Medicine and Health Sciences Commons^™

Higher Coffee Consumption Is Associated With Slower Cognitive Decline And Less Cerebral Aβ-Amyloid Accumulation Over 126 Months: Data From The Australian Imaging, Biomarkers, And Lifestyle Study, Samantha L. Gardener, Stephanie R. Rainey-Smith, Victor L. Villemagne, Jurgen Fripp, Vincent Doré, Pierrick Bourgeat, Kevin Taddei, Christopher Fowler, Colin L. Masters, Paul Maruff, Christopher C. Rowe, David Ames, Ralph N. Martins, Aibl Investigators

Research outputs 2014 to 2021

Background:

Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer’s disease (AD). However, there is limited longitudinal data from cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning any such associations.

Methods: The aim of the current study was to investigate the relationship between self-reported habitual coffee intake, and cognitive decline assessed using a comprehensive neuropsychological battery in 227 cognitively normal older adults from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, over …

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 …

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 …

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 …

Relationship Between Cognitive Performance, Physical Activity, And Socio-Demographic/ Individual Characteristics Among Aging Americans, Imtiaz Masfique Dowllah

Theses and Dissertations

Despite the attenuation of association following adjustments for covariates, participants who engaged in 3–6 hr/wk of vigorous- and > 1 hr/wk of moderate-intensity PA scored significantly higher in tests that assessed executive function and processing speed domains of cognition compared to inactive peers (η2 = 0.005 & 0.007 respectively, p < 0.05). Also, after adjustment, the effects of 1–3 hr/wk of vigorous-intensity PA became trivial for the delayed recall memory domain test scores (β = 0.33; 95% CI: –0.01, 0.67; η2 = 0.002; p = 0.56). There was no clear dose-response relationship between the cognitive test scores and weekly moderate-intensity PA. Interestingly, higher handgrip strength and higher late-life body-mass-index were associated with a higher performance across all cognitive domains. Observed associations provide evidence linking habitual PA with superior cognition health among older adults. Furthermore, increased muscle strength and higher late-life adiposity may …

Rule Out Screening For Undiagnosed Dementia And Alzheimer’S Disease Using An Ehr Based Machine Learning Solution, Branum Stephan, David A. Julovich, Dustin Bracy, Jeff Nguyen

SMU Data Science Review

Abstract. Current detection methods for Dementia and Alzheimer’s disease include cerebral spinal fluid (CSF) markers and/or the use of positron emission tomography (PET) imaging, both being high-cost, highly invasive testing methods. The need for low-cost, minimally invasive methods to prescreen individuals for cognitive impairment has been a challenge for many years. Today’s costs associated with an annual screen for all adults 65 and above using current methods (CSF, PET) reach well beyond trillions of dollars per year. Motivated by the limited accessibly and high costs, an alternative tool presented within this paper demonstrates an effective rule out screening for Dementia …

Cross-Sectional Exploration Of Plasma Biomarkers Of Alzheimer's Disease In Down Syndrome: Early Data From The Longitudinal Investigation For Enhancing Down Syndrome Research (Life-Dsr) Study, James A. Hendrix, David C. Airey, Angela Britton, Anna D. Burke, George T. Capone, Ronelyn Chavez, Jacqueline Chen, Brian Chicoine, Alberto C. S. Costa, Jeffrey L. Dage, Eric Doran, Anna Esbensen, Casey L. Evans, Kelley M. Faber, Tatiana M. Foroud, Sarah Hart, Kelsey Haugen, Elizabeth Head, Suzanne Hendrix, Hampus Hillerstrom, Frederick A. Schmitt

Sanders-Brown Center on Aging Faculty Publications

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer’s disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ_1-40, Aβ_1-42), and glial fibrillary acidic protein (GFAP) were undertaken with …

CertL Reduces C16 Ceramide, Amyloid-Β Levels, And Inflammation In A Model Of Alzheimer’S Disease, Simone M. Crivelli, Qian Luo, Jo A. A. Stevens, Caterina Giovagnoni, Daan Van Kruining, Gerard Bode, Sandra Den Hoedt, Barbara Hobo, Anna-Lena Scheithauer, Jochen Walter, Monique T. Mulder, Christopher Exley, Matthew Mold, Michelle M. Mielke, Helga E. De Vries, Kristiaan Wouters, Daniel L. A. Van Den Hove, Dusan Berkes, María Dolores Ledesma, Joost Verhaagen, Mario Losen, Erhard Bieberich, Pilar Martinez-Martinez

Physiology Faculty Publications

BACKGROUND: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.

METHODS: A plasmid expressing CERT_L, the long isoform of CERTs, was used to study the interaction of CERT_L with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERT_L protein …

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction In Tauopathy, Shon A. Koren, Matthew J. Hamm, Ryan Cloyd, Sarah N. Fontaine, Emad Chishti, Chiara Lanzillotta, Jennifer Rodriguez-Rivera, Alexandria Ingram, Michelle Bell, Sara M. Galvis-Escobar, Nicholas Zulia, Fabio Di Domenico, Duc Duong, Nicholas T. Seyfried, David K. Powell, Moriel Vandsburger, Tal Frolinger, Anika M. S. Hartz, John Koren Iii, Jeffrey M. Axten, Nicholas J. Laping, Jose F. Abisambra

Sanders-Brown Center on Aging Faculty Publications

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging …

Arginase 1 Insufficiency Precipitates Amyloid-Β Deposition And Hastens Behavioral Impairment In A Mouse Model Of Amyloidosis, Chao Ma, Jerry B. Hunt, Maj-Linda B. Selenica, Awa Sanneh, Leslie A. Sandusky-Beltran, Mallory Watler, Rana Daas, Andrii Kovalenko, Huimin Liang, Devon Placides, Chuanhai Cao, Xiaoyang Lin, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1 …

Therapeutic Potential Of Mitophagy-Inducing Microflora Metabolite, Urolithin A For Alzheimer’S Disease, Dona Pamoda W. Jayatunga, Eugene Hone, Harjot Khaira, Taciana Lunelli, Harjinder Singh, Gilles J. Guillemin, Binosha Fernando, Manohar L. Garg, Giuseppe Verdile, Ralph N. Martins

Research outputs 2014 to 2021

Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neuro-degenerative disorders including Alzheimer’s disease (AD). Apart from traditionally targeting amyloid beta (Aβ), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bi-oactive food components, known as nutraceuticals, may serve as such agents to combat AD. Uro-lithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, …

Core Alzheimer’S Disease Cerebrospinal Fluid Biomarker Assays Are Not Affected By Aspiration Or Gravity Drip Extraction Methods, James D. Doecke, Cindy Francois, Christopher J. Fowler, Erik Stoops, Pierrick Bourgeat, Stephanie R. Rainey-Smith, Qiao-Xin Li, Colin L. Masters, Ralph N. Martins, Victor L. Villemagne, Steven J. Collins, Hugo Marcel Vanderstichele

Research outputs 2014 to 2021

Background: CSF biomarkers are well-established for routine clinical use, yet a paucity of comparative assessment exists regarding CSF extraction methods during lumbar puncture. Here, we compare in detail biomarker profiles in CSF extracted using either gravity drip or aspiration. Methods: Biomarkers for β-amyloidopathy (Aβ1–42, Aβ1–40), tauopathy (total tau), or synapse pathology (BACE1, Neurogranin Trunc-p75, α-synuclein) were assessed between gravity or aspiration extraction methods in a sub-population of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study (cognitively normal, N = 36; mild cognitive impairment, N = 8; Alzheimer’s disease, N = 6). Results: High biomarker concordance between extraction methods was seen …