Geriatrics Commons^™

Secure Human Action Recognition By Encrypted Neural Network Inference, Miran Kim, Xiaoqian Jiang, Kristin Lauter, Elkhan Ismayilzada, Shayan Shams

Faculty, Staff and Student Publications

Advanced computer vision technology can provide near real-time home monitoring to support "aging in place" by detecting falls and symptoms related to seizures and stroke. Affordable webcams, together with cloud computing services (to run machine learning algorithms), can potentially bring significant social benefits. However, it has not been deployed in practice because of privacy concerns. In this paper, we propose a strategy that uses homomorphic encryption to resolve this dilemma, which guarantees information confidentiality while retaining action detection. Our protocol for secure inference can distinguish falls from activities of daily living with 86.21% sensitivity and 99.14% specificity, with an average …

Characterization And Comparison Of Human Glioblastoma Models, Julia A. Schulz, Louis T. Rogers, Richard J. Kryscio, Anika M. S. Hartz, Björn Bauer

Sanders-Brown Center on Aging Faculty Publications

Abstract
Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate diferent aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess …

Elucidating The Role Of Cerebellar Synaptic Dysfunction In C9orf72-Als/Ftd - A Systematic Review And Meta-Analysis, Aleksandra Kaliszewska, Joseph Allison, Tarik-Tarkan Col, Christopher Shaw, Natalia Arias

Faculty, Staff and Student Publications

A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with synaptic dysfunction identified as an early pathological hallmark. Although TDP-43 pathology and overt neurodegeneration are largely absent from the cerebellum, the pathological hallmarks of RNA foci and dipeptide repeat protein (DPR) inclusions are most abundant. Here, we present a systematic literature search in the databases of PubMed, Scopus, Embase, Web of Science and Science Direct up until March 5, 2021, which yielded 19,515 publications. Following the exclusion criteria, 72 articles were included having referred to C9orf72 …

An Il1rl1 Genetic Variant Lowers Soluble St2 Levels And The Risk Effects Of Apoe-Ε4 In Female Patients With Alzheimer’S Disease, Yuanbing Jiang, Xiaopu Zhou, Hui Yi Wong, Li Ouyang, Fanny C. F. Ip, Vicky M. N. Chau, Shun-Fat Lau, Wei Wu, Daniel Y. K. Wong, Heukjin Seo, Wing-Yu Fu, Nicole C. H. Lai, Yuewen Chen, Alzheimer’S Disease Neuroimaging Initiative, Charles D. Smith, Gregory A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad

Sanders-Brown Center on Aging Faculty Publications

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD …

Exogenous Short Chain Fatty Acid Effects In App/Ps1 Mice, Diana J. Zajac, Benjamin C. Shaw, David J. Braun, Stefan J. Green, Joshua M. Morganti, Steven Estus

Sanders-Brown Center on Aging Faculty Publications

Elucidating the impact of the gut microbiome on Alzheimer’s Disease (AD) is an area of intense interest. Short chain fatty acids (SCFAs) are major microbiota metabolites that have been implicated as a mediator of gut microbiome effects in the brain. Here, we tested the effects of SCFA-treated water vs. saline-treated water on APPswe/PSEN1dE9 mice maintained under standard laboratory conditions. Mice were treated with SCFAs from five months of age until ten months of age, when they were evaluated for microbiome profile, impaired spatial memory as evaluated with the radial arm water maze, astrocyte activation as measured by Gfap expression and …

Enlarged Perivascular Spaces Are Negatively Associated With Montreal Cognitive Assessment Scores In Older Adults, Timothy J. Libecap, Valentinos Zachariou, Christopher E. Bauer, Donna M. Wilcock, Gregory A. Jicha, Flavius D. Raslau, Brian T. Gold

Sanders-Brown Center on Aging Faculty Publications

Emerging evidence suggests that enlarged perivascular spaces (ePVS) may be a clinically significant neuroimaging marker of global cognitive function related to cerebral small vessel disease (cSVD). We tested this possibility by assessing the relationship between ePVS and both a standardized measure of global cognitive function, the Montreal Cognitive Assessment (MoCA), and an established marker of cSVD, white matter hyperintensity volume (WMH) volume. One hundred and eleven community-dwelling older adults (56–86) underwent neuroimaging and MoCA testing. Quantification of region-specific ePVS burden was performed using a previously validated visual rating method and WMH volumes were computed using the standard ADNI pipeline. Separate …

Impact Of The Covid-19 Pandemic On Daily Life, Mood, And Behavior Of Adults With Down Syndrome, Sigan L. Hartley, Victoria Fleming, Brianna Piro-Gambetti, Annie Cohen, Beau M. Ances, Michael A. Yassa, Adam M. Brickman, Benjamin L. Handen, Elizabeth Head, Mark Mapstone, Bradley T. Christian, Ira T. Lott, Eric Doran, Shahid Zaman, Sharon Krinsky-Mchale, Frederick A. Schmitt, Christy L. Hom, Nicole Schupf

Sanders-Brown Center on Aging Faculty Publications

Background: The Down syndrome population has been disproportionately affected by Coronavirus 2019 (COVID-19) in terms of experiencing severe illness and death. Societal efforts to curb the spread of COVID-19 may also have taken a heavy toll on the daily lives of individuals with Down syndrome.

Objective/hypothesis: The goal of the study was to understand how the COVID-19 pandemic has altered daily life (including residence, employment, and participation in adult disability day programs) and influenced the mood and behavior of adults with Down syndrome.

Methods: Between September 2020 and February 2021, caregivers of 171 adults with Down syndrome (aged …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer’S Disease, Jaclyn M. Eissman, Logan Dumitrescu, Emily R. Mahoney, Alexandra N. Smith, Shubhabrata Mukherjee, Michael L. Lee, Phoebe Scollard, Seo Eun Choi, William S. Bush, Corinne D. Engelman, Qiongshi Lu, David W. Fardo, Emily H. Trittschuh, Jesse Mez, Catherine C. Kaczorowski, Hector Hernandez Saucedo, Keith F. Widaman, Rachel F. Buckley, Michael J. Properzi, Elizabeth C. Mormino, Hyun Sik Yang, Theresa M. Harrison, Trey Hedden, Kwangsik Nho, Shea J. Andrews, Douglas Tommet, Niran Hadad, R. Elizabeth Sanders, Douglas M. Ruderfer, Katherine A. Gifford, Xiaoyuan Zhong, Neha S. Raghavan, Badri Vardarajan, Margaret A. Pericak-Vance, Lindsay A. Farrer, Li San Wang, Carlos Cruchaga, Gerard D. Schellenberg, Nancy J. Cox, Jonathan L. Haines, C. Dirk Keene, Andrew J. Saykin, Eric B. Larson, Reisa A. Sperling, Richard Mayeux, Michael L. Cuccaro, David A. Bennett, Julie A. Schneider, Paul K. Crane, Angela L. Jefferson, Timothy J. Hohman

Sanders-Brown Center on Aging Faculty Publications

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience.

We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Plasmalogen Deficiency: A Risk Factor For Dementias And Potential Treatment Target, Mitchel A. Kling, Mallika Mendu, Rima F. Kaddurah-Daouk, Sheldon Jordan, Dayan B. Goodenowe

Rowan-Virtua Research Day

Altered lipid metabolism is implicated in the risk of sporadic Alzheimer’s disease (AD) and related dementias (ADRD); however, the precise mechanisms accounting for findings from observational studies remains to be fully elucidated.

Plasmalogens are a subclass of integral membrane phospholipids with unique properties that appear to play important roles relevant to the pathophysiology of AD and ADRD, including vesicle fusion necessary for synaptic neurotransmitter release, modulation of membrane fluidity and microdomain dynamics, membrane antioxidant functions, and neuroprotection. Like the more familiar phosphatides, plasmalogens are synthesized on a 3-carbon glycerol backbone; however, they differ from phosphatides by the presence of a …

Extracellular Vesicles Released After Cranial Radiation: An Insight Into An Early Mechanism Of Brain Injury, Suriyan Sukati, Jenni Ho, Luksana Chaiswing, Pradoldej Sompol, Harshul Shreekant Pandit, Wendy Wei, Tadahide Izumi, Quan Chen, Heidi Weiss, Teresa Noel, Subbarao Bondada, D. Allan Butterfield, Daret K. St. Clair

Sanders-Brown Center on Aging Faculty Publications

Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) …

Association Between Concussions And Suicidality In High School Students In The United States, Grant L. Iverson, Justin E. Karr

Sanders-Brown Center on Aging Faculty Publications

Importance: Prior research has shown a statistically significant association between sustaining a concussion and suicidality in adolescents, but this prior research controlled for relatively few variables predictive of suicidality.

Objective: To examine whether sustaining a concussion remained a significant predictor of suicidality after controlling for relevant covariates (e.g., sexual abuse/assault, bullying, substance use, depression), hypothesizing that the relationship between concussion and suicidality would become non-significant after controlling for these variables.

Design: This study involved secondary data analysis of the 2019 Youth Risk Behavior Surveillance (YRBS) System, a national cross-sectional study of adolescents. Analyses were stratified by gender. …

Manifestations Of Alzheimer’S Disease Genetic Risk In The Blood Are Evident In A Multiomic Analysis In Healthy Adults Aged 18 To 90, Laura Heath, John C. Earls, Andrew T. Magis, Sergey A. Kornilov, Jennifer C. Lovejoy, Cory C. Funk, Noa Rappaport, Benjamin A. Logsdon, Lara M. Mangravite, Brian W. Kunkle, Eden R. Martin, Adam C. Naj, Nilüfer Ertekin-Taner, Todd E. Golde, Leroy Hood, Nathan D. Price, Erin Abner, David W. Fardo, Linda J. Van Eldik, Alzheimer’S Disease Genetics Consortium

Sanders-Brown Center on Aging Faculty Publications

Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical …

Patterns Of Amygdala Region Pathology In Late-Nc: Subtypes That Differ With Regard To Tdp-43 Histopathology, Genetic Risk Factors, And Comorbid Pathologies, Matthew D. Cykowski, Anithachristy S. Arumanayagam, Suzanne Z. Powell, Andreana L. Rivera, Erin L. Abner, Gustavo C. Roman, Joseph C. Masdeu, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant agerelated TDP-43 encephalopathy (LATE). The amygdala is afected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age=85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, …

New Insights Into The Genetic Etiology Of Alzheimer’S Disease And Related Dementias, Céline Bellenguez, Fahri Küçükali, Iris Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C. Naj, Rafael Campos-Martin, David W. Fardo, Yuriko Kastumata, Erin L. Abner, Radb, Gr@Ace, Degesco, Eadi, Gerad, Demgene, Finngen, Adgc, Charge

Sanders-Brown Center on Aging Faculty Publications

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly …

Dissociation Of Tau Pathology And Neuronal Hypometabolism Within The Atn Framework Of Alzheimer’S Disease, Michael Tran Duong, Sandhitsu R. Das, Xueying Lyu, Long Xie, Hayley Richardson, Sharon X. Xie, Paul A. Yushkevich, Alzheimer’S Disease Neuroimaging Initiative, David A. Wolk, Ilya M. Nasrallah, Charles D. Smith, Gregory A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Michael W. Weiner, Paul Aisen, Ronald C. Petersen, Clifford R. Jack Jr.

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in ¹⁸F-flortaucipir vs. ¹⁸F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (N_M) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/N_M clusters with differing limbic and cortical patterns. The canonical group was defined as the T/N_M pattern with lowest regression residuals. Groups resilient to …

Region-Based Analysis Of Rare Genomic Variants In Whole-Genome Sequencing Datasets Reveal Two Novel Alzheimer’S Disease-Associated Genes: Dtnb And Dlg2, Dmitry Prokopenko, Sanghan Lee, Julian Hecker, Kristina Mullin, Sarah Morgan, Yuriko Katsumata, Michael W. Weiner, David W. Fardo, Nan Laird, Lars Bertram, Winston Hide, Cristoph Lange, Rudolph E. Tanzi

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10⁻⁶, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (p_meta= 4.74 × 10⁻⁸ ). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) …

Second Heart Field–Derived Cells Contribute To Angiotensin Ii–Mediated Ascending Aortopathies, Hisashi Sawada, Yuriko Katsumata, Hideyuki Higashi, Chen Zhang, Yanming Li, Stephanie Morgan, Lang H. Lee, Sasha A. Singh, Jeff Z. Chen, Michael K. Franklin, Jessica J. Moorleghen, Deborah A. Howatt, Debra L. Rateri, Ying H. Shen, Scott A. Lemaire, Masanori Aikawa, Mark W. Majesky, Hong S. Lu, Alan Daugherty

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: The ascending aorta is a common location for aneurysm and dissection. This aortic region is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field (SHF) or the cardiac neural crest. SHF-derived cells populate areas that coincide with the spatial specificity of thoracic aortopathies. The purpose of this study was to determine whether and how SHF-derived cells contribute to ascending aortopathies.

METHODS: Ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin II (AngII)–infused mice. Ascending aortas without overt pathology from AngII-infused mice were subjected …

Cognitive Reserve And Mild Cognitive Impairment, Maryam Iraniparast, Yidan Shi, Ying Wu, Leilei Zeng, Colleen J. Maxwell, Richard J. Kryscio, Philip D. St. John, Karen S. Santacruz, Suzanne L. Tyas

Sanders-Brown Center on Aging Faculty Publications

Background and Objectives Little is known about the effect of education or other indicators of cognitive reserve on the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) or the relative rate (RR) of reversion from MCI to NC vs progression from MCI to dementia. Our objectives were to (1) estimate transition rates from MCI to NC and dementia and (2) determine the effect of age, APOE, and indicators of cognitive reserve on the RR of reversion vs progression using multistate Markov modeling.

Methods We estimated instantaneous transition rates between NC, MCI, and dementia after accounting …

Prostacyclin Promotes Degenerative Pathology In A Model Of Alzheimer’S Disease, Tasha R. Womack, Craig T. Vollert, Odochi Ohia-Nwoko, Monika Schmitt, Saghi Montazari, Tina L. Beckett, David Mayerich, Michael Paul Murphy, Jason L. Eriksen

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression …

Human Microrna (Mir-20b-5p) Modulates Alzheimer’S Disease Pathways And Neuronal Function, And A Specific Polymorphism Close To The Mir20b Gene Influences Alzheimer’S Biomarkers, Ruizhi Wang, Nipun Chopra, Kwangsik Nho, Bryan Maloney, Alexander G. Obukhov, Peter T. Nelson, Scott E. Counts, Debomoy K. Lahiri

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, …

Therapeutic Treatment With The Anti-Inflammatory Drug Candidate Mw151 May Partially Reduce Memory Impairment And Normalizes Hippocampal Metabolic Markers In A Mouse Model Of Comorbid Amyloid And Vascular Pathology, David J. Braun, David K. Powell, Christopher J. Mclouth, Saktimayee M. Roy, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly, but therapeutic options are lacking. Despite long being able to effectively treat the ill-effects of pathology present in various rodent models of AD, translation of these strategies to the clinic has so far been disappointing. One potential contributor to this situation is the fact that the vast majority of AD patients have other dementia-contributing comorbid pathologies, the most common of which are vascular in nature. This situation is modeled relatively infrequently in basic AD research, and almost never in preclinical studies. As part of our efforts to develop …

Sensory Processing Abnormalities In Community-Dwelling Older Adults With Cognitive Impairment: A Mixed Methods Study, Elizabeth K. Rhodus, Elizabeth G. Hunter, Graham D. Rowles, Shoshana H. Bardach, Kelly Parsons, Justin M. Barber, Maryellen Thompson, Gregory A. Jicha

Sanders-Brown Center on Aging Faculty Publications

Mild cognitive impairment (MCI) or dementia often leads to behavioral and psychiatric symptoms of dementia (BPSD). Sensory processing abnormalities may be associated with BPSD. The purpose of this study was to explore relationships among sensory processing, behavior, and environmental features within the homes of people with MCI or dementia. This project used mixed methods to assess participants’ sensory processing, care partner perspectives on behaviors, and in situ observations of the home environment. Nine participants with cognitive impairment (MCI n = 8, early dementia = 1) and their care partners were included. Seven participants with cognitive impairment were reported to have …

Dementia Risk Reduction: Why Haven't The Pharmacological Risk Reduction Trials Worked? An In-Depth Exploration Of Seven Established Risk Factors, Ruth Peters, John Breitner, Sarah James, Gregory A. Jicha, Pierre-Francois Meyer, Marcus Richards, A. David Smith, Hussein N. Yassine, Erin L. Abner, Atticus H. Hainsworth, Patrick G. Kehoe, Nigel Beckett, Christopher Weber, Craig Anderson, Kaarin J. Anstey, Hiroko H. Dodge

Neurology Faculty Publications

Identifying the leading health and lifestyle factors for the risk of incident dementia and Alzheimer's disease has yet to translate to risk reduction. To understand why, we examined the discrepancies between observational and clinical trial evidence for seven modifiable risk factors: type 2 diabetes, dyslipidemia, hypertension, estrogens, inflammation, omega-3 fatty acids, and hyperhomocysteinemia. Sample heterogeneity and paucity of intervention details (dose, timing, formulation) were common themes. Epidemiological evidence is more mature for some interventions (eg, non-steroidal anti-inflammatory drugs [NSAIDs]) than others. Trial data are promising for anti-hypertensives and B vitamin supplementation. Taken together, these risk factors highlight a future need …

Pairwise Correlation Analysis Of The Alzheimer’S Disease Neuroimaging Initiative (Adni) Dataset Reveals Significant Feature Correlation, Erik D. Huckvale, Matthew W. Hodgman, Brianna B. Greenwood, Devorah O. Stucki, Katrisa M. Ward, Mark T. W. Ebbert, John S. K. Kauwe, The Alzheimer’S Disease Neuroimaging Initiative, The Alzheimer’S Disease Metabolomics Consortium, Justin B. Miller

Sanders-Brown Center on Aging Faculty Publications

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) contains extensive patient measurements (e.g., magnetic resonance imaging [MRI], biometrics, RNA expression, etc.) from Alzheimer’s disease (AD) cases and controls that have recently been used by machine learning algorithms to evaluate AD onset and progression. While using a variety of biomarkers is essential to AD research, highly correlated input features can significantly decrease machine learning model generalizability and performance. Additionally, redundant features unnecessarily increase computational time and resources necessary to train predictive models. Therefore, we used 49,288 biomarkers and 793,600 extracted MRI features to assess feature correlation within the ADNI dataset to determine the …

Expanding The Horizon Of Research Into The Pathogenesis Of The White Matter Diseases Proceedings Of The 2021 Annual Workshop Of The Albert Research Institute For White Matter And Cognition, Shawn N. Whitehead, Askiel Bruno, Jeffrey M. Burns, S. Thomas Carmichael, Anna Csiszar, Jodi D. Edwards, Fanny Elahi, Giuseppe Faraco, Douglas B. Goulding, Deborah R. Gustafson, Vladimir Hachinski, Gary A. Rosenberg, Farzaneh A. Sorond, Andy Y. Shih, Kai Hei Tse, Zoltan Ungvari, Donna M. Wilcock, Kristen L. Zuloaga, Frank C. Barone

Sanders-Brown Center on Aging Faculty Publications

White matter pathologies are critically involved in the etiology of vascular cognitive impairment–dementia (VCID), Alzheimer’s disease (AD), and Alzheimer’s disease and related diseases (ADRD), and therefore need to be considered a treatable target (Roseborough A, Hachinski V, Whitehead S. White matter degeneration - a treatable target? Roseborough et al. JAMA Neurol [Internet]. 2020 Apr 27;77(7):793–4, [1]. To help address this often-missed area of research, several workshops have been sponsored by the Leo and Anne Albert Charitable Trust since 2015, resulting in the incorporation of “The Albert Research Institute for White Matter and Cognition” in 2020. The first annual “Institute” meeting …

Committee On High-Quality Alzheimer’S Disease Studies (Chads) Consensus Report, Gregory A. Jicha, Erin L. Abner, Steven E. Arnold, Maria C. Carrillo, Hiroko H. Dodge, Steven D. Edland, Keith N. Fargo, Howard H. Feldman, Larry B. Goldstein, James A. Hendrix, Ruth Peters, Julie M. Robillard, Lon S. Schneider, Jodi R. Titiner, Christopher J. Weber

Sanders-Brown Center on Aging Faculty Publications

Background: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials.

Methods: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations.

Results: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement …

Longitudinal Cognitive Performance Of Alzheimer's Disease Neuropathological Subtypes, Madeline Uretsky, Laura E. Gibbons, Shubhabrata Mukherjee, Emily H. Trittschuh, David W. Fardo, Patricia A. Boyle, C. Dirk Keene, Andrew J. Saykin, Paul K. Crane, Julie A. Schneider, Jesse Mez

Sanders-Brown Center on Aging Faculty Publications

Introduction: Alzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments.

Methods: Two hundred ninety-two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed-effects models that included subtype, time, and a subtype-time interaction as predictors and four cognitive …

Associations Between Air Pollution Exposure And Empirically Derived Profiles Of Cognitive Performance In Older Women, Andrew J. Petkus, Diana Younan, Xinhui Wang, Daniel P. Beavers, Mark A. Espeland, Margaret Gatz, Tara Gruenewald, Joel D. Kaufman, Helena C. Chui, Joshua Millstein, Stephen R. Rapp, Joann E. Manson, Susan M. Resnick, Gregory A. Wellenius, Eric A. Whitsel, Keith Widaman, Jiu-Chiuan Chen

Psychology Faculty Articles and Research

Background:Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. Objective:We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women. Method:Women (N = 2,142) from the Women’s Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant’s addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. Result:Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10–1.52) or superior attention (OR = 1.30; 95% CI = 1.10–1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17–1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67–0.97). Conclusion:Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains.

Random Forest-Integrated Analysis In Ad And Late Brain Transcriptome-Wide Data To Identify Disease-Specific Gene Expression, Xinxing Wu, Chong Peng, Peter T. Nelson, Qiang Cheng

Sanders-Brown Center on Aging Faculty Publications

Alzheimer's disease (AD) is a complex neurodegenerative disorder that affects thinking, memory, and behavior. Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently identified common neurodegenerative disease that mimics the clinical symptoms of AD. The development of drugs to prevent or treat these neurodegenerative diseases has been slow, partly because the genes associated with these diseases are incompletely understood. A notable hindrance from data analysis perspective is that, usually, the clinical samples for patients and controls are highly imbalanced, thus rendering it challenging to apply most existing machine learning algorithms to directly analyze such datasets. Meeting this data analysis challenge is …

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Physiology Faculty Publications

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

RESULTS: Single-cell …