Browsing by Subject "Alzheimer Disease"
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Item A Precision Medicine Approach to Treating Alzheimer's Disease Using Rosiglitazone Therapy: A Biomarker Analysis of the REFLECT Trials(IOS Press, 2021-05-18) O'Bryant, Sid E.; Zhang, Fan; Petersen, Melissa E.; Johnson, Leigh A.; Hall, James R.; Rissman, Robert A.Background: The REFLECT trials were conducted to examine the treatment of mild-to-moderate Alzheimer's disease utilizing a peroxisome proliferator-activated receptor gamma agonist. Objective: To generate a predictive biomarker indicative of positive treatment response using samples from the previously conducted REFLECT trials. Methods: Data were analyzed on 360 participants spanning multiple negative REFLECT trials, which included treatment with rosiglitazone and rosiglitazone XR. Support vector machine analyses were conducted to generate a predictive biomarker profile. Results: A pre-defined 6-protein predictive biomarker (IL6, IL10, CRP, TNFɑ, FABP-3, and PPY) correctly classified treatment response with 100% accuracy across study arms for REFLECT Phase II trial (AVA100193) and multiple Phase III trials (AVA105640, AV102672, and AVA102670). When the data was combined across all rosiglitazone trial arms, a global RSG-predictive biomarker with the same 6-protein predictive biomarker was able to accurately classify 98%of treatment responders. Conclusion: A predictive biomarker comprising of metabolic and inflammatory markers was highly accurate in identifying those patients most likely to experience positive treatment response across the REFLECT trials. This study provides additional proof-of-concept that a predictive biomarker can be utilized to help with screening and predicting treatment response, which holds tremendous benefit for clinical trials.Item Accelerating Hyperparameter Tuning in Machine Learning for Alzheimer's Disease With High Performance Computing(Frontiers Media S.A., 2021-12-08) Zhang, Fan; Petersen, Melissa E.; Johnson, Leigh A.; Hall, James R.; O'Bryant, Sid E.Driven by massive datasets that comprise biomarkers from both blood and magnetic resonance imaging (MRI), the need for advanced learning algorithms and accelerator architectures, such as GPUs and FPGAs has increased. Machine learning (ML) methods have delivered remarkable prediction for the early diagnosis of Alzheimer's disease (AD). Although ML has improved accuracy of AD prediction, the requirement for the complexity of algorithms in ML increases, for example, hyperparameters tuning, which in turn, increases its computational complexity. Thus, accelerating high performance ML for AD is an important research challenge facing these fields. This work reports a multicore high performance support vector machine (SVM) hyperparameter tuning workflow with 100 times repeated 5-fold cross-validation for speeding up ML for AD. For demonstration and evaluation purposes, the high performance hyperparameter tuning model was applied to public MRI data for AD and included demographic factors such as age, sex and education. Results showed that computational efficiency increased by 96%, which helped to shed light on future diagnostic AD biomarker applications. The high performance hyperparameter tuning model can also be applied to other ML algorithms such as random forest, logistic regression, xgboost, etc.Item Acute Regression in Down Syndrome(MDPI, 2021-08-23) Handen, Benjamin; Clare, Isabel; Laymon, Charles; Petersen, Melissa E.; Zaman, Shahid; O'Bryant, Sid E.; Minhas, Davneet; Tudorascu, Dana; Brown, Stephanie; Christian, BradleyAcute regression has been reported in some individuals with Down syndrome (DS), typically occurring between the teenage years and mid to late 20s. Characterized by sudden, and often unexplained, reductions in language skills, functional living skills and reduced psychomotor activity, some individuals have been incorrectly diagnosed with Alzheimer's disease (AD).|This paper compares five individuals with DS who previously experienced acute regression with a matched group of 15 unaffected individuals with DS using a set of AD biomarkers.|While the sample was too small to conduct statistical analyses, findings suggest there are possible meaningful differences between the groups on proteomics biomarkers (e.g., NfL, total tau). Hippocampal, caudate and putamen volumes were slightly larger in the regression group, the opposite of what was hypothesized. A slightly lower amyloid load was found on the PET scans for the regression group, but no differences were noted on tau PET.|Some proteomics biomarker findings suggest that individuals with DS who experience acute regression may be at increased risk for AD at an earlier age in comparison to unaffected adults with DS. However, due to the age of the group (mean 38 years), it may be too early to observe meaningful group differences on image-based biomarkers.Item ApoE Genotype-Dependent Response to Antioxidant and Exercise Interventions on Brain Function(MDPI, 2020-06-25) Chaudhari, Kiran; Wong, Jessica M.; Vann, Philip H.; Como, Tori; O'Bryant, Sid E.; Sumien, NathalieThis study determined whether antioxidant supplementation is a viable complement to exercise regimens in improving cognitive and motor performance in a mouse model of Alzheimer's disease risk. Starting at 12 months of age, separate groups of male and female mice expressing human Apolipoprotein E3 (GFAP-ApoE3) or E4 (GFAP-ApoE4) were fed either a control diet or a diet supplemented with vitamins E and C. The mice were further separated into a sedentary group or a group that followed a daily exercise regimen. After 8 weeks on the treatments, the mice were administered a battery of functional tests including tests to measure reflex and motor, cognitive, and affective function while remaining on their treatment. Subsequently, plasma inflammatory markers and catalase activity in brain regions were measured. Overall, the GFAP-ApoE4 mice exhibited poorer motor function and spatial learning and memory. The treatments improved balance, learning, and cognitive flexibility in the GFAP-ApoE3 mice and overall the GFAP-ApoE4 mice were not responsive. The addition of antioxidants to supplement a training regimen only provided further benefits to the active avoidance task, and there was no antagonistic interaction between the two interventions. These outcomes are indicative that there is a window of opportunity for treatment and that genotype plays an important role in response to interventions.Item Cell-Free mtDNA Quantification in Alzheimer's Patients from the Mexican American Population(2020-05) House, Sara R.; Phillips, Nicole R.; Hodge, Lisa M.; Zascavage, Roxanne R.Abstract Background AD is a continuous problem in the 65+ population but it is especially challenging in the Hispanic population where not only is it more prevalent but more severe than Caucasian populations. This study explores the efficacy of using peripheral blood plasma as an alternative tissue for testing as well as the usefulness for future research assisting in identifying the population structure most at risk for developing AD based upon CF-mtDNA quantity results. Materials and Methods Samples tested included a total cohort (Mexican American and Caucasian) of 177 individuals (AD=45, MCI=74, NC=58). The Mexican American subset contained 92 individuals (AD=21, MCI=53, and NC=18). Peripheral blood plasma was collected from the TARCC biobank and quantified. CF-mtDNA was then tested for significance using correlation analyses, logistic and linear regression models. Results CF-mtDNA was significantly negatively correlated with education, age, sex, and hypertensive samples in the total and Mexican American populations. The greatest difference was expected to be in CF-mtDNA quantity from NC to AD samples. Instead, the most significant difference was between MCI and NC samples. As CF-mtDNA quantity increased, the MMSE and CDRSOB scores were less impaired. Conclusion In conclusion, CF-mtDNA is an easily accessible and easily tested molecular marker of diseases that are relevant to studies for cognitive decline. Although our findings were inconsistent with current literature, they bring to light the weight of confounding factors within limited sample studies. With the completion of the full sample set associated with this study, more power is needed to overcome these issues.Item Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry(Informa UK Limited, trading as Taylor & Francis Group, 2017-10-27) Lewczuk, Piotr; Riederer, Peter; O'Bryant, Sid E.; Verbeek, Marcel M.; Dubois, Bruno; Visser, Pieter Jelle; Jellinger, Kurt A.; Engelborghs, Sebastiaan; Ramirez, Alfredo; Parnetti, Lucilla; Jack, Clifford R.; Teunissen, Charlotte E.; Hampel, Harald; Lleó, Alberto; Jessen, Frank; Glodzik, Lidia; de Leon, Mony J.; Fagan, Anne M.; Molinuevo, José Luis; Jansen, Willemijn J.; Winblad, Bengt; Shaw, Leslie M.; Andreasson, Ulf; Otto, Markus; Mollenhauer, Brit; Wiltfang, Jens; Turner, Martin R.; Zerr, Inga; Handels, Ron; Thompson, Alexander G.; Johansson, Gunilla; Ermann, Natalia; Trojanowski, John Q.; Karaca, Ilker; Wagner, Holger; Oeckl, Patrick; van Waalwijk van Doorn, Linda; Bjerke, Maria; Kapogiannis, Dimitrios; Kuiperij, H. Bea; Farotti, Lucia; Li, Yi; Gordon, Brian A.; Epelbaum, Stéphane; Vos, Stephanie J.B.; Klijn, Catharina J.M.; Van Nostrand, William E.; Minguillon, Carolina; Schmitz, Matthias; Gallo, Carla; Lopez Mato, Andrea; Thibaut, Florence; Lista, Simone; Alcolea, Daniel; Zetterberg, Henrik; Blennow, Kaj; Kornhuber, JohannesIn the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.Item Characterization of the Meal-Stimulated Incretin Response and Relationship With Structural Brain Outcomes in Aging and Alzheimer's Disease(Frontiers Media S.A., 2020-11-30) Morris, Jill K.; John, Casey S.; Green, Zachary D.; Wilkins, Heather M.; Wang, Xiaowan; Kamat, Ashwini; Swerdlow, Russell S.; Vidoni, Eric D.; Petersen, Melissa E.; O'Bryant, Sid E.; Honea, Robyn A.; Burns, Jeffrey M.Background: Individuals with Alzheimer's Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear. Methods: Here, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; n = 32) and AD (n = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging. Results: The meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions. Conclusion: Our findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.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 Current state of Alzheimer's fluid biomarkers(Springer, 2018-11-28) Molinuevo, José Luis; Ayton, Scott; Batrla, Richard; Bednar, Martin M.; Bittner, Tobias; Cummings, Jeffrey; Fagan, Anne M.; Hampel, Harald; Mielke, Michelle M.; Mikulskis, Alvydas; O'Bryant, Sid E.; Scheltens, Philip; Sevigny, Jeffrey; Shaw, Leslie M.; Soares, Holly D.; Tong, Gary; Trojanowski, John Q.; Zetterberg, Henrik; Blennow, KajAlzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, ɑ-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.Item Genetic characterization of comorbidity patterns in aging associated diseases using integrative genomics(2019-08) Pathak, Gita A.; Phillips, Nicole R.; Planz, John V.; Barber, Robert C.; Zhou, Zhengyang; Gryczynski, IgnacyThe aging population in the US continues to grow at an exponential rate estimated to reach more than 90 million by 2060. The coexistence of two or more diseases (comorbidity) is prevalent in ages 65 years and above, and the number of comorbidities increases with age. The genetic factors underlying presence and absence of comorbidities is a severely understudied research domain. Alzheimer's disease (AD) is a type of dementia affecting 5.5 million people with an average age of diagnosis at 70 years. Hypertension is a coexisting condition in 60% AD individuals, also known as direct comorbidity. On the other hand, cancer is reported to be inversely comorbid with AD; individuals with cancer history have been reported to have lower risk of AD and vice versa. Furthermore, individuals with cancer history are diagnosed with long term side effects of radiation therapy — radiotoxicity. Twin-based studies have reported that certain gene variants are associated with radiotoxicity phenotypes with a heritability of 66%. This study proposes to investigate genetic factors associated with the direct and inverse comorbidity of AD with hypertension and cancer, and proctitis — a radiotoxicity phenotype observed in survivors of prostate cancer. The study aims to integrate gene variants, derived-gene expression and copy number variation (CNV), followed by functional and pathway-based prioritization of observed findings. We used genome-wide and cerebral spinal fluid profile to investigate presence of hypertension with AD to evaluate individual-level differences, followed by targeted investigation of neighboring gene expression profiles of identified variants. We found several novel genes associated with AD-hypertension comorbidity. The investigation between AD and cancer identified regions in chromosomes 4, 5 and 19 that are targeted by miRNA-17 family along with other miRNAs reported to be inversely expressed and play opposite role in pathogenicity of both diseases. The SNP-derived transcriptomic profile between AD and cancer highlighted involvement of sirtuin signaling. The findings together indicate involvement of mitochondrial and metabolic dysregulation which possibly contribute in differences of the epithelial-mesenchymal-transition. The SNP-derived expression and CNV association with proctitis highlighted genes involved in DNA-repair and mitochondrial ROS damage pathways.Item How often parents make decisions with their children is associated with obesity(BioMed Central Ltd., 2018-09-25) Rahman, Adrita; Fulda, Kimberly G.; Franks, Susan F.; Fernando, Shane I.; Habiba, Nusrath; Muzaffar, OmairBackground: Evidence supports that better parental involvement and communication are related to reduced obesity in children. Parent-child collaborative decision-making is associated with lower BMI among children; while child-unilateral and parent-unilateral decision-making are associated with overweight children. However, little is known about associations between joint decision-making and obesity among Hispanic youth. The purpose of this analysis was to determine the relationship between parent-child decision making and obesity in a sample of predominantly Hispanic adolescents. Methods: Data from two studies focused on risk for type II diabetes were analyzed. A total of 298 adolescents 10-14 years of age and their parent/legal guardian were included. Parents completed questionnaires related to psychosocial, family functioning, and environmental factors. Multiple logistic regression was used to determine the association between obesity (≥ 95th percentile for age and gender), the dependent variable, and how often the parent felt they made decisions together with their child (rarely/never, sometimes, usually, always), the primary independent variable. Covariates included gender, age, ethnicity, total family income, and days participated in a physical activity for at least 20 min. ORs and 95% CIs were calculated. Results: Adolescent participants were predominantly Hispanic n = 233 (78.2%), and approximately half n = 150 (50.3%) were female. In multivariate analyses, adolescents who rarely/never made decisions together with their family had significantly higher odds (OR = 3.50; 95% CI [1.25-9.83]) of being obese than those who always did. No association was observed between either those who sometimes make decisions together or those who usually did and those that always did. Conclusions: Parents and children not making decisions together, an essential aspect of parent-child communication, is associated with increased childhood obesity. The results of our study contribute to evidence of parental involvement in decision-making as an important determinant of adolescent health. Further studies should explore temporal relationships between parenting or communication style and obesity.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 Next Generation Sequencing Assessment of Mitochondrial Oxidative DNA Damage in Cognitive Impairment: Shedding Light on Health Disparities in Mexican Americans(2022-08) Reid, Danielle M.; Phillips, Nicole R.; Barber, Robert C.; Sumien, Nathalie; Thorpe, Roland; Planz, John V.; Maddux, Scott D.Currently, Alzheimer's Disease (AD) is listed as the 5th and 7th leading cause of death in the US aging (individuals 65+ years of age) and general population, respectively. The US aging population has been expanding over time and is projected to triple over the next two to three decades. As this demographic shift occurs, the impact of age-related diseases, including AD will increase. Due to differences in biology, behavior, socio-economic status and health care access, this impact will not be distributed evenly across racial and ethnic divides in the US population. Unfortunately, most scientific data exists for non-Hispanic Whites (NHWs). Although limited in scope, the observations that we have for admixed populations such as Hispanics clearly show that racial/ethnic disparities and etiologies for AD exist; however, the details of these disparities remain to be elucidated. Collaborative research efforts from the Texas Alzheimer's Research and Care Consortium (TARCC) aim to identify ethnicity-specific factors that influence the development and progression of AD among Mexican Americans (MAs) compared to their NHW counterparts, and to better understand the role these factors play. Common risk factors for developing cognitive impairment (CI) in the MA population are stroke, diabetes, obesity, and depression. Although the reasons for the association between cognitive decline and comorbidities remain unclear, the incidence of these comorbid conditions is known to vary greatly across race and ethnicity. Diabetes for example is three times more prevalent among MAs relative to NHWs. Accumulating evidence indicates a correlation between common pathological changes observed in AD and DNA damage, particularly within the mitochondrial genome (mtDNA), which is positioned to be particularly vulnerable to DNA damage. Age-associated decline in mitochondrial function generates an accumulation of reactive oxygen species that are capable of damaging essential biomolecules including DNA and may help explain some of the racial and ethnic differences in etiology that exist for AD. Many forms of oxidative DNA damage exist, but oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is one of the most prevalent lesions and an indicator of mitochondrial dysfunction. Damaged mtDNA, such as 8oxoG serve as important markers of age-related systemic inflammation and upon release into peripheral circulation may exacerbate the physiology and pathophysiology contributing to AD development and/or progression. Current methods for the detection of oxidized bases are limited, costly, cumbersome, and lack reproducibility. Here we describe the use of Illumina-based next-generation sequencing to quantify variants of oxidatively modified G residues in mtDNA of MA vs NHW TARCC participants. Our first study focused on investigating whether impaired mitochondrial function, represented by levels of oxidative DNA damage indicative of 8oxoG differed between MAs and NHWs. Additionally, we evaluated the effects of sex, CI, and type-2 diabetes (T2D) on risk for AD. We discovered variants representing 8oxoG from buffy coat were significantly higher in MAs compared to NHWs. Interestingly, MA females were especially affected, and years of education was significantly associated with 8oxoG load in MAs. We report suggestive evidence that 8oxoG mutational load is associated with cognitive impairment. Further, we identified individual mtDNA haplotypes that render an increased risk for oxidative DNA damage. Our second study used blood-based measurements of 8oxoG from both buffy coat and plasma to determine associations with population, sex, and T2D, for AD risk. We investigate genomic regions specially burdened by 8oxoG affecting mitochondrial function in relation to population and disease. Lastly, we characterize differences in 8oxoG mutational load between buffy coat and plasma portions of blood on assessing AD risk and endophenotype. Our results show that both buffy coat and plasma were significantly associated with population, sex, years of education, and suggest association with AD.Item PERICYTE AND CAPILLARY MAY DECLINE DEPENDING ON THE AGING PROCESS IN MICE(2022-05) Omoba, Oluwaseun E.; Jin, Kunlin; Rickards, Caroline A.; Mathis, Keisa W.Purpose. In this study, we explore the effects of aging on pericytes and capillaries using mice. Pericytes are important components of the neurovascular unit and function as contractile cells around the walls of capillaries. They play many important roles in the brain, such as blood vessel formation, cerebral brain blood flow, maintenance of the blood-brain barrier, and regulation of immune cell entry into the CNS. Dysfunction of pericytes contribute to a wide range of illnesses that result in cognitive impairments such as cerebrovascular disease, stroke, Alzheimer's disease (AD), and other neurological disorders. Aging has been studied and shown to be an established risk for vascular dysfunction that affects the integrity of the neurovascular unit. Furthermore, studies have shown significant reductions in pericyte density during age-related disorders, but these studies are few. Most nutrients in the brain are supplied by capillaries, and because pericytes are embedded on capillaries, studying their patterns and effects may lead to a better understanding of the pathophysiology and preliminary triggers of age-related disorders. In this study, we explore whether both pericyte and capillary numbers are affected in the adult brain of mice as they age. Methods. All experiments were performed on young (3 month old; n=3) and old (20-23 month old; n=3) C57BL/6 male mice. To identify pericytes and capillaries for quantification, immunohistochemistry and immunofluorescence were used. Pericytes were stained using the biomarker PDGFrβ and capillaries were stained using Lectin. CA1, CA2, CA3, and DG sites were chosen for quantification in the hippocampus, and layers I-VI in the somatosensory cortex of each mouse. Confocal imaging was used to study and quantify the population of PDGFrβ and lectin-positive cells. T-tests were performed to compare the number of pericytes in the hippocampus and somatosensory cortex of the two groups of mice (young and old). Results. Old mice exhibited significantly lower capillary (via lectin) and pericyte (via PDGFrβ) numbers than young mice (p < 0.0001) in the hippocampus. There was no significant reduction in the number of pericyte (p = 0.1448) and capillary (p = 0.0967) in the somatosensory cortex. Pericytes that expressed PDGFrβ were only classified as such when colocalized to capillaries. To record the number of pericytes embedded on capillaries, the number of PDGFrβ + Lectin that expressed a "bump-on-a-log" morphology was also quantified and showed a significant reduction in the hippocampus (p < 0.0001) and somatosensory cortex (p = 0.0110) with age. Conclusion. Since cerebrovascular dysfunction plays a vital role in the development of cognitive impairment disorders, understanding the aging patterns of neurovasculature cells such as pericytes may aid in the early prevention of age-related illnesses.Item Proteomic profiles of prevalent mild cognitive impairment and Alzheimer's disease among adults with Down syndrome(Wiley Periodicals, Inc., 2020-04-17) Petersen, Melissa E.; Zhang, Fan; Krinsky-McHale, Sharon J.; Silverman, Wayne; Lee, Joseph H.; Pang, Deborah; Hall, James R.; Schupf, Nicole; O'Bryant, Sid E.Introduction: We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease (AD) in the general population would apply to adults with Down syndrome (DS). Methods: Plasma samples were obtained from 398 members of a community-based cohort of adults with DS. A total of n = 186 participants were determined to be non-demented and without mild cognitive impairment (MCI) at baseline and throughout follow-up; n = 50 had prevalent MCI; n = 42 had prevalent AD. Results: The proteomic profile yielded an area under the curve (AUC) of 0.92, sensitivity (SN) = 0.80, and specificity (SP) = 0.98 detecting prevalent MCI. For detecting prevalent AD, the proteomic profile yielded an AUC of 0.89, SN = 0.81, and SP = 0.97. The overall profile closely resembled our previously published profile of AD in the general population. Discussion: These data provide evidence of the applicability of our blood-based algorithm for detecting MCI/AD among adults with DS.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.