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The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment

Reiss, Allison B; Ahmed, Saba; Dayaramani, Christopher; Glass, Amy D; Gomolin, Irving H; Pinkhasov, Aaron; Stecker, Mark M; Wisniewski, Thomas; De Leon, Joshua
BACKGROUND:Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. METHODS:Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. RESULTS:This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. CONCLUSIONS:There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.
PMID: 35508280
ISSN: 1873-6815
CID: 5216242

Prostate cancer treatment and the relationship of androgen deprivation therapy to cognitive function

Reiss, A B; Saeedullah, U; Grossfeld, D J; Glass, A D; Pinkhasov, A; Katz, A E
Prostate cancer is the second most common form of cancer in men. For advanced, high risk prostate cancer, androgen deprivation therapy (ADT) is the preferred treatment and can induce remission, but resistance to ADT brings biochemical recurrence and progression of cancer. ADT brings adverse effects such as erectile dysfunction, decreased libido, and diminished physical strength. It is estimated that between 25 and 50% of men on ADT manifest some form of cognitive dysfunction that may be self-reported or reported by a family member. There is concern that impaired cognitive function with ADT is due to loss of testosterone support. Testosterone and its metabolites are known to possess neuroprotective properties. While a direct causal relationship between ADT and cognitive decline in prostate cancer patients has not been established, this review describes the controversy surrounding the possible connection between ADT and neurocognitive deterioration. The cellular and molecular mechanisms believed to underlie the protection of neuronal integrity by androgens are discussed. Results from animal models and human clinical studies are presented. Finally, we call attention to lifestyle modifications that may minimize cognitive issues in prostate cancer patients.
PMID: 34743290
ISSN: 1699-3055
CID: 5217912

The Effect of Abuse and Mistreatment on Healthcare Providers (TEAM): A Survey Assessing the Prevalence of Aggression From Patients and Their Families and Its Impact

Pinkhasov, Aaron; Filangieri, Carole; Rzeszut, Mary; Wilkenfeld, Marc; Akerman, Meredith; Divers, Jasmin; Oliveras, Jessica; Bostwick, J Michael; Svoronos, Alexander; Peltier, Morgan R
OBJECTIVE:Aggression from patients and families on health care providers (HCP) is common yet understudied. We measured its prevalence and impact on HCPs in inpatient and outpatient settings. METHODS:Four thousand six hundred seven HCPs employed by a community teaching hospital received an anonymous survey with results analyzed. RESULTS:Of 1609 HCPs (35%) completing the survey, 88% of inpatient staff reported experiencing different types of aggression compared to 82% in outpatient setting. Almost half did not report it to their supervisor. Younger staff were more likely to report abuse. Negative impacts on productivity and patient care were reported. A third of all responders' indicated negative effects on mental health. CONCLUSIONS:Despite negative impacts on staff wellbeing and productivity, patient/family aggression toward HCPs is highly prevalent and underreported. Our healthcare system needs measures to address staff security and wellness.
PMID: 34935679
ISSN: 1536-5948
CID: 5203382

Cognitive changes mediated by adenosine receptor blockade in a resveratrol-treated atherosclerosis-prone lupus mouse model

Kasselman, Lora J.; Renna, Heather A.; Voloshyna, Iryna; Pinkhasov, Aaron; Gomolin, Irving H.; Teboul, Isaac; De Leon, Joshua; Carsons, Steven E.; Reiss, Allison B.
Background and aim: Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Prior work showed that resveratrol's anti-atherogenic properties are mediated in part through the adenosine A2A receptor. The present study explores the potential contribution of adenosine A2A receptor activation to neuroprotective action of resveratrol on cognitive deficits in a model of atherosclerosis-prone systemic lupus erythematosus. Experimental procedure: Using behavioral analysis (open field, static rod, novel object recognition) and QRT-PCR, this study measured working memory, anxiety, motor coordination, and expression of mRNA in the brain. Results and conclusion: Data indicate that resveratrol increases working memory, on average but not statistically, and shows a trend towards improved motor coordination (p = 0.07) in atherosclerosis-prone lupus mice. Additionally, resveratrol tends to increase mRNA levels of SIRT1, decrease vascular endothelial growth factor and CX3CL1 mRNA in the hippocampus. Istradefylline, an adenosine A2A receptor antagonist, antagonizes the effects of resveratrol on working memory (p = 0.04) and the expression of SIRT1 (p = 0.03), vascular endothelial growth factor (p = 0.04), and CX3CL1 (p = 0.03) in the hippocampus. This study demonstrates that resveratrol could potentially be a therapeutic candidate in the modulation of cognitive dysfunction in neuropsychiatric lupus, especially motor incoordination. Further human studies, as well as optimization of resveratrol administration, could confirm whether resveratrol may be an additional resource available to reduce the burden of cognitive impairment associated with lupus. Additionally, further studies need to address the role of A2A blockade in cognitive function among the autoimmune population. Section: 3. Dietary therapy/nutrients supplements. Taxonomy (classification by EVISE): autoimmunity, inflammation, neurology.
ISSN: 2225-4110
CID: 5165922

Management of SIADH-related hyponatremia due to psychotropic medications - An expert consensus from the Association of Medicine and Psychiatry

Pinkhasov, Aaron; Xiong, Glen; Bourgeois, James A; Heinrich, Thomas W; Huang, Heather; Coriolan, Shanice; Annamalai, Aniyizhai; Mangal, Jed P; Frankel, Steven; Lang, Michael; Raj, Y Pritham; Dandois, Matthew; Barth, Kelly; Stewart, Anne Louise; Rado, Jeffrey; Pesek, Justin; Sanders, Aaron; Spearman-McCarthy, E Vanessa; Gagliardi, Jane; Fiedorowicz, Jess G
OBJECTIVE:Hyponatremia is the most common electrolyte imbalance encountered in clinical practice and is associated with negative healthcare outcomes and cost. SIADH is thought to account for one third of all hyponatremia cases and is typically an insidious process. Psychotropic medications are commonly implicated in the etiology of drug induced SIADH. There is limited guidance for clinicians on management of psychotropic-induced SIADH. METHODS:After an extensive review of the existing literature, clinical-educators from the Association of Medicine and Psychiatry developed expert consensus recommendations for management of psychotropic-induced SIADH. A risk score was proposed based on risk factors for SIADH to guide clinical decision-making. RESULTS:SSRIs, SNRIs, antipsychotics, carbamazepine, and oxcarbazepine have moderate to high level of evidence demonstrating their association with SIADH. Evaluation for an avoidance of medications that cause hyponatremia is particularly important. Substitution with medication that is less likely to cause SIADH should be considered when appropriate. We propose an algorithmic approach to monitoring hyponatremia with SIADH and corresponding treatment depending on symptom severity. CONCLUSIONS:The proposed algorithm can help clinicians in determining whether psychotropic medication should be stopped, reduced or substituted where SIADH is suspected with recommendations for sodium (Na+) monitoring. These recommendations preserve a role for clinical judgment in the management of hyponatremia with consideration of the risks and benefits, which may be particularly relevant for complex patients that present with medical and psychiatric comorbidities. Further studies are needed to determine whether baseline and serial Na+ monitoring reduces morbidity and mortality.
PMID: 34739943
ISSN: 1879-1360
CID: 5038512

Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans

Reiss, Allison B; Montufar, Natalie; DeLeon, Joshua; Pinkhasov, Aaron; Gomolin, Irving H; Glass, Amy D; Arain, Hirra A; Stecker, Mark M
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.
PMID: 33646990
ISSN: 2331-2637
CID: 4801212

Identification of a Novel Natriuretic Protein in Patients With Cerebral-Renal Salt Wasting-Implications for Enhanced Diagnosis

Maesaka, John K; Imbriano, Louis J; Pinkhasov, Aaron; Muralidharan, Rajanandini; Song, Xiaomin; Russo, Leileata M; Comper, Wayne D
BACKGROUND:The most vexing problem in hyponatremic conditions is to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C-RSW). Both have identical clinical parameters but diametrically opposite therapeutic goals of water- restricting water-logged patients with SIADH or administering salt and water to dehydrated patients with C-RSW. While C-RSW is considered a rare condition, the report of a high prevalence of C-RSW in the general hospital wards creates an urgency to differentiate one syndrome from the other on first encounter. We decided to identify the natriuretic factor (NF) we previously demonstrated in plasma of neurosurgical and Alzheimer diseases (AD) who had findings consistent with C-RSW. METHODS:We performed the same rat renal clearance studies to determine natriuretic activity (NA) in serum from a patient with a subarachnoid hemorrhage (SAH) and another with AD and demonstrated NA in their sera. The sera were subjected to proteomic and SWATH (Sequential Windowed Acquisition of All) analyses which identified increased levels of haptoglobin related protein (Hpr) without signal peptide (Hpr-WSP). RESULTS:Recombinant Hpr with His tag at the N terminus had no NA. Hpr-WSP had a robust NA in a dose-dependent manner when injected into rats. Serum after recovery from C-RSW in the SAH patient had no NA. CONCLUSIONS:Hpr-WSP may be the NF in C-RSW which should be developed as a biomarker to differentiate C-RSW from SIADH on first encounter, introduces a new syndrome of C-RSW in AD and can serve as a proximal diuretic to treat congestive heart failure.
PMID: 33526214
ISSN: 1538-2990
CID: 4776002

Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages

Karten, Ariel; Vernice, Nicholas A; Renna, Heather A; Carsons, Steven E; DeLeon, Joshua; Pinkhasov, Aaron; Gomolin, Irving H; Glass, Daniel S; Reiss, Allison B; Kasselman, Lora J
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.
PMID: 33434610
ISSN: 1096-0945
CID: 4746722

Alzheimer's disease: many failed trials, so where do we go from here?

Reiss, Allison Bethanne; Glass, Amy D; Wisniewski, Thomas; Wolozin, Benjamin; Gomolin, Irving H; Pinkhasov, Aaron; De Leon, Joshua; Stecker, Mark M
Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid β and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.
PMID: 32699179
ISSN: 1708-8267
CID: 4532512

Toward prevention of behavioral emergencies in a general hospital insights from a one-year series

Pinkhasov, Aaron; Hallo, Carlos; Avishai, Adri; Akerman, Meredith; Brand, Donald A
BACKGROUND:Behavioral emergencies endanger hospital staff and patients. The objective of this study was to identify patient characteristics that could be used to predict and prevent these incidents. METHODS:We analyzed a one-year consecutive series of behavioral emergencies that triggered the rapid response team at a general hospital, comparing study patients with controls who did not trigger a rapid response. Standard parametric or nonparametric tests, as appropriate, were used to compare the 2 groups in univariate analyses, and multivariable logistic regression analysis was used to identify the best combination of variables for stratifying the risk of such an event. RESULTS:There were 109 behavioral emergencies involving 83 patients. Comparison of patients who did (n = 83) or did not (n = 22,849) trigger a rapid response revealed marked differences between the two groups with respect to age, sex, and the prevalence of psychiatric comorbidities and various conditions that can diminish cognitive function. Substance use disorder was the most frequent principal diagnosis in the study group, accounting for 10.8% (9/83) of study patients vs. 0.6% (132/22849) of controls (p < 0.0001). The presence of a condition that can impair cognition (substance intoxication and withdrawal, epilepsy, cerebrovascular disease, traumatic brain injury, delirium, dementia) was associated with a 13-fold increase in the risk of a behavioral disturbance (95% CI, 8 to 22-fold). CONCLUSIONS:Brief cognitive assessment of patients susceptible to cognitive impairment, along with diligent prophylaxis and management of substance withdrawal and delirium, may facilitate prevention of behavioral emergencies.
PMID: 32688093
ISSN: 1873-7714
CID: 4552602