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17 Education Moderates the Association Between Hippocampal CBF and Memory in Women but Not Men
- Einat K Brenner, Alexandra J Weigand, Lauren C Edwards, Amanda T Calcetas, Maria Bordyug, Sarah J Banks, Erin E Sundermann, Kelsey R Thomas, Mark W Bondi, Katherine J Bangen
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 227-228
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Objective:
Higher educational attainment is associated with reduced risk for Alzheimer's disease (AD) dementia, and its protective effect may act through alterations in cerebral blood flow (CBF) that allow for better coping with accumulating neuropathology. Additionally, there are sex differences in both the risk of developing AD as well as the potential protective effects of education. We therefore sought to investigate whether education moderates the association of hippocampal CBF and memory in cognitively unimpaired older adults, and to examine if these interactions were moderated by sex.
Participants and Methods:Cognitively unimpaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 51 men, 50 women) underwent neuropsychological evaluation and arterial spin labeling MRI, which was used to quantify bilateral hippocampal CBF. Sex was defined as sex at birth. Multiple linear regressions assessed (1) the independent associations among education, CBF, and memory performance separately in men and women and (2) the three-way interactions among CBF, sex, and education, followed by sex-stratified analyses. Three outcome measures were examined: Logical Memory Story A immediate and delayed recall, and Rey Auditory Verbal Learning Test (RAVLT) intrusions. All models adjusted for age and APOE epsilon-4 allele frequency, and all models with CBF additionally adjusted for cerebral metabolism (baseline FDG-PET composite) and pulse pressure.
Results:CBF was not associated with education or memory in either women or men. There was a positive association between education and delayed memory in women (ß=0.14, t=2.64, p=0.008) as well as trending, positive associations between education and immediate memory in women (ß=0.09, t=1.79, p=0.074) and education and delayed memory in men (ß=0.09, t=1.94, p=0.054). Three-way interactions among sex, CBF, and education were significant on immediate recall (ß=2.55, t=2.53, p=0.013), delayed recall (ß=2.56, t=2.44, p=0.017), and RAVLT intrusions (ß=-2.28, t=-2.27, p=0.026). In women, there were interactions between education and hippocampal CBF on both immediate (ß=2.49, t=2.90, p=0.006) and delayed recall (ß=2.30, t=2.78, p=0.009), such that as education increased, the strength of the association between CBF and immediate memory increased. There was also an interaction between education and hippocampal CBF on RAVLT intrusions in women (ß=-2.42, t=-3.05, p=0.004), such that as education increased, the strength of the association between CBF and number of intrusions decreased; there was a main effect where in women with lower education, as CBF increased, the number of intrusions increased (ß=0.76, t=2.59, p=0.032); in women with higher education, there was no association between CBF and intrusions. In men, none of these two-way interactions were significant.
Conclusions:These results suggest that, in cognitively unimpaired older women, the relationship between hippocampal CBF and memory is moderated by education level, even when adjusting for several other factors. Specifically, higher education may serve as a protective factor in the hippocampal CBF-memory relationship, and this relationship was sex-dependent, occurring in women only. Further research is needed to examine these relationships longitudinally across the clinical continuum of AD. Additionally, this work needs to be conducted in more diverse samples to allow for analyses investigating the impact of education on the intersection of race/ethnicity and sex/gender.
5 From Advantage to Disadvantage: Women’s Clinical Trajectory in Early-Stage Alzheimer’s Disease
- Erin E. Sundermann, Sarah J. Banks, Mark W. Bondi, Anat Biegon, Thomas Hildebrandt
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 101-102
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Objective:
There are critical and perplexing sex/gender differences in Alzheimer’s disease (AD). Women show a more favorable clinical profile in preclinical AD particularly with verbal memory, but a steeper decline post mild cognitive impairment (MCI) diagnosis and, ultimately, higher rates of AD. Longitudinal studies are needed to understand sex differences across the AD trajectory. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we identified profiles of memory trajectories among those with evidence of preclinical AD or MCI at baseline and how these trajectories differ by sex.
Participants and Methods:In our sample of 659 participants (age range: 55-90, mean age=72.9 [SD=7.4], 95% non-Hispanic White; mean follow-up=41.2 [SD=32.3] months), 233 were labelled “preclinical” AD (51% women) at baseline based on a cognitively normal status but positivity for either the cerebrospinal fluid p-Tau/Aß42, Amyloid PET or Tau PET biomarkers, and 426 participants (44% women) were MCI at baseline based on Jak/Bondi criteria. We applied latent class growth curve modeling to the heterogeneous change in the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall within preclinical and MCI groups separately. Models in MCI group included Non-Linear Spline to account for differential change rates within subgroups. Models were compared on Bayesian Information Criterion, Entropy, and Class distribution to determine a best-fitting model. Effects of sex on trajectories were the primary outcomes. All models included APOE4 carrier status and age.
Results:Women outperformed men on Immediate and Delayed Recall at baseline in the preclinical and MCI groups (ps<.05). Within the preclinical group, 3-class models representing stable, decline, and accelerated decline provided optimal fit for both Immediate and Delayed Recall. Whereas, on average, preclinical women showed more stable Immediate Recall than men (beta=6.24, SE=.82, p<.0001), they were more likely to be in the Immediate Recall accelerated decline class (23.4% vs. 16.25%; female:male; Chi-square=36.29, p<.00001). On average, preclinical women and men did not differ in Delayed Recall trajectories (beta=.31, SE=.30, p=.28); however, preclinical women were more likely to be in the stable Delayed Recall class (11.04% vs. 6.5%; Chi-Square=19.19, p<.0001). Within the MCI group, 2-class models representing a stable decline group and an accelerated decline group provided optimal fit for both outcomes. Whereas, on average, MCI women showed more stable Immediate Recall than men (beta=3.55, SE=.79, p<.0001), they were more likely to be in the Immediate Recall accelerated decline class, although not significantly. Women and men did not differ, on average, in their Delayed Recall trajectories; however, women were significantly more likely to be in the Delayed Recall accelerated decline class (Chi-square=32.24, p<.0001).
Conclusions:Our findings indicate that sex is an important determinant of the variability observed in early-stage AD trajectories; however, sex differences varied by Immediate versus Delayed Recall likely due, in-part, to psychometric test properties. Our results suggest that, when looking at sex differences in AD trajectories on average, women’s superior stability in verbal learning masks their higher likelihood of rapid decline. Our findings have implications for our ability to optimally diagnose and track disease progression in both sexes.
55 Sleep Quality, Tau Burden, and Memory in Older Women with Higher Alzheimer’s Disease Risk
- Kitty K Lui, Alyx L Shepherd, Xin Wang, Rachel A Bernier, Tasnuva Chowdhury, Naa-Oye Bosompra, Pamela DeYoung, Atul Malhotra, Erin E Sundermann, Sarah J Banks
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 926-927
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Objective:
Compared to older men, Alzheimer’s Disease (AD) is more common in older women, who present with higher levels of pathological tau and accelerated memory decline, although it is unclear why. Furthermore, sleep complaints increase with age, with older women reporting worse sleep quality than older men, and past studies have linked sleep disturbances to tau. Because of the life-long “verbal memory advantage” in women over men, nonverbal memory may more accurately reflect tau burden in women since sex differences are not as apparent. Here, in a sample of older women in the Women Inflammation Tau Study (WITS), we examined the associations between subjective sleep quality, tau in temporal regions, and memory, and whether tau would be more strongly related to nonverbal memory than verbal memory.
Participants and Methods:In WITS, women have elevated AD polygenic hazard scores and have mild cognitive impairment as indicated by the telephone Montreal Cognitive Assessment (range:13-20). This preliminary sample of 20 women (aged 72.0±3.7) completed the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality in 7 domains of sleep health over the past month. A global score (range:0-21) is calculated, with a score >5 indicative of being a poor sleeper. Participants also underwent positron emission tomography (PET) with the 18F-MK6240 tracer and T1-weighted magnetic resonance imagining (MRI) to determine tau deposition. Standardized uptake value ratio (SUVR) was calculated using the inferior cerebellum grey matter as the reference region, which was created from Automated Anatomic Labeling atlas in native T1 space. The region of interest (ROI) was a composite meta-temporal region. The Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) Story A and B were administered to assess verbal memory. The Brief Visuospatial Memory Test-Revised (BVMT-R) was administered to assess nonverbal memory. Analysis focused on the delayed recall scores from the memory tests. Partial correlation was used to analyze the associations between PSQI global score, tau-PET SUVR in meta-temporal ROI, and memory delayed recall scores, while adjusting for age and education years.
Results:8 women were poor sleepers indicated by the PSQI global score (mean:4.9±2). Worse subjective sleep quality was associated with greater tau in meta-temporal ROI (r=0.63, p=0.005) and lower BVMT-R delayed recall (r=-0.46, p=0.05). Sleep quality was not significantly related to either RAVLT or LM delayed recall (all p’s>0.40). Tau in meta-temporal ROI was not significantly associated with nonverbal (p=0.23) or verbal memory (all p’s>0.40) delayed recall.
Conclusions:In this preliminary analysis, subjective sleep quality was linked to temporal tau deposition and nonverbal memory delayed recall, which may suggest that poor sleep exacerbates pathogenesis of tau that leads to memory difficulties in older women at increased risk for AD. Although tau was not significantly related to any memory measures, we will explore whether tau will mediate or moderate the relationship between sleep quality and nonverbal memory once we are powered to do so. Continual evaluation and treatment of sleep may be imperative in mitigating AD risk, especially for older women, however, future longitudinal studies will be necessary to investigate this.
57 CSF Markers of AD-Related Pathology Relate to aMCI among People with HIV
- Judith D. Lobo, Erin E. Sundermann, Laura M. Campbell, Ben Gouaux, Scott Letendre, Mark W. Bondi, David J. Moore
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 53-54
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Objective:
Older people with HIV (PWH) are at-risk for Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). Identifying aMCI among PWH is challenging because memory impairment is also common in HIV-associated neurocognitive disorders (HAND). The neuropathological hallmarks of aMCI/AD are amyloid-ß42 (Aß42) plaque and phosphorylated tau (p-tau) accumulation. Neurofilament light chain protein (NfL) is a marker of neuronal injury in AD and other neurodegenerative diseases. In this study, we assessed the prognostic value of the CSF AD pathology markers of lower Aß42, and higher p-tau, p-tau/Aß42 ratio, and NfL levels to identify an aMCI-like profile among older PWH and differentiating it from HAND. We assessed the relationship between aMCI and HAND diagnosis and AD biomarker levels
Participants and Methods:Participants included 74 PWH (Mean age=48 [SD=8.5]; 87.4% male, 56.5% White) from the National NeuroAIDS Tissue Consortium (NNTC). CSF Aß42, Aß40, p-tau and NfL were measured by commercial immunoassay. Participants completed a neurocognitive evaluation assessing the domains of learning, recall, executive function, speed of information processing, working memory, verbal fluency, and motor. Memory domains were assessed with the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised, and aMCI was defined as impairment (<1.0 SD below normative mean) on two or more memory outcomes among HVLT-R and BVMT-R learning, delayed recall and recognition with at-least one recognition impairment required. HAND was defined as impairment (<1.0 SD below normative mean) in 2 or more cognitive domains. A series of separate linear regression models were used to examine how the levels of CSF p-tau, Aß42, p-tau/Aß42 ratio, and NfL relate to aMCI and HAND status while controlling for demographic variables (age, gender, race and education). Covariates were excluded from the model if they did not reach statistical significance.
Results:58% percent of participants were diagnosed with HAND, 50.5% were diagnosed with aMCI. PWH with aMCI had higher levels of CSF p-tau/Aß42 ratio compared to PWH without aMCI (ß=.222, SE=.001, p=.043) while controlling for age (ß=.363, p=.001). No other AD biomarker significantly differed by aMCI or HAND status.
Conclusions:Our results indicate that the CSF p-tau/Aß42 ratio relates specifically to an aMCI-like profile among PWH with high rates of cognitive impairment across multiple domains in this advanced HIV disease cohort. Thus, the p-tau/Aß42 ratio may have utility in disentangling aMCI from HAND and informing the need for further diagnostic procedures and intervention. Further research is needed to fully identify, among a broader group of PWH, who is at greatest risk for aMCI/AD and whether there is increased risk for aMCI/AD among PWH as compared to those without HIV.
3 The Relationship Between Apolipoprotein-E4 Genotype, Memory, and the Medial Temporal Lobe and How These Relationships Vary by Race in Middle-Aged Persons with HIV
- Laura M Campbell, Maulika Kohli, Erin E Sundermann, Christine Fennema-Notestine, Averi Barrett, Cinnamon Bloss, Mark W Bondi, David B Clifford, Ronald J Ellis, Donald Franklin, Benjamin Gelman, Igor Grant, Robert K Heaton, Scott Letendre, Payal B Patel, David J Moore, Susan Morgello, Raeanne C Moore
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 683-684
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Objective:
Many people with HIV (PWH) are at risk for age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Studies on the association between cognition, neuroimaging outcomes, and the Apolipoprotein E4 (APOE4) genotype, which is associated with greater risk of AD, have yielded mixed results in PWH; however, many of these studies have examined a wide age range of PWH and have not examined APOE by race interactions that are observed in HIV-negative older adults. Thus, we examined how APOE status relates to cognition and medial temporal lobe (MTL) structures (implicated in AD pathogenesis) in mid- to older-aged PWH. In exploratory analyses, we also examined race (African American (AA)/Black and non-Hispanic (NH) White) by APOE status interactions on cognition and MTL structures.
Participants and Methods:The analysis included 88 PWH between the ages of 45 and 68 (mean age=51±5.9 years; 86% male; 51% AA/Black, 38% NH-White, 9% Hispanic/Latinx, 2% other) from the CNS HIV Antiretroviral Therapy Effects Research multi-site study. Participants underwent APOE genotyping, neuropsychological testing, and structural MRI; APOE groups were defined as APOE4+ (at least one APOE4 allele) and APOE4- (no APOE4 alleles). Eighty-nine percent of participants were on antiretroviral therapy, 74% had undetectable plasma HIV RNA (<50 copies/ml), and 25% were APOE4+ (32% AA/Black/15% NH-White). Neuropsychological testing assessed seven domains, and demographically-corrected T-scores were calculated. FreeSurfer 7.1.1 was used to measure MTL structures (hippocampal volume, entorhinal cortex thickness, and parahippocampal thickness) and the effect of scanner was regressed out prior to analyses. Multivariable linear regressions tested the association between APOE status and cognitive and imaging outcomes. Models examining cognition covaried for comorbid conditions and HIV disease characteristics related to global cognition (i.e., AIDS status, lifetime methamphetamine use disorder). Models examining the MTL covaried for age, sex, and
relevant imaging covariates (i.e., intracranial volume or mean cortical thickness).
Results:APOE4+ carriers had worse learning (ß=-0.27, p=.01) and delayed recall (ß=-0.25, p=.02) compared to the APOE4- group, but APOE status was not significantly associated with any other domain (ps>0.24). APOE4+ status was also associated with thinner entorhinal cortex (ß=-0.24, p=.02). APOE status was not significantly associated with hippocampal volume (ß=-0.08, p=0.32) or parahippocampal thickness (ß=-0.18, p=.08). Lastly, race interacted with APOE status such that the negative association between APOE4+ status and cognition was stronger in NH-White PWH as compared to AA/Black PWH in learning, delayed recall, and verbal fluency (ps<0.05). There were no APOE by race interactions for any MTL structures (ps>0.10).
Conclusions:Findings suggest that APOE4 carrier status is associated with worse episodic memory and thinner entorhinal cortex in mid- to older-aged PWH. While APOE4+ groups were small, we found that APOE4 carrier status had a larger association with cognition in NH-White PWH as compared to AA/Black PWH, consistent with studies demonstrating an attenuated effect of APOE4 in older AA/Black HIV-negative older adults. These findings further highlight the importance of recruiting diverse samples and suggest exploring other genetic markers (e.g., ABCA7) that may be more predictive of AD in some races to better understand AD risk in diverse groups of PWH.
Persistence of cognitive impairment among well-treated older adults with HIV in low- to middle-income countries: Commentary on “Prevalence and 1-year incidence of HIV-associated neurocognitive disorder (HAND) in adults aged ≥ 50 years attending standard HIV clinical care in Kilimanjaro, Tanzania” by Flatt et al.
- Erin E. Sundermann, Leah H. Rubin
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- International Psychogeriatrics / Volume 35 / Issue 7 / July 2023
- Published online by Cambridge University Press:
- 04 October 2022, pp. 319-322
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Estrogen and performance in recognition memory for olfactory and visual stimuli in females diagnosed with Alzheimer's disease
- ERIN SUNDERMANN, PAUL E. GILBERT, CLAIRE MURPHY
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- Journal of the International Neuropsychological Society / Volume 12 / Issue 3 / May 2006
- Published online by Cambridge University Press:
- 17 May 2006, pp. 400-404
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Patients with Alzheimer's disease (AD) exhibit a deficit in episodic recognition memory for odors. It is hypothesized that the higher rate of AD in women may be due to estrogen-deprivation in postmenopausal women. Research suggests that estrogen may help to minimize cognitive decline in AD as well as postmenopausal olfactory loss. The current study examined the effects of estrogen replacement therapy (ERT) on performance of a recognition memory task for olfactory and visual stimuli in women AD patients. Participants included 24 women AD patients who were ERT users and 77 women AD patients who never used ERT. Compared with the ERT non-users, the ERT users committed significantly less false-positive memory errors for olfactory stimuli, whereas performance for visual stimuli did not differentiate between ERT users and non-users. The results suggest benefits of ERT could help ameliorate the earliest symptoms of AD, olfactory dysfunction, and memory impairment. (JINS, 2006, 12, 400–404.)