THE PATIENT IN YOUR ALZHEIMER’S DISEASE STUDY MAY BE IN ANOTHER: DUPLICATION AND DECEPTION IN CLINICAL TRIALS OF ALZHEIMER’S DISEASE

2020 ◽  
pp. 1-4
Author(s):  
T. Shiovitz ◽  
B. Steinmiller ◽  
C. Steinmetz ◽  
S. Perez ◽  
R. Oseas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Active Treatment ◽  
Memory Loss ◽  
Mechanisms Of Action ◽  
Efficacy And Safety ◽  
Significant Issue ◽  
Disease Study ◽  
Safety Signals

Duplicate and deceptive subjects, a significant issue in CNS studies, are not often considered in Alzheimer’s Disease (AD) clinical trials. However, AD patients and their study partners may be motivated to take advantage of different mechanisms of action, increase odds of receiving active treatment, and/or obtain financial compensation, which may lead them to participate in multiple studies. CTSdatabase reviewed memory loss subjects (n=1087) from January 2017 through May 2019 to determine how many attempted to screen at multiple sites. 117 subjects (10.8%) visited more than one site within two years. When these potential AD subjects went to additional sites, it was predominantly for non-memory indications (often MDD or schizophrenia). For those that participated in studies, the rate of duplication approached 4% of screened AD subjects. This data indicates that significant numbers of AD subjects attempt to enroll at multiple sites, which confounds efficacy and safety signals in clinical trials.

Rosiglitazone and Pioglitazone for the Treatment of Alzheimer's Disease

2011 ◽  
Vol 45 (11) ◽  
pp. 1416-1424 ◽  
Author(s):  
Benjamin W Miller ◽  
Kristine C Willett ◽  
Alicia R Desilets
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Search Terms ◽  
Primary Endpoints ◽  
Study Selection ◽  
Antiinflammatory Effects

Objective: To review the literature on the efficacy and safety of rosiglitazone and pioglitazone for the treatment of Alzheimer's disease (AD). Data Sources: Literature was accessed through MEDLINE (1948-August 2011 week 2) and EMBASE (1980-2011 week 32) using the search terms rosiglitazone, pioglitazone, and Alzheimer's disease. Results were limited to studies conducted in humans and published in English. Study Selection And Data Ektraction: Clinical trials evaluating the efficacy and safety of rosiglitazone or pioglitazone in patients with AD were critically evaluated. Data Synthesis: The mechanism for development of AD has been linked to both inflammation and decreased insulin sensitivity. Because of this, rosiglitazone and pioglitazone have been evaluated as potential treatments for AD because of their insulin-sensitizing and antiinflammatory effects. Five clinical trials were evaluated (3 assessing rosiglitazone, 2 assessing pioglitazone); 1 trial evaluating rosiglitazone demonstrated a beneficial effect on cognition in patients with probable AD. However, the largest randomized, double-blind, placebo-controlled trials conducted to date failed to demonstrate a difference between rosiglitazone and placebo when assessing primary endpoints. Two small trials evaluating pioglitazone produced conflicting results regarding efficacy in AD; numerous limitations make results difficult to interpret. The safety of these agents was also evaluated in these trials; edema was seen more commonly in patients receiving rosiglitazone or pioglitazone than in those receiving placebo; however, each drug was generally well tolerated. Conclusions: Resufts from clinical trials and current safety data suggest that rosiglitazone should not be used for the treatment of AD. Application of results from trials evaluating pioglitazone in the treatment of AD is limited because of major trial limitations; therefore, it should not be recommended at this time. Although these drugs are not commonly used in the treatment of AD, further pharmacoepidemiologic studies are warranted before their use can be recommended.

scholarly journals The Chick as a Model for the Study of the Cellular Mechanisms and Potential Therapies for Alzheimer's Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Radmila Mileusnic ◽  
Steven Rose
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Experiments ◽  
Memory Loss ◽  
Treatment Strategies ◽  
Cellular Mechanisms ◽  
Sequence Homologies ◽  
Species Specific ◽  
Close Sequence

While animal experiments have contributed much to our understanding of the mechanisms of Alzheimer's disease (AD), their value in predicting the effectiveness of treatment strategies in clinical trials has remained controversial. The disparity between the results obtained in animal models and clinical trials may in part be explained by limitations of the models and species-specific differences. We propose that one trial passive avoidance in the day-old chick is a useful system to study AD because of the close sequence homologies of chick and human amyloid precursor protein (APP). In the chick, APP is essential for memory consolidation, and disrupting its synthesis or structure results in amnesia. RER, a tripeptide sequence corresponding to part of the growth domain of APP, can restore memory loss and act as a cognitive enhancer. We suggest that RER and its homologues may form the basis for potential pharmacological protection against memory loss in AD.

scholarly journals Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Camryn Berk ◽  
Marwan Sabbagh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Nicotinic Receptor ◽  
Acetylcholinesterase Inhibitor ◽  
Symptomatic Treatment ◽  
Mechanisms Of Action ◽  
Receptor Stimulation ◽  
App Processing ◽  
Higher Doses

Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer's disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD.

scholarly journals Deep learning detection of informative features in tau PET for Alzheimer’s disease classification

2020 ◽  
Vol 21 (S21) ◽  
Author(s):  
Taeho Jo ◽  
◽  
Kwangsik Nho ◽  
Shannon L. Risacher ◽  
Andrew J. Saykin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Deep Learning ◽  
Early Detection ◽  
Medial Temporal Lobe ◽  
Memory Loss ◽  
Disease Classification ◽  
Classification Model ◽  
Tau Pet

Abstract Background Alzheimer’s disease (AD) is the most common type of dementia, typically characterized by memory loss followed by progressive cognitive decline and functional impairment. Many clinical trials of potential therapies for AD have failed, and there is currently no approved disease-modifying treatment. Biomarkers for early detection and mechanistic understanding of disease course are critical for drug development and clinical trials. Amyloid has been the focus of most biomarker research. Here, we developed a deep learning-based framework to identify informative features for AD classification using tau positron emission tomography (PET) scans. Results The 3D convolutional neural network (CNN)-based classification model of AD from cognitively normal (CN) yielded an average accuracy of 90.8% based on five-fold cross-validation. The LRP model identified the brain regions in tau PET images that contributed most to the AD classification from CN. The top identified regions included the hippocampus, parahippocampus, thalamus, and fusiform. The layer-wise relevance propagation (LRP) results were consistent with those from the voxel-wise analysis in SPM12, showing significant focal AD associated regional tau deposition in the bilateral temporal lobes including the entorhinal cortex. The AD probability scores calculated by the classifier were correlated with brain tau deposition in the medial temporal lobe in MCI participants (r = 0.43 for early MCI and r = 0.49 for late MCI). Conclusion A deep learning framework combining 3D CNN and LRP algorithms can be used with tau PET images to identify informative features for AD classification and may have application for early detection during prodromal stages of AD.

Stem Cell-based Therapeutic and Diagnostic Approaches in Alzheimer's Disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Sadaf Abdi ◽  
Nima Javanmehr ◽  
Maryam Ghasemi-Kasman ◽  
Hanie Yavarpour Bali ◽  
Marzieh Pirzadeh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cells ◽  
Clinical Trials ◽  
Stem Cell ◽  
Memory Loss ◽  
Stem Cell Therapies ◽  
Cell Therapies ◽  
Advantages And Disadvantages ◽  
Diagnostic Approaches

Background: Alzheimer’s disease (AD) is a neurodegenerative impairment mainly recognized by memory loss and cognitive deficits. However, the current therapies against AD are mostly limited to palliative medications, prompting researchers to investigate more efficient therapeutic approaches for AD, such as stem cell therapy. Recent evidence has proposed that extensive neuronal and synaptic loss and altered adult neurogenesis, which is perceived pivotal in terms of plasticity and network maintenance, occurs early in the course of AD, which exacerbates neuronal vulnerability to AD. Thus, regeneration and replenishing the depleted neuronal networks by strengthening the endogenous repair mechanisms or exogenous stem cells and their cargoes is a rational therapeutic approach. Currently, several stem cell-based therapies as well as stem cell products like exosomes, have shown promising results in the early diagnosis of AD. Objective: This review begins with a comparison between AD and normal aging pathophysiology and a discussion on open questions in the field. Next, summarizing the current stem cell-based therapeutic and diagnostic approaches, we declare the advantages and disadvantages of each method. Also, we comprehensively evaluate the human clinical trials of stem cell therapies for AD. Methodology: Peer-reviewed reports were extracted through Embase, PubMed, and Google Scholar until 2021. Results: With several ongoing clinical trials, stem cells and their derivatives (e.g., exosomes) are an emerging and encouraging field in diagnosing and treating neurodegenerative diseases. Although stem cell therapies have been successful in animal models, numerous clinical trials in AD patients have yielded unpromising results, which we will further discuss.

scholarly journals Reversal of Calcium Dysregulation as Potential Approach for Treating Alzheimer's Disease

2020 ◽  
Vol 17 (4) ◽  
pp. 344-354 ◽  
Author(s):  
Elena Popugaeva ◽  
Daria Chernyuk ◽  
Ilya Bezprozvanny
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Memory Loss ◽  
Preclinical Models ◽  
Calcium Dysregulation ◽  
Novel Drugs ◽  
Alternative Approaches ◽  
Disease Modifying ◽  
Disease Modifying Treatment

Despite decades of research and effort, there is still no effective disease-modifying treatment for Alzheimer’s Disease (AD). Most of the recent AD clinical trials were targeting amyloid pathway, but all these trials failed. Although amyloid pathology is a hallmark and defining feature of AD, targeting the amyloid pathway has been very challenging due to low efficacy and serious side effects. Alternative approaches or mechanisms for our understanding of the major cause of memory loss in AD need to be considered as potential therapeutic targets. Increasing studies suggest that Ca2+ dysregulation in AD plays an important role in AD pathology and is associated with other AD abnormalities, such as excessive inflammation, increased ROS, impaired autophagy, neurodegeneration, synapse, and cognitive dysfunction. Ca2+ dysregulation in cytosolic space, Endoplasmic Reticulum (ER) and mitochondria have been reported in the context of various AD models. Drugs or strategies, to correct the Ca2+ dysregulation in AD, have been demonstrated to be promising as an approach for the treatment of AD in preclinical models. This review will discuss the mechanisms of Ca2+ dysregulation in AD and associated pathology and discuss potential approaches or strategies to develop novel drugs for the treatment of AD by targeting Ca2+ dysregulation.

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