Patterns of Brain Activation and Hippocampal Functional Connectivity Supporting Verbal Memory in Midlife Women.

BackgroundThe APOE4 genotype appears to confer differential risk of Alzheimer’s disease for women compared to men. As APOE4 effects in midlife women can be subtle (e.g., negligible main effects of APOE4 genotype on cognition and brain outcomes), there is a need for early markers of APOE4‐related brain vulnerabilities to identify those at early risk and guide treatment. We therefore examined whether patterns of brain activity and hippocampal functional connectivity that support verbal memory differ by APOE4 status in midlife women participating in MsBrain, a cohort study of brain health in midlife women.MethodParticipants completed functional magnetic resonance imaging (fMRI) assessments during verbal encoding and recognition tasks. Generalized psychophysiological interaction (gPPI) analyses estimated hippocampal functional connectivity using SPM12 and Conn, with AlphaSim (AFNI) to correct for multiple comparisons. Associations between CVLT indices and brain outcomes (regional activation, left [LHipp] and right hippocampal [RHipp] functional connectivity) were tested via multiple linear regression controlling for age, education, race, and MoCA score. Interactions by APOE4 status (carriers [E3E4 and E4E4] versus non‐carriers [E3E3]) were tested.ResultIn 166 women (mean age=59.31 years, 83.7% white, 32% APOE4 carriers), there was no main effect of APOE4 on verbal memory performance, activation, or hippocampal connectivity. During encoding, APOE4 status moderated the associations between semantic clustering and fMRI measures (e.g., activation of the left superior frontal gyrus and connectivity from LHipp to left middle frontal gyrus and to right parahippocampal gyrus; Figure 1). These associations during encoding were stronger in APOE4 carriers versus noncarriers. During recognition, APOE4 status moderated the associations between: a) total learning and activation of right inferior, middle, and superior frontal gyri; b) clustering and activation of the right superior frontal gyrus; c) total learning and LHipp connectivity to left middle temporal gyrus; and d) clustering and RHipp connectivity to right superior temporal gyrus (Figure 2). For recognition, APOE4 carriers typically showed decreased activation/connectivity, while noncarriers showed neutral or enhanced activation/connectivity.ConclusionThese findings may indicate early compensatory mechanisms in female midlife APOE4 carriers that support verbal memory, serving as potential markers of risk and targets for intervention in midlife APOE4 carriers.

BackgroundAmong older adults, APOE4‐related associations with neuroimaging outcomes are more pronounced in women than men. At midlife, a critical period for prevention and treatment of risk factors for cognitive decline, the influence of APOE4 genotype on women's cognitive and brain health is subtle. Therefore, there is a need for early biomarkers of brain vulnerabilities in female APOE4 carriers. Here, we examined APOE4‐related differences in patterns of activation and hippocampal functional connectivity during word encoding in cognitively normal midlife women and the associations of these patterns with verbal memory performance and plasma Alzheimer's disease (AD) biomarkers.MethodWomen participating in MsBrain, a cohort study of brain health in midlife women, completed functional magnetic resonance imaging assessments during verbal encoding and recognition tasks. We measured both activation patterns and hippocampal functional connectivity, the latter using generalized psychophysiological interaction analyses (SPM12, Conn) with AlphaSim (AFNI) to correct for multiple comparisons. APOE4 group differences (carriers [E3E4 and E4E4] vs. non‐carriers [E3E3]) were tested using linear regression. Associations of neuroimaging indices with verbal memory (California Verbal Learning Test measures [CVLT learning, semantic clustering]) and plasma AD biomarkers (Aβ42/40, p‐tau 181, p‐tau 231) were tested via linear regression. All analyses adjusted for age, race, and education.ResultIn 145 women (mean age=59.1 years, 86.2% white, 24.1% APOE4+), APOE4 carriers and non‐carriers did not significantly differ on in‐scanner verbal recognition performance, CVLT measures, or plasma AD biomarkers. During verbal encoding, APOE4 non‐carriers had significantly greater activation and hippocampal functional connectivity in several regions compared to APOE4 carriers (Figure 1). Of the regions showing greater activation among non‐carriers, left inferior frontal gyrus activation was positively associated with CVLT measures, and greater connectivity from the left hippocampus to the left declive/fusiform was associated with lower p‐tau 181 levels (Figure 2).ConclusionFemale midlife APOE4 carriers have decreased activity and connectivity in key memory regions during word encoding compared to non‐carriers, despite showing similar cognitive performance and plasma amyloid and tau levels. Associations of certain connectivity outcomes with AD biomarkers suggest relevance to AD pathogenesis. These functional brain patterns may emerge earlier than the adverse effects of APOE4 genotype on cognition and brain.

BackgroundThe hippocampus plays an important role in learning and integrating events to form episodic memory. Many ischemic stroke survivors experience memory impairments, and some report decline in memory function. We examined changes in functional connectivity (FC) of the hippocampus and its subregions in stroke survivors over 3 years compared to age‐matched stroke‐free healthy controls (HC), and the associations between hippocampal FC and verbal memory performance.MethodParticipants from the Cognition And Neocortical Volume After Stroke Study were analysed at 3‐months, 1‐year and 3‐years post‐stroke. Verbal memory performance at each timepoint was evaluated with delayed recall of the Hopkins Verbal Learning Test‐Revised that was standardized using appropriate age stratified normative data. Evaluable resting‐state functional magnetic resonance imaging sequences were compared with age‐matched healthy controls (see Table 1 for demographics) following pre‐processing. The hippocampus was parcellated into whole hippocampus and four subregions (body, head‐medial, head‐lateral and tail) and bilateral seed‐based FC analyses were conducted for each region using CONN toolbox (V20.b). Longitudinal changes of FC between two timepoints were computed by the direct subtraction.ResultGroups were age‐ and sex‐matched but HC had significantly greater years of education (see Table 1). Greater FC change was seen in stroke survivors between 3‐months to 1‐year in left hippocampal head‐medial (right lateral occipital; p‐FDR = 0.012) with years of education adjusted. Stroke patients displayed significant decline in verbal memory between the 1‐ and 3‐year timepoints. Significantly decreased FC of left hippocampal head‐medial (precuneus; p‐FDR = 0.011) correlated with verbal memory decline between 3‐months and 3 years after adjusting years of education and gender. There was no significant decline or change of verbal memory observed in HC, and the correlated hippocampal FC changes were not present in HC group either.ConclusionChange in left hippocampal subregional FC is different in stroke survivors compared to HC. Subregional hippocampal FC changes correlate with verbal memory decline. Subfield FC analyses may shed new light into mechanisms of post‐stroke memory impairment.

Background: The “primacy effect,” i.e., increased memory recall for the first items of a series compared to the following items, is reduced in amnestic mild cognitive impairment (aMCI). Memory task-fMRI studies demonstrated that primacy recall is associated with higher activation of the hippocampus and temporo-parietal and frontal cortical regions in healthy subjects. Functional magnetic resonance imaging (fMRI) at resting state revealed that hippocampus functional connectivity (FC) with neocortical brain areas, including regions of the default mode network (DMN), is altered in aMCI. The present study aimed to investigate whether resting state fMRI FC between the hippocampus and cortical brain regions, especially the DMN, is associated with primacy recall performance in aMCI.Methods: A number of 87 aMCI patients underwent resting state fMRI and verbal episodic memory assessment. FC between the left or right hippocampus, respectively, and all other voxels in gray matter was mapped voxel-wise and used in whole-brain regression analyses, testing whether FC values predicted delayed primacy recall score. The delayed primacy score was defined as the number of the first four words recalled on the California Verbal Learning Test. Additionally, a partial least squares (PLS) analysis was performed, using DMN regions as seeds to identify the association of their functional interactions with delayed primacy recall.Results: Voxel-based analyses indicated that delayed primacy recall was mainly (positively) associated with higher FC between the left and right hippocampus. Additionally, significant associations were found for higher FC between the left hippocampus and bilateral temporal cortex, frontal cortical regions, and for higher FC between the right hippocampus and right temporal cortex, right frontal cortical regions, left medial frontal cortex and right amygdala (p < 0.01, uncorr.). PLS analysis revealed positive associations of delayed primacy recall with FC between regions of the DMN, including the left and right hippocampus, as well as middle cingulate cortex and thalamus (p < 0.04). In conclusion, in the light of decreased hippocampus function in aMCI, inter-hemispheric hippocampus FC and hippocampal FC with brain regions predominantly included in the DMN may contribute to residual primacy recall in aMCI.

HIV infection is often associated with frontal systems pathology and related deficits in the strategic encoding and retrieval aspects of episodic memory. However, no prior HIV studies have explicitly examined source memory, which refers to recall of information regarding the context in which a declarative memory was formed. Source memory is heavily reliant upon frontal systems and strategic cognitive processes and is singly dissociable from the content of the memory (i.e., item memory), which is more dependent upon medial temporal systems and automatic processes. The present study examined item and source memory in 60 individuals with HIV infection and 35 demographically similar seronegative participants. The primary finding of interest was a significant HIV effect on source (but not item) memory for complex visual stimuli. Follow-up correlational analyses showed a significant association between visual source memory errors and impairment on measures of executive functions, working memory, and higher-level list learning encoding strategies. These findings extend the hypothesized profile of strategic encoding and retrieval deficits in HIV to the construct of source memory, which may be differentially affected relative to item memory for complex visual stimuli.

Language and the Modulation of Impulsive Aggression

Background: Huntington’s disease is a progressive neurodegenerative disorder that results in deterioration and atrophy of various brain regions. Aim: To assess the functional connectivity between prefrontal brain regions in patients...

Compromised Memory Function in Schizophrenia and Temporal Lobe Epilepsy

Introduction Due to sex differences in cognitive aging and dementia burden, there is increased focus on the role of the menopause transition on cognitive functioning across midlife. This study aimed to characterize cognitive profiles among midlife women and to examine the demographic, social, and health factors associated with profile membership. Method Midlife women (N = 202; Age 40–60 years) from the Human Connectome Project – Aging completed NIH Toolbox cognitive and emotion measures. Latent profile analysis was used to identify cognitive profiles utilizing nine performance-based measures. Emergent profiles were then characterized in terms of demographic, cardiovascular and metabolic health indicators, and medication use (e.g. hormone therapy). Multinomial regression was then used to determine whether sleep, physical activity, depressive symptoms, and psychological stress varied by cognitive profile. Results Four distinct cognitive profiles were identified, the most common reflecting strength in verbal learning and memory (43% of women) and the next most common reflecting weaknesses in those same domains (39%). Black race and elevated depressive and anxiety symptoms were associated with the latter profile. A third profile (12%) reflected weakness in executive function (e.g. divided attention, picture vocabulary, working memory, task switching). The fourth (6%) was a mixed group showing strengths in pattern recognition and picture vocabulary but weaknesses in verbal memory and inhibitory control. Conclusion Midlife women show heterogeneity in cognitive performance, with nearly half showing a profile of strength in verbal memory. However, two menopause-relevant profiles emerged that were characterized by subtle weaknesses. One was in the domain of verbal memory and, consistent with earlier work, related to sadness and anxiety. The second was in executive function. Though less common, that vulnerability is notable given reports of attention-deficit hyperactivity disorder (ADHD)-like symptoms at menopause. Longitudinal studies are underway to determine the stability and predictors of cognitive profiles among midlife women.

The hippocampus is a crucial pathological node for minimal hepatic encephalopathy (MHE) and it is associated with various cognitive impairments. Investigations on alterations involving hippocampal morphology and functional connectivity (FC) in MHE are limited. This study aimed to simultaneously evaluate hippocampal volume and FC alterations and their association with cognitive decline in MHE. Twenty-two cirrhotic patients with MHE, 31 cirrhotic patients without MHE (NHE), and 43 healthy controls underwent high-resolution T1-weighted imaging, resting-state functional magnetic resonance imaging, and cognition assessment based on Psychometric Hepatic Encephalopathy Score (PHES). The structural images were preprocessed using a voxel-based morphometry method, during which hippocampal volume was measured. The hippocampal connectivity network was identified using seed-based correlation analysis. Hippocampal volume and FC strength were compared across the three groups and correlated against the PHES results of the cirrhotic patients. Compared to the controls, MHE patients exhibited a significantly lower bilateral hippocampal volume. A slight decrease in hippocampal volume was obtained from NHE to MHE, but it did not reach statistically significance. In addition, the average FC strength of the bilateral hippocampal connectivity network was significantly lower in the MHE patients. In particular, the MHE patients showed a decrease in FC involving the left hippocampus to bilateral posterior cingulate gyrus and left angular gyrus. The MHE patients also showed FC reduction between the right hippocampus and bilateral medial frontal cortex. A progressive reduction in hippocampal FC from NHE to MHE was also observed. The bilateral hippocampal FC strength (but not hippocampal volume) was positively correlated with the PHES results of the cirrhotic patients. Our assessment of MHE patients revealed decreased hippocampal volume, which suggests regional atrophy, and reduced hippocampal connectivity with regions that are primarily involved in the default-mode network, thereby suggesting a functional disconnection syndrome. These alterations reveal the mechanisms underlying cognitive deterioration with disease progression.

Among midlife and older women, menopause symptoms and menopausal hormone therapy have been linked to mental health disorders and other comorbidities related to suicide. However, the role of hormone therapy as a prognostic factor of suicide risk is largely unknown. To examine associations between menopausal hormone therapy, suicide attempts, and suicide among midlife and older women Veterans. In this longitudinal analysis of national Veterans Health Administration data from women Veterans aged 50 years and above, we used Fine-Gray proportional hazards models to examine associations between menopausal hormone therapy (prescribed in 2012-2013) and incident suicide attempts and suicide (index date-2016). Menopausal hormone therapy and psychoactive medications from pharmacy records; suicide attempts and suicide from national suicide data repositories; demographic variables, medical and psychiatric diagnoses, and substance use disorders from electronic medical record data and International Classification Diagnoses-9-CM codes. In this national sample of 291,709 women Veterans (mean age 60.47, SD 9.81), 6% were prescribed menopausal hormone therapy at baseline. Over an average of 4.5 years, 2673 had an incident suicide attempt (93%) or death by suicide (7%). Adjusting for age, race, and medical diagnoses, menopausal hormone therapy was associated with increased risk of suicide attempt (hazard ratio 1.41; 95% confidence interval, 1.22-1.64) and over 2-fold increased risk of death by suicide (hazard ratio 2.47; 95% confidence interval, 1.58-3.87). Associations with death by suicide remained significant after accounting for psychiatric comorbidity and psychoactive medications. Menopausal hormone therapy may be an important indicator of suicide risk among midlife and older women.

BackgroundAPOE4 genotype is a stronger risk factor for Alzheimer’s disease (AD) in women than men, and its influence on memory and AD biomarkers differs by disease stage. Among cognitively normal older APOE4 carriers, APOE4 status influences memory similarly in males and females but adversely influences hippocampal volume in males. The effect of APOE4 status on regional brain volumes earlier in life, and in relation to memory, are less well understood. We examined whether associations between verbal memory performance and regional brain volumes differed by APOE4 status in cognitively normal midlife women. We hypothesized that APOE4 carriers would show weaker associations between memory performance and brain volumes than non‐carriers, particularly in the temporal lobe.MethodParticipants were enrolled in MsBrain, a cohort study of midlife women. Verbal memory was assessed with the California Verbal Learning Test (CVLT‐II). Cortical thickness was measured and segmented by FreeSurfer using individual T1w MPRAGE images. Multiple regressions were conducted to determine associations between memory (learning, free recall) and regional brain volumes by APOE4 status (carriers versus non‐carriers), controlling for age, education, and race.ResultIn 148 cognitively normal postmenopausal women (mean age = 59.17 years, 84.4% white, n = 37 APOE4 carriers), APOE4 status had no main effect on CVLT‐II measures or brain volumes, except the volume of the left supramarginal gyrus. However, APOE4 status modified the magnitude of association between verbal memory and brain volumes, specifically the association between: a) verbal learning and volume in the left caudal middle frontal gyrus (CMFG), left isthmus cingulate gyrus, left parahippocampal gyrus, left insula, right precuneus, right lateral orbitofrontal gyrus (LOG), and right temporal pole (TP); and b) free recall and volume in the left CMFG, right LOG, right posterior cingulate gyrus, and right TP. The direction of the associations between verbal memory and brain volumes was positive in non‐carriers and negative in carriers.ConclusionIn cognitively normal midlife women, APOE4 carrier status may influence the extent to which the hippocampal, temporal, and frontal lobe structures support verbal memory performance. This subtle effect may emerge before the main effect of this genetic risk factor on brain volume and memory.

The last decade has seen an increase in neuroimaging studies examining structural (i.e., structural integrity of white matter tracts) and functional connectivity (e.g., correlations in neural activity throughout the brain). Although structural and functional connectivity changes have often been measured independently, examining the relation between these two measures is critical to understanding the specific function of neural networks and the ways they may differ across tasks and individuals. The current study addressed this question by examining the effect of age (treated as a continuous variable) and emotional valence on the relation between functional and structural connectivity. As prior studies have suggested that prefrontal regions may guide and regulate emotional memory search via functional connections with the amygdala, the current analysis focused on functional connectivity between the left amygdala and the left prefrontal cortex, and structural integrity of the uncinate fasciculus, a white matter tract connecting prefrontal and temporal regions. Participants took part in a scanned retrieval task in which they recalled positive, negative, and neutral images associated with neutral titles. Aging was associated with a significant increase in the relation between measures of structural integrity (specifically, fractional anisotropy, or FA) along the uncinate fasciculus and functional connectivity between the left ventral prefrontal cortex and amygdala during positive event retrieval, but not negative or neutral retrieval. Notably, during negative event retrieval, age was linked to stronger structure-function relations between the amygdala and the dorsal anterior cingulate cortex, such that increased structural integrity predicted stronger negative functional connectivity in older adults only. These findings suggest that young and older adults may utilize a structural pathway to engage different retrieval and regulatory strategies, even when structural integrity along that pathway does not differ.

Subregion-specific, modality-dependent and timescale-sensitive hippocampal connectivity alterations in patients with first-episode, drug-naïve major depression disorder

Background.Scar theory proposes that heightened depression and anxiety precede and predict worse cognitive functioning outcomes, whereas the vulnerability theory posits the opposite pathway. However, most investigations on this topic have been cross-sectional, precluding causal inferences. Thus, we used cross-lagged prospective network analyses to facilitate causal inferences in understanding the relations between psychopathology and cognitive functioning components.Methods.Racially-diverse midlife women (n = 1816) participated in the Study of Women’s Health Across the Nation at two time-points, spanning one year apart. Five psychopathology (anxiety severity, depressed mood, somatic symptoms, positive affect, interpersonal problems) and four cognitive functioning nodes (working memory (WM), processing speed (PS), facial recognition (FCR), and verbal memory (VRM)) were assessed. All analyses adjusted for age, menopausal status, estradiol, and follicle-stimulating hormones.Results.Contemporaneous networks yielded notable inverse between-node relations (edges) between interpersonal problems and reduced FCR and PS, and between depressed mood and lower FCR, VRM, or PS. Nodes that had the highest likelihood to bridge other constructs were positive affect, anxiety severity, WM, and VRM. Temporal networks produced edges consistent with the scar (v. vulnerability) hypotheses. Higher somatic symptoms were related to reduced PS and WM, and greater depressed mood was correlated with lower future PS and WM. Also, higher anxiety severity coincided with decreased future PS and WM. Greater positive affect was associated with stronger future PS, FCR, and WM. Also, positive affect had the strongest relations with other nodes.Conclusions.Findings suggest the importance of targeting symptoms and cognitive functioning simultaneously.