Faculty Bibliography

Primary care professionals play a critical role in the care of their patients. In clinical practice, early detection and diagnosis of Mild Cognitive Impairment, Alzheimer's disease and related dementia are often missed or delayed. Disclosure of diagnosis is not timely or not revealed. Though the methods that could improve early detection and diagnosis have remained the same over the decades with little change, they provide opportunities for early intervention, treatment and improvement in patient care. Emerging research suggests that though the disease process begins years prior to the clinical diagnosis, the healthcare system and health care professionals remain distant and reluctant to provide the service of annual cognitive assessment, which has been recommended by the Medicare program for older adults aged 65 years and older. Findings support that Alzheimer's disease and related cognitive impairments have gone under detected, underdiagnosed and undertreated. This article seeks to provide valuable and equitable information in the form of a clinician's guide for removing the barriers to early detection and diagnosis of cognitive impairments and offers an unprecedented opportunity to improve the clinical outcomes and care of older adults with various levels of cognitive decline, including mild cognitive impairment, Alzheimer's disease, and related dementias. This article provides information on understanding and addressing the challenges faced by health care professionals, including primary care clinicians; removing the barriers to cognitive assessments; educating this professional group on the importance of brain health, early detection, and diagnosis for their older adult patients; and providing these professionals with the ability to transfer their knowledge into more defined care planning. Until cognitive screening has been fully accepted and implemented for the optimal the care of older adults, health-related efforts should include the promotion and education of brain health, early detection, and diagnosis in the education of health care providers.

There is conflicting information on the relationship between diet and dementia. The purposes of this pilot study were twofold. First, to use publicly available data regarding food consumption (United Kingdom Family Food), dementia, risk and demographic factors to find relationships between the consumption of various foods to dementia prevalence. The second purpose was to identify elements of study design that had important effects on the results. Multiple analyses were performed on different data sets derived from the existing data. Statistical testing began with univariate correlation analyses corrected for multiple testing followed by global tests for significance. Subsequently, a number of multivariate techniques were applied including stepwise linear regression, cluster regression, regularized regression, and principal components analysis. Permutation tests and simulations highlighted the strength and weakness of each technique. The univariate analyses demonstrated that the consumption of certain foods was highly associated with the prevalence of dementia. However, because of the complexity of the data set and the high degree of correlation between variables, different multivariate analyses yielded different results, explainable by the correlations. Some factors identified as having potential associations were the consumption of rice, sugar, fruit, potatoes, meat products and fish. However, within a given dietary category there were often a number of different elements with different relations to dementia. This pilot study demonstrates some critical elements for a future study: (1) dietary factors must be very narrowly defined, (2) large numbers of cases are needed to support multivariable analyses. (3) Multiple statistical methods along with simulations must be used to confirm results.

Despite intensive research, effective treatments for many common and devastating diseases are lacking. For example, huge efforts and billions of dollars have been invested in Alzheimer's disease (AD), which affects over 50 million people worldwide. However, there is still no effective drug that can slow or cure AD. This relates, in part, to the absence of an animal model or cellular system that incorporates all the relevant features of the disease. Therefore, large scale studies on human populations and tissues will be key to better understanding dementia and developing methods to prevent or treat it. This is especially difficult because the dementia phenotype can result from many different processes and is likely to be affected by multiple personal and environmental variables. We hypothesize that analyzing massive volumes of demographic data that are currently available and combining this with genomic, proteomic, and metabolomic profiles of AD patients and their families, new insights into pathophysiology and treatment of AD may arise. While this requires much coordination and cooperation among large institutions, the potential for advancement would be life-changing for millions of people. In many ways this represents the next step in the information revolution started by the Human Genome Project.

SARS-CoV-2 continues to have devastating consequences worldwide. Though vaccinations have helped reduce spread, new strains still pose a threat. Therefore, it is imperative to identify treatments that prevent severe COVID-19 infection. Recently, acute use of SSRI antidepressants in COVID+ patients was shown to reduce symptom severity. The aim of this retrospective observational study was to determine whether COVID+ patients already on SSRIs upon hospital admission had reduced mortality compared to COVID+ patients not on chronic SSRI treatment. Electronic medical records of 9044 patients with laboratory-confirmed COVID-19 from six hospitals were queried for demographic and clinical information. Using R, a logistic regression model was run with mortality as the outcome and SSRI status as the exposure. In this sample, no patients admitted on SSRIs had them discontinued. There was no significant difference in the odds of dying between COVID+ patients on chronic SSRIs vs. those not taking SSRIs, after controlling for age category, gender, and race. This study shows the utility of large clinical databases in determining what commonly prescribed drugs might be useful in treating COVID-19. During pandemics due to novel infectious agents, it is critical to evaluate safety and efficacy of drugs that might be repurposed for treatment.

Rheumatoid arthritis (RA) carries significant risk for atherosclerotic cardiovascular disease (ASCVD). Traditional ASCVD risk factors fail to account for this accelerated atherosclerosis. Shared inflammatory pathways are fundamental in the pathogenesis of both diseases. Considering the impact of RA in increasing cardiovascular morbidity and mortality, the characterization of therapies encompassing both RA and ASCVD management merit high priority. Despite little progress, several drugs discussed here promote remission and or lower rheumatoid disease activity while simultaneously conferring some level of atheroprotection. Methotrexate, a widely used disease-modifying drug used in RA, is associated with significant reduction in cardiovascular adverse events. MTX promotes cholesterol efflux from macrophages, upregulates free radical scavenging and improves endothelial function. Likewise, the sulfonamide drug sulfasalazine positively impacts the lipid profile by increasing HDL-C, and its use in RA has been correlated with reduced risk of myocardial infraction. In the biologic class, inhibitors of TNF-α and IL-6 contribute to improvements in endothelial function and promote anti-atherogenic properties of HDL-C, respectively. The immunosuppressant hydroxychloroquine positively affects insulin sensitization and the lipid profile. While no individual therapy has elicited optimal atheroprotection, further investigation of combination therapies are ongoing.

Apolipoprotein (apo) B, the critical structural protein of the atherogenic lipoproteins, has two major isoforms: apoB48 and apoB100. ApoB48 is found in chylomicrons and chylomicron remnants with one apoB48 molecule per chylomicron particle. Similarly, a single apoB100 molecule is contained per particle of very-low-density lipoprotein (VLDL), intermediate density lipoprotein, LDL and lipoprotein(a). This unique one apoB per particle ratio makes plasma apoB concentration a direct measure of the number of circulating atherogenic lipoproteins. ApoB levels indicate the atherogenic particle concentration independent of the particle cholesterol content, which is variable. While LDL, the major cholesterol-carrying serum lipoprotein, is the primary therapeutic target for management and prevention of atherosclerotic cardiovascular disease, there is strong evidence that apoB is a more accurate indicator of cardiovascular risk than either total cholesterol or LDL cholesterol. This review examines multiple aspects of apoB structure and function, with a focus on the controversy over use of apoB as a therapeutic target in clinical practice. Ongoing coronary artery disease residual risk, despite lipid-lowering treatment, has left patients and clinicians with unsatisfactory options for monitoring cardiovascular health. At the present time, the substitution of apoB for LDL-C in cardiovascular disease prevention guidelines has been deemed unjustified, but discussions continue.

Systemic lupus erythematosus (SLE) carries a significant risk of cardiovascular disease (CVD). The prevalence of premature CVD is especially noteworthy because it occurs in premenopausal women with SLE who would otherwise have very low rates of CVD. While traditional risk factors likely play a role in development of CVD in the setting of SLE, they do not fully explain the excess risk. The pathogenesis of CVD in SLE is not fully understood, but the inflammatory nature of SLE is believed to be a key factor in accelerating atherosclerosis. Systemic inflammation may lead to an abnormal lipid profile with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol and dysfunctional high-density lipoprotein cholesterol. Additionally, the inflammatory milieu of SLE plasma promotes endothelial dysfunction and vascular injury, early steps in the progression of atherosclerotic CVD. Despite the overall headway that has been achieved in treating lupus, innovative therapeutics specifically targeting the progression of atherosclerosis within the lupus population are currently lacking. However, there have been advancements in the development of promising modalities for diagnosis of subclinical atherosclerosis and detection of high CVD risk patients. Due to the significant impact of CVD on morbidity and mortality, research addressing prevention and treatment of CVD in SLE needs to be prioritized. This review explores the intricate interplay of SLE-specific properties that contribute to atherosclerosis and CVD within this population, as well as screening methods and possible therapies.

BACKGROUND:The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-β and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered. REVIEW SUMMARY/RESULTS:In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway. CONCLUSION/CONCLUSIONS:Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.

INTRODUCTION AND AIMS/OBJECTIVE:Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS:THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while ox-LDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS:RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of ox-LDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION/CONCLUSIONS:We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.