Browsing by Subject "Alzheimer's 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 A Retrospective Medication Chart Review of Patients Clinically Diagnosed With Alzheimer’s Disease, Vascular Dementia and Mild Cognitive Impairment Disease.(2009-06-01) Longoria, Sandra; Dr. Patricia GwirtzItem 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 Application of Structural Retinal Biomarkers to Detect Cognitive Impairment in a Primary Care Setting(IOS Press, 2023-02-02) Mozdbar, Sima; Petersen, Melissa E.; Zhang, Fan; Johnson, Leigh A.; Tolman, Alex; Nyalakonda, Ramyashree; Gutierrez, Alejandra; O'Bryant, Sid E.BACKGROUND: Despite the diagnostic accuracy of advanced neurodiagnostic procedures, the detection of Alzheimer's disease (AD) remains poor in primary care. There is an urgent need for screening tools to aid in the detection of early AD. OBJECTIVE: This study examines the predictive ability of structural retinal biomarkers in detecting 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. RESULTS: Data were examined on n = 91 participants. 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, and the inferior quadrant of the macular retinal nerve fiber layer. CONCLUSION: The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD.Item Centralizing prescreening data collection to inform data-driven approaches to clinical trial recruitment(BioMed Central Ltd., 2023-05-03) Kirn, Dylan R.; Grill, Joshua D.; Aisen, Paul; Ernstrom, Karin; Gale, Seth; Heidebrink, Judith; Jicha, Gregory; Jimenez-Maggiora, Gustavo; Johnson, Leigh A.; Peskind, Elaine; McCann, Kelly; Shaffer, Elizabeth; Sultzer, David; Wang, Shunran; Sperling, Reisa; Raman, RemaBACKGROUND: Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening. METHODS: We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer's Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3-45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3-45 participant ID for those who continued to an in-person screening visit after study enrollment. RESULTS: Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3-611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch. CONCLUSION: Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.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 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 ELEVATED SERUM CREATININE LEVELS DIFFERENTIALLY IMPACT COGNITIVE FUNCTIONING AMONG MEXICAN AMERICAN ELDERS AND NON-HISPANIC WHITES: A PROJECT FRONTIER STUDY(2014-03) Regina, Stephen P.; Johnson, LeighObjective: Kidney function decreases with age and is commonly observed in the elderly. Even mildly decreased kidney function is associated with increased vascular disease and cerebrovascular disease, and is believed to influence risk of Alzheimer’s disease (AD). Mexican Americans are reported to exhibit a decreased serum creatinine (SCr) distribution relative to that of Non-Hispanic Whites . It has been suggested that blood-based measures of kidney function may have a predictive role in the future for identifying patients who may benefit from detailed cognitive screening . The aim of this study was to determine the effects of impaired renal function as assessed by elevated SCr on cognition among Mexican American and Non-Hispanic White elders. Method: Data were analyzed from 487 participants (n= 192, Mexican American; n= 295, Non-Hispanic White) enrolled in Project FRONTIER, a community-based study of health issues in rural-dwelling adults and elders. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum creatinine was reported by CMP. Linear regressions were utilized to examine the relationships between decreased measures of cognitive functioning and ethnicity when SCr level is elevated. Results: Among those who are Non-Hispanic white, elevated SCr levels were associated with poorer performance on tasks related to immediate memory (RBANS Immediate Memory Index, B[SE]= -3.12[1.32], t=-2.36, p=0.019) and language (RBANS Language Index, B[SE]=-2.04[0.79], t= -2.56, p=0.011). Concerning those who were Hispanic and of Mexican American decent, elevated SCr levels were found to be significantly negative associated with attention (RBANS Attention Index, B[SE]= -4.57[2.18], t=-2.08, p=0.038) and executive functioning (EXIT25, B[SE]= 1.90[0.82], t=2.29, p=0.023). Conclusions: This study emphasizes the ethnic differences observed with elevated levels of serum creatinine, which is a marker of kidney function. The results supported a differential relationship between creatinine and cognitive functioning, implicating that among Non-Hispanic Whites, elevated levels were associated with decreased performance on tasks of memory and language; whereas, among Hispanic Mexican Americans, there was a relationship between decreased performance on tasks of attention and executive functioning with elevations in the level of creatinine in serum.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 Hypermethylation at CREBBP Is Associated with Cognitive Impairment in a Mexican American Cohort(IOS Press, 2023-03-07) Abraham Daniel, Ann; Silzer, Talisa; Sun, Jie; Zhou, Zhengyang; Hall, Courtney; Phillips, Nicole; Barber, Robert C.BACKGROUND: The aging Mexican American (MA) population is the fastest growing ethnic minority group in the US. MAs have a unique metabolic-related risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI), compared to non-Hispanic whites (NHW). This risk for cognitive impairment (CI) is multifactorial involving genetics, environmental, and lifestyle factors. Changes in environment and lifestyle can alter patterns and even possibly reverse derangement of DNA methylation (a form of epigenetic regulation). OBJECTIVE: We sought to identify ethnicity-specific DNA methylation profiles that may be associated with CI in MAs and NHWs. METHODS: DNA obtained from peripheral blood of 551 participants from the Texas Alzheimer's Research and Care Consortium was typed on the Illumina Infinium® MethylationEPIC chip array, which assesses over 850K CpG genomic sites. Within each ethnic group (N = 299 MAs, N = 252 NHWs), participants were stratified by cognitive status (control versus CI). Beta values, representing relative degree of methylation, were normalized using the Beta MIxture Quantile dilation method and assessed for differential methylation using the Chip Analysis Methylation Pipeline (ChAMP), limma and cate packages in R. RESULTS: Two differentially methylated sites were significant: cg13135255 (MAs) and cg27002303 (NHWs) based on an FDR p < 0.05. Three suggestive sites obtained were cg01887506 (MAs) and cg10607142 and cg13529380 (NHWs). Most methylation sites were hypermethylated in CI compared to controls, except cg13529380 which was hypomethylated. CONCLUSION: The strongest association with CI was at cg13135255 (FDR-adjusted p = 0.029 in MAs), within the CREBBP gene. Moving forward, identifying additional ethnicity-specific methylation sites may be useful to discern CI risk in MAs.Item Hyperparameter Tuning with High Performance Computing Machine Learning for Imbalanced Alzheimer's Disease Data(MDPI, 2022-11-17) Zhang, Fan; Petersen, Melissa E.; Johnson, Leigh A.; Hall, James R.; O'Bryant, Sid E.Accurate detection is still a challenge in machine learning (ML) for Alzheimer's disease (AD). Class imbalance in imbalanced AD data is another big challenge for machine-learning algorithms working under the assumption that the data are evenly distributed within classes. Here, we present a hyperparameter tuning workflow with high-performance computing (HPC) for imbalanced data related to prevalent mild cognitive impairment (MCI) and AD in the Health and Aging Brain Study-Health Disparities (HABS-HD) project. We applied a single-node multicore parallel mode to hyperparameter tuning of gamma, cost, and class weight using a support vector machine (SVM) model with 10 times repeated fivefold cross-validation. We executed the hyperparameter tuning workflow with R's bigmemory, foreach, and doParallel packages on Texas Advanced Computing Center (TACC)'s Lonestar6 system. The computational time was dramatically reduced by up to 98.2% for the high-performance SVM hyperparameter tuning model, and the performance of cross-validation was also improved (the positive predictive value and the negative predictive value at base rate 12% were, respectively, 16.42% and 92.72%). Our results show that a single-node multicore parallel structure and high-performance SVM hyperparameter tuning model can deliver efficient and fast computation and achieve outstanding agility, simplicity, and productivity for imbalanced data in AD applications.Item Interdisciplinary Research in Alzheimer's Disease and the Roles International Societies Can Play(JKL International, 2021-02-01) Tan, Shawn Zheng Kai; Zhao, Robert Chunhua; Chakrabarti, Sasanka; Stambler, Ilia; Jin, Kunlin; Lim, Lee WeiAn ever-increasing ageing population has elevated Alzheimer's disease to be one of the biggest challenges in modern medicine. Alzheimer's disease is highly complex, and we are still no closer to understanding the causes, let alone an effective treatment. The lack of good experimental models and lack of critical understanding has led to high failure rates of clinical trials with high associated costs, as well as difficulties in implementing treatments. The multifaceted nature of this disease highlights the need for an interdisciplinary approach to address these concerns. In this essay, we suggest how collaborative work can be useful in addressing some of the above issues. We then propose that international organisations and publishers need to support interdisciplinary research by creating platforms, lobbying funders, and pushing for interdisciplinary publications. We further highlight some of the issues involved in implementing these suggestions and argue that willpower of the research community, together with a re-evaluation of evaluation metrics and incentive systems, are needed in order to foster interdisciplinary research. Overall, we emphasise the need for interdisciplinary research in Alzheimer's disease and suggest that international societies should play a huge role in this endeavour.Item Mitochondrial SOS: how mtDNA may act as a stress signal in Alzheimer's disease(BioMed Central Ltd., 2023-10-12) Gorham, Isabelle K.; Barber, Robert C.; Jones, Harlan P.; Phillips, Nicole R.BACKGROUND: Alterations in mitochondrial DNA (mtDNA) levels have been observed in Alzheimer's disease and are an area of research that shows promise as a useful biomarker. It is well known that not only are the mitochondria a key player in producing energy for the cell, but they also are known to interact in other important intracellular processes as well as extracellular signaling and communication. BODY: This mini review explores how cells use mtDNA as a stress signal, particularly in Alzheimer's disease. We investigate the measurement of these mtDNA alterations, the mechanisms of mtDNA release, and the immunological effects from the release of these stress signals. CONCLUSION: Literature indicates a correlation between the release of mtDNA in Alzheimer's disease and increased immune responses, showing promise as a potential biomarker. However, several questions remain unanswered and there is great potential for future studies in this area.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 Novel pharmacotherapy: NNI-362, an allosteric p70S6 kinase stimulator, reverses cognitive and neural regenerative deficits in models of aging and disease(BioMed Central Ltd., 2021-01-13) Sumien, Nathalie; Wells, Matthew S.; Sidhu, Akram; Wong, Jessica M.; Forster, Michael J.; Zheng, Qiao-Xi; Kelleher-Andersson, Judith A.Aging is known to slow the neurogenic capacity of the hippocampus, one of only two mammalian adult neurogenic niches. The reduction of adult-born neurons with age may initiate cognitive decline progression which is exacerbated in chronic neurodegenerative disorders, e.g., Alzheimer's disease (AD). With physiologic neurogenesis diminished, but still viable in aging, non-invasive therapeutic modulation of this neuron regeneration process remains possible. The discovery of truly novel neuron regenerative therapies could be identified through phenotypic screening of small molecules that promote adult-born neurons from human neural progenitor cells (hNPCs). By identifying neuron-generating therapeutics and potentially novel mechanism of actions, therapeutic benefit could be confirmed through in vivo proof-of-concept studies. The key aging and longevity mTOR/p70S6 kinase axis, a commonly targeted pathway, is substrate for potential selective kinase modulators to promote new hippocampal neurons from NPCs. The highly regulated downstream substrate of mTOR, p70S6 kinase, directly controls pleiotropic cellular activities, including translation and cell growth. Stimulating this kinase, selectively in an adult neurogenic niche, should promote NPC proliferation, and cell growth and survival in the hippocampus. Studies of kinase profiling and immunocytochemistry of human progenitor neurogenesis suggest that the novel small molecule NNI-362 stimulates p70S6 kinase phosphorylation, which, in turn, promotes proliferation and differentiation of NPCs to neurons. NNI-362 promoted the associative reversal of age- and disease-related cognitive deficits in aged mice and Down syndrome-modeled mice. This oral, allosteric modulator may ultimately be beneficial for age-related neurodegenerative disorders involving hippocampal-dependent cognitive impairment, specifically AD, by promoting endogenous hippocampal regeneration.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.