Browsing by Subject "Cognitive Dysfunction"
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Item Cardiovascular Risk Factors, Cognitive Dysfunction, and Mild Cognitive Impairment(S. Karger AG, 2020-11-16) Vintimilla, Raul; Balasubramanian, Kishore; Hall, James R.; Johnson, Leigh A.; O'Bryant, Sid E.Objectives: The present study sought to evaluate the contribution of cardiovascular risk factors to cognitive functioning in a sample of Mexican Americans diagnosed with mild cognitive impairment (MCI). Methods: Hypertension, diabetes, dyslipidemia, and obesity were diagnosed based on self-report and/or standardized procedures. Cognitive function was measured with MMSE, Logical Memory I and II, Trail A & B, FAS, animal naming, and digit span tests. Independent samples t tests and two-way ANOVAs were conducted for analyses, adjusting for relevant covariates. We studied 100 Mexican Americans (65 female) with MCI, ages 50-86, from a longitudinal study of cognitive aging conducted at the University of North Texas Health Science Center. Results: A difference between subjects with and without obesity and memory scores was shown by t tests. Two-way ANOVAs detected an association between the coexistence of hypertension and diabetes with language measures, diabetes and dyslipidemia with executive function, and diabetes and obesity with memory and language measures. Conclusions: This study provides additional evidence about the link between cardiovascular risk factors and cognitive dysfunction in MCI subjects, and also demonstrated that comorbid risk factors increased the degree of cognitive deficit in many areas, which may indicate a higher risk of developing dementia.Item Circulating mitochondrial DNA: New indices of type 2 diabetes-related cognitive impairment in Mexican Americans(PLoS, 2019-03-12) Silzer, Talisa K.; Barber, Robert C.; Sun, Jie; Pathak, Gita A.; Johnson, Leigh A.; O'Bryant, Sid E.; Phillips, NicoleMitochondrial function has been implicated and studied in numerous complex age-related diseases. Understanding the potential role of mitochondria in disease pathophysiology is of importance due to the rise in prevalence of complex age-related diseases, such as type 2 diabetes (T2D) and Alzheimer's disease (AD). These two diseases specifically share common pathophysiological characteristics which potentially point to a common root cause or factors for disease exacerbation. Studying the shared phenomena in Mexican Americans is of particular importance due to the disproportionate prevalence of both T2D and AD in this population. Here, we assessed the potential role of mitochondria in T2D and cognitive impairment (CI) in a Mexican American cohort by analyzing blood-based indices of mitochondrial DNA copy number (mtDNACN) and cell-free mitochondrial DNA (CFmtDNA). These mitochondrial metrics were also analyzed for correlation with relevant neuropsychological variables and physiological data collected as indicators of disease and/or disease progression. We found mtDNACN to be significantly decreased in individuals with CI, while CFmtDNA was significantly elevated in T2D; further, CFmtDNA elevation was significantly exacerbated in individuals with both diseases. MtDNACN was found to negatively correlate with age and fatty acid binding protein concentration, while positively correlating with CFmtDNA as well as CERAD total recall score. Candidate gene SNP-set analysis was performed on genes previously implicated in maintenance and control of mitochondrial dynamics to determine if nuclear variants may account for variability in mtDNACN. The results point to a single significant locus, in the LRRK2/MUC19 region, encoding leucine rich repeat kinase 2 and mucin 19. This locus has been previously implicated in Parkinson's disease, among others; rs7302859 was the driver SNP. These combined findings further indicate that mitochondrial dysfunction (as assessed by proxy via mtDNACN) is intimately linked to both T2D and CI phenotypes as well as aging.Item Depression, inflammation, and memory loss among Mexican Americans: analysis of the HABLE cohort(Cambridge University Press, 2017-06-20) Johnson, Leigh A.; Edwards, Melissa; Gamboa, Adriana; Hall, James R.; Robinson, Michelle; O'Bryant, Sid E.Background: This study explored the combined impact of depression and inflammation on memory functioning among Mexican-American adults and elders. Methods: Data were analyzed from 381 participants of the Health and Aging Brain study among Latino Elders (HABLE). Fasting serum samples were collected and assayed in duplicate using electrochemiluminesce on the SECTOR Imager 2400A from Meso Scale Discovery. Positive DepE (depression endophenotype) was codified as any score >1 on a five-point scale based on the GDS-30. Inflammation was determined by TNFɑ levels and categorized by tertiles (1st, 2nd, 3rd). WMS-III LMI and LMII as well as CERAD were utilized as measures of memory. ANOVAs examined group differences between positive DepE and inflammation tertiles with neuropsychological scale scores as outcome variables. Logistic regressions were used to examine level of inflammation and DepE positive status on the risk for MCI. Results: Positive DepE as well as higher inflammation were both independently found to be associated with lower memory scores. Among DepE positive, those who were high in inflammation (3rd tertile) were found to perform significantly worse on WMS-III LM I (F = 4.75, p = 0.003), WMS-III LM II (F = 8.18, p < 0.001), and CERAD List Learning (F = 17.37, p < 0.001) when compared to those low on inflammation (1st tertile). The combination of DepE positive and highest tertile of inflammation was associated with increased risk for MCI diagnosis (OR = 6.06; 95% CI = 3.9-11.2, p < 0.001). Conclusion: Presence of elevated inflammation and positive DepE scores increased risk for worse memory among Mexican-American older adults. Additionally, the combination of DepE and high inflammation was associated with increased risk for MCI diagnosis. This work suggests that depression and inflammation are independently associated with worse memory among Mexican-American adults and elders; however, the combination of both increases risk for poorer memory beyond either alone.Item Neurodegeneration from the AT(N) framework is different among Mexican Americans compared to non-Hispanic Whites: A Health & Aging Brain among Latino Elders (HABLE) Study(Wiley Periodicals, LLC, 2022-02-09) O'Bryant, Sid E.; Zhang, Fan; Petersen, Melissa E.; Hall, James R.; Johnson, Leigh A.; Yaffe, Kristine; Braskie, Meredith N.; Rissman, Robert A.; Vig, Rocky; Toga, Arthur W.Introduction: We sought to examine a magnetic resonance imaging (MRI)-based marker of neurodegeneration from the AT(N) (amyloid/tau/neurodegeneration) framework among a multi-ethnic, community-dwelling cohort. Methods: Community-dwelling Mexican Americans and non-Hispanic White adults and elders were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing and 3T MRI of the brain. A neurodegeneration MRI meta-region of interest (ROI) biomarker for the AT(N) framework was calculated. Results: Data were examined from n = 1305 participants. Mexican Americans experienced N at significantly younger ages. The N biomarker was significantly associated with cognitive outcomes. N was significantly impacted by cardiovascular factors (e.g., total cholesterol, low-density lipoprotein) among non-Hispanic Whites whereas diabetes (glucose, HbA1c, duration of diabetes) and sociocultural (household income, acculturation) factors were strongly associated with N among Mexican Americans. Discussion: The prevalence, progression, timing, and sequence of the AT(N) biomarkers must be examined across diverse populations.Item Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome(Wiley Periodicals, Inc., 2020-05-21) O'Bryant, Sid E.; Zhang, Fan; Silverman, Wayne; Lee, Joseph H.; Krinsky-McHale, Sharon J.; Pang, Deborah; Hall, James R.; Schupf, NicoleIntroduction: We sought to determine if proteomic profiles could predict risk for incident mild cognitive impairment (MCI) and Alzheimer's disease (AD) among adults with Down syndrome (DS). Methods: In a cohort of 398 adults with DS, a total of n = 186 participants were determined to be non-demented and without MCI or AD at baseline and throughout follow-up; n = 103 had incident MCI and n = 81 had incident AD. Proteomics were conducted on banked plasma samples from a previously generated algorithm. Results: The proteomic profile was highly accurate in predicting incident MCI (area under the curve [AUC] = 0.92) and incident AD (AUC = 0.88). For MCI risk, the support vector machine (SVM)-based high/low cut-point yielded an adjusted hazard ratio (HR) = 6.46 (P < .001). For AD risk, the SVM-based high/low cut-point score yielded an adjusted HR = 8.4 (P < .001). Discussion: The current results provide support for our blood-based proteomic profile for predicting risk for MCI and AD among adults with DS.Item Role of DNA Methylation in Risk for Cognitive Impairment in Mexican Americans(2023-05) Abraham Daniel, Ann; Barber, Robert C.; Phillips, Nicole R.; Zhou, Zhengyang; Planz, John V.Mexican Americans (MA) are the largest growing aging ethnic minority group in the US and have a unique risk for cognitive impairment (CI). The risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI) in MAs is largely metabolism-based compared to non-Hispanic whites (NHW). This risk for CI is multifactorial involving both genetic and epigenetic factors. During DNA methylation (an epigenetic process influenced by environment and lifestyle), a methyl group is added to the cytosine base of DNA; typically, at cytosine-phosphate-guanine (CpG) sites. The aim of this study was to identify differentially methylated regions of the genome associated with CI and determine ethnicity-specific DNA methylation profiles in MAs and NHWs. A total of 551 participants (299 MAs and 252 NHWs) from the Texas Alzheimer's Research and Care Consortium were selected and stratified by cognitive status (control vs CI). DNA from participants' peripheral blood was typed on the Illumina Infinium® MethylationEPIC chip array assessing >850,000 CpG sites. Beta values representing degree of methylation at CpG sites were normalized using the Beta MIxture Quantile dilation method. The Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R were used to assess differential methylation. Two differentially methylated sites at a false discovery rate (FDR) p-value <0.05 were significant: cg13135255 in MAs and cg27002303 in NHWs. Three suggestive hits at additional sites cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs) based on an FDR p-value <0.1 were also obtained. Most significant sites were hypermethylated in CI versus controls, except for hypomethylated cg13529380. Strongest CI association (FDR-adjusted p-value = 0.029) was at cg13135255 within the CREBBP gene in MAs. Ingenuity Pathway Analysis was used to identify CI associated disease pathways and upstream regulators from the significant CpG hits obtained using a nominal p-value <0.0005. Metabolic diseases for MAs and inflammatory diseases for NHWs were among the top five pathways. Upstream regulators in MAs, PHLPP1 and PHLPP2, have been associated with AD. The results display a more metabolism-related methylation-based risk for CI in MAs compared to NHWs in this cohort. Identifying additional ethnicity-specific methylation sites could help develop CI risk assessments for MAs in the future.Item The Effects of Cognitive Impairment on Hospitalizations in Heart Failure Patients(2018-05) Bhatti, MeganBackground: Heart failure (HF) is a major health problem in the United States (US) linked to poor survival rates, high rehospitalization rates and high healthcare cost. HF is positively associated with aging and its impact on US health and healthcare systems is expected to grow as the baby boomer generation enters their retirement years. The same is true for another chronic health risk, cognitive impairment. There is a clear, negative impact on prognosis and healthcare outcomes associated with cognitive impairment in HF patients, but less is known about how these affect systems outcomes such as overall hospitalization. The aim of this study is to compare hospitalization patterns among HF patients with and without comorbid cognitive impairment to identify associated risks and outcomes. Methods: We performed a cross-sectional study of adults over the age of 45 with a diagnosis of heart failure. The data for this analysis was obtained from the 2014 Medical Expenditure Panel Survey (MEPS). Statistical analyses were performed using SPSS. Differences in the distribution of risk for patients with and without cognitive disorders were evaluated using weighted Chi-squared tests. A weighted logistic regression was used to find factors associated with hospitalization risk by examining associations among demographic and other characteristics with the outcome. Results: A total of 175 adults were studied. There was evidence of a statistically significant association between the presence of cognitive impairment and hospitalization (X² = 5661.545, p<0.0001). However, the association between the two was very weak (Cramer's V = 0.053, p<0.000; Pearson's R = -0.053, p<0.000). A logistic regression model was fit to assess associations between the outcome and insurance coverage, cognitive impairment, race, sex, age, annual family income and education. The odds of hospitalization were 1.15 times more when a subject is uninsured, as compared to those who were insured (p<0.0001), all other factors held constant. Similarly, those without cognitive impairment had 1.33 times the odds of hospitalization compared to that of those with cognitive impairment (p<0.0001). White subjects were found to have an 88% increase in odds of hospitalization compared to their non-White counterparts (p<0.0001). Men were expected to have a 13% increase in odds of hospitalization (p<0.0001). Younger age was a protective factor; there was a 40% reduction in odds of hospitalization for subjects under 65 years old (p<0.0001). Subjects with an annual family income under $35,000 were at 2.5-fold increased odds of hospitalization (p<0.0001). Education also showed to be a significant protective factor. Subjects with less than a high school education had 5.3 times the odds of hospitalization compared to subjects with at least a Bachelor's degree. Subjects with a high school diploma and/ or some college had a 2.4-fold increase in odds of hospitalization compared to those with at least a Bachelor's degree (p<0.0001). Conclusions: Consistent with the literature, populations with older age, less education and lower income were at a higher risk of hospitalization. However, this study ultimately found no evidence that supports the theory that cognitive impairment affects hospitalizations in heart failure patients. It is plausible that the high prevalence and relatedness of comorbidities between cognitive impairment, race, socioeconomic status, education, and age simply mask the effects of cognitive impairment on hospitalizations. These results warrant the continued study of the effects of cognitive impairment and number of hospitalizations, in addition to overall risk of hospitalization.Item The Health & Aging Brain among Latino Elders (HABLE) study methods and participant characteristics(Wiley Periodicals, LLC, 2021-06-21) O'Bryant, Sid E.; Johnson, Leigh A.; Barber, Robert C.; Braskie, Meredith N.; Christian, Bradley; Hall, James R.; Hazra, Nalini; King, Kevin; Kothapalli, Deydeep; Large, Stephanie; Mason, David; Matsiyevskiy, Elizabeth; McColl, Roderick; Nandy, Rajesh; Palmer, Raymond; Petersen, Melissa E.; Philips, Nicole; Rissman, Robert A.; Shi, Yonggang; Toga, Arthur W.; Vintimilla, Raul; Vig, Rocky; Zhang, Fan; Yaffe, KristineIntroduction: Mexican Americans remain severely underrepresented in Alzheimer's disease (AD) research. The Health & Aging Brain among Latino Elders (HABLE) study was created to fill important gaps in the existing literature. Methods: Community-dwelling Mexican Americans and non-Hispanic White adults and elders (age 50 and above) were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T magnetic resonance imaging (MRI) of the brain. Amyloid and tau positron emission tomography (PET) scans were added at visit 2. Blood samples were stored in the Biorepository. Results: Data was examined from n = 1705 participants. Significant group differences were found in medical, demographic, and sociocultural factors. Cerebral amyloid and neurodegeneration imaging markers were significantly different between Mexican Americans and non-Hispanic Whites. Discussion: The current data provide strong support for continued investigations that examine the risk factors for and biomarkers of AD among diverse populations.Item The Intersection of Type 2 Diabetes and Cognitive Impairment in Mexican Americans: Insights from the Mitochondria(2018-05) Silzer, Talisa K.; Phillips, Nicole R.; Barber, Robert C.; Singh, Meharvan; Maddux, Scott D.Mitochondrial dysfunction is common in numerous complex age-related diseases. The role of mitochondrial dysfunction in cognitive impairment has yet to be studied in Mexican American populations. This population serves as a group of interest due to their high prevalence of type 2 diabetes (T2D). T2D is known to be associated with cognitive impairment (CI), suggesting that Mexican American populations may be at greater risk for CI. In this study, mtDNA copy number (mtDNACN), cell-free mtDNA (CFmtDNA) levels and mitochondrial gene expression was assessed. MtDNACN was found to be decreased in CI, while CFmtDNA was found to be elevated in T2D. Cross-condition comparisons of mitochondrial expression elucidated characteristic expression profiles perhaps associated with the co-occurrence of T2D and CI pathology.Item Transcriptomic Signatures of Cognitive Impairment(2020-08) Silzer, Talisa K.; Phillips, Nicole R.; Barber, Robert C.; Planz, John V.; Nejtek, Vicki; Rickards, Caroline A.The dramatic shift in population demographics and rapid growth of the aging population has resulted in a drastic increase in the prevalence of complex age-related diseases. Of the most common age-related complex diseases, Alzheimer's disease (AD) remains the primary cause of dementia. The increased prevalence of this disease presents a major burden on our healthcare system and caregivers. Among the many pathophysiological hallmarks, there is a substantial amount of literature implicating mitochondrial dysfunction as an important signature of early AD pathophysiology. Use of 'omics' technologies and system-based approaches have become increasingly more common for studying AD. Though each data type (i.e. genomics, transcriptomics and proteomics) has advantages and disadvantages, transcriptomics serves as a cost-efficient method for obtaining a snapshot of functional molecular changes underlying the disease. Here we detail two distinct and innovative studies of the transcriptome using different analytical strategies to investigate the underlying molecular signatures of cognitive impairment in its varying forms. We report the first study of differential gene expression in mild cognitively impaired Mexican Americans. This study revealed 30 differentially expressed transcripts that were enriched for a number of biological processes previously implicated in AD pathophysiology. The second study is also the first of its kind (in the context of this phenotype) examining posttranscriptional methylation at functionally important sites within the mitochondrial transcriptome of individuals diagnosed with AD, progressive supranuclear palsy (PSP) or pathological aging(PA). We observed similar hypermethylation at these key sites in individuals diagnosed with tauopathies such as AD or PSP. Several nuclear-encoded genes were identified as associated and the expression of 5300 nuclear-encoded transcripts was correlated with this hypermethylation. These correlated transcripts were enriched for a number of biological and molecular processes. Though these studies are quite distinct in methodology, we observed overlap in the enriched processes identified in each respective study (i.e. mitochondrial dysfunction, chromatin binding/remodeling, protein degradation pathways, autophagy); many of these processes have been previously implicated in AD. Replication of these findings in larger cohorts and different racial/ethnic populations will be vital for gaining a more complete understanding of the molecular dysfunction that underlies cognitive impairment phenotypes.