Alzheimer's Disease Treatment: The Search for a Breakthrough.

As the search for modalities to cure Alzheimer's disease (AD) has made slow progress, research has now turned to innovative pathways involving neural and peripheral inflammation and neuro-regeneration. Widely used AD treatments provide only symptomatic relief without changing the disease course. The recently FDA-approved anti-amyloid drugs, aducanumab and lecanemab, have demonstrated unclear real-world efficacy with a substantial side effect profile. Interest is growing in targeting the early stages of AD before irreversible pathologic changes so that cognitive function and neuronal viability can be preserved. Neuroinflammation is a fundamental feature of AD that involves complex relationships among cerebral immune cells and pro-inflammatory cytokines, which could be altered pharmacologically by AD therapy. Here, we provide an overview of the manipulations attempted in pre-clinical experiments. These include inhibition of microglial receptors, attenuation of inflammation and enhancement of toxin-clearing autophagy. In addition, modulation of the microbiome-brain-gut axis, dietary changes, and increased mental and physical exercise are under evaluation as ways to optimize brain health. As the scientific and medical communities work together, new solutions may be on the horizon to slow or halt AD progression.

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

INTRODUCTION AND AIMS: 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 oxLDL 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 oxLDL 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: 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.

Mitochondria in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-ß and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer's Disease.

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-ß accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-ß generation and improving neuronal health by maintaining mitochondrial function in neurons.

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

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.

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

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.

Absence of COVID-19 Disease Among Chronically Ventilated Nursing Home Patients.

OBJECTIVE: To describe the experience of COVID-19 disease among chronically ventilated and nonventilated nursing home patients living in 3 separate nursing homes. DESIGN: Observational study of death, respiratory illness and COVID-19 polymerase chain reaction (PCR) results among residents and staff during nursing home outbreaks in 2020. SETTING AND PARTICIPANTS: 93 chronically ventilated nursing home patients and 1151 nonventilated patients living among 3 separate nursing homes on Long Island, New York, as of March 15, 2020. Illness, PCR results, and antibody studies among staff are also reported. MEASUREMENTS: Data were collected on death rate among chronically ventilated and nonventilated patients between March 15 and May 15, 2020, compared to the same time in 2019; prevalence of PCR positivity among ventilated and nonventilated patients in 2020; reported illness, PCR positivity, and antibody among staff. RESULTS: Total numbers of deaths among chronically ventilated nursing home patients during this time frame were similar to the analogous period 1 year earlier (9 of 93 in 2020 vs 8 of 100 in 2019, P = .8), whereas deaths among nonventilated patients were greatly increased (214 of 1151 in 2020 vs 55 of 1189 in 2019, P < .001). No ventilated patient deaths were clinically judged to be COVID-19 related. No clusters of COVID-19 illness could be demonstrated among ventilated patients. Surveillance PCR testing of ventilator patients failed to reveal COVID-19 positivity (none of 84 ventilator patients vs 81 of 971 nonventilator patients, P < .002). Illness and evidence of COVID-19 infection was demonstrated among staff working both in nonventilator and in ventilator units. CONCLUSIONS AND IMPLICATIONS: COVID-19 infection resulted in illness and death among nonventilated nursing home residents as well as among staff. This was not observed among chronically ventilated patients. The mechanics of chronic ventilation appears to protect chronically ventilated patients from COVID-19 disease.

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

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-ß 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: 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: Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.

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

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 ß 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.

COX-2-dependent and independent effects of COX-2 inhibitors and NSAIDs on proatherogenic changes in human monocytes/macrophages.

It is the second decade of controversy regarding the cardiovascular effects of cyclo-oxygenase-2 (COX-2) inhibitors. At this time, celecoxib is the only available COX-2-specific inhibitor for treatment of pain and inflammation. Therefore, the present study was designed primarily to determine the impact of celecoxib on cholesterol handling (uptake via scavenger receptors and efflux from the cells) and foam cell formation in human THP-1 macrophages, followed by comparison to rofecoxib and other non-steroidal anti-inflammatory drugs (NSAIDs). THP-1 human macrophages and peripheral blood mononuclear cells were incubated with: celecoxib, rofecoxib, naproxen (at 5, 10, 25 µM) and acetaminophen (0.5 mM, 1 mM)±oxidized low-density lipoprotein (oxLDL, 25 µg/mL). Scavenger receptors: CD36, LOX-1, SR-A1, and CXCL16 and cholesterol efflux proteins: ATP-binding cassette transporter (ABC) A1 and G1, and 27-hydroxylase were detected. The adhesion of monocytes to cultured endothelial cells with/ without COX-2 inhibitors/NSAIDs was also analyzed. The presence of celecoxib and rofecoxib (at high concentrations) significantly decreased expression of 27-hydroxylase and ABCA1, interfering with normal cholesterol outflow from macrophages. Acetaminophen and the non-specific COX inhibitor naproxen had no significant effect on these proteins. Only celecoxib had a profound effect on the class B scavenger receptor CD36 and the class E receptor LOX1. We demonstrate that in contrast to celecoxib, rofecoxib and naproxen increased adhesive properties of monocytes to endothelial cells. This work might contribute to our understanding of multiple mechanisms underlying elevated cardiovascular risk upon the use of COX-2 inhibitors and uncover new possibilities to enhance the safety profile of existing COX-2 inhibitors.

Cefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review.

A 67-year-old woman with diabetes mellitus, chronic renal insufficiency, and recurrent urinary tract infections experienced encephalopathy and myoclonus while receiving cefepime. The adverse drug event was accompanied by elevated cefepime levels and abnormal electroencephalograms. This syndrome resolved after discontinuation of cefepime. Neurotoxicity is a known but possibly underreported adverse event associated with cefepime in patients with renal impairment who receive relatively excessive doses. Most cases reverse on drug cessation. In patients with renal disease, the maintenance dosage should be reduced and the patient monitored for neurotoxicity. Cefepime toxicity should be suspected whenever a patient receiving the drug experiences a change in mental status or myoclonus.

Older is colder: temperature range and variation in older people.

OBJECTIVES: To ascertain body temperatures in older people. DESIGN: Analysis of oral temperatures obtained from elderly subjects residing in the community and nursing home. SETTING: A single nursing home, office setting, and community center. PARTICIPANTS: One hundred nursing home residents and 50 subjects residing in the community. MEASUREMENTS: Three oral temperatures were measured in nursing home residents and once in community dwellers using an electronic digital thermometer. RESULTS: The average age of subjects was 80.7. Temperatures ranged from 94.0 degrees F to 99.6 degrees F. In nursing home subjects, the 6 a.m. mean temperature was 97.3 degrees F, 4 p.m. mean was 97.4 degrees F, and 10 p.m. mean was 97.8 degrees F. The single midday mean temperature in community dwellers was 97.7 degrees F. Ninety-seven of 100 (97%), 94 of 100 (94%), and 83 of 96 (86%) recordings were below 98.6 degrees F in nursing home residents at 6 a.m., 4 p.m., and 10 p.m., respectively. Similarly, 45 of 50 (90%) community dwellers had midday temperatures below 98.6 degrees F. Repeated-measures analysis demonstrated an increase in temperature during the day. The increase was greatest in the youngest old, with no significant change in body temperature over the course of the day in the oldest old. CONCLUSION: Older subjects have mean oral body temperatures lower than 98.6 degrees F. Relatively few even achieve this temperature. In nursing home residents, the oldest were coldest and failed to demonstrate a diurnal rise in body temperature.

Impact of computerized physician order entry alerts on prescribing in older patients.

BACKGROUND: A computerized physician order entry (CPOE) system provides opportunity for real-time alerts to prescribers. Winthrop University Hospital began using CPOE in 2009. OBJECTIVE: We sought to improve prescribing among older hospitalized patients by adding alerts to the CPOE system for potentially inappropriate medications. METHODS: In January 2011, informational alerts were integrated into the CPOE system for selected high-risk medications: diphenhydramine, metoclopramide, and all antipsychotics. We evaluated the effect of these alerts on prescribing frequency by comparing the number of prescriptions during the second quarters of 2010 ("pre-alert") with the second quarters of 2011 through 2013 ("post-alert"). Prescribing patterns were evaluated through a pharmacy database of medication orders. Frequency of prescribing was adjusted for total discharges. A comparison was made to ages 18-64 years, and comparing "as needed" vs standing orders. RESULTS: In the 65 years of age and older group, there were significant reductions in prescription rates pre-alert vs post-alert for diphenhydramine (p < 0.001) and metoclopramide (p < 0.001). There was no decrease in prescription rates for antipsychotics in older patients (p = 0.80). In the younger comparison group, no decreases in prescription rates for those drugs were observed. Our analysis is based on numbers of written prescriptions and not actual doses administered; therefore, no conclusions concerning the effect of these alerts on communication or documentation of risk/benefits of these medications can be ascertained. CONCLUSION: The data suggest that prescribing rates for drugs with the least efficacy and potential for harm and with alternative agents (i.e., diphenhydramine and metoclopramide) can be modified by CPOE alerts for older patients.

Influenza. How to prevent and control nursing home outbreaks.

Influenza is an important cause of acute respiratory illness among older adults in general and within the nursing home in particular. Epidemics typically are reported in the late fall and throughout the winter. In the nursing home, vaccination may not prevent clinical illness but can reduce the risk of pneumonia, hospitalization, and death. Atypical presentations, including delirium and nonspecific functional changes, are common in older patients. Rapid diagnosis is imperative, as early antiviral treatment and prophylaxis can control a nursing home outbreak.

Cholinesterase inhibitors: applying pharmacokinetics to clinical decision making.

BACKGROUND: Cholinesterase inhibitors are indicated for the treatment of Alzheimer-type dementia. There are few direct comparative studies of adverse effects or studies to suggest clinical superiority of one inhibitor over the others. OBJECTIVE: The objective of this study was to relate pharmacokinetic differences among the agents to potential clinical considerations. METHODS: Population pharmacokinetics were obtained from US Food and Drug Administration-approved label information and published literature. Plasma concentration-time profiles were derived from these parameters using noncompartmental pharmacokinetic modeling. RESULTS: Plasma concentration profiles differed significantly among different agents and between different formulations of the same agent. CONCLUSIONS: The initial choice among the various cholinesterase inhibitors requires consideration to adherence and cost. Consideration to differences in pharmacokinetics among these drugs provides a better understanding for the clinical practice of dose titration, identification and management of drug-related side effects, and lapses in therapy. Pharmacokinetic considerations among the various agents and formulations provide the clinician with options to enhance therapy when these agents are chosen for treatment of patients with Alzheimer-type dementia.

Donepezil dosing strategies: pharmacokinetic considerations.

Donepezil (Aricept) is a cholinesterase inhibitor approved for the treatment of Alzheimer's disease. Immediate release formulations of 5- and 10-mg tablets were approved by the Food and Drug Administration in the United States in 1996. In July 2010, the Food and Drug Administration approved a 23-mg sustained release (SR) formulation. The SR formulation may provide additional benefit to patients receiving 10 mg daily but the incidence of adverse reactions is increased. We derived plasma concentration profiles for higher dose immediate-release formulations (15 mg once daily, 10 mg twice daily, and 20 mg once daily) and for the profile anticipated to result from the 23-mg SR formulation. Our model predicts similar steady-state concentration profiles for 10 mg twice daily, 20 mg once daily, and 23 mg SR once daily. This provides the theoretical basis for incremental immediate release dose escalation to minimize the emergence of adverse reactions and the potential to offer a cost-effective alternative to the SR formulation with currently approved generic immediate release formulations.