Aging / Alzheimer's

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    Association of Cancer with Alzheimer's Disease and related Dementias among older adults with chronic pains: TriNetX analysis with Multi-institutional Electronic Health Records
    (2023) PITHUA, PATRICK; PAHAK, MONA; Bo, Zhou; Pinnamraju, Jahnvani; Sambamoorthi, Usha
    Introduction Recent retrospective cohort studies have reported that non-cancer chronic pain, specifically non-cancer pain conditions (NCPCs), are associated with an increased risk of Alzheimer's disease and related dementias (ADRD) in older adults. However, a recent case-control study found that cancer-induced pain had a protective association with ADRD, suggesting that cancer pain's association with ADRD is inconclusive. Therefore, we analyzed the association of cancer with ADRD among older adults with chronic pain. Methods We adopted a retrospective cohort analysis. The cohort consisted of older adults with chronic pain in 2016 and 2017. The data used in this study is from the TriNetX Research Network, which provided access to electronic medical records (diagnoses, procedures, medications, and laboratory values) for patients from 64 healthcare organizations (HCOs). A propensity score-matched analysis of cancer and non-cancer patients used age, sex, race/ethnicity, surgery, factors influencing health status and contact with health services; endocrine, nutritional, and metabolic diseases; diseases of the circulatory system; nervous system; digestive system; musculoskeletal system and connective tissue; and mental, behavioral and neurodevelopmental disorders. The outcome variable was ADRD incidence, which occurred at least one year after the first chronic pain diagnosis. Results Before matching, among older adults with cancer, there were 212,739 and 465,316 with and without cancer, respectively. The 3-year cumulative incidence of ADRD was 2.97% (N = 6320) in the cancer group and 1.96% (N = 9096) in the non-cancer group. After propensity matching, there were 195289 participants in both groups. The cumulative incidence of ADRD was 2.79% (N = 5457) in the cancer group and 2.62% (N = 5124) in the non-cancer group (Risk Ratio = 1.07, 95% CI: 1.02-1.10). Secondary analysis of ADRD incidence in adults who died did not reveal a significant association between cancer with ADRD. Conclusion Our research has found that cancer is not associated with the risk of ADRD among patients with chronic pain. Our study estimates of ADRD incidence are lower than the national rates, suggesting the limitations of electronic health records in capturing true ADRD incidence. The study's findings must be interpreted in the context of the study's strengths and limitations. For example, data were from 64 HCOs, and the study did not adjust for case-mix or practice differences. In addition, the study is limited to those seeking care in these HCOs and may have missed care obtained outside of these organizations. Thus, our estimates of ADRD incidence are substantially lower than the national ADRD incidence. Nevertheless, the study's strengths are the use of multi-institutional electronic health records, large numbers of cases and controls, and the ability to conduct propensity score-matched analysis with a comprehensive list of risk factors. Keywords: Dementia, Alzheimer's disease, and Related Disorders, Cancer, Chronic Pain, EHR
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    Effects of Amyloid β on Recollective Memory: Sex and Hormone Differences
    (2023) Vera, Edward; Mabry, Steve; Wilson, Nicole; Bradshaw, Jessica L.; Gardner, Jennifer J.; Little, Joel; Rybalchenko, Nataliya; Cunningham, Rebecca L.
    PURPOSE: Alzheimer’s disease (AD) is linked with increased memory loss and inability to learn new topics. One of the defining neuropathological features of AD is amyloid beta (Aβ) plaques in brain regions, such as the hippocampus. The hippocampus brain region is important for memory and learning. AD risk is elevated in individuals older than 65 years old, especially menopausal women. Menopause is an aging associated endocrine event in which the ovaries stop producing estradiol but continue producing testosterone. Testosterone can be aromatized to estradiol, but aromatase is not functional in women with AD. Therefore, post-menopausal women with AD have more androgens than estrogens than pre-menopausal women and aged men. Androgens can be neuroprotective or neurotoxic depending on the cellular environment. It is unknown what the impact of androgens and sex are on amyloid beta’s effects on the brain, (e.g., hippocampus) and behavior (e.g., memory). We hypothesize that females with the hormonal condition of androgens in the absence of estrogens will exhibit increased recollective memory in response to hippocampal injection of Aβ. METHODS: To investigate the role of androgens and sex on Aβ associated memory impairments, adult male and female Sprague-Dawley rats were gonadectomized to remove circulating sex hormones. A subset of these rats was given either cholesterol or dihydrotestosterone (DHT), which cannot be converted into estrogen. To model AD, rats were injected with 5ug/ul of Aβ oligomer fibrils 1-40 or vehicle shams in the CA1 region of the hippocampus. One week after Aβ hippocampal injections, the rats were assayed for short term and long-term recollective memory via a 1-hour and 24-hour Novel Object behavioral test. The Novel Objective behavioral tests examines recollective memory by quantifying the time spent with a novel object versus the time spent with a known object. Data was quantified with a three-way ANOVA with sex, hormone, and Aβ as independent variables. Tukey’s was used as a post-hoc test. RESULTS: Sex differences were observed between hormone-deficient rats exposed to Aβ. Specifically, males exhibited worse short term recollective memory (1 hour novel object) compared to females. DHT had no effect on recollective memory, regardless of Aβ exposure. No effects were observed in the long-term recollective memory (24-hour novelty test). CONCLUSIONS: Our results indicate that Aβ 's effects on short term recollective memory is influenced by sex chromosomes, as we observed sex differences in the hormone deficient (cholesterol) treated animals. However, DHT did not impact these recollective memory. These results indicate that recollective memory in AD is impacted by the sex chromosomes and not androgens.
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    A mendelian randomization analysis of obesity on the development of Alzheimer’s disease
    (2023) Nolan, Emma; Zhou, Zhengyang
    Purpose: To assess the causal associations between obesity and Alzheimer’s disease (AD) using Mendelian randomization analysis based on summary statistics from genome-wide association studies (GWAS). The most recent GWAS as of November 2021 for AD and obesity were used, including newly identified risk single nucleotide polymorphisms (SNPs) that were associated with AD and obesity. Specifically, the AD GWAS identified 42 new risk loci, which have not been utilized in other studies. Thus, this study provides novel evidence for the causal associations of AD and obesity. Methods: Genetic associations for the exposure (i.e., obesity; BMI ≥ 30kg/m2) were evaluated from a GWAS conducted on European individuals over age 18 in the FinnGen project (n = 218,792). Genetic associations for AD were evaluated from the whole exome sequencing data among European individuals aged 37-73 years in the UK Biobank study (n = 111,326 AD cases and 677,633 controls). Based on the above summary statistics, a Two Sample Mendelian randomization (MR) analysis using the Inverse-Variance Weighted (IVW) method was conducted to evaluate the causal association between obesity and AD. Sensitivity analyses including median-based, mode-based, and MR-Egger MR methods were conducted to confirm findings from the main MR analysis. Results: Obesity was found to be associated with a decreased odds in the development of AD (Odds ratio = 0.91, 95% CI = [0.86, 0.95], p = 0.0001) according to the IVW method, suggesting a protective effect of obesity. The results of all sensitivity analyses were consistent with the main findings and determined the absence of horizontal pleiotropy and heterogeneity. Specifically, significant causal relationship between AD and obesity was identified in the IVW method and Weighted Median MR methods. Conclusion: The protective effect of obesity on the development of AD is supported by the MR analysis in this study. Further research should be conducted on the underlying pathological mechanism to inform potential health interventions such as weight modification in mid versus late life.
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    Characterization of Bilingual Mexican Americans among a Community Dwelling Cohort: An HABS-HD Study
    (2023) Goehring, Leah; Petersen, Melissa
    Introduction: Bilingualism has been increasingly studied in the context of neuroprotection particularly as it relates to cognitive decline. Despite higher rates of English/Spanish bilingualism, Mexican Americans also experience a higher risk of cognitive decline related to Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (ADRDs) as compared to Non-Hispanic Whites. Few studies to date have broadly examined the link between bilingualism and specific demographic, cognitive, and biomarkers among this ethnic group.The aim of this study is to examine the relationship between language status (monolingual/bilingual) on select demographic, cognitive, and AD specific blood biomarkers among this racial/ethnic group. Methods: Data were analyzed on n=890 Mexican Americans from the The Health & Aging Brain Study - Health Disparities (HABS-HD) study. Participants completed a clinical interview, which includes a self-report of language status (monolingual/bilingual) as well as various neuropsychological tests and an informant interview in order for clinicians to determine cognitive and functional status. Plasma amyloid (A), tau (T), and neurofilament light chain [NfL](N) blood biomarkers were assayed using the ultra-sensitive Single molecule array (Simoa) technology. Demographic characteristics were generated utilizing independent t-tests or chi square analyses for continuous and/or categorical variables. ANCOVAs were conducted with covariates of age, sex, and education for cognitive test performance and A/T/(N) blood biomarkers split by language status (monolingual, bilingual) as well as by cognitive status (cognitively unimpaired, cognitively impaired). Results: Of the n=890 Mexican Americans, n=393 self reported as monolingual and n=497 as bilingual. Among monolinguals, 70% were diagnosed as cognitively unimpaired, 20% with mild cognitive impairment (MCI), and 10% with Dementia while among bilinguals, 78% received a diagnosis of cognitively unimpaired, 17% with MCI, and 5% with Dementia. Regarding neuropsychological testing, bilingual individuals performed significantly better across measures of global cognition, attention, and processing speed (ps<0.001). While examining blood biased biomarkers, a trending significance of higher total tau was found among bilinguals compared to monolinguals. When separated by cognitive status, total tau was higher among bilingual Mexican Americans who were cognitively unimpaired (p=0.044). Higher Aβeta 40 levels were found to be significantly associated with reduced performance on measures of attention, processing speed, and executive functioning among bilinguals who were cognitively unimpaired (ps<0.001). Among bilinguals with cognitive impairment, higher total tau levels were associated with lower performance on a measure of working memory (p=0.001) and higher NfL levels were associated with lower performance on measures of global cognitive screening measure and working memory (ps=0.001). Discussion: As rates of AD and ADRDs increase in Mexican Americans, their bilingualism may be advantageous in delaying this pathology. Bilingualism is differentially related to cognitive and AD biomarkers. Better understanding the relationship between bilingualism and these markers might be informative regarding potential protective effects for this at risk group.
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    Carotid arterial stiffness and cerebral blood flow variability in individuals with mild cognitive impairment
    (2023) Bhuiyan, Nasrul; Davis, K. Austin; Vintimilla, Raul; Borzage, Matthew; Pahlevan, Niema; King, Kevin; Johnson, Leigh; O'Bryant, Sid; Rickards, Caroline
    Purpose: It is unclear whether cerebral blood flow variability is a sign of impaired vascular function or an adaptation to chronic cerebral hypoperfusion in individuals with cognitive dysfunction. Elevated arterial stiffness increases transmission of pulsatile pressure to the brain, but the relationship between arterial stiffness, the magnitude of cerebral blood flow variability, and cognitive dysfunction is unknown. In this pilot study, we hypothesized that carotid artery stiffness would be higher in individuals with mild cognitive impairment (MCI) compared with individuals with normal cognition (NC), resulting in higher cerebral blood flow variability. Methods: In individuals with MCI (N=5) or NC (N=7), R-wave to common carotid artery (CCA) pulse wave velocity (PWV) was assessed as an index of arterial stiffness (via tonometry). CCA velocity (CCAv) and middle cerebral artery velocity (MCAv) were measured via transcranial Doppler ultrasound, with concurrent measurements of mean arterial pressure (MAP) via finger photoplethysmography. The amplitude of MAP, CCAv, and MCAv oscillations in the low frequency range (LF; 0.07-0.15 Hz) were assessed via fast Fourier transformation, and normalized to total power (0.04-0.4 Hz) for each participant to account for high inter-individual variability. Relationships between R-wave-carotid PWV and LF variability in CCAv and MCAv were assessed via correlational analyses. Results: There were no between-group differences for R-wave-carotid PWV (MCI: 0.91±0.16 m/s vs. NC: 0.87±0.07 m/s; P=0.70), mean CCAv (MCI: 31.8±8.8 cm/s vs. NC: 29.7±2.0 cm/s; P=0.54), mean MCAv (MCI: 50.9±6.5 cm/s vs. NC: 47.9±12.7 cm/s; P=0.63), or MAP (MCI: 102.1±10.2 mmHg vs. 104.7±13.8 mmHg; P=0.73). While there was also no difference between groups for nLF power of CCAv (MCI: 0.28±0.03 au vs. NC: 0.33±0.10 au; P=0.41), nLF power for MCAv was lower in the MCI group (MCI: 0.26±0.07 au vs. 0.43±0.12; P=0.02). Overall, there was a strong positive correlation between R-wave-carotid PWV and CCAv nLF power (R=0.81, P=0.005), but a weaker relationship for MCAv nLF power (R=0.56, P=0.09). While sub-group correlational analyses are limited based on the small sample sizes, relationships between R-wave-carotid PWV and CCAv nLF power were high for both MCI (R=0.98, P=0.02) and NC (R=0.79, P=0.06) groups, but were lower for MCAv nLF power (MCI: R=-0.12, P=0.88; NC: R=0.69, P=0.13). Conclusion: Contrary to our hypothesis, there were no differences in R-wave-carotid PWV between groups, and blood flow variability was either similar between groups (for CCAv), or lower in the MCI group (for MCAv). Overall, there was a strong positive relationship between R-wave-carotid PWV and blood flow variability in the CCA, which was also observed in sub-analysis of the MCI and NC groups. Future investigations with a larger sample size are needed to definitively determine the role of arterial stiffness on cerebral blood flow variability with cognitive dysfunction.
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    Role of methylation in risk for cognitive impairment in Mexican Americans
    (2023) Abraham Daniel, Ann; Silzer, Talisa; Sun, Jie; Zhou, Zhengyang; Hall, Courtney; Phillips, Nicole R.; Barber, Robert C.
    Purpose: Mexican Americans (MAs) are the largest aging (›65 years old) and growing US ethnic minority group, with a unique risk for cognitive impairment (CI) in comparison to non-Hispanic whites (NHWs). MAs have an earlier age of onset and a risk for CI that is largely metabolism related in contrast to NHWs who have a more inflammation-based risk for CI. CI is defined in this study as individuals diagnosed with either Alzheimer’s disease (AD), or mild cognitive impairment (MCI) (a likely precursor to AD). Risk for CI is multifactorial and involves an epigenetic form of gene regulation called DNA methylation, which involves the addition of a methyl group to the cytosine base of DNA. DNA methylation patterns can be altered or possibly reversed through changes in environmental factors such as diet and lifestyle. Our aim was to identify differentially methylated sites of the genome associated with CI and determine DNA methylation profiles that are specific to MAs and NHWs. Methods: Peripheral blood was drawn from 551 Texas Alzheimer's Research and Care Consortium participants (299 MAs and 252 NHWs) and DNA was typed on the Illumina Infinium MethylationEPIC chip array, assessing >850,000 CpG genomic sites. Participants were compared according to cognitive status (control versus CI(AD/MCI)) among each ethnic group. Beta values that represent relative degree of methylation were normalized using the Beta MIxture Quantile dilation (BMIQ) method. Differential methylation between control and CI was assessed using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages within R studio. Results: Two significant differentially methylated sites were associated with CI at an FDR-adjusted p-value threshold <0.05: cg13135255 in MAs and cg27002303 in NHWs. Three differentially methylated sites were suggestively associated with CI at an FDR-adjusted p-value threshold <0.1: cg01887506 and cg10607142 in MAs, and cg13529380 in NHWs. Four of the five significant and suggestively differentially methylated sites were hypermethylated in CI compared to normal controls, except for hypomethylated site cg13529380. The site most significantly associated with CI was cg13135255 within the CREBBP gene in MAs (FDR-adjusted p-value = 0.029). The CREBBP protein is a histone acetyltransferase, involved in epigenetic regulation, and plays a role in memory formation. Conclusion: This is the first study to report these specific CpG sites as either significantly or suggestively associated with CI among MAs and NHWs. These sites may be used in addition to other methylated sites to develop risk assessments that are ethnicity specific for CI. Following further validation and replication in other cohorts these sites may aid development of ethnic specific therapeutics that could deter or delay CI in the future.
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    Application of Structural Retinal Biomarkers to Detect Cognitive Impairment in a Primary Care Setting
    (2023) Nyalakonda, Ramyashree; Petersen, Melissa; Zhang, Fan; Johnson, Leigh; Tolman, Alex; Gutierrez, Alejandra; O'Bryant, Sid; Mozdbar, Sima
    Introduction Alzheimer’s Disease (AD) is the most prevalent form of dementia and a leading cause of death in the elderly. The detection of AD remains poor in primary care despite the advancement of neurodiagnostic procedures. There are no rapid and cost-effective tools available to primary care providers to conduct cognitive examinations to diagnose AD. The goal of this study is to determine the predictive ability of structural retinal biomarkers to identify cognitive impairment in a primary care setting. Methods Participants were recruited from Alzheimer’s Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging and fundus imaging was performed. Exclusion criteria included high intraocular pressure defines as greater than or equal to 30 mmHg in either eye, history of adverse effects with pupillary relation, known hypersensitivity to tropicamide or any ingredient in the formulation, active ocular infection or inflammation, history of angle closure glaucoma, or having undergone ocular surgery within the last 6 months. Cognitive diagnoses were assigned algorithmically and verified at consensus review by an expert in the field of dementia. Results Data were examined on a total of 91 participants (59 cognitively unimpaired, 32 cognitively impaired (26 mild cognitive impairment (MCI), 6 AD)). The top biomarkers for predicting cognitive impairment included the inferior quadrant of the outer retinal layers, all four quadrants of the peripapillary retinal nerve fiber layer (pRNFL), and the inferior quadrant of the macular retinal nerve fiber layer. While all four quadrants of the pRNFL are highly important biomarkers for identifying those with cognitive impairment, the inferior and superior quadrants displayed higher relative importance compared to the temporal and nasal quadrants. Conclusion This study was the first to examine the utility of retinal biomarkers in diagnosis cognitive impairment in a primary care setting with models reflecting how it could be employed as a screening tool in practice. The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD. In prior studies, preferential thinning of the inner retinal layers is found in AD compared to healthy controls. This study can help distinguish those with cognitive impairment from those cognitively unimpaired. The availability of such a biomarker could increase access to disease modifying treatments once available.
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    Correlation Between Timed Up and Go Test and Neuroimaging in Mexican American and Non-Hispanic Americans with Alzheimer’s Disease
    (2023) Campbell, Blake; Lee, Yein; Peterson, Melissa; Meza, Sebastian; Hurt, Paige; Patterson, Rita
    Purpose: Alzheimer's Disease (AD) is a progressive neurodegenerative disease that causes cognitive and functional impairments. Abnormal amyloid plaque accumulation is known to be specific for AD, demonstrated by previous amyloid Positron Emission Tomography (PET) studies showing abnormal amyloid plagues levels in subjects in the early stages of the disease, not exhibiting clinical manifestations. 1,2 Hispanic Americans are underrepresented in AD research. This study explores the possible relationship between the amyloid plaque level visible on amyloid PET scans and non-specific Physical Performance Tests such as Timed Up and Go (TUG) among Mexican Americans and non-Hispanic white American subjects. Furthermore, this study explores the possible correlation between rising amyloid plaque levels and declining function measured by simple physical performance tests such as TUG in outpatient clinics for AD patients. Methods: Data were analyzed on n= 2076 Participants (n= 1037 Non-Hispanic White, n=1039 Hispanic, Mexican American) from the Health and Aging Brain Study- Health Disparities All participants underwent as part of the HABS-HD protocol cognitive testing, functional/medical examination, blood draw, and neuroimaging. Amyloid PET scans (with Neuraceq/florbetaben F18) were conducted with defined regions of intertest (ROIs) included the frontal, anterior/posterior cingulate, lateral parietal, and lateral temporal cortex. All participants completed the Timed UP and Go (TUG) test along with other gait measures as part of the functional examine. The TUG is a measure of functional mobility, higher scores mean worse performance on the measure. Chi-square (Sex) and t-tests (Age, Education, TUG performance) were used to examine differences in demographic characteristics across ethnic groups. Linear regression models were conducted to examine the relationship between Amyloid PET imaging and a functional measure (TUG) and the significance was set at p<0.05 Results: In our study, we found a statistically significant correlation between TUG time and increased amyloid uptake only in the lateral parietal region in Mexican American subjects (p=0.049). The other ROIs in Mexican American subjects showed no statistically significant correlation between TUG time and increased amyloid uptake. All ROIs in Non-Hispanic Whites showed no statistically significant correlation between TUG time and increased amyloid uptake. Conclusion: This study aimed to examine the relationship between physical performance measures (such as the TUG) and amyloid uptake. TUG is a non-specific physical performance measure often used in outpatient offices with older adult patients and is shown to correlate with cognitive decline.3 Using PET scans, we theorized that TUG results might correlate with the amyloid plaque level; however, our results were inconsistent with our initial hypothesis. On the other hand, this study did reveal a correlation between TUG time and increased amyloid uptake (only in the lateral parietal region) with subjects of Mexican descent, therefore; highlighting the importance of exploring ethnic differences in AD research. Finally, this study is limited by a small sample size, and future work with additional samples should help examine the TUG and amyloid uptake relationship and ethnic differences.
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    Area deprivation index and cognitive function: A cross-sectional study of the HABS-HD cohort
    (2023) Benton, Abigail; Vintimilla, Raul; Hall, James; Johnson, Leigh; O'Bryant, Sid
    Purpose: Dementia is an ever-growing group of disorders worldwide. It is proposed that neighborhood socioeconomic status (NSES) is linked with overall health, and this study will evaluate whether NSES is cross-sectionally associated with cognition in non-Hispanic White, African American, and Mexican American participants of the Health and Aging Brain: Health Disparities Study (HABS-HD). Methods: The HABS-HD is a longitudinal study conducted by the Institute for Translational Research at the University of North Texas Health Science Center. Participants (n=1634) were age 50 years or older, and underwent a clinical interview, neuropsychological exam battery, functional examination, head MRI, amyloid PET scan, and blood draw for clinical and biomarker analysis. NSES was measured using the national area deprivation index (ADI) percentile ranking, which considered the variables of education, employment, income, occupation, and housing. Cognition was assessed by the Mini-Mental State Examination, Trails B Exam, FAS Test, Spanish English Verbal Learning Test, and Digit-Symbol Substitution Test. The cognitive performance in those living in the 20% most disadvantaged neighborhoods was compared to those in the 80% least disadvantaged neighborhoods using multiple linear regression models with age, sex, education, and ethnicity as control variables. Results: Those in the most deprived neighborhood group were statistically significantly (p<0.05) younger, less educated, more likely to be female, and more likely to be Mexican American. The means of MMSE and Trails B test were lower in those living in the more deprived neighborhood group (p<0.05). When looking at the linear model of ADI and cognition, after adjusting for covariates, only Trails B scores were related to the higher deprived neighborhood group (t = -0.62, p <0.0001). Conclusion: Our study revealed that some measures of cognitive impairment were higher in people living in the top 20% disadvantaged neighborhoods. In future studies, specific markers of deprivation should be analyzed along with cognitive impairment to more specifically advocate for beneficial change. Further, due to sex and ethnicity being significant cofounders, analysis should be run by ethnicity to investigate this distinction.
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    Use of VMAT2 Inhibitors for Tardive Dyskinesia in Geriatrics - A Case Study
    (2023) Haag, Morgan; Davis, Sandra
    Background: Tardive dyskinesia is a persistent, often irreversible movement disorder that may develop after chronic, cumulative exposure to antipsychotics. Geriatric populations are at increased risk of developing tardive dyskinesia as they age, leading to increased risk of injuries secondary to impaired gait and balance. VMAT2 inhibitors such as valbenazine, deutetrabenazine, and tetrabenazine are the first-line treatment and control of tardive dyskinesia. Case Information: After developing tardive dyskinesia on aripiprazole, our patient was started on valbenazine before developing Parkinsonian symptoms and was subsequently switched to deutetrabenazine for management of the tardive dyskinesia. It has taken years of trial and error to adequately manage her tardive dyskinesia without significant untoward effects. Conclusion: As use of VMAT2 inhibitors in managing antipsychotic induced tardive dyskinesia increases, special consideration regarding their efficacy and safety must be taken when starting in older patients. The case presented here highlights the increased risk of development of movement disorders in older adults on even short courses of antipsychotics, as well as the variability in response to VMAT2 inhibitors in resultant treatment. This case also represents the need for caution and concern when prescribing antipsychotics in patients >55, as older adults may have increased susceptibility to the development of tardive dyskinesia even with shorter term second generation antipsychotic use.
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    Proteomic Profiles of Tau Positivity among an Ethnically Diverse Cohort: An HABS-HD Study
    (2023) Do, Tony; Petersen, Melissa; Zhang, Fan; Hall, James; O'Bryant, Sid
    Purpose: PET tau has been well documented to precede Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). In the pursuit of increasing the accessibility of AD diagnosis, studies have shown that blood biomarkers including ptau181 trend with PET tau in Non-Hispanic Whites (NHW). Current literature shows limited studies on Mexican Americans (MA) who have a higher risk of AD at earlier ages. MA populations have shown to have significantly higher burden of blood biomarkers/metabolic markers that are associated with MCI including ptau181, insulin, and glucagon, but lower in plasma amyloid. Our aim is to look at the utility of AT(N) (amyloid, tau, neurodegeneration) biomarkers in the detection of PET Tau positivity status among MA and NHWs Methods: Data were analyzed from n=401 participants (Total sample [n=21 Tau positive, n=380 Tau negative]; Black [n=11 Tau positive, n=216 Tau negative]; Hispanic [n=5 Tau positive, n=50 Tau negative]; Non-Hispanic whites [n=5 Tau positive, n=114 Tau negative]) from a community-based study of brain aging the Health and Aging Brain Study- Health Disparities (HABS-HD). HABS-HD participants underwent a clinical interview, neuropsychological testing, blood draw, functional medical exam and neuroimaging as a part of the study’s protocol. Plasma blood biomarkers used in this study consisted of Amyloid Beta 40, 42, Total Tau, Ptau181 and NFL derived using Single Molecule Array Technology (SIMOA) on an HDX platform. PET Tau positivity status was determined based on a clinical read. Support Vector Machine (SVM) models were used with plasma ATN biomarkers as predictors of PET Tau positivity status (Positive; Negative). SVM models were run with 10 times, five-fold repeated cross--validation and included models with and without demographics. Results: In the total sample, ATN biomarkers produced an area under the curve (AUC) of 98% with a sensitivity [SN] of 100% and Specificity [SP] of 73% for distinguishing PET Tau Positive cases from PET Tau Negative. The same ATN biomarkers produced for Black participants an AUC of 98% (SN=100%, SP=80%), for Hispanic participants an AUC of 100% (SN=100%, SP=100%), and for Non-Hispanic White participants an AUC of 98% (SN=100%, SP=70%). The addition of demographic variables of age, gender, and education produced a slight increase in the AUC for both black and non-Hispanic white participants by 1%. The top biomarkers were shown to vary by race and ethnic group. Conclusions: The results further support the AT(N) biomarkers as a viable method in predicting AD/PET tau positivity, as well as confirming that ptau181 has heavy influence in MA. The varying results of top biomarkers between groups confirm that ethnic background plays a strong role in biomarker profiles contributing to AD. An interesting finding was that demographic factors were ranked higher in black participants in distinguishing PET Tau positivity as compared to NHW and MA. Future work should expand on ptau181 value in relation to MCI state/AD progression in MA.