Medicine and Health Sciences Commons^™

Aberrant Crosstalk Between Insulin Signaling And Mtor In Young Down Syndrome Individuals Revealed By Neuronal-Derived Extracellular Vesicles, Marzia Perluigi, Anna Picca, Elita Montanari, Riccardo Calvani, Federico Marini, Roberto Matassa, Antonella Tramutola, Alberto Villani, Giuseppe Familiari, Fabio Di Domenico, D. Allan Butterfield, Kenneth J. Oh, Emanuele Marzetti, Diletta Valentini, Eugenio Barone

Chemistry Faculty Publications

INTRODUCTION: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing.

METHODS: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways.

RESULTS: nEVs isolated from DS children were characterized by a significant increase in pIRS1^Ser636, a marker of …

From Reaction Kinetics To Dementia: A Simple Dimer Model Of Alzheimer’S Disease Etiology, Michael R. Lindstrom, Manuel B. Chavez, Elijah A. Gross-Sable, Eric Y. Hayden, David B. Teplow

School of Mathematical and Statistical Sciences Faculty Publications and Presentations

Oligomers of the amyloid β-protein (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD) through their toxicity towards neurons. Understanding the process of oligomerization may contribute to the development of therapeutic agents, but this has been difficult due to the complexity of oligomerization and the metastability of the oligomers thus formed. To understand the kinetics of oligomer formation, and how that relates to the progression of AD, we developed models of the oligomerization process. Here, we use experimental data from cell viability assays and proxies for rate constants involved in monomerdimer-trimer kinetics to develop a simple mathematical model …

Evaluating Trajectories Of Episodic Memory In Normal Cognition And Mild Cognitive Impairment: Results From Adni, Xiuhua Ding, Richard J. Charnigo, Frederick A. Schmitt, Richard J. Kryscio, Erin L. Abner, Alzheimer’S Disease Neuroimaging Initiative

Statistics Faculty Publications

BACKGROUND: Memory assessment is a key factor for the diagnosis of cognitive impairment. However, memory performance over time may be quite heterogeneous within diagnostic groups.

METHOD: To identify latent trajectories in memory performance and their associated risk factors, we analyzed data from Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who were classified either as cognitively normal or as Mild Cognitive Impairment (MCI) at baseline and were administered the Rey Auditory Verbal Learning test (RAVLT) for up to 9 years. Group-based trajectory modeling on the 30-minute RAVLT delayed recall score was applied separately to the two baseline diagnostic groups.

RESULTS: There were …

Treatment Of Mci And Alzheimer's Disease, Mark A. Lovell, Bert C. Lynn

Chemistry Faculty Patents

The present invention provides, among other things, therapeutic compositions and methods that can effectively treat, slow or prevent a neurological disease (e.g., a neurodegenerative disease, e.g., mild cognitive impairment (MCI) or Alzheimer's disease (AD)), in particular, based on therapeutically effective amount of nifedipine, oxidized or nitroso nifedipine derivatives, lactam (e.g., a compound of formula (Ic) or (Ic-i), e.g., NFD-L1), thyroxine (T4), triiodothyronine (T3) and combinations thereof.

Systems Biology Approach To Late-Onset Alzheimer's Disease Genome-Wide Association Study Identifies Novel Candidate Genes Validated Using Brain Expression Data And Caenorhabditis Elegans Experiments, Shubhabrata Mukherjee, Joshua C. Russell, Daniel T. Carr, Jeremy D. Burgess, Mariet Allen, Daniel J. Serie, Kevin L. Boehme, John S. K. Kauwe, Adam C. Naj, David W. Fardo, Dennis W. Dickson, Thomas J. Montine, Nilufer Ertekin-Taner, Matt R. Kaeberlein, Paul K. Crane

Biostatistics Faculty Publications

Introduction—We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.

Methods—We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

Results—We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ …

Longitudinal Measurement And Hierarchical Classification Framework For The Prediction Of Alzheimer's Disease, Meiyan Huang, Wei Yang, Qianjin Feng, Wufan Chen, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack Jr., William Jagust, John Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew Saykin, John Morris, Leslie M. Shaw, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Charles D. Smith, Greg A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad

Neurology Faculty Publications

Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important …

Diabetes Is Associated With Cerebrovascular But Not Alzheimer's Disease Neuropathology, Erin L. Abner, Peter T. Nelson, Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo, Randall L. Woltjer, Nigel J. Cairns, Lei Yu, Hiroko H. Dodge, Chengjie Xiong, Kamal Masaki, Suzanne L. Tyas, David A. Bennett, Julie A. Schneider, Zoe Arvanitakis

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: The relationship of diabetes to specific neuropathologic causes of dementia is incompletely understood.

METHODS: We used logistic regression to evaluate the association between diabetes and infarcts, Braak neurofibrillary tangle stage, and neuritic plaque score in 2365 autopsied persons. In a subset of >1300 persons with available cognitive data, we examined the association between diabetes and cognition using Poisson regression.

RESULTS: Diabetes increased odds of brain infarcts (odds ratio [OR] = 1.57, P < .0001), specifically lacunes (OR = 1.71, P < .0001), but not Alzheimer's disease neuropathology. Diabetes plus infarcts was associated with lower cognitive scores at end of life than infarcts or diabetes alone, and diabetes plus high level of Alzheimer's neuropathologic changes was associated with lower mini-mental state examination scores than the pathology alone.

DISCUSSION: This study supports the conclusions that diabetes increases the risk of cerebrovascular but not Alzheimer's disease pathology, and at least some of diabetes' relationship to …

Stress Granules Modulate Syk To Cause Microglial Cell Dysfunction In Alzheimer's Disease, Soumira Ghosh, Robert Geahlen

Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Microglial cells in the brains of Alzheimer's patients are known to be recruited to amyloid-beta (Aβ) plaques where they exhibit an activated phenotype, but are defective for plaque removal by phagocytosis. In this study, we show that microglia stressed by exposure to sodium arsenite or Aβ(1–42) peptides or fibrils form ex- tensive stress granules (SGs) to which the tyrosine kinase, SYK, is recruited. SYK enhances the formation of SGs, is active within the resulting SGs and stimulates the production of reactive oxygen and nitrogen species that are toxic to neuronal cells. This sequestration of SYK inhibits the ability of microglial …

Fusing Heterogeneous Data For Alzheimer's Disease Classification, P. S. Pillai, Tze-Yun Leong

Research Collection School Of Computing and Information Systems

In multi-view learning, multimodal representations of a real world object or situation are integrated to learn its overall picture. Feature sets from distinct data sources carry different, yet complementary, information which, if analysed together, usually yield better insights and more accurate results. Neuro-degenerative disorders such as dementia are characterized by changes in multiple biomarkers. This work combines the features from neuroimaging and cerebrospinal fluid studies to distinguish Alzheimer's disease patients from healthy subjects. We apply statistical data fusion techniques on 101 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We examine whether fusion of biomarkers helps to improve diagnostic …

Self-Reported Head Injury And Risk Of Late-Life Impairment And Ad Pathology In An Ad Center Cohort, Erin L. Abner, Peter T. Nelson, Frederick A. Schmitt, Steven R. Browning, David W. Fardo, Lijie Wan, Gregory A. Jicha, Gregory E. Cooper, Charles D. Smith, Allison M. Caban-Holt, Linda J. Van Eldik, Richard J. Kryscio

Sanders-Brown Center on Aging Faculty Publications

Aims: To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimer's disease (AD)-type pathological changes. Methods: Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (n = 649) were analyzed to assess the chronic effects of self-reported head injury. Results: The effect of self-reported head injury on the clinical state depended on the age at assessment: for a 1-year increase in age, the OR for the transition to clinical mild cognitive impairment (MCI) at the next visit for participants with a history of head injury was 1.21 and 1.34 …

White Matter Diffusion Alterations In Normal Women At Risk Of Alzheimer's Disease, Charles D. Smith, Himachandra Chebrolu, Anders H. Andersen, David A. Powell, Mark A. Lovell, Shuling Xiong, Brian T. Gold

Neurology Faculty Publications

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal …

Focus On Rna Isolation: Obtaining Rna For Microrna (Mirna) Expression Profiling Analyses Of Neural Tissue, Wang-Xia Wang, Bernard R. Wilfred, Donald A. Baldwin, R. Benjamin Isett, Na Ren, Arnold J. Stromberg, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are present in all known plant and animal tissues and appear to be somewhat concentrated in the mammalian nervous system. Many different miRNA expression profiling platforms have been described. However, relatively little research has been published to establish the importance of 'upstream' variables in RNA isolation for neural miRNA expression profiling. We tested whether apparent changes in miRNA expression profiles may be associated with tissue processing, RNA isolation techniques, or different cell types in the sample. RNA isolation was performed on a single brain sample using eight different RNA isolation methods, and results were correlated using a conventional …

Adjusting For Non-Ignorable Verification Bias In Clinical Studies For Alzheimer’S Disease, Xiao-Hua Zhou, Pete Castelluccio

UW Biostatistics Working Paper Series

A common problem for comparing the relative accuracy of two screening tests for Alzheimer’s disease (D) in a two-stage design study is verification bias. If the verification bias can be assumed to be ignorable, Zhou and Higgs (2000) have proposed a maximum likelihood approach to compare the relative accuracy of screening tests in a two-stage design study. However, if the verification mechanism also depends on the unobserved disease status, the ignorable assumption does not hold. In this paper, we discuss how to use a profile likelihood approach to compare the relative accuracy of two screening tests for AD without assuming …