Establishing linkages between distributed survey responses and consumer wearable device datasets: A pilot protocol

Background: As technology increasingly becomes an integral part of everyday life, many individuals are choosing to use wearable technology such as activity trackers to monitor their daily physical activity and other health-related goals. Researchers would benefit from learning more about the health of these individuals remotely, without meeting face-to-face with participants and avoiding the high cost of providing consumer wearables to participants for the study duration. Objective: The present study seeks to develop the methods to collect data remotely and establish a linkage between self-reported survey responses and consumer wearable device biometric data, ultimately producing a de-identified and linked dataset. Establishing an effective protocol will allow for future studies of large-scale deployment and participant management. Methods: A total of 30 participants who use a Fitbit will be recruited on Mechanical Turk Prime and asked to complete a short online self-administered questionnaire. They will also be asked to connect their personal Fitbit activity tracker to an online third-party software system, called Fitabase, which will allow access to 1 month's retrospective data and 1 month's prospective data, both from the date of consent. Results: The protocol will be used to create and refine methods to establish linkages between remotely sourced and de-identified survey responses on health status and consumer wearable device data. Conclusions: The refinement of the protocol will inform collection and linkage of similar datasets at scale, enabling the integration of consumer wearable device data collection in cross-sectional and prospective cohort studies

Allopregnanolone: Regenerative therapeutic to restore neurological health

Chronic stress has been proposed as a driver of altered brain structure and function, including the pathogenesis of neurodegenerative diseases and a driver of disease progression. A key outcome of stress in the brain is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicate failed resilience. Neuroendocrine homeostasis and stress response are mainly dependent upon the functioning of the hypothalamic–pituitary–adrenal axis. Neurosteroids will fluctuate depending on whether the stress is acute or chronic. Advancements in neurosteroid research have led to the identification of multiple targets for drug development, but the most promising innovative target may be neurogenesis, given its potential impact in neurodegenerative disorders like Alzheimer's disease. Allopregnanolone is an endogenous pregnane neurosteroid and a reduced metabolite of progesterone, which acts as a potent allosteric modulator and direct activator of the GABA-chloride channel complex. Perhaps the most intriguing finding related to the potential therapeutic effects of allopregnanolone is its potential to promote neuroregeneration. © 2022Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Preventing Alzheimer's disease within reach by 2025: Targeted-risk-AD-prevention (TRAP) strategy

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease that currently affects 6.2 million people in the United States and is projected to impact 152 million worldwide in 2050 with no effective disease-modifying therapeutic or cure. In 2011 as part of the National Alzheimer's Project Act, the National Plan to Address Alzheimer's Disease was signed into law which proposed to effectively prevent AD by 2025, which is rapidly approaching. The preclinical phase of AD can begin 20 years prior to diagnosis, which provides an extended window for preventive measures that would exert a transformative impact on incidence and prevalence of AD. Methods: A novel combination of text-mining and natural language processing strategies to identify (1) AD risk factors, (2) therapeutics that can target risk factor pathways, and (3) studies supporting therapeutics in the PubMed database was conducted. To classify the literature relevant to AD preventive strategies, a relevance score (RS) based on STRING (search tool for the retrieval of interacting genes/proteins) score for protein–protein interactions and a confidence score (CS) on Bayesian inference were developed. To address mechanism of action, network analysis of protein targets for effective drugs was conducted. Collectively, the analytic approach, referred to as a targeted-risk-AD-prevention (TRAP) strategy, led to a ranked list of candidate therapeutics to reduce AD risk. Results: Based on TRAP mining of 9625 publications, 364 AD risk factors were identified. Based on risk factor indications, 629 Food and Drug Administration-approved drugs were identified. Computation of ranking scores enabled identification of 46 relevant high confidence (RS & CS > 0.7) drugs associated with reduced AD risk. Within these candidate therapeutics, 16 had more than one clinical study supporting AD risk reduction. Top-ranked therapeutics with high confidence emerged within lipid-lowering, anti-inflammatory, hormone, and metabolic-related drug classes. Discussion: Outcomes of our novel bioinformatic strategy support therapeutic targeting of biological mechanisms and pathways underlying relevant AD risk factors with high confidence. Early interventions that target pathways associated with increased risk of AD have the potential to support the goal of effectively preventing AD by 2025. © 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Sex and apoe genotype differences related to statin use in the aging population

Background: Significant evidence suggests that the cholesterol-lowering statins can affect cognitive function and reduce the risk for Alzheimer’s disease (AD) and dementia. These potential effects may be constrained by specific combinations of an individual’s sex and apolipoprotein E (APOE) genotype. Methods: Here we examine data from 252,327 UK Biobank participants, aged 55 or over, and compare the effects of statin use in males and females. We assessed difference in statin treatments taking a matched cohort approach, and identified key stratifiers using regression models and conditional inference trees. Using statistical modeling, we further evaluated the effect of statins on survival, cognitive decline over time, and on AD prevalence. Results: We identified that in the selected population, males were older, had a higher level of education, better cognitive scores, higher incidence of cardiovascular and metabolic diseases, and a higher rate of statin use. We observed that males and those participants with an APOE ε4–positive genotype had higher probabilities of being treated with statins; while participants with an AD diagnosis had slightly lower probabilities. We found that use of statins was not significantly associated with overall higher rates of survival. However, when considering the interaction of statin use with sex, the results suggest higher survival rates in males treated with statins. Finally, examination of cognitive function indicates a potential beneficial effect of statins that is selective for APOE ε4–positive genotypes. Discussion: Our evaluation of the aging population in a large cohort from the UK Biobank confirms sex and APOE genotype as fundamental risk stratifiers for AD and cognitive function, furthermore it extends them to the specific area of statin use, clarifying their specific interactions with treatments. © 2021 The Authors. Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism

Objective: Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer’s disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways. Methods: Mechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses. Results: In hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca2+/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABAA and L-type Ca2+ channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABAA and L-type Ca2+ channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics. Conclusion: Collectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain. Copyright © 2023 Wang, Chen, Mao, Shang and Brinton.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics

Background: The association between exposure to anti-hyperglycemic medications (A-HgM) for Type 2 Diabetes Mellitus (T2D) treatment and Multiple Sclerosis (MS) in T2D patients is unclear. Methods: This retrospective cohort analysis used the Mariner claims database. Patient records were surveyed for a diagnosis of MS starting 12 months after diagnosis of T2D. Patients were required to be actively enrolled in the Mariner claims records for six months prior and at least three years after the diagnosis of T2D without a history of previous neurodegenerative disease. Survival analysis was used to determine the association between A-HgM exposure and diagnosis of MS. A propensity score approach was used to minimize measured and unmeasured selection bias. The analyses were conducted between January 1st and April 28th, 2021. Findings: In T2D patients younger than 45, A-HgM exposure was associated with a reduced risk of developing MS (RR: 0.22, 95%CI: 0.17–0.29, p-value <0.001). In contrast, A-HgM exposure in patients older than 45 was associated with an increased risk of MS with women exhibiting greater risk (RR: 1.53, 95%CI: 1.39–1.69, p < 0.001) than men (RR: 1.17, 95%CI: 1.01–1.37, p = 0 · 04). Patients who developed MS had a higher incidence of baseline comorbidities. Mean follow-up was 6.2 years with a standard deviation of 1.8 years. Interpretation: In this study, A-HgM exposure in patients with T2D was associated with reduced risk of MS in patients younger than 45 whereas in patients older than 45, exposure to A-HgM was associated with an increased risk of newly diagnosed MS, particularly in women. © 2022 The Author(s)Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism

Alzheimer's disease (AD) risk gene ApoE4 perturbs brain lipid homeostasis and energy transduction. However, the cell-type-specific mechanism of ApoE4 in modulating brain lipid metabolism is unclear. Here, we describe a detrimental role of ApoE4 in regulating fatty acid (FA) metabolism across neuron and astrocyte in tandem with their distinctive mitochondrial phenotypes. ApoE4 disrupts neuronal function by decreasing FA sequestering in lipid droplets (LDs). FAs in neuronal LDs are exported and internalized by astrocytes, with ApoE4 diminishing the transport efficiency. Further, ApoE4 lowers FA oxidation and leads to lipid accumulation in both astrocyte and the hippocampus. Importantly, diminished capacity of ApoE4 astrocytes in eliminating neuronal lipids and degrading FAs accounts for their compromised metabolic and synaptic support to neurons. Collectively, our findings reveal a mechanism of ApoE4 disruption to brain FA and bioenergetic homeostasis that could underlie the accelerated lipid dysregulation and energy deficits and increased AD risk for ApoE4 carriers. © 2020 The Author(s)Qi et al. reveal a role of Alzheimer's disease risk gene ApoE4 in disrupting fatty acid metabolism coupled between neuron and astrocyte. A systematic impairment in neuronal sequestering, neuron-to-astrocyte transport, and astrocytic degradation of fatty acids could contribute to lipid dysregulation, bioenergetic deficits, and increased Alzheimer's risk in ApoE4 carriers. © 2020 The Author(s)Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Androgen-targeting therapeutics mitigate the adverse effect of GnRH agonist on the risk of neurodegenerative disease in men treated for prostate cancer

Background: Prostate cancer and multiple neurodegenerative diseases (NDD) share an age-associated pattern of onset. Therapy of prostate cancer is known to impact cognitive function. The objective of this study was to determine the impact of multiple classes of androgen-targeting therapeutics (ATT) on the risk of NDD. Methods: A retrospective cohort study of men aged 45 and older with prostate within the US-based Mariner claims data set between January 1 and 27, 2021. A propensity score approach was used to minimize measured and unmeasured selection bias. Disease risk was determined using Kaplan–Meier survival analyses. Results: Of the 1,798,648 men with prostate cancer, 209,722 met inclusion criteria. Mean (SD) follow-up was 6.4 (1.8) years. In the propensity score-matched population, exposure to ATT was associated with a minimal increase in NDD incidence (relative risk [RR], 1.07; 95% CI, 1.05–1.10; p < 0.001). However, GnRH agonists alone were associated with significantly increased NDD risk (RR, 1.47; 95% CI, 1.30–1.66; p <0.001). Abiraterone, commonly administered with GnRH agonists and low-dose prednisone, was associated with a significantly decreased risk (RR, 0.77; 95% CI, 0.68–0.87; p < 0.001) of any NDD. Conclusions: Among patients with prostate cancer, GnRH agonist exposure was associated with an increased NDD risk. Abiraterone acetate reduced the risks of Alzheimer's disease and Parkinson's disease conferred by GnRH agonists, whereas the risk for ALS was reduced by androgen receptor inhibitors. Outcomes of these analyses contribute to addressing controversies in the field and indicate that GnRH agonism may be a predictable instigator of risk for NDD with opportunities for risk mitigation in combination with another ATT. © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]