Aging / Alzheimer's

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    Epigenetic Changes of Nuclear-Encoded Oxidative Phosphorylation Genes and Cognitive Function: A Study of Mexican Americans and Non-Hispanic Whites
    (2024-03-21) Swami, Anjana; Daniel, Ann Abraham; Silzer, Talisa; Sun, Jie; Barber, Robert; Phillips, Nicole
    Purpose: There is a higher prevalence of metabolic disease and Alzheimer’s Disease (AD) in Mexican Americans (MA). Despite this data, there has been minimal research done on the methylation status of genes involved in mitochondrial oxidative phosphorylation (OXPHOS)/cellular metabolism and how this influences the risk for developing cognitive impairment (CI). Methods: Results were derived from 299 MAs and 252 non-Hispanic Whites (NHW), all of whom were participants of the Texas Alzheimer’s Research and Care Consortium (TARCC). Themethylation status of CpG sites was assessed by running peripheral blood samples on the InfiniumMethylationEPIC BeadChip array. Results: Based on a Bonferroni adjusted alpha of7.36485 x 10⁶, six differentially methylated sites were significant in MAs: cg07470503, cg10057295, cg13823120, cg26891598, cg21490662, and cg17904988. All the sites were hypomethylated in CI/AD cohorts compared to NC except for cg26891598. There were no sites of significance in NHWs. Conclusions: The strongest association with CI/AD within the MA cohort was at cg07470503, with a p-value of 1.00 x 10⁶ in MAs. This CpG site is found within the DGUOK gene. The DGUOK gene is responsible for making the enzyme deoxyguanosine kinase, which is needed to properly create mitochondrial DNA; a dysfunctional gene leads to impaired mitochondrial function that could decrease the efficiency of OXPHOS. The abnormal cellular metabolism that ensues could set up the foundation for neurodegeneration to occur. Moving forward, the cg07470503 site could serve as a marker to identify the risk of metabolic disease and consequent CI/AD in MA patients.
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    Neuroprotection by Novel Sigma 1 ligands
    (2024-03-21) Kinariwala, Kush; Taylor, Michelle; Schreihofer, Derek
    Purpose: Identify neuroprotective compounds that could potentially be used for conditions like Alzheimer’s disease. Sigma 1 receptors are an intracellular chaperone protein involved in endoplasmic reticulum stress response. Ligands of sigma 1 receptor have been shown to be acutely neuroprotective in a number of in vitro and in vivo brain injury models including stroke and traumatic brain injury. We are examining potential for novel sigma 1 compounds to protect the mouse hippocampal cell line HT22 from oxidative stress and endoplasmic reticulum stress. Among the compounds tested are haloperidol, cutamesine, oxeladin which are neuroprotective in stroke, and additional proprietary ligands derived from substituted haloperidol. Methods: Cell death in HT22 cells was determined using Cell Counting Kit 8. Cells were plated in quadruplicate in 96 well plates for 24 hours in DMEM/10%FBS. Cells were then treated with either hydrogen peroxide (H2O2, 0.5 mM) or Tunicamycin (50 ng/mL) for 24 hours with or without sigma 1 ligands (100 nM). Results: Haloperidol, a mixed sigma 1 and dopamine agonist, dose dependently protected cells from both H2O2 and Tunicamycin induced cell death. However, the sedative actions of Haloperidol make it unsuitable for use against neuroprotective diseases in vivo. We tested 3 sigma 1 compounds without dopamine activity to determine whether sigma 1 activity would protect cells against these insults. Preliminary results suggests that all sigma 1 compounds tested show some efficacy against oxidative stress and ER stress dependent cell death. Average percent live cells after treatment with 0.5 mM hydrogen peroxide was 59.55% (n = 3) and average percent live cells after treatment with 0.5 mM hydrogen peroxide and 100 nM Haloperidol was 101.06% (n = 5). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM Haloperidol was 85.8% (n = 2). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM Oxeladin was 49.7% (n = 2). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM Cutamesine was 74.4% (n = 2). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM of a novel sigma 1 agonist was 85.7% (n = 2). Ongoing studies are examining the intracellular pathways responsible for neuroprotective effects. Conclusion: Novel sigma 1 agonists may be suitable for protecting neurons against neurodegenerative diseases like Alzheimer’s. In terms of examining mechanisms, we are exploring endoplasmic reticulum stress pathways and more traditional apoptotic signaling.
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    Making Dementia Blood-based Biomarker Data More Interpretable Through Machine Learning
    (2024-03-21) Kim, Andrew
    Background: Research and data have linked many possible factors that contribute to the cause and progression of Alzeheimer’s disease and dementia. These include traits such as age, gender, ethnicity, and specific blood-based biomarkers. There has been a great deal of work gathering this information, but comparatively less work has been done to consolidate and present it in an easily coherent and comprehensible form. This study aims to use and sort relevant data related to Alzheimer’s disease with machine learning and make it more interpretable through visualization. Methods: The data being analyzed was collected from n = 1705 Hispanic and Non-Hispanic participants with and without cognitive impairment (n = 1328 NC, n = 261 MCI, n = 116 AD) from the HABS-HD cohort. Associated factors measured and considered from each participant included: gender, Hispanic or Non-hispanic ethnicity, education level, and various blood biomarker levels (CRP, FABP3, IL-10, IL-6, Ab40, Ab42, Tau, NFL, PPY, sICAM-1, sVCAM-1, TNF-alpha, GLP-1, Glucagon, PYY, Insulin, HOMA-IR). The Decision Tree classifier tool was applied to the dataset incorporating the scikit-learn Python coding program and the use of multiple parameters in generating the decision tree. The dtreeviz method was also applied in order to provide further visualization to the data. Results: Decision trees were capable of being generated from the given data set of participants based on cognitive status and blood-based biomarkers for Alzheimer’s disease and dementia. Visualized versions of these decision trees were also capable of being successfully generated. The quality and parameters of the decision trees as well as the appearance of the visualization could also be modified. There appears to be some limitations in the Scikit-learn and dtreeviz package that could warrant further troubleshooting or acknowledgement. Conclusion: Based on the results, it appears that visualized decision trees are capable of being generated from a large set of data. Such visualized decision trees compared to the raw data tables or decision trees themselves are much simpler to interpret and recognize patterns. Such patterns could prove useful in determining future areas of study to focus on or affirm already completed studies.
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    Exploring the Association between Reproductive Health and Cognitive Function in Hispanic and Non-Hispanic Women: Insights from a HABS-HD Study
    (2024-03-21) Pham, Theresa; Johnson, Leigh
    Purpose: Alzheimer’s disease (AD), a progressive neurodegenerative disease with nearly two-thirds of dementia cases found in women, leads to memory loss, cognitive deficits, and behavioral changes, significantly impacting daily life. Given the disproportionate effect of AD on women, it is crucial to understand the risk factors, including reproductive health variables, that may contribute to the development of dementia and AD. Such understanding can provide valuable insights for dementia prevention and the development of personalized, gender-specific medicine. This study aimed to examine the association between reproductive health variables such as bilateral oophorectomy and pregnancy complications and cognitive performance in Hispanic and non-Hispanic women. Method: Self-reported data from 309 cognitively normal women (165 non-Hispanic white and 144 Hispanic) enrolled in the Health and Aging Brain Study: Health Disparities (HABS-HD) project, an epidemiological study of aging in community-based participants, were analyzed. Reproductive health variables examined included bilateral oophorectomy, pregnancy complications, number of pregnancies, and number of children. The cognitive assessment comprised neuropsychological test scores in five domains: memory (logical memory I & II), executive functioning (digit symbol substitution), attention (digit span), language (F-A-S), and global cognition (mini‐mental state examination). Linear regression statistical analyses were conducted, with ethnicity serving as a stratification variable. Results: Linear regression analyses revealed significant associations between reproductive health variables and cognitive domains, with distinct patterns observed among ethnic groups. Bilateral oophorectomy was linked to decreased immediate memory in Hispanic women (B=.176, SE=1.691, t=2.211, p=.029) and lower language performance in non-Hispanic white women (B=-.228, SE=1.980, t=-2.682, p=.008). Pregnancy complications were associated with poorer attention scores in Hispanic women (B=.163; SE=.000, T=2.203, p=.029). However, the number of children and pregnancies were not associated with cognitive performance. Conclusion: This study suggests that reproductive health variables, such as bilateral oophorectomy and pregnancy complications, were differentially associated with cognitive assessment performance among Hispanic and non-Hispanic women. A surgical history of bilateral oophorectomy may be associated with a decline in cognitive performance in both Hispanic and non-Hispanic women. Limitations, including sample size constraints and reliance on self-reported medical history, are acknowledged. Nonetheless, this study underscores the need for continued investigation into the intersection of reproductive health and cognitive function to inform targeted interventions and personalized healthcare approaches for dementia prevention across diverse communities.
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    Methylation of IL-6 & TNF-α Associated Genes in Cognitive Impairment: A Texas Alzheimer's Research & Care Consortium (TARCC) Study
    (2024-03-21) Deleon, Justin; Sotelo, Joseph; Housini, Mohammad; Phillips, Nicole; Barber, Robert
    Purpose: The Mexican American (MA) population poses one of the highest risk groups for the development of Alzheimer’s Disease (AD). Inflammatory biomarkers, such as IL-6 and TNF-a, have been associated with cognitive decline but most only in non-Hispanic Whites (NHWs). Epigenetic DNA methylation of CpG islands associated with inflammatory markers (IL-6 and TNF-a) have been studied and identified in other diseases but literature for its effects on cognitive impairment (CI), especially in MAs, is quite sparse. This study aims to determine if DNA methylation of CpG islands for IL-6 and TNF-a are associated with CI in a MA and NHW cohort. Methods: Utilizing the TARCC cohort (N = 551), participants within ethnic groups (N = 299 MAs, N = 252 NHWs) were stratified by cognitive status (normal cognition (NC) or CI). Methylation data at CpG sites were measured as beta values by array probes using the Illumina EPIC array. Linear regression analysis was performed in R comparing the beta value and cognitive diagnosis (NC or CI) for MA and NHW. Covariates include age, sex, education, CD8T cells, CD4T cells, B cells, monocytes, neutrophils, and the APOE gene. Result: The methylation sites cg04381957 and cg04583842 (both associated with IL-6) were significant within MAs. Those sites suggest hypomethylation and hypermethylation, respectively, in CI compared to the NC. Methylation site cg16411857 (associated with TNF-a) was not significant with CI in either MAs or NHWs. Conclusion: There was a stronger association with IL-6 related CpG sites and CI especially in MA at cg04381957 (p = 0.0035) within the RFTN1 gene. Future research plans to include inflammatory syndromes, such as diabetes, which could be a potential confounding variable affecting levels of IL-6 or TNF-a.
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    The Association of Sleep Problems with Mild Cognitive Impairment in Older Adults in the United States (US): A Cohort Study
    (2024-03-21) Nguimatsa, Arthur; Pinnamraju, Jahnavi; Sambamoorthu, Usha
    Background: The neuroprotective aspects of sleep include improvement of memory, problem-solving, creativity, emotional processing, and judgment. Sleep problems lead to neurological damage in the hippocampus. People with sleep problems have a higher risk of developing MCI. Examining the association of sleep problems with MCI is important for surveillance and prevention efforts of dementia because MCI often leads to dementia in 10%-15% of older adults. Objective: To examine the association of type of sleep problems with MCI among older adults (age > 50 years) using Health and Retirement Study (HRS), a nationally representative prospective cohort of older adults in the US. Methods: We used baseline (2018) and follow-up (2020) data from the HRS. We restricted the analysis to adults aged 50 years or older at baseline, alive in 2020, and did not have dementia in baseline and follow-up. All sleep variables were measured at baseline and MCI was measured during the follow-up period. The dependent variable (MCI) was based on the composite measure (immediate word recall test, delayed word recall, the serial 7s, counting backward), and total scores between 7-11 represent MCI without dementia. Sleep variables were based on responses (most of the time, some, and rare/never) to the following questions: “How often do you have trouble falling asleep?”, “How often do you have trouble waking up during the night?”, “How often do you have trouble with waking up too early and not being able to fall asleep again?” and “How often do you feel rested in the morning?”. Rao- unadjusted associations were tested with Rao-Scott chi-square and adjusted associations were examined with multivariable logistic regressions. All analyses accounted for the complex survey design, and SAS 9.4 Survey procedures were used. Results: Overall, 49.1% had trouble falling asleep, 62.2% had trouble waking up, 46.1% waking up too early, and 84.1% did not feel rested in the morning. A higher percentage of adults with trouble falling asleep (18.6% vs.11.7%), trouble waking up(15.5% vs, 12.3%), and waking up too early(18.9% vs. 11.1%) had MCI compared to those without sleep problems. In logistic regression that adjusted for sex, age, race and ethnicity, living alone, education, employment, poverty, and health insurance, those with sleep problems had higher odds of MCI (trouble sleeping: aOR=1.28(95%CI:1.05 1.56), waking up too early: aOR=1.48(95%CI:1.14, 1.94) compared to those without sleep problems. However, these associations became statistically insignificant when adjusted for health status and depression. In the fully-adjusted logistic regression, never feeling rested in the morning was associated with lower odds of MCI (aOR= 0.71,95% CI=0.55, 0.91, P<0.01). Conclusion: Most older adults reported sleep problems in trouble waking up or not feeling rested in the morning. Our study adds to the conflicting evidence in the literature; some studies report no association between sleep disturbance and cognition while others even report slightly better cognitive functioning in those with sleep problems. Our study findings suggest that the association of sleep disturbances with MCI varies by type of sleep problems.
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    Utility of Blood Based Biomarkers in Detecting Cerebral Amyloid among Mexican Americans: A HABS-HD Study
    (2024-03-21) Alexander, Angel; Zhang, Fan; Hall, James; O'Bryant, Sid; Petersen, Melissa
    Background: Alzheimer's disease (AD) is the leading cause of dementia in our nation's aging population. Minority groups, such as Hispanics, are 1.5 times more likely than non-Hispanic whites (NHW) to develop AD during their lifetime. Several studies have shown that blood biomarkers can be used to detect dementia related to AD. However, limited research has analyzed the relationship between blood biomarkers and cerebral amyloid, an AD biomarker, in minority groups. This study aims to address this gap and examine the utility of blood-based biomarkers to detect cerebral amyloid and predict AD among NHW and Mexican Americans (MA). Methods: Data were analyzed on 232 participants (n=148 NHW; n=84 MA) from the Health & Aging Brain Study – Health Disparities (HABS-HD) study. Of those selected for inclusion in this study, 46 participants had a positive cerebral amyloid scan, while 186 had a negative scan. Plasma samples were assayed for amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau181), and neurofilament light (NfL) using the Simoa (single molecule array) technology platform ( PET amyloid imaging was performed using a Neuraceq (florbetaben) tracer to measure cerebral amyloid positivity based on a clinical read and global standardized uptake value ratios (SUVRs). Covariates included age, gender, and education. Certain models were also split by ethnic groups. Correlation models were run separately for each blood biomarker and total cerebral amyloid SUVR. The plasma proteomic profiles were generated without transformations using Random forest (RF) analysis in R package. Regression coefficients examined the relationship between the proteomic biomarkers, the independent variable, and cerebral amyloid, the dependent variable. Logistic regressions were conducted to examine the ability of the proteomic profiles to predict cerebral amyloid positivity status. Results: Biomarkers Aβ40, Aβ42, p-tau181, and NfL were all significantly correlated with cerebral amyloid (ps< 0.05). The entire cohort had a high regression performance (R2=0.905) between the proteomic biomarkers and cerebral amyloid, with p-tau181 as the driving biomarker. Among the MA group, the biomarkers comprising the proteomic profile yielded excellent accuracy in detecting cerebral amyloid (Area Under the Curve [AUC] = 1.00, Sensitivity [SN] = 1.00, Specificity [SP] = 0.97, and positive predictive value [PPV] = 88%). Among the NHW group, the biomarkers also detected cerebral amyloid with a high level of accuracy (AUC = 0.99, SN = 1, SP = 0.99, and PPV = 92%). Cerebral amyloid positivity was predicted with 100% accuracy in both groups, with false positive rates of 1.19% and 2.03% in the MA and NHW groups, respectively. Conclusions: This study supports the application of plasma proteomic profiles to predict cerebral amyloid-related to AD. The findings highlighted that p-tau181 is the most important biomarker for cerebral amyloid detection in the MA population. This is relevant as prior work in NHW have focused on Aβ being the primary biomarker for AD detection. Future work should examine these findings in a larger population subset in order to validate the predictive utility of blood biomarkers as a screening tool in clinical settings for early AD detection.
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    Epistatic impact of APOE and ACE2 genetic variants on SARS-CoV-2 and RAS dependent blood-brain barrier dysregulation.
    (2024-03-21) Tate, Amanda; Barber, Robert; Park, Inwoo; Jones, Harlan; Phillips, Nicole
    Coronavirus disease 2019 (COVID-19) is associated with respiratory and neurodegenerative symptoms, creating a need to understand the additional impact the pandemic might have on neurodegeneration and risk for neurodegenerative diseases, such as Alzheimer’s disease (AD) in aging populations post 2020. The blood-brain barrier (BBB) is an important interface that connects the periphery to the brain through the vasculature. When this protective barrier becomes dysregulated, the brain is vulnerable to infection, neuroinflammation, and cellular stress, which over time can lead to neurodegeneration and cognitive decline. The renin-angiotensin system (RAS) is an important regulator of vasculature via the activity of the hormone angiotensin II (Ang II). As a mediator of vasoconstrictive, oxidation, and inflammatory responses, its prolonged activity can be damaging and promote neurodegeneration at the BBB. Angiotensin-converting enzyme 2 (ACE2) is highly expressed in endothelial cells which cleaves Ang II into less harmful fragments to offset these potentially toxic effects. Genetic variants of ACE2 are increasingly considered risk factors for the development of vascular disorders (e.g. hypertension) due to their role in RAS-mediated dysregulation of body vasculature. Recent genetic studies have identified a relationship between genetic variants for ACE2, an obligate receptor for the severe acute respiratory syndrome coronavirus 2 (SCoV2), and increased risk and or/severity of COVID-19. Alzheimer’s disease (AD) is the greatest neurological risk among aging individuals and can be caused by both environmental & genetic risk factors. The strongest genetic risk factor for AD is variants in the apolipoprotein E gene (APOE), with the ɛ4 allele being associated with increased levels of amyloid β (Aβ), Tau proteins (p-Tau), neuroinflammation, and BBB permeability. A recent study by Wang et al also suggests a correlation between APOE ɛ4 and increased severity of COVID-19, suggesting some interplay between APOE and host factors related to SCoV2 infection. Furthermore, both ACE2 and APOE genetic variants disproportionately impact minority populations, highlighting a need to understand the health disparity of AD and COVID-19 risk across demographic groups. We hypothesize gene interactions (epistatic interactions) between genetic variants in ACE2 and APOE may exacerbate RAS-mediated BBB dysregulation, leading to increased AD phenotypes and SCoV2 neurological dysregulation. To address this hypothesis, we will create endothelial cells, astrocytes, and neurons containing APOE and ACE2 genetic variants of interest. These epistatic cells will be assessed for expression and functional changes related to BBB integrity. Using Ang II treatments and SCoV2 pseudo-virus models, we will assess the impact of COVID-19 and RAS on BBB integrity and functions. This study will help us understand the mechanisms and interplay of genetic risks for AD and COVID-19 related to RAS-mediated BBB dysregulation, potentially highlighting comorbidities among the aging population. By focusing on ACE2 variants disproportionately found in minority populations, we will provide knowledge surrounding two co-morbidities for neurodegeneration and elevate those at the highest risk for developing AD and/or COVID-19. Funding: This work is supported by the Neurobiology of Aging and Alzheimer’s Disease T32 Training Fellowship, and the IMSD Fellowship, Grant # 5 R25 GM125587-05 from the National Institutes of General Medical Sciences (NIGMS).
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    Re-evaluating Person-Centeredness in Relation to the Workforce and Care for Older Adults
    (2024-03-21) Saavedra, Antonio; Sloane, Philip; Zimmerman, Sheryl; Fazio, Sam
    Background: The term “person-centeredness” has been widely referenced and identified as a gold standard practice, especially in the care for older adults. However, many inconsistencies exist regarding its definition and implementation. With the recognition of caregivers being paramount to the improvement of healthcare quality, a clearer understanding of the term and its application to the healthcare workforce is needed. To address this issue, we aimed to identify key themes regarding the role of person-centeredness as it relates the workforce and care for older adults. Methods: Six think-tank meetings (two in-person; four virtual) were convened. The 38 participants included nurses, direct care workers, and dining staff from long-term care (LTC) settings; leaders of LTC organizations; and academic researchers in aging and LTC policy. Qualitative methods were used to analyze notes and transcripts. Results: Four overarching themes were identified: (1) Staff attitudes and practices toward person-centeredness tend to vary by care setting, due to differences in each setting’s inherent characteristics and goals of care. (2) Person-centeredness at the care level is conveyed through concrete practices of individual care providers; barriers involve both interpersonal competencies and organizational structures. (3) Supportive leadership is critical for staff to be empowered to approach care in a person-centered manner. (4) The lack of operationalized person-centeredness definitions has created inconsistencies in implementation. Conclusion: The definition of person-centeredness has grown from its original interpretation. These think-tanks centered on the workforce and care for older adults identified four themes that both align with and expand the current literature on person-centeredness and its implementation.
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    Acculturation Stress Among Older Indian Americans: Understanding the Challenges of Cultural Transition.
    (2024-03-21) PATIL, SHILPA; Nhpang, Roi San; Griner, Stacey; Kline, Nolane; Neelamegam, Malinee
    Background: Acculturation involves the process through which immigrants assimilate the attitudes, values, traditions, beliefs, and practices of a new culture. Acculturation stress, a form of psychological distress stemming from conflicts between an immigrant or ethnic minority group's values and those of the dominant culture, is a prevalent concern among Asian Indians. This study examines acculturation stress among older Asian Indian Americans, a growing subpopulation facing unique challenges in navigating cultural transitions. Methods: The study adopted a mixed-method approach targeting older Asian Indian Americans (aged 55 and above) in the DFW area, combining survey responses with in-depth interviews. Financial incentives were provided to participants. Utilizing a qualitative framework, the research analyzed participant responses to a series of statements to elucidate their experiences of cultural stress, including perceptions of discrimination, feelings of foreignness, identity conflicts, and concerns over cultural assimilation. Data analysis was conducted using descriptive statistics in SAS 9.4, offering insights into the acculturation stress experienced by this demographic. Results: Respondents comprised of 74.19% (n=23) women and 25.81% (n=8) men. Ages range from 12.90 % (n = 4) at 50-54 years, 32.26% (n = 10) at 55-64, 35.48% (n=11) at 65-74 years, and 19.35% (n=6) at 75 and older. Several significant acculturation stress themes were identified. Key issues include identity conflict, leading to feelings of isolation; discrimination, contributing to marginalization; cultural loss, causing grief and anxiety; intergenerational conflict, straining family dynamics; and adverse mental health outcomes like depression. Most participants feel acculturated, except for notable feelings of missing their home country and family. Conclusion: The findings highlight the complexity of acculturation stress among older Asian Indian Americans, revealing a significant impact of identity conflict, discrimination, cultural loss, intergenerational conflict, and mental health issues. While age appears to be a notable factor in acculturation experiences, further research is essential to explore additional variables affecting acculturation, such as immigration status, age at immigration, and geographical location. This study underscores the need for a broader understanding of the multifaceted acculturation process within the Asian Indian American community to inform targeted support and interventions.
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    Comparing Methylation of CRP and IL-6 Associated Genes in Cognitively Impaired Mexican Americans to Non-Hispanic Whites
    (2024-03-21) Sotelo, Joseph; DeLeon, Justin; Housini, Mohammad; Phillips, Nicole; Barber, Robert
    Purpose: A large pool of literature shows that Alzheimer’s Disease (AD) results from inflammatory processes and neuronal loss via tau proteins and amyloid-β plaques. Mexican Americans are among those with the highest risk of developing Alzheimer’s and research into the epigenetics of this association is lacking. Methylation alterations are influenced by both genetic and lifestyle factors, which can help us identify the root cause of mild cognitive impairment, a precursor for Alzheimer’s Disease. C-reactive protein and interleukin 6 are well known for their roles in measuring systemic inflammation. This study seeks to explore if there is a significant difference between DNA methylation of CpG Islands for CRP and IL6-associated genes in Cognitively Impaired Mexican Americans (MA) and Non-Hispanic Whites (NHW). Methods: Participants were selected from the Texas Alzheimer’s Research and Care Consortium (TARCC) database. The final cohort (n = 551) consisted of 252 NHW (143 normal cognition (NC), and 109 cognitively impaired (CI)) and 299 MA participants (177 NC and 122 CI). Each participant underwent neurocognitive tests such as Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) to determine cognitive status. Methylation at CpG sites was measured by array probes as beta values with 0=unmethylated, to 1=fully methylated site. CpG sites associated with CRP are cg06126421, cg10636246, cg18181703, cg19821297, and cg25325512. CpG sites associated with IL6 are cg12929678, cg17412005, cg19638572, cg20789595. Any differences between cognitively impaired participants and normal controls were assessed using the standard two-sample t-test assuming unequal variances in Rstudio. Linear Regression was performed in Rstudio, and covariates that were adjusted for include age, sex, education level (in years), APOE ɛ4 allele status, CD8 T-cells, CD4 T-cells, natural killer cells, B-cells, monocytes, and neutrophils. Results: In Mexican Americans, the CRP-associated sites showed: cg25325512 (gene FGD2) with significant hypomethylation in the CI group (p=0.0003). Cg19821297 (gene DNASE2) with significant hypomethylation in the CI group (p=0.015). Cg10636246 (genes AIM2 & IF116) had significant CI group hypomethylation (p=0.02). In Non-Hispanic Whites, one CRP-associated site showed significant hypermethylation in the CI group, cg06690548 (gene TUBB) (p=0.026). In Mexican Americans, the IL6-associated sites showed: cg17412005 (gene MUTYH & TOE1) with significant hypomethylation in the CI group (p=0.022). Cg19638572 (gene RASSF5) with significant hypermethylation in the CI group (p=0.013). Cg20789595 (gene ADCY5) with significant hypomethylation in the CI group (p<0.001). In Non-Hispanic Whites, zero IL6-associated sites showed any significant methylation between the CI and NC groups. Conclusion: Epigenetics related to AD is still being further investigated. This study suggests an association between hypomethylated CRP and IL6 genes and cognitive impairment in the Mexican American population. Limitations in this study include a limited number of CpG sites investigated, as well as possible comorbidities that should be adjusted for. There were also an unequal number of MA to NHW participants. Further studies should adjust for inflammatory comorbidities, such as metabolic syndrome, and further investigation is warranted into the FGD2 gene and ADCY5 gene as they were strongly correlated with hypomethylation in the cognitively impaired Mexican American population.
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    Association between everyday perceived discrimination and cognitive function as mediated by depression in diverse populations: A HABS-HD Study
    (2024-03-21) Mendoza, Edna Patricia; Nolan, Emma; Phillips, Nicole; Barber, Robert; O'Bryant, Sid; Zhou, Zhengyang
    Purpose: Previous research suggests that perceived discrimination is associated with cognitive function impairment, and such association is mediated by depression. With minority populations continuously growing, it is crucial to investigate such relationships in diverse populations. This study aims to examine and compare the above relationships among non-Hispanic white (NHW), Mexican American (MA), and African American (AA) participants. Method: A sample size of 1,129 participants (640 AAs, 248 NHWs, 241 MAs) aged 50+ came from the Health and Aging Brain Study – Health Disparities (HABS-HD). Structural equation modelling (SEM) was conducted to explore the effect between perceived discrimination, measured by the Everyday Discrimination Scale mean score, and cognitive function, measured by the Mini Mental State Examination (MMSE) Score. The mediation effect of depression, measured by the Geriatric Depression Scale total score, was evaluated by the indirect effect estimate using SEM. Result: Everyday perceived discrimination negatively influenced cognitive function, and the effect was mediated by depression across the three populations (β= -0.15, 95% CI = [-0.22, -0.08]). When stratified, the mediation effect of depression on the association between discrimination and cognitive function remained significant for NHW (β= -0.37, 95% CI = [-0.60, -0.15]) and MA (β = -0.27, 95% CI = [-0.50, -0.05]). However, such mediation effect was not observed for the AA population. Conclusion: Depression mediates the link between everyday discrimination and cognitive decline, but differences between racial/ethnic groups underscore the need for further research into underlying mechanisms among minority groups, including Mexican American and African American populations. Depression interventions may mitigate negative cognitive effects from discrimination. Tailoring such interventions by race/ethnicity and targeting at-risk groups could optimally promote cognitive health.
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    Assessing Cognitive Function: The Role of the Memory Alteration Test in Predicting Stroop Color-Word Performance within the Self-Management Program for Brain Health
    (2024-03-21) Aboutaj, Amin; Ross, Sarah; Soto, Isabel; Severance, Jennifer
    Purpose: The Self-Management Program for Brain Health is designed to empower participants to make lifestyle changes that enhance cognitive function and potentially delay dementia onset. This study investigates the predictive relationship between the Memory Alteration test and Stroop Color-Word (Stroop CW) performance in these participants, aiming to contribute valuable insights to the complex interplay between memory and executive processing abilities. Methods: Cognitively healthy adults (n = 21, age range 56–90) participated in the study, meeting inclusion criteria and undergoing vital sign assessment, Memory Alteration, and Stroop CW tests. The Memory Alteration test, a reliable screening tool, employed a cut-off of < 40 for cognitive impairment. Stroop CW raw scores were age-corrected, and T-scores were obtained. Statistical analyses included correlation coefficient (r) and p-value calculations. Results: A statistically significant positive correlation (r = 0.55, p = 0.009) between Memory Alteration and Stroop CW scores was observed. Subgroup analysis confirmed the hypothesis, revealing a consistent correlation pattern for those scoring below (mean Memory Alteration 37.86±0.55, Stroop CW 48.43±2.32, r = 0.88, p = 0.009) and above (mean Memory Alteration 44.93±0.85, Stroop CW 50.79±1.89, r = 0.67, p = 0.009) the normal Memory Alteration cut-off of 40. Conclusions: The study supports the predictive ability of the Memory Alteration test on Stroop CW performance in cognitively healthy adults. It underscores the clinical relevance of the Memory Alteration test as a reliable screening tool for early cognitive impairment and processing speed changes. Clinicians are encouraged to become familiar with the Memory Alteration test, considering its inclusion as an additional cognitive screening tool. By adding this brief and non-invasive assessment into routine practice, healthcare professionals can enhance their ability to identify subtle cognitive changes early on, facilitating proactive interventions and contributing to improved patient outcomes. Limitations include sample size and variability, suggesting the need for larger, more diverse samples in future research. The ongoing Self-Management Program for Brain Health presents an opportunity to address these limitations and advance our understanding of cognitive assessment and brain health.
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    Identifying Training Needs for Informal Caregivers to Support Activity and Mobility for Community-Dwelling Individuals with Cognitive and Physical Impairments
    (2024-03-21) Wu, Ko-Lin; Camp, Kathelene; Oderberg, Jane
    Background: With the aging population and the rise in disabilities, there is a growing need for caregiving. In the United States, an overwhelming 83% of older adults receive support from family members, friends, or unpaid caregivers, with almost half of these caregivers aiding individuals with Alzheimer's or other types of dementia. As cognitive decline progresses to the middle and late stages, caregivers play an increasingly critical role in tasks such as feeding, bathing, transferring, and providing mobility assistance. However, informal caregivers usually lack the formal training that professional caregivers in care facilities undergo to carry out these tasks effectively. This study aims to hold focus groups to identify the needs of informal caregivers of persons with dementia in order to develop and deliver support training. Methods: Researchers conducted a focus group using members from a dementia caregiver support group. The specialists in dementia care and mobility worked together collaboratively to develop the topic guide. The guide aimed to explore participants' experiences with the physical and mental challenges of caregiving for persons with dementia. It also aimed to uncover the aspects of their care that held the greatest challenge and to identify areas for potential improvement in their care or condition. Results: A total of six participants were engaged in two focus groups. Through analyzing transcripts from these groups, several main themes have emerged: understanding how relationship influences the role of a caregiver, challenges regarding specific conditions and needs, mobility challenges, reliable strategies and resources, and the caregiver burden. Participants expressed the need for different options to include online and in-person training- with a potential need for individualized attention. Conclusions: The results of this study offer insights into research priorities in dementia care. These findings have played a crucial role in shaping the content of developing workshops and courses that aim to address the mobility and activity needs of the patient while considering their informal caregiver’s burden.
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    Dyslipidemia in Hispanic Prediabetics with Mild Cognitive Impairment
    (2024-03-21) Koester, Paul; Large, Stephanie
    Purpose: Prediabetes or impaired glucose tolerance affects an estimated 96 million adults in the United States and may be a modifiable risk factor for cognitive impairment. Several studies have shown that prediabetics experience poorer longitudinal cognitive outcomes compared to non-diabetics; however, the exact mechanism is still a matter of debate. Furthermore, prediabetic patients often experience metabolic syndrome-related comorbidities like dyslipidemia that may be related to in the development and progression of cognitive impairment in prediabetic patient populations. The aim of this study was to examine the relationship between lipid levels between ethnic groups in prediabetic, mildly cognitively impaired, Hispanics, Non-Hispanic Whites, and African Americans. Methods: Data from 144 mildly cognitively impaired prediabetic participants (Hispanics, Non-Hispanic Whites, and African Americans) was collected and analyzed from the Health and Aging Brain Study: Health Disparities (HABS-HD), a community-based epidemiological study of aging. Participants of the study undergo cognitive and functional testing, as well as brain imaging (MRI and PET). Basic demographic information is also collected, and blood samples are used to determine HbA1c, fasting blood glucose, and lipid profiles. One-way ANOVAs examined differences in total cholesterol, triglyceride, and LDL measurements based on ethnicity. Results: Results showed significant differences in total cholesterol levels between the Hispanic (M = 193.98, SD = 38.17), non-Hispanic white (M = 169.54, SD = 37.26), and African American (M = 170.41, SD = 35.52) populations (F = 7.20, p <0.001), triglyceride levels between the Hispanic (M = 154.25, SD = 80.47), non-Hispanic white (M = 124.62, SD = 50.81), and African American (M = 95.17, SD – 57.77) populations (F = 10.96, p<0.000), and LDL levels between the Hispanic (M = 111.86, SD = 31.88), non-Hispanic white (M = 95.62, SD = 29.91), and African American (M = 94.77, SD = 27.38) populations (F = 5.37, p<0.006). Conclusion: Prediabetic Hispanic participants in the study with MCI were shown to have higher lipid profiles (triglycerides, LDL, and total cholesterol) as compared to non-Hispanic white and African American participants. Future studies should further examine the relationship between prediabetes and dyslipidemia, including clinical outcomes regarding the treatment of elevated lipids.
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    The Association of Subjective Cognitive Decline and Demographic, Social, Clinical, and Neuropsychological Factors in the HABS-HD Cohort
    (2024-03-21) Johnson, Darrian
    Background: The number of people with Alzheimer’s Disease and Related Dementias (ADRD) is projected to double by 2060 with the greatest increases in Hispanics. Mexican Americans experience an earlier onset of Alzheimer’s disease, but research shows that the illness is diagnosed much later in their lives. Sociodemographic projections predict a larger percentage of Hispanics with subjective cognitive decline (SCD) in the future. SCD is related to cognitive decline and dementia risk. This study will explore how SCD is associated with sociodemographic and clinical factors along with cognitive performance amongst Mexican Americans (MA) and non-Hispanic white (NHW) participants of the Health and Aging Brain – Health Disparities Study (HABS -HD). Methods: The HABS-HD is a longitudinal study led by the Institute for Translational Research at the University of North Texas Health Science Center. A cross-sectional analysis of data from (n=1342) cognitively normal participants aged 30 years and older was performed. The cohort (662 NHW and 690 MA) underwent a clinical interview to collect information on depression, anxiety, and co-morbidities, neurocognitive and functional examinations, brain MRI, amyloid and tau PET scans, and blood collection for biomarker review. Worry and perceived social support were evaluated using the Penn State Worry Questionnaire (PSWQ) while subjective cognitive decline was assessed using the Subjective Memory Complaints Questionnaire. Neighborhood socioeconomic status (NSES) was measured using the national area deprivation index (ADI) percentile ranking composed of education, employment, income, occupation, and housing. Global cognition was graded using the Mini-Mental State Examination (MMSE) and memory was assessed using the logical memory 1 and 2 tests. Statistical analysis was based on binary logistic regression using SCD as the dependent variable and was stratified by ethnicity with sex, age, education, and BMI as co-variants. Results: SCD was present in 49% of the sample.MA were younger, less educated, more likely to live in the most deprived neighborhoods, and had less social support (p≤0.005) In addition, they were more likely to be depressed and diabetic along with having a higher Body Mass Index (BMI) and experiencing more SCD than NHW (p≤0.005). MMSE scores were lower in in MA (p≤0.005). When looking at the logistic regression, model 1 confirmed associations of SCD with age and GDS scores in NHW, and MA. After adjustment for cognitive scores, only GDS remained significant in both races. MA living in the most deprived neighborhoods had 2.45 more chance to present SCD than those living in the least deprived neighborhoods (95% CI 1.15 to 5.19). There was no difference in NHW. Conclusion: Our study showed that individuals with a higher degree of SCD were more likely to live in high ADI neighborhoods. The idea of SCD as a proxy for objective memory impairment and AD faces many barriers in minorities. However, while chronic stress and depression burden vulnerable communities, it is possible that SCD may serve as an indicator for future cognitive impairment and prompt the establishment of strategies to address these issues in neighborhoods influenced by inequitable circumstances.
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    A Study on the Utility of Blood-Based Biomarkers for Alzheimer’s Disease in Predicting Cerebral Amyloid among Individuals with Down Syndrome
    (2024-03-21) Awasthi, Shubhangi; Zhang, Fan; Hall, James; Mapstone, Mark; O'Bryant, Sid; Petersen, Melissa
    Purpose: Down Syndrome (DS) is one of the most common genetic disorders. Individuals with DS show Alzheimer’s Disease (AD)-related neuropathology at a younger age, placing them at an increased risk for developing dementia. Limited research has explored the relationship between blood-based biomarkers and cerebral amyloid positivity. Our study examines the association between blood-based biomarkers and the presence of cerebral amyloid detected by PET scans in participants with DS. Methods: Data were analyzed on a cohort of n=368 participants with DS aged 30 and above. Proteomic assays of amyloid beta 40 (Aꞵ40) and 42 (Aꞵ42), total tau, neurofilament light (NfL), and phosphorylated tau181 (pTau181) were performed on plasma samples using Single Molecule Array (Simoa). Cerebral amyloid levels were obtained through PET Amyloid imaging. Covariates included age, gender, and presence of at least one APOε4 allele. Correlations were run using R statistical software. Random Forest analyses were conducted to examine the link between the select biomarkers and cerebral amyloid SUVR levels. Logistic regressions were also used in examining the utility of AD biomarkers in detecting cerebral amyloid positivity. Significance was set at p<0.05. Results: The biomarkers that significantly correlated with cerebral amyloid SUVR levels were Aꞵ42 (p=0.020), total tau (p<0.001), NfL (p<0.001), and pTau181 (p<0.001). There was no significant correlation between Aꞵ40 (p=0.888) and levels of cerebral amyloid. Regression analysis demonstrated a high correlation (R2 = 0.956) between the biomarkers and cerebral amyloid positivity. Our profile was accurate in detecting the presence of cerebral amyloid, yielding an area under the curve (AUC) of 0.9984, a positive predictive value (PPV/Precision) of 0.9571, sensitivity of 0.9853, and specificity of 0.9404. Conclusion: Our findings demonstrate that our proteomic profile consisting of the biomarkers Aꞵ40, Aꞵ42, total tau, NfL, and pTau181, and select demographics was highly accurate in predicting the presence of cerebral amyloid in our cohort. Having a less invasive and less costly screening tool, such as a blood-based biomarker profile, will allow for earlier detection of dementia in individuals who are at risk. Future research should explore these findings in the context of a larger cohort for increased generalizability.
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    Longitudinal microRNA profiling of neuronal-enriched exosomes associated with cognitive function and decline
    (2024-03-21) Subasinghe, Kumudu; Hall, Courtney; Zhou, Zhengyang; Barber, Robert; Phillips, Nicole
    Background. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that disproportionately affects several racial/ethnic groups, including Mexican Americans (MAs). Evidence suggests that early alterations in the AD brain can propagate to local and distal cells through small biological packages called exosomes. Exosomes secreted by neurons are capable of mediating cell-to-cell communication through their bioactive cargo, leading to metabolic and epigenetic reprogramming in target cells. Exosomes derived from neurons have been detected in plasma and isolated from other subpopulations using the neural cell adhesion molecule CD171. These neuronal-enriched exosomes (NEEs) cross the blood-brain barrier and thus represent an easily accessible derivative of otherwise inaccessible brain tissue in living humans. Small, non-coding RNAs called microRNAs (miRNA) are transcribed from nuclear DNA and function as strong intracellular expression regulators. miRNAs, which can be selectively packaged and transported by exosomes, have been shown to significantly alter the expression patterns of target cells. This project aims to identify the aberrant miRNA profiles that correlate with disease progression and key comorbidities (e.g., type 2 diabetes (T2D), hyperlipidemia, hypertension) in NEEs of plasma from MAs and Non-Hispanic Whites (NHWs). Hypothesis. We hypothesize that population-specific differences in NEE miRNA cargo will reflect cognitive function and decline. Methods. Longitudinal plasma samples (two time points, 2 years apart) received from the Texas Alzheimer’s Research and Care Consortium (TARCC) were processed using a two-step method that involves precipitation of total exosomes followed by NEE capture with a biotinylated antibody against the neuronal surface marker, CD171. After isolating RNA from NEEs, miRNAs were then profiled using next-generation sequencing. These profiles were then analyzed for differential miRNA expression in individuals with cognitive impairment compared to the normal control group. Results. Our preliminary quality control and sequencing data confirmed the successful isolation of miRNA from NEEs. We identified specific miRNA candidates that were differentially expressed in NEEs from cognitively impaired subjects compared to healthy controls. These miRNAs target gene networks that have been implicated in AD pathophysiology. Conclusion. This innovative workflow along with the unique sample type provides novel insight into the role of exosomal miRNA cargo in AD pathogenesis, identifying novel, population-specific targets for biomarker/diagnosis as well as therapeutic design. Further, this approach provides a conceptual framework for blood-based exosomal profiling in other complex diseases characterized by epigenetic dysregulation and systemic inflammation.
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    Vascular and metabolic profiles related to white matter hyperintensities in a multiethnic cohort from the HABS-HD study
    (2024-03-21) Taylor, Douglas; Vintimilla, Raul; Hall, James; Johnson, Leigh; O'Bryant, Sid
    Purpose: There are more than 6 million people living with Alzheimer’s disease (AD) in the United States. Mexican-Americans (MA) and African-Americans (AA) are disproportionally affected by AD and related dementias, and it is expected that these disparities will increase in the coming years. AD commonly presents with vascular dementia and research has shown the relationship between the two to be complex, with many individuals presenting with mixed dementia. Vascular dementia is commonly related to small vessel disease. Small vessel disease occurs when endothelial damage in cerebrovascular circulation causes ischemia, leading to microinfarcts. The microinfarcts show up as white matter hyperintensities (WMH) in MRI. Most research using WMH to study dementia has been completed with non-Hispanic whites (NHW), though studies have shown a higher incidence of metabolic factors related to AD in MA. It is our goal to use WMH to find further differences in vascular and metabolic factors related to AD among a cohort of NHW, MA, and AA. Method: A cross-sectional analysis of 2363 subjects from the HABS-HD cohort was conducted (967 NHW, 410 AA, and 986 MA). Participants underwent a clinical evaluation and a 3T brain MRI (Siemens Skyra). WMH volume was measured from FLAIR using the Statistical Parametric Mapping (SPM) Lesion Segmentation Tool. WMH were Log transform to achieve normality, and were adjusted for intracranial volume derived from Free3Surfer V6.0 analysis of T1MPRAGE. Fasting blood samples were collected, and clinical measures were conducted using standard procedures. Clinical, vascular, and metabolic risk factors (table 1) were used in linear regression models as predictors of WMH volume adjusted by intracranial volume (ICV). Age, sex, and education were entered as covariates. Results: The total sample was 62.3 percent female with a mean age of 65.4 years and 13.07 years of education. NHW were older, had more years of education, had lower BMI, lower systolic and diastolic blood pressure, and levels of triglycerides, HA1c, and EGFR when compared to AA and MA (p ≤0.005). In NHW, age, sex, education, SBP, DBP, and hypertension significantly predicted WMH volumes (p ≤ 0.005). Age, years of education and BMI were the only significant predictors of WMH volume in AA (p ≤ 0.005), while age, total cholesterol and T4 levels were significant predictors of WMH volume in MA (p ≤ 0.005). Having a diagnosis of diabetes or dyslipidemia, also predicted WMH volume in MA. Conclusion: Results showed that different factors contribute to WMH volume among different ethnicities. Results suggest that in NHW, a vascular profile is most relevant, while in MA and AA, a metabolic profile seems to be driven the association with WMH. Prospective studies are needed to further understand the how the different profiles among different ethnicities affect the presentation of WMH and pathology of SVD.