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Bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) prior to age 48 is associated with elevated risk for both Alzheimer's disease (AD) and sleep disorders such as insomnia and sleep apnea. In early midlife, individuals with BSO show reduced hippocampal volume, function, and hippocampal-dependent verbal episodic memory performance associated with changes in sleep. It is unknown whether BSO affects fine-grained sleep measurements (sleep microarchitecture) and how these changes might relate to hippocampal-dependent memory. We recruited thirty-six early midlife participants with BSO. Seventeen of these participants were taking 17β-estradiol therapy (BSO+ET) and 19 had never taken ET (BSO). Twenty age-matched control participants with intact ovaries (AMC) were also included. Overnight at-home polysomnography recordings were collected, along with subjective sleep quality and hot flash frequency. Multivariate Partial Least Squares (PLS) analysis was used to assess how sleep varied between groups. Compared to AMC, BSO without ET was associated with significantly decreased time spent in non-rapid eye movement (NREM) stage 2 sleep as well as increased NREM stage 2 and 3 beta power, NREM stage 2 delta power, and spindle power and maximum amplitude. Increased spindle maximum amplitude was negatively correlated with verbal episodic memory performance. Decreased sleep latency, increased sleep efficiency, and increased time spent in rapid eye movement sleep were observed for BSO+ET. Findings suggest there is an association between ovarian hormone loss and sleep microarchitecture, which may contribute to poorer cognitive outcomes and be ameliorated by ET., Competing Interests: Declaration of competing interest The authors have no financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Decline in spatial context memory emerges in midlife, the time when most females transition from pre- to post-menopause. Recent evidence suggests that, among post-menopausal females, advanced age is associated with functional brain alterations and lower spatial context memory. However, it is unknown whether similar effects are evident for white matter (WM) and, moreover, whether such effects contribute to sex differences at midlife. To address this, we conducted a study on 96 cognitively unimpaired middle-aged adults (30 males, 32 pre-menopausal females, 34 post-menopausal females). Spatial context memory was assessed using a face-location memory paradigm, while WM microstructure was assessed using diffusion tensor imaging. Behaviorally, advanced age was associated with lower spatial context memory in post-menopausal females but not pre-menopausal females or males. Additionally, advanced age was associated with microstructural variability in predominantly frontal WM (e.g., anterior corona radiata, genu of corpus callosum), which was related to lower spatial context memory among post-menopausal females. Our findings suggest that post-menopausal status enhances vulnerability to age effects on the brain's WM and episodic memory., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Menopause is associated with declines in cognitive control. However, there is individual variability in the slope of this decline. Recent work suggests that indices of cognitive control are mediated by communicative demands of the language environment. However, little is known about how the impact of bilingual experience generalizes across the lifespan, particularly in females who exhibit steeper cognitive decline due to increasing age and menopausal transition. Thus, we investigated whether diversity of language use in distinct communicative contexts modulated the effects of aging and menopause on cognitive control in an adult lifespan sample of healthy females. We performed robust linear regressions on a sample of 120 females (age range 20-65 years) to characterize age- ( n = 120) and menopause-related ( n = 59) declines in cognitive control (as assessed by the Wisconsin Card Sorting Test) and to determine whether they are modulated by different facets of bilingual language experience, including the diversity of language use (i.e., language entropy) in home and workplace environments. Workplace but not home language diversity modulated age- and menopause-related declines in cognitive control, suggesting that females may compensate for decline by virtue of adapting to the externally imposed demands of the language environment. These findings have implications for identifying which aspects of bilingual experience may contribute to cognitive reserve in healthy aging. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Age-related cognitive decline is accelerated by vascular risk factors for cerebral small vessel disease. However, the association of vascular risk factors with cerebral small vessel disease contributing to the sex differences in cognitive decline remains unclear., Objectives: The purpose of this study was to evaluate sex differences in cognitive decline and the association between vascular risk factors and cognitive decline by sex., Methods: We used data from the UK Biobank (>55 years of age; n = 19,067) to assess cognitive tests (executive function, processing speed, and memory) while adjusting for baseline measurements to examine how vascular risk factors affect cognition. A univariate regression analysis was used to assess sex differences at the first time point (2014). A repeated measure analysis with a mixed effect model was used to determine cognitive decline (between 2014 and 2019). Any significant interaction between vascular risk factors and sex was investigated., Results: Females had lower scores in all 3 domains at the first cognitive tests (2014). We found a significant sex-by-time interaction over a 5-year period in matrix pattern completion ( P  = 0.03). After adjusting for vascular risk factors, this interaction was reduced ( P  = 0.08). High low-density lipoprotein, low education, and high blood pressure had a greater effect on the rate of cognitive decline in the executive function for females compared to males for the sex∗vascular risk factor interaction ( P  < 0.05)., Conclusions: The rate of cognitive decline did not differ significantly between males and females. However, the impact of several vascular risk factors on cognitive decline was greater in females than in males., Competing Interests: This work was supported by 10.13039/100004411Heart and Stroke (Grant: G-22-0031987). Dr Fouad has received McGill Summer student bursary. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated-specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Sex differences exist in the likelihood of cognitive decline. The age at hypertension diagnosis is a unique contributor to brain structural changes associated with cerebral small vessel disease. However, whether this relationship differs between sexes remains unclear. Therefore, our objective was to evaluate sex differences in the association between the age at hypertension diagnosis and cerebral small vessel disease-related brain structural changes., Methods: We used data from the UK Biobank to select participants with a known age at hypertension diagnosis and brain magnetic resonance imaging (n=9430) and stratified them by sex and age at hypertension diagnosis. Control participants with magnetic resonance imaging scans but no hypertension were chosen at random matched by using propensity score matching. For morphological brain structural changes, generalized linear models were used while adjusting for other vascular risk factors. For the assessment of white matter microstructure, principal component analysis led to a reduction in the number of fractional anisotropy variables, followed by regression analysis with major principal components as outcomes., Results: Males but not females with a younger age at hypertension diagnosis exhibited lower brain gray and white matter volume compared with normotensive controls. The volume of white matter hyperintensities was greater in both males and females with hypertension than normotensive controls, significantly higher in older females with hypertension. Compared with normotensive controls, white matter microstructural integrity was lower in individuals with hypertension, which became more prominent with increasing age., Conclusions: Our study demonstrates that the effect of hypertension on cerebral small vessel disease-related brain structure differs by sex and by age at hypertension diagnosis., Competing Interests: Disclosures None.

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife-a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged premenopausal and postmenopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal females (age range, 39.55-53.30 years; mean age, 44.28 years; SD age, 3.12 years) and 41 postmenopausal females (age range, 46.70-65.14 years; mean age, 57.56 years; SD age, 3.93 years). We found that postmenopausal status, and advanced age within postmenopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal cortices during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife. SIGNIFICANCE STATEMENT This is the first fMRI study to examine how premenopause and postmenopause status affect the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age-related and performance-related correlations with brain activity in inferior parietal, parahippocampal, and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at premenopause compared with postmenopause., (Copyright © 2023 the authors.)

Women with early bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) have greater Alzheimer's disease (AD) risk than women in spontaneous/natural menopause (SM), but early biomarkers of this risk are not well-characterized. Considering associative memory deficits may presage preclinical AD, we wondered if one of the earliest changes might be in associative memory and whether younger women with BSO had changes similar to those observed in SM. Women with BSO (with and without 17β-estradiol replacement therapy (ERT)), their age-matched premenopausal controls (AMC), and older women in SM completed a functional magnetic resonance imaging face-name associative memory task shown to predict early AD. Brain activation during encoding was compared between groups: AMC (n=25), BSO no ERT (BSO; n=15), BSO+ERT (n=16), and SM without hormone therapy (n=16). Region-of-interest analyses revealed AMC did not contribute to functional group differences. BSO+ERT had higher hippocampal activation than BSO and SM. This hippocampal activation correlated positively with urinary metabolite levels of 17β-estradiol. Multivariate partial least squares analyses showed BSO+ERT had a different network-level activation pattern than BSO and SM. Thus, despite being approximately 10 years younger, women with BSO without ERT had similar brain function to those with SM, suggesting early 17β-estradiol loss may lead to an altered functional brain phenotype which could influence late-life AD risk, making face-name encoding a potential biomarker for midlife women with increased AD risk. Despite similarities in activation, BSO and SM groups showed opposite within-hippocampus connectivity, suggesting menopause type is an important consideration when assessing brain function., (© 2023. The Author(s).)

Introduction: Women with early ovarian removal (<48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored., Methods: We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed., Results: Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume., Discussion: Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Gervais, Gravelsins, Brown, Reuben, Perovic, Karkaby, Nicoll, Laird, Ramana, Bernardini, Jacobson, Velsher, Foulkes, Rajah, Olsen, Grady and Einstein.)

A classical early sign of typical Alzheimer's disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer's disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-β+ individuals with mild cognitive impairment and 29 amyloid-β+ Alzheimer's disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent [ 18 F]MK6240 tau and [ 18 F]AZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Episodic memory decline is an early symptom of Alzheimer's disease (AD) - a neurodegenerative disease that has a higher prevalence rate in older females compared to older males. However, little is known about why these sex differences in prevalence rate exist. In the current longitudinal task fMRI study, we explored whether there were sex differences in the patterns of memory decline and brain activity during object-location (spatial context) encoding and retrieval in a large sample of cognitively unimpaired older adults from the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD) program who are at heightened risk of developing AD due to having a family history (+FH) of the disease. The goal of the study was to gain insight into whether there are sex differences in the neural correlates of episodic memory decline, which may advance knowledge about sex-specific patterns in the natural progression to AD. Our results indicate that +FH females performed better than +FH males at both baseline and follow-up on neuropsychological and task fMRI measures of episodic memory. Moreover, multivariate data-driven task fMRI analysis identified generalized patterns of longitudinal decline in medial temporal lobe activity that was paralleled by longitudinal increases in lateral prefrontal cortex, caudate and midline cortical activity during successful episodic retrieval and novelty detection in +FH males, but not females. Post-hoc analyses indicated that higher education had a stronger effect on +FH females neuropsychological scores compared to +FH males. We conclude that higher educational attainment may have a greater neuroprotective effect in older +FH females compared to +FH males., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

The risk of developing Alzheimer's disease dementia is higher in females compared to males and is greater in individuals with subjective cognitive decline and mild cognitive impairment than in healthy controls. We used a multivariate behavioral partial least square correlation analysis to examine how relationships between memory-related activation and associative memory performance vary as a function of sex and clinical status. This was assessed in 182 participants from the Consortium for the Early Identification of Alzheimer's Disease-Quebec cohort, which were stratified according to sex (Male, Female) and clinical status (healthy controls, subjective cognitive decline, mild cognitive impairment). We found 6 significant latent variables mainly expressing: (1) overall sex differences; (2) between-sex differences according to clinical status; and (3) within-sex differences according to clinical status in relationships between whole-brain memory-related activation and memory performance. These patterns of activation mostly involved the default mode and fronto-parietal networks. Our results have implication in understanding the macro-scale functional processes possibly contributing to the higher risk of cognitive decline in females compared to males in the context of aging and early Alzheimer's disease., (Copyright © 2022. Published by Elsevier Inc.)

Recent work suggests that the relationship between age and memory-related brain activity are different for men and women. We sought to extend this work by examining sex differences in the association between age, memory performance, and brain signal variability during context memory tasks in neurotypical adults (aged 19-76 years; N = 128, 87 women). We measured blood oxygen level-dependent standard deviation (BOLD SD) during encoding and retrieval in easy and difficult spatial context memory tasks and investigated sex-specific, age- and performance-associated BOLD SD patterns. Behavioral analysis revealed age-related decreases in memory retrieval, but no sex differences nor an age-by-sex interaction. Imaging results indicated that both sexes showed a negative correlation between BOLD SD and retrieval accuracy in memory-related regions. We also identified significant sex differences: women exhibited age-associated increases in BOLD SD which were negatively associated with performance. Men exhibited both age-associated decreases and increases, which were not related to performance. Our results revealed sex differences in the relationship between age and BOLD SD during high-demand episodic memory tasks., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The present study explored whether early midlife bilateral salpingo-oophorectomy (BSO), a female-specific risk factor for dementia, is associated with reduced medial temporal lobe structure and function. Younger middle-aged women with the BRCA1/2 mutation and a BSO prior to spontaneous menopause (SM) were recruited. We determined the performance of women with BSO not taking estradiol-based hormone therapy (n = 18) on a task measuring object and scene recognition and quantified medial temporal lobe subregion volumes using manually segmented high-resolution T2-weighted MRI scans. Comparisons were made to those with BSO taking estradiol-based hormone therapy (n = 20), age-matched premenopausal controls (n = 28), and older women in SM not taking hormone therapy matched for duration of hormone deprivation (n = 17). Reduced hippocampal integrity specific to the BSO group not taking hormone therapy was observed, reflected by significantly smaller dentate gyrus/CA2/CA3 volumes and lower scene recognition memory performance. These findings show that hippocampal subfield volume may be useful for identifying early midlife changes in women at elevated risk for dementia., (Copyright © 2022. Published by Elsevier Inc.)

Aging is associated with episodic memory decline and changes in functional brain connectivity. Understanding whether and how biological sex influences age- and memory performance-related functional connectivity has important theoretical implications for the cognitive neuroscience of memory and aging. Here, we scanned 161 healthy adults between 19 and 76 years of age in an event-related fMRI study of face-location spatial context memory. Adults were scanned while performing easy and difficult versions of the task at both encoding and retrieval. We used multivariate whole-brain partial least squares connectivity to test the hypothesis that there are sex differences in age- and episodic memory performance-related functional connectivity. We examined how individual differences in age and retrieval accuracy correlated with task-related connectivity. We then repeated this analysis after disaggregating the data by self-reported sex. We found that increased encoding and retrieval-related connectivity within the dorsal attention network (DAN), and between DAN and frontoparietal network and visual networks, were positively correlated to retrieval accuracy and negatively correlated with age in both sexes. We also observed sex differences in age- and performance-related functional connectivity: (a) Greater between-networks integration was apparent at both levels of task difficulty in women only, and (b) increased DAN-default mode network connectivity with age was observed in men and was correlated with poorer memory performance. Therefore, the neural correlates of age-related episodic memory decline differ in women and men and have important theoretical and clinical implications for the cognitive neuroscience of memory, aging, and dementia prevention., (© 2022 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

Healthy aging is associated with episodic memory decline, particularly in the ability to encode and retrieve object-context associations (context memory). Neuropsychological and neuroimaging studies have highlighted the importance of the medial temporal lobes (MTL) in supporting episodic memory across the lifespan. However, given the functional heterogeneity of the MTL, volumetric declines in distinct regions may impact performance on specific episodic memory tasks, and affect the function of the large-scale neurocognitive networks supporting episodic memory encoding and retrieval. In the current study, we investigated how MTL structure may mediate age-related differences in performance on spatial and temporal context memory tasks, in a sample of 125 healthy adults aged 19-76 years old. Standard T1-weighted MRIs were segmented into the perirhinal, entorhinal and parahippocampal cortices, as well as the anterior and posterior hippocampal subregions. We observed negative linear and quadratic associations between age and volume of the parahippocampal cortex, and anterior and posterior hippocampal subregions. We also found that volume of the posterior hippocampus fully mediated the association between age and spatial, but not temporal context memory performance. Further, we employed a multivariate behavior partial-least-squares analysis to assess how age and regional MTL volumes correlated with brain activity during the encoding and retrieval of spatial context memories. We found that greater activity within lateral prefrontal, parietal, and occipital regions, as well as within the anterior MTL was related to older age and smaller volume of the posterior hippocampus. Our results highlight the heterogeneity of MTL contributions to episodic memory across the lifespan and provide support for the posterior-anterior shift in aging, and scaffolding theory of aging and cognition., (Copyright © 2022. Published by Elsevier Inc.)

Many magnetic resonance imaging (MRI) measures are being studied longitudinally to explore topics such as biomarker detection and clinical staging. A pertinent concern to longitudinal work is MRI scanner upgrades. When upgrades occur during the course of a longitudinal MRI neuroimaging investigation, there may be an impact on the compatibility of pre- and post-upgrade measures. Similarly, subject motion is another issue that may be detrimental to MRI work and embedding volumetric navigators (vNavs) within acquisition sequences has emerged as a technique that allows for prospective motion correction. Our research group recently underwent an upgrade from a Siemens MAGNETOM 3T Tim Trio system to a Siemens MAGNETOM 3T Prisma Fit system. The goals of the current work were to: 1) investigate the impact of this upgrade on commonly used structural imaging measures and proton magnetic resonance spectroscopy indices ("Prisma Upgrade protocol") and 2) examine structural imaging measures in a sequence with vNavs alongside a standard acquisition sequence ("vNav protocol"). While high reliability was observed for most of the investigated MRI outputs, suboptimal reliability was observed for certain indices. Across the scanner upgrade, increases in frontal, temporal, and cingulate cortical thickness (CT) and thalamus volume, along with decreases in parietal CT and amygdala, globus pallidus, hippocampus, and striatum volumes, were observed. No significant impact of the upgrade was found in 1 H-MRS analyses. Further, CT estimates were found to be larger in MPRAGE acquisitions compared to vNav-MPRAGE acquisitions mainly within temporal areas, while the opposite was found mostly in parietal brain regions. The results from this work should be considered in longitudinal study designs and comparable prospective motion correction investigations are warranted in cases of marked head movement., Competing Interests: Declaration of Competing Interest Authors report no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Late-onset Alzheimer's disease (AD) disproportionately affects women compared to men. Episodic memory decline is one of the earliest and most pronounced deficits observed in AD. However, it remains unclear whether sex influences episodic memory-related brain function in cognitively intact older adults at risk of developing AD. Here we used task-based multivariate partial least squares analysis to examine sex differences in episodic memory-related brain activity and brain activity-behavior correlations in a matched sample of cognitively intact older women and men with a family history of AD from the PREVENT-AD cohort study in Montreal, Canada (M age =63.03±3.78; M education =15.41±3.40). We observed sex differences in task-related brain activity and brain activity-behavior correlations during the encoding of object-location associative memories and object-only item memory, and the retrieval of object only item memories. Our findings suggest a generalization of episodic memory-related brain activation and performance in women compared to men. Follow up analyses should test for sex differences in the relationship between brain activity patterns and performance longitudinally, in association with risk factors for AD development. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

The apolipoprotein E gene ( APOE ) is the most important genetic risk factor for sporadic Alzheimer disease, with the ε4 allele being associated with increased cerebral amyloid-β and tau pathologies. Although APOE has been suggested to have a stronger effect in women as compared to men, there is a lack of comprehensive assessment on how the interactive effect of APOE and sex modulates regional vulnerability to tau accumulation. We previously have shown the regional vulnerability to the interactive effect of tau and APOE , yet the sex difference was not specifically addressed. In this study, we leveraged PET imaging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University Research Centre for Studies in Aging to elucidate the APOE- by-sex interactive effect on tau burden. We hypothesized sex-dependent regional vulnerability to tau deposition. PET radiopharmaceuticals [ 18 F]AZD4694 and [ 18 F]MK6240 were used to assess amyloid-β and tau level respectively in 277 subjects from the Translational Biomarkers in Aging and Dementia cohort. We found that the interaction between APOE and sex, rather than their independent main effects, was associated with abnormal tau accumulation in medial temporal regions. Specifically, we found that female APOEε4 carriers showed significantly higher tau burden in early tau deposition regions including the hippocampus, entorhinal and parahippocampal cortices, after accounting for age, educational attainment, clinical diagnosis and neocortical amyloid load. We replicated these findings in 221 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort, in which a different tau-PET radioligand, [ 18 F]flortaucipir, was used to assess tau burden. In conclusion, this study provides evidence from two cohort studies that interactive rather than independent effect of APOE and sex potentiates early tau deposition in women. Our results have important implications for clinical trials and practice, which should take into consideration both APOEε4 carriage status and sex for identifying individuals with the highest probability of developing tau accumulation and clinical progression., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The goal of this study was to assess how task-related hyperactivation relates to brain network dysfunction and memory performance in individuals at risk of Alzheimer's disease (AD). Eighty participants from the CIMA-Q cohort were included, of which 28 had subjective cognitive decline plus (SCD + ), as they had memory complaints and worries in addition to a smaller hippocampal volume and/or an APOE4 allele, 26 had amnestic mild cognitive impairment (MCI) and 26 were healthy controls without memory complaints. Functional magnetic resonance imaging (fMRI) activation was measured during an object-location memory task. Seed-partial least square analyses (seed-PLS) were conducted in controls and in the SCD + /MCI groups to yield sets of orthogonal latent variables (LVs) assessing the triple association between: i) seed activity in brain regions found to be hyperactive in individuals at risk of AD (left hippocampus, left superior parietal lobule, right inferior temporal lobe), ii) latent patterns of whole-brain task-related activation, and iii) associative memory performance. Three LVs in the SCD + and MCI groups (67.88% of total covariance explained) and two LVs in the controls (77.85% of total covariance explained) were significant. While controls and SCD + /MCI groups shared a common pattern of memory-related connectivity, patterns of hyperactivation-networks interactions were unique to the clinical groups. Interestingly, higher hippocampal connectivity was associated with poorer memory performance whereas higher neocortical connectivity predicted better memory performance in SCD + and MCI groups. Our data provides empirical evidence that early dysfunction in brain activation and connectivity is present in the very early stages of AD and offers new insights on the relationship between functional brain alterations and memory performance., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Emerging evidence suggests that Alzheimer's Disease (AD) risk factors may differentially contribute to disease trajectory in women than men. Determining the effect of AD risk factors on brain aging in women, compared to men, is critical for understanding whether there are sex differences in the pathways towards AD in cognitively intact but at-risk adults. Brain Age Gap (BAG) is a concept used increasingly as a measure of brain health; BAG is defined as the difference between predicted age (based on structural MRI) and chronological age, with negative values reflecting preserved brain health with age. Using BAG, we investigated whether there were sex differences in the brain effects of AD risk factors (i.e., family history of AD, and carrying an apolipoprotein E ε4 allele [+APOE4]) in cognitively intact adults, and if this relationship was moderated by modifiable factors (i.e. body mass index [BMI], blood pressure and physical activity). We undertook a cross-sectional study of structural MRIs from 1067 cognitively normal adults across four neuroimaging datasets. An elastic net regression model found that women with a family history of AD and +APOE4 genotype had more advanced brain aging than their male counterparts. In a sub-cohort of women with those risk factors, higher BMI was associated with less brain aging whereas lower BMI was not. In a sub-cohort of women and men with +APOE4, engaging in physical activity was more beneficial to men's brain aging than women's. Our results demonstrate that AD risk factors are associated with greater brain aging in women than men, although there may be more unexplored modifiable factors that influence this relationship. These findings suggest that the complex interplay between unmodifiable and modifiable AD risk factors can potentially protect against brain aging in women and men., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

A functional gradient has been proposed across the medial temporal lobes (MTL) such that the anterior MTL is thought to support processing of individual items (e.g., item memory and complex object perception), whereas the posterior MTL is thought to support item-context retrieval (e.g., source memory). Whereas functional imaging studies have provided evidence supporting this anatomical organization, results from structural analyses remain inconclusive. The current study examined the relationship between volume of MTL regions of interest (ROIs), and performance on a source memory task and a fine-grain complex object perception task, in healthy young adults (mean age = 21.5, range = 18-29). Using a semiautomated procedure, we segmented the parahippocampal and perirhinal cortices (PHC, PRC), posteromedial and anterolateral entorhinal cortices (pmERC, alERC), and posterior and anterior hippocampus (postHC, antHC) on high-resolution T2-weighted MRIs. Regional volumes were computed as proportions of intracranial volume, and as posterior-anterior volumetric ratios (PHC:PRC, pmERC:alERC, postHC:antHC). Partial-least squares regressions were applied to predict source and item memory, and perceptual discrimination accuracy, based on ROI and ratio volumes. In our ROI regressions, we found that postHC volume was positively correlated with a latent factor predicting source memory, and PRC and antHC volumes were negatively correlated to this latent factor. In our ratio regressions, we observed an effect relating the posterior-anterior distribution of gray matter across the MTL with source memory. Our results demonstrate differential associations between anterior and posterior MTL and source memory performance. Findings from this study highlight the importance of considering patterns of structure-behavior associations in the neurobiology of episodic memory., (© 2020 Wiley Periodicals LLC.)

Remembering associations between encoded items and their contextual setting is a feature of episodic memory. Although this ability generally deteriorates with age, there is substantial variability in how older individuals perform on episodic memory tasks. A current topic of debate in the cognitive neuroscience of aging literature revolves around whether this variability may stem from genetic and/or environmental factors related to reserve, allowing some individuals to compensate for age-related decline through differential recruitment of brain regions. In this fMRI study spanning a large adult lifespan sample (N = 154), we tested whether higher cognitive reserve was associated with better task-fMRI context memory performance, and functional compensatory activity patterns in the aging brain. We used multivariate Behaviour Partial Least Squares (B-PLS) analysis to examine how age, retrieval accuracy, and a proxy measure of cognitive reserve [i.e., a composite score consisting of years of education (EDU) and crystallized IQ], impacted brain activity during the encoding and retrieval of spatial and temporal contextual details. The results indicated that age-related increases in encoding activity within anterior and lateral frontal, inferior parietal, occipito-temporal and medial temporal cortices, was correlated with better subsequent memory performance; and may be indicative of age-related functional compensation at encoding. Interestingly this compensatory pattern was not correlated with our proxy measure of cognitive reserve but was associated with total brain volume (a measure of brain reserve). However, cognitive reserve was associated with age-invariant and task-general activity in superior temporal, occipital, and left inferior frontal regions. We conclude that the relationship between cognitive reserve, brain reserve and age-related functional compensation is complex, and that EDU and IQ may not fully account for individual differences in cognitive reserve when studying well educated, healthy aging cohorts., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Previous studies have only investigated age-related differences in emotional processing and encoding in response to, not in anticipation of, emotional stimuli. In the current study, we investigated age-related differences in the impact of emotional anticipation on affective responses and episodic memory for emotional images. Young and older adults were scanned while encoding negative and neutral images preceded by cues that were either valid or invalid predictors of image valence. Participants were asked to rate the emotional intensity of the images and to complete a recognition task. Using multivariate behavioral partial least squares (PLS) analysis, we found that greater anticipatory recruitment of the amygdala, ventromedial prefrontal cortex (vmPFC), and hippocampus in older adults predicted reduced memory for negative than neutral images and the opposite for young adults. Seed PLS analysis further showed that following negative cues older adults, but not young adults, exhibited greater activation of vmPFC, reduced activation of amygdala, and worse memory for negative compared with neutral images. To the best of our knowledge, this is the first study to provide evidence that the "positivity effect" seen in older adults' memory performance may be related to the spontaneous emotional suppression of negative affect in anticipation of, not just in response to, negative stimuli., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer's disease (AD). Older adults with the apolipoprotein E ɛ4 (+APOE4) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset., Objective: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent's conversion to AD., Methods: Volunteers were scanned as they encoded and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares (PLS) to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (-APOE4). We also examined group differences in the correlation between event-related brain activity and memory performance., Results: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding., Conclusion: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD.

Aging is associated with episodic memory decline and alterations in memory-related brain function. However, it remains unclear if age-related memory decline is associated with similar patterns of brain aging in women and men. In the current task fMRI study, we tested the hypothesis that there are sex differences in the effect of age and memory performance on brain activity during episodic encoding and retrieval of face-location associations (spatial context memory). Forty-one women and 41 men between the ages of 21 and 76 years participated in this study. Between-group multivariate partial least squares analysis of the fMRI data was conducted to directly test for sex differences and similarities in age-related and performance-related patterns of brain activity. Our behavioral analysis indicated no significant sex differences in retrieval accuracy on the fMRI tasks. In relation to performance effects, we observed similarities and differences in how retrieval accuracy related to brain activity in women and men. Both sexes activated dorsal and lateral PFC, inferior parietal cortex, and left parahippocampal gyrus at encoding, and this supported subsequent memory performance. However, there were sex differences in retrieval activity in these same regions and in lateral occipital-temporal and ventrolateral PFC. In relation to age effects, we observed sex differences in the effect of age on memory-related activity within PFC, inferior parietal cortex, parahippocampal gyrus, and lateral occipital-temporal cortices. Overall, our findings suggest that the neural correlates of age-related spatial context memory decline differ in women compared with men.

Major hardware/software changes to MRI platforms, either planned or unplanned, will almost invariably occur in longitudinal studies. Our objective was to assess the resulting variability on relevant imaging measurements in such context, specifically for three Siemens Healthcare Magnetom Trio upgrades to the Prisma fit platform. We report data acquired on three healthy volunteers scanned before and after three different platform upgrades. We assessed differences in image signal [contrast-to-noise ratio (CNR)] on T1-weighted images (T1w) and fluid-attenuated inversion recovery images (FLAIR); brain morphometry on T1w image; and small vessel disease (white matter hyperintensities; WMH) on FLAIR image. Prisma fit upgrade resulted in higher (30%) and more variable neocortical CNR and larger brain volume and thickness mainly in frontal areas. A significant relationship was observed between neocortical CNR and neocortical volume. For FLAIR images, no significant CNR difference was observed, but WMH volumes were significantly smaller (-68%) after Prisma fit upgrade, when compared to results on the Magnetom Trio. Together, these results indicate that Prisma fit upgrade significantly influenced image signal, brain morphometry measures and small vessel diseases measures and that these effects need to be taken into account when analyzing results from any longitudinal study undergoing similar changes.

Previous research on age-related associative memory deficits has generally focused on memory for single associations. However, our real-world experiences contain a multitude of details that must be effectively integrated and encoded into coherent representations to facilitate subsequent retrieval of the event as a whole. How aging interferes with the processes necessary for multielement encoding is still unknown. We investigated this issue in the current fMRI study. While undergoing scanning, young and older adults were presented with an occupation and an object and were asked to judge how likely the two were to interact, either in general or within the context of a given scene. After scanning, participants completed recognition tasks for the occupation-object pairs and the sources/contexts with which the pairs were studied. Using multivariate behavioral partial least squares analyses, we identified a set of regions including anterior pFC and medial-temporal lobes whose activity was beneficial to subsequent memory for the pairs and sources in young adults but detrimental in older adults. An additional behavioral partial least squares analysis found that, although both groups recruited anterior pFC areas to support context memory performance, only in the young did this activity appear to reflect integration of the occupation, object, and scene features. This was also consistent with behavioral results, which found that young adults showed greater conditional dependence between pair and context memory compared with older adults. Together, these findings suggest that binding and/or retrieving multiple details as an integrated whole becomes increasingly difficult with age.

Altered functional connectivity between dorsolateral prefrontal cortex (DLPFC), posterior hippocampus (HC) and other brain regions with advanced age may contribute to age-related differences in episodic memory. In the current fMRI study of spatial context memory, we used seed connectivity analysis to test for age-related differences in the correlations between activity in DLPFC and HC seeds, and the rest of the brain, in an adult life span sample. In young adults, we found that connectivity between right DLPFC and other prefrontal cortex regions, parietal cortex, precuneus, and ventral visual cortices during encoding was positively related to performance. Positive seed connectivity among these regions, and negative connectivity with posterior HC at retrieval was also positively correlated with retrieval accuracy in young adults. In older adults, activity in right DLPFC was positively correlated with activity in this same set of brain regions, and with posterior HC during encoding and retrieval. Interestingly, this pattern of seed connectivity in older adults was negatively correlated with retrieval accuracy. Thus, age-related differences in context memory may be related to altered frontal-parietal and visual cortical interactions with posterior HC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

In Figure 3b of the originally published article, the colours of the bars were incorrectly reversed. The bars shown in green should have been shown in blue to represent the findings from older adults, whereas the bars shown in blue should have been shown in green to represent the findings from young adults. This has been corrected in the HTML and PDF versions of the article. Images of the original figure are shown in the correction notice.

Cognitive ageing research examines the cognitive abilities that are preserved and/or those that decline with advanced age. There is great individual variability in cognitive ageing trajectories. Some older adults show little decline in cognitive ability compared with young adults and are thus termed 'optimally ageing'. By contrast, others exhibit substantial cognitive decline and may develop dementia. Human neuroimaging research has led to a number of important advances in our understanding of the neural mechanisms underlying these two outcomes. However, interpreting the age-related changes and differences in brain structure, activation and functional connectivity that this research reveals is an ongoing challenge. Ambiguous terminology is a major source of difficulty in this venture. Three terms in particular - compensation, maintenance and reserve - have been used in a number of different ways, and researchers continue to disagree about the kinds of evidence or patterns of results that are required to interpret findings related to these concepts. As such inconsistencies can impede progress in both theoretical and empirical research, here, we aim to clarify and propose consensual definitions of these terms.

Purpose: In vivo carbon-13 ( 13 C) MR spectroscopy (MRS) is capable of measuring energy metabolism and neuroenergetics, noninvasively in the brain. Indirect ( 1 H-[ 13 C]) MRS provides sensitivity benefits compared with direct 13 C methods, and normally includes a 1 H surface coil for both localization and signal reception. The aim was to develop a coil platform with homogenous B1+ and use short conventional pulses for short echo time proton observed carbon edited (POCE) MRS., Methods: A 1 H-[ 13 C] MRS coil platform was designed with a volumetric resonator for 1 H transmit, and surface coils for 1 H reception and 13 C transmission. The Rx-only 1 H surface coil nullifies the requirement for a T/R switch before the 1 H preamplifier; the highpass filter and preamplifier can be placed proximal to the coil, thus minimizing sensitivity losses inherent with POCE-MRS systems described in the literature. The coil platform was evaluated with a PRESS-POCE sequence (TE = 12.6 ms) on a rat model., Results: The coil provided excellent localization, uniform spin nutation, and sensitivity. 13 C labeling of Glu-H4 and Glx-H3 peaks, and the Glx-H2 peaks were observed approximately 13 and 21 min following the infusion of 1- 13 C glucose, respectively., Conclusion: A convenient and sensitive platform to study energy metabolism and neurotransmitter cycling is presented. Magn Reson Med 79:628-635, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Background: Preclinical neuroimaging allows for the assessment of brain anatomy, connectivity and function in laboratory animals, such as mice and rats. Most of these studies are performed under anesthesia to avoid movement during the scanning sessions., Method: Due to the limitations associated with anesthetized imaging, recent efforts have been made to conduct rodent imaging studies in awake animals, habituated to the restraint systems used in these instances. As of now, only one such system is commercially available for mouse scanning (Animal Imaging Research, Boston, MA, USA) integrating the radiofrequency coil electronics with the restraining element, an approach which, although effective in reducing head motion during awake imaging, has some limitations. In the current report, we present a novel mouse restraining system that addresses some of these limitations., Results/comparison to Other Methods: The effectiveness of the restraining system was evaluated in terms of three-dimensional linear head movement across two consecutive functional MRI scans (total 20min) in 33 awake mice. Head movement was minimal, recorded in roughly 12% of the time-series. Respiration rate during the acclimation procedure dropped while the bolus count remained unchanged. Body movement during functional acquisitions did not have a significant effect on magnetic field (B 0 ) homogeneity., Conclusion/novelty: Compared to the commercially available system, the benefit of the current design is two-fold: 1) it is compatible with a range of commercially-available coils, and 2) it allows for the pairing of neuroimaging with other established techniques involving intracranial cannulation (i.e. microinfusion and optogenetics)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We describe the fabrication and performance of a chronic in situ coil system designed to allow focal brain stimulation in rats while acquiring functional MRI data., New Method: An implantable receive-only surface radiofrequency coil (iCoil) was designed to be fitted subcutaneously, directly onto to the rat skull surface during the intracerebral cannulation procedure. The coil is fixed in place using acrylic dental cement anchored to four screws threaded into the skull. To demonstrate the use of this coil system in situ, whole-brain functional MRI scans were acquired during various stimuli, including intracranial microinfusions of bicuculline and morphine in the prefrontal cortex and ventral tegmental area, respectively., Results/comparison to Other Methods: SNR performance of the iCoil was superior to three commercially-available coils, in some instances by a factor of two. Widespread BOLD activation was observed in response to bicuculline and morphine microinfusions., Conclusion: A new approach was demonstrated for high-SNR MR imaging of the brain in rats with intracranial implants using an implantable surface coil. This approach enables mapping the functional response to highly targeted stimuli such as intracranial microinfusions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Studies investigating age-related functional differences associated with source memory have recently focused on the importance of clarifying the relationship between effects of age and performance on memory-related brain activations. One methodological challenge has been in discriminating between effects of age on memory-related brain activations that are independent from age-related differences in performance. In the current study, event-related functional magnetic resonance imaging (fMRI) was used to identify brain activity during spatial and temporal source encoding and retrieval across the adult lifespan. We used multivariate behavior partial least squares (B-PLS) to identify patterns of brain activity during source encoding and source retrieval that were associated with age and/or retrieval accuracy. The PLS analysis identified three significant effects. The first effect indicated that encoding and retrieval activity in fusiform, middle occipital-temporal and inferior parietal cortices increased with age and decreased with performance. The second effect showed that dorsolateral prefrontal cortex and limbic activity increased with age at encoding, and increased with performance at retrieval. The third effect indicated that activity in right ventrolateral prefrontal and bilateral hippocampus increased with age during retrieval and was differentially related to performance during encoding versus retrieval. We conclude that although some age-related differences in brain activity observed during source encoding and retrieval are associated with individual differences in performance, age-related differences in prefrontal and hippocampal areas exhibit more complex patterns of interactions between age, performance, and phase-related activity., (Copyright © 2017. Published by Elsevier Ltd.)

Distinctive encoding is greatly influenced by gist-based processes and has been shown to suffer when highly similar items are presented in close succession. Thus, elucidating the mechanisms underlying how presentation format affects gist processing is essential in determining the factors that influence these encoding processes. The current study utilised multivariate partial least squares (PLS) analysis to identify encoding networks directly associated with retrieval performance in a blocked and intermixed presentation condition. Subsequent memory analysis for successfully encoded items indicated no significant differences between reaction time and retrieval performance and presentation format. Despite no significant behavioural differences, behaviour PLS revealed differences in brain-behaviour correlations and mean condition activity in brain regions associated with gist-based vs. distinctive encoding. Specifically, the intermixed format encouraged more distinctive encoding, showing increased activation of regions associated with strategy use and visual processing (e.g., frontal and visual cortices, respectively). Alternatively, the blocked format exhibited increased gist-based processes, accompanied by increased activity in the right inferior frontal gyrus. Together, results suggest that the sequence that information is presented during encoding affects the degree to which distinctive encoding is engaged. These findings extend our understanding of the Fuzzy Trace Theory and the role of presentation format on encoding processes.

Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimer's disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40-58 yrs) with a family history of late onset AD (MA + FH ), or a combined + FH and apolipoprotein E ε4 allele risk factors for AD (MA + FH + APOE4 ), will exhibit differences in encoding and retrieval-related brain activity, compared to - FH - APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving the hippocampus, inferior parietal cortex, cingulate, and precuneus cortex in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior-medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MA controls . Our results indicate that functional differences in episodic memory-related regions are present by early midlife in adults with + FH and + APOE-4 risk factors for late onset AD, compared to middle-aged controls.

Age-related deficits in context memory may arise from neural changes underlying both encoding and retrieval of context information. Although age-related functional changes in the brain regions supporting context memory begin at midlife, little is known about the functional changes with age that support context memory encoding and retrieval across the adult lifespan. We investigated how age-related functional changes support context memory across the adult lifespan by assessing linear changes with age during successful context encoding and retrieval. Using functional magnetic resonance imaging (fMRI), we compared young, middle-aged and older adults during both encoding and retrieval of spatial and temporal details of faces. Multivariate behavioral partial least squares (B-PLS) analysis of fMRI data identified a pattern of whole-brain activity that correlated with a linear age term and a pattern of whole-brain activity that was associated with an age-by-memory phase (encoding vs. retrieval) interaction. Further investigation of this latter effect identified three main findings: 1) reduced phase-related modulation in bilateral fusiform gyrus, left superior/anterior frontal gyrus and right inferior frontal gyrus that started at midlife and continued to older age, 2) reduced phase-related modulation in bilateral inferior parietal lobule that occurred only in older age, and 3) changes in phase-related modulation in older but not younger adults in left middle frontal gyrus and bilateral parahippocampal gyrus that was indicative of age-related over-recruitment. We conclude that age-related reductions in context memory arise in midlife and are related to changes in perceptual recollection and changes in fronto-parietal retrieval monitoring., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

The ability to encode and retrieve spatial and temporal contextual details of episodic memories (context memory) begins to decline at midlife. In the current study, event-related fMRI was used to investigate the neural correlates of context memory decline in healthy middle aged adults (MA) compared with young adults (YA). Participants were scanned while performing easy and hard versions of spatial and temporal context memory tasks. Scans were obtained at encoding and retrieval. Significant reductions in context memory retrieval accuracy were observed in MA, compared with YA. The fMRI results revealed that overall, both groups exhibited similar patterns of brain activity in parahippocampal cortex, ventral occipito-temporal regions and prefrontal cortex (PFC) during encoding. In contrast, at retrieval, there were group differences in ventral occipito-temporal and PFC activity, due to these regions being more activated in MA, compared with YA. Furthermore, only in YA, increased encoding activity in ventrolateral PFC, and increased retrieval activity in occipital cortex, predicted increased retrieval accuracy. In MA, increased retrieval activity in anterior PFC predicted increased retrieval accuracy. These results suggest that there are changes in PFC contributions to context memory at midlife., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Recent evidence indicates that young adults frequently exhibit task-unrelated thoughts (TUTs) such as mind-wandering during episodic encoding tasks and that TUTs negatively impact subsequent memory. In the current study, we assessed age-related differences in the frequency and neural correlates of TUTs during a source memory encoding task, as well as age-related differences in the relationship between the neural correlates of TUTs and subsequent source forgetting effects (i.e., source misses). We found no age-related differences in frequency of TUTs during fMRI scanning. Moreover, TUT frequency at encoding was positively correlated with source misses at retrieval across age groups. In both age groups, brain regions including bilateral middle/superior frontal gyri and precuneus were activated to a greater extent during encoding for subsequent source misses versus source hits and during TUTs versus on-task episodes. Overall, our results reveal that, during a source memory encoding task in an fMRI environment, young and older adults exhibit a similar frequency of TUTs and that experiencing TUTs at encoding is associated with decreased retrieval performance. In addition, in both age groups, experiencing TUTs at encoding is associated with increased activation in some of the same regions that exhibit subsequent source forgetting effects.

Healthy aging is associated with declines in episodic memory. This reduction is thought to be due in part to age-related differences in encoding-related processes. In the current study, we performed an activation likelihood estimation meta-analysis of functional magnetic resonance imaging (fMRI) studies assessing age-related differences in the neural correlates of episodic encoding. Only studies using the subsequent memory paradigm were included. We found age-related under-recruitment of occipital and fusiform cortex, but over-recruitment in a set of regions including bilateral middle/superior frontal gyri, anterior medial frontal gyrus, precuneus and left inferior parietal lobe. We demonstrate that all of the regions consistently over-recruited by older adults during successful encoding exhibit either direct overlap, or occur in close vicinity to regions consistently involved in unsuccessful encoding in young adults. We discuss the possibility that this overall pattern of age-related differences represents an age-related shift in focus: away from perceptual details, and toward evaluative and personal thoughts and feelings during memory tasks. We discuss whether these age-related differences in brain activation benefit performance in older adults, and additional considerations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We investigated the role of distinct regions of the default-mode network (DMN) during memory encoding with fMRI. Subjects encoded words using either a strategy that emphasized self-referential (pleasantness) processing, or one that emphasized semantic (man-made/natural) processing. During encoding subjects were intermittently presented with thought probes to evaluate if they were concentrated and on-task or exhibiting task-unrelated thoughts (TUT). After the scanning session subjects performed a source retrieval task to determine which of two judgments they performed for each word at encoding. Source retrieval accuracy was higher for words encoded with the pleasantness vs. the man-made/natural task and there was a trend for higher performance for words preceding on-task vs. TUT reports. fMRI results show that left anterior medial PFC and left angular gyrus activity was greater during successful vs. unsuccessful encoding during both encoding tasks. Greater activity in left anterior cingulate and bilateral lateral temporal cortex was related successful vs. unsuccessful encoding only in the pleasantness task. In contrast, posterior cingulate, right anterior cingulate and right temporoparietal junction were activated to a greater extent in unsuccessful vs. successful encoding across tasks. Finally, activation in posterior cingulate and bilateral dorsolateral prefrontal cortex was related to TUT across tasks; moreover, we observed a conjunction in posterior cingulate between encoding failure and TUT. We conclude that DMN regions play dissociable roles during memory formation, and that their association with subsequent memory may depend on the manner in which information is encoded and retrieved., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Functional neuroimaging studies have consistently reported age-related changes in prefrontal cortex (PFC) activity during a variety of cognitive tasks, including episodic memory. These changes are often interpreted within the context of one of the following three neural models of age-related changes in brain function: dedifferentiation, neural inefficiency, and neural plasticity and compensation models. Distinguishing between these competing models has proven difficult when interpreting results using functional imaging data alone. In this paper we suggest that a more accurate interpretation of age-related changes in PFC activity requires consideration of age-related differences in gray matter volume (GMv) in PFC and the medial temporal lobes (MTL). We review fMRI studies of cognitive aging that have directly examined the relationship between PFC activity and both local (PFC) and distal (MTL) GMv in older versus younger adults. We also considered how structure-function relationships may be further modified in pathological aging (i.e. mild cognitive impairment (MCI) and Alzheimer's disease (AD)). We found that when task performance was matched between age-groups there was a negative association between regional PFC volume and activity in older adults. However, when older adults performed worse than young adults we observed a positive association between volume and activity in right lateral PFC. Additionally during memory tasks, several studies revealed that PFC activity is positively related to GM volume in MTL in healthy older adults, but negatively related in MCI and AD patients. We conclude that PFC activity is related to age-related changes in local and distal GM volume reductions and that consideration of these structural measures aids the interpretation of fMRI results. Furthermore, the study of structure-function relationships may provide important insights into the biological mechanisms underlying healthy versus pathological aging., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

During the performance of cognitive tasks such as memory encoding, attention can become decoupled from the external environment and instead focused on internal thoughts related to the appraisal of the current task (task-related interferences; TRI), or personal thoughts unrelated to the task at hand (mind-wandering; MW). However, the association between the frequency of these thoughts experienced at encoding and retrieval accuracy in young and older adults remains poorly understood. In this study young and older adults encoded lists of words using one of two encoding tasks: judging whether words are man-made/natural (objective task), or whether they are pleasant/neutral (subjective task). We measured the frequency of TRI and MW at encoding, and related them to retrieval accuracy in both age groups. We found that encoding task influenced the type of internal thoughts experienced by young, but not older, adults: young exhibited greater MW in the subjective vs the objective task, and greater TRI in the objective vs subjective encoding task. Second, across both tasks we found marked age-related decreases in both MW and TRI at encoding, and frequency of these thoughts negatively impacted memory retrieval in young adults only. We discuss these findings in relation to current theories of ageing, attention and memory.

Age-related deficits in episodic retrieval have been associated with volume reductions in the middle frontal gyrus (MFG). However, it remains unclear how this age-related reduction in MFG volume correlates with neural activity during retrieval. To address this, we conducted in vivo volumetry of the frontal cortex in young and older human adults and found more volume loss on the right than on the left MFG with age. We then examined how left and right MFG volume correlated with fMRI activity during successful retrieval of item, spatial context, and temporal context information in both age groups. In young adults, larger right MFG volume was positively correlated with greater activity in a commonly found episodic retrieval network that included bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal cortex. Within this network, left DLPFC and right inferior parietal cortex activity predicted memory performance. In older adults, a positive structure-function association in DLPFC for either left or right MFG/DLPFC was not observed. Instead, right MFG volume was negatively correlated with activity in several regions in older adults, including the parahippocampal cortex (PHC) and anterior cingulate. Less activity in the PHC region predicted better item memory, and less activity in the anterior cingulate predicted better spatial context accuracy in older adults. We conclude that age-related change in the structure-function association in MFG/DLPFC impacts retrieval activity and performance, and those older adults with larger right MFG volume attempt to compensate for this change by modifying activity in other brain regions to help retrieval performance.

Age-related declines in memory for context have been linked to volume loss in the hippocampal head (HH) with age. However, it remains unclear how this volumetric decline correlates with age-related changes in whole-brain activity during context encoding, and subsequent context retrieval. In the current study we examine this. We collected functional magnetic resonance imaging data in young and older adults during the encoding of item, spatial context and temporal context. HH volume and subsequent retrieval performance was measured in all participants. In young adults only there was a positive three-way correlation between larger HH volumes, better memory retrieval, and increased activity in right hippocampus, right ventrolateral prefrontal cortex (VLPFC) and midline brain regions during episodic encoding. In contrast, older adults exhibited a positive three-way association between HH volume, generalized activity in bilateral hippocampus and dorsolateral PFC across all encoding tasks, and subsequent spatial context retrieval. Young adults also engaged this network, but only during the most difficult temporal context encoding task and activity in this network correlated with subsequent temporal context retrieval. We conclude that age-related volumetric reductions in HH disrupted the structure-function association between the hippocampus and activity in the first general encoding network recruited by young adults. Instead, older adults recruited those brain regions young adults only engaged for the most difficult temporal task, at lower difficulty levels. This altered pattern of association correlated with spatial context retrieval in older adults, but was not sufficient to maintain context memory abilities overall., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Event-related functional magnetic resonance imaging was used to assess healthy adults while they performed spatial and temporal context memory tasks matched in task structure. After equating task structure between spatial versus temporal context tasks, subjects reported using similar strategies across tasks and we observed no significant differences in accuracy and reaction time performance between tasks. We used three methods of statistical analysis to interrogate similarities and differences in whole-brain activity across retrieval tasks, while focussing on prefrontal cortex (PFC) activations: multivariate partial least squares analysis (PLS), univariate statistical parametric mapping (SPM) and conjunction analysis. The PLS and conjunction analyses indicated that the overall pattern of PFC activity was similar across both temporal and spatial context retrieval tasks; but the SPM results indicated that some of these PFC regions exhibited differences in the degree to which they were engaged between tasks. However, none of these methods identified unique PFC activations specific to mediating spatial and/or temporal context retrieval. These results indicate that, overall, similar patterns of PFC activity were observed during temporal and spatial context memory retrieval once task structure and performance were equated., (Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.)