediation. METHOD AND RESULTS: This review article presents recent work using medication-based strategies for slowing cognitive changes in aging. The primary method presented is a hormonal approach for affecting cognition in older women. In addition, a summary of the work examining modifiable lifestyle factors that have shown promise in benefiting cognition in both older men and women is described. CONCLUSIONS: Much work remains to be done so that evidence-based recommendations can be made for slowing cognitive decline in healthy older adults. The success of some of these methods thus far indicates that the brains of healthy older adults are plastic enough to be able to respond to these cognitive decline prevention strategies, and further work is needed to define the most beneficial methods.

Impaired working memory in geriatric depression: an FMRI study.

OBJECTIVE: Older adults with major depressive disorder (MDD) experience poor cognitive and behavioral outcomes as MDD occurs in the context of other age-related brain changes. Patients with depression often have impairments on measures of frontal lobe functioning such as working memory. Understanding the effects of depression on cognitive functioning in older adults is important for the development of treatment strategies that focus on cognitive changes as well as mood. METHODS: Eleven older adults with current MDD and 12 nondepressed comparison participants (all aged 60 years and older) performed the N-back test of working memory during fMRI. RESULTS: Depressed older adults performed worse than nondepressed participants on the N-back task. Depressed older adults had decreased lateral frontal and parietal activation during the most difficult working memory load condition on the N-back compared with nondepressed older adults. CONCLUSION: Cognitive dysfunction in geriatric depression may be related to reorganization of brain networks involved in working memory.

Age-related increase of resting metabolic rate in the human brain.

With age, many aspects of the brain structure undergo a pronounced decline, yet individuals generally function well until advanced old age. There appear to be several compensatory mechanisms in brain aging, but their precise nature is not well characterized. Here we provide evidence that the brain of older adults expends more energy when compared to younger adults, as manifested by an age-related increase (P=0.03) in cerebral metabolic rate of oxygen (CMRO2) (N=118, men=56, ages 18 to 74). We further showed that, before the mean menopausal age of 51years old, female and male groups have similar rates of CMRO2 increase (P=0.015) and there was no interaction between age and sex effects (P=0.85). However, when using data from the entire age range, women have a slower rate of CMRO2 change when compared to men (P<0.001 for age×sex interaction term). Thus, menopause and estrogen level may have played a role in this sex difference. Our data also revealed a possible circadian rhythm of CMRO2 in that brain metabolic rate is greater at noon than in the morning (P=0.02). This study reveals a potential neurobiological mechanism for age-related compensation in brain function and also suggests a sex-difference in its temporal pattern.

Subclinical Metabolic and Cardiovascular Factors and Brain White Matter Microstructural Integrity in Young Women.

Women who have experienced pregnancy complications, specifically preeclampsia and gestational diabetes, have well documented increased risks of cardiovascular, metabolic, and neurological disease later in life. This study examined how specific cardiovascular and metabolic risk factors for preeclampsia assessed in a non-pregnant state were associated with brain white matter microstructural integrity. This study examined sixty-two healthy women (mean age 31 ± 5 years) who received metabolic and cardiovascular assessments as well as multiple modality MRI imaging. Participants were either nulliparous (n = 31) or had a history of preterm preeclampsia (n = 31). Imaging included acquisition Diffusion Tensor Imaging (DTI) to assess white matter integrity within the brain. We hypothesized that healthy, young, non-pregnant women with cardiovascular and metabolic profiles suggesting elevated risk would have decreased white matter integrity, represented by lower Fractional Anisotropy (FA) and increased Mean Diffusivity (MD) estimates in the posterior cortical areas of the brain. We observed increased white matter degradation (lower FA and increased MD) in posterior and occipital tracts, commissural fibers, and subcortical structures in women with increased adiposity, worse measures of cardiovascular and metabolic function, including greater insulin resistance (HOMA-IR), hyperlipidemia, elevated blood pressure, and increased arterial stiffness. The relationships detected between subclinical cardiovascular and metabolic phenotypes and increased white matter disruption at a young age, outside of pregnancy, are indicative that adverse changes are detectable long before cognitive clinical presentation. This may suggest that many of the long-term cardiovascular and metabolic risks of aging are influenced by physiologic aging trajectories rather than damage caused by pregnancy complications.

Estradiol associations with brain functional connectivity in postmenopausal women.

OBJECTIVE: Previous studies have found that estrogens play a role in functional connectivity in the brain; however, little research has been done regarding how estradiol is associated with functional connectivity in postmenopausal women. The purpose of this study was to examine the relationship between estradiol and functional connectivity in postmenopausal women. METHODS: Structural and blood oxygenation level-dependent resting-state magnetic resonance imaging scans of 88 cognitively healthy postmenopausal individuals were obtained along with blood samples collected the same day as the magnetic resonance imaging to assess hormone levels. We generated connectivity values in CONN toolbox version 20.b, an SPM-based software. RESULTS: A regression analysis was run using estradiol level and regions of interest (ROI), including the hippocampus, parahippocampus, dorsolateral prefrontal cortex, and precuneus. Estradiol level was found to enhance parahippocampal gyrus anterior division left functional connectivity during ROI-to-ROI regression analysis. Estradiol enhanced functional connectivity between the parahippocampal gyrus anterior division left and the precuneus as well as the parahippocampal gyrus anterior division left and parahippocampal gyrus posterior division right. An exploratory analysis showed that years since the final menstrual period was related to enhanced connectivity between regions within the frontoparietal network. CONCLUSIONS: These results illustrated the relationship between estradiol level and functional connectivity in postmenopausal women. They have implications for understanding how the functioning of the brain changes for individuals after menopause that may eventually lead to changes in cognition and behavior in older ages.

Choline kinase alpha genotype is related to hippocampal brain volume and cognition in postmenopausal women.

This study examined how single nucleotide polymorphisms (SNPs) related to choline synthesis and metabolism, processes largely regulated by estrogen, influenced hippocampal volume and neuropsychological function following menopause. We investigated the effect of choline kinase alpha (CHKA) genotype on brain volume and neuropsychological performance in postmenopausal women. The effect alleles of certain CHKA SNPs (rs6591331 T, rs10791957 A) are associated with varied responses to choline deficiency and delegation of choline to physiological pathways. The presence of these alleles was hypothesized to correlate with worse cognitive performance in women after menopause. Results from structural MRI scans revealed larger right hippocampal volumes in subjects with a T/T CHKA rs6591331 genotype compared to A/A subjects. Delayed memory scores from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were lower in subjects with T/T genotypes compared to those with the A/T genotype and the A/A genotype. Based on these findings, we proposed a CHKA-dependent mechanism present within the brain to compensate for the decreased estrogen and biosynthesized choline associated with menopause.

Cigarette smoking and cognitive task performance: Experimental effects of very-low nicotine-content cigarettes.

Reductions in the nicotine content of cigarettes decrease smoking rate and dependence severity, but effects on cognition are less well established. The potential impacts of very-low nicotine-content (VLNC) cigarettes on cognitive task performance must be evaluated, especially in vulnerable populations. The aim of the present study is to experimentally examine the effects of VLNC cigarettes on cognitive performance. Adults who smoked daily (n = 775) from three vulnerable populations (socioeconomically disadvantaged reproductive-age women, individuals with opioid use disorder, affective disorders) were examined. Participants were randomly assigned to normal nicotine content (NNC; 15.8 mg nicotine/g tobacco) or VLNC (2.4 mg/g or 0.4 mg/g) cigarettes for 12 weeks. Response inhibition (stop-signal task), working memory (n-back task; n of 2-n of 0), and cognitive interference (nicotine Stroop task) were assessed at baseline, 2, 6, and 12 weeks. Results were analyzed using mixed-model repeated-measures analyses of variance. Extended exposure to VLNC cigarettes produced no significant changes in any measure of cognitive performance compared to NNC cigarettes. Over weeks, response times on the n-back task decreased across doses. No significant effects were observed on the stop-signal or nicotine Stroop tasks. All three vulnerable populations performed comparably on all three cognitive tasks. Extended exposure to VLNC cigarettes produced no impairments in cognitive performance on any of the assessed tasks compared to NNC cigarettes. These findings are consistent with the larger literature detailing other consequences following exposure to VLNC cigarettes and are encouraging for the adoption of a nicotine-reduction policy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Alteration of brain function and systemic inflammatory tone in older adults by decreasing the dietary palmitic acid intake.

Prior studies in younger adults showed that reducing the normally high intake of the saturated fatty acid, palmitic acid (PA), in the North American diet by replacing it with the monounsaturated fatty acid, oleic acid (OA), decreased blood concentrations and secretion by peripheral blood mononuclear cells (PBMCs) of interleukin (IL)-1ß and IL-6 and changed brain activation in regions of the working memory network. We examined the effects of these fatty acid manipulations in the diet of older adults. Ten subjects, aged 65-75 years, participated in a randomized, cross-over trial comparing 1-week high PA versus low PA/high OA diets. We evaluated functional magnetic resonance imaging (fMRI) using an N-back test of working memory and a resting state scan, cytokine secretion by lipopolysaccharide (LPS)-stimulated PBMCs, and plasma cytokine concentrations. During the low PA compared to the high PA diet, we observed increased activation for the 2-back minus 0-back conditions in the right dorsolateral prefrontal cortex (Broadman Area (BA) 9; p < 0.005), but the effect of diet on working memory performance was not significant (p = 0.09). We observed increased connectivity between anterior regions of the salience network during the low PA/high OA diet (p < 0.001). The concentrations of IL-1ß (p = 0.026), IL-8 (p = 0.013), and IL-6 (p = 0.009) in conditioned media from LPS-stimulated PBMCs were lower during the low PA/high OA diet. This study suggests that lowering the dietary intake of PA down-regulated pro-inflammatory cytokine secretion and altered working memory, task-based activation and resting state functional connectivity in older adults.