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1.
Alzheimers Res Ther ; 13(1): 201, 2021 12 20.
Article in English | MEDLINE | ID: covidwho-1582016

ABSTRACT

BACKGROUND: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made. METHODS: We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined. RESULTS: Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned. DISCUSSION: These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials' validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.


Subject(s)
Alzheimer Disease , COVID-19 , Alzheimer Disease/drug therapy , Computer Simulation , Humans , Pandemics , SARS-CoV-2
3.
Med Sci Monit ; 27: e934077, 2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1326004

ABSTRACT

Current treatments for patients with Alzheimer's disease aim to improve behavioral, cognitive, and non-cognitive symptoms. There have been no new drug approvals for preventing or treating Alzheimer's disease for more than two decades. Drug development in Alzheimer's disease aims to identify disease-modifying therapies that will delay or slow the clinical course of this disease. More than 50% of the current Alzheimer's disease drug pipeline now involves immunotherapies or oral small molecule agents. The most promising disease-modifying drug targets are amyloid ß and tau protein. In June 2021, aducanumab, a humanized recombinant monoclonal antibody to amyloid ß, was the first potential disease-modifying therapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer's disease and mild cognitive impairment. Accelerated approval of aducanumab was based on the results of only one of two phase 3 clinical trials. Several clinical trials of targeted disease-modifying immunotherapies to the tau protein and amyloid ß that commenced before the current COVID-19 pandemic have been delayed. This Editorial aims to provide an update on past, present, and future disease-modifying therapies in Alzheimer's disease, including targeted therapies for amyloid ß and tau protein.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , tau Proteins/metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/immunology , Humans , Immunotherapy/methods , Immunotherapy/trends , Tauopathies/drug therapy
4.
J Prev Alzheimers Dis ; 8(4): 513-519, 2021.
Article in English | MEDLINE | ID: covidwho-1308555

ABSTRACT

The 2020 COVID-19 pandemic has disrupted Alzheimer's disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer's Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.


Subject(s)
Advisory Committees , Alzheimer Disease/drug therapy , Biomedical Research , COVID-19 , Clinical Trials as Topic , Digital Technology , Biomedical Research/organization & administration , Clinical Trials as Topic/organization & administration , European Union , Humans , United States
5.
Contemp Clin Trials ; 107: 106488, 2021 08.
Article in English | MEDLINE | ID: covidwho-1275181

ABSTRACT

The LUCINDA Trial (Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's) is a 52 week, randomized, placebo-controlled trial of leuprolide acetate (Eligard) in women with Alzheimer's disease (AD). Leuprolide acetate is a gonadotropin analogue commonly used for hormone-sensitive conditions such as prostate cancer and endometriosis. This repurposed drug demonstrated efficacy in a previous Phase II clinical trial in those women with AD who also received a stable dose of the acetylcholinesterase inhibitor donepezil (Bowen et al., 2015). Basic biological, epidemiological and clinical trial data suggest leuprolide acetate mediates improvement and stabilization of neuropathology and cognitive performance via the modulation of gonadotropin and/or gonadotropin-releasing hormone signaling. LUCINDA will enroll 150 women with mild-moderate AD who are receiving a stable dose of donepezil from three study sites in the United States. Cognition and function are the primary outcome measures as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Blood and MRI biomarkers are also measured to assess hormonal, inflammatory and AD biomarker changes. We present the protocol for LUCINDA and discuss trial innovations and challenges including changes necessitated by the covid-19 pandemic and study drug procurement issues.


Subject(s)
Alzheimer Disease , Acetylcholinesterase , Alzheimer Disease/drug therapy , COVID-19 , Cholinesterase Inhibitors/therapeutic use , Double-Blind Method , Female , Humans , Indans , Leuprolide/therapeutic use , Pandemics
6.
J Alzheimers Dis ; 82(1): 107-127, 2021.
Article in English | MEDLINE | ID: covidwho-1231319

ABSTRACT

Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) disproportionally affect Hispanic and Latino populations, yet Hispanics/Latinos are substantially underrepresented in AD/ADRD clinical research. Diverse inclusion in trials is an ethical and scientific imperative, as underrepresentation reduces the ability to generalize study findings and treatments across populations most affected by a disease. This paper presents findings from a narrative literature review (N = 210) of the current landscape of Hispanic/Latino participation in clinical research, including the challenges, facilitators, and communication channels to conduct culturally appropriate outreach efforts to increase awareness and participation of Hispanics/Latinos in AD/ADRD clinical research studies. Many challenges identified were systemic in nature: lack of culturally relevant resources; staffing that does not represent participants' cultures/language; eligibility criteria that disproportionately excludes Hispanics/Latinos; and too few studies available in Hispanic/Latino communities. The paper also details facilitators and messaging strategies to improve engagement and interest among Hispanics/Latinos in AD/ADRD research, starting with approaches that recognize and address the heterogeneity of the Hispanic/Latino ethnicity, and then, tailor outreach activities and programs to address their diverse needs and circumstances. The needs identified in this article represent longstanding failures to improve engagement and interest among Hispanics/Latinos in AD/ADRD research; we discuss how the field can move forward learning from the experiences of the COVID-19 pandemic.


Subject(s)
Alzheimer Disease , COVID-19 , Clinical Trials as Topic , Dementia , /statistics & numerical data , Alzheimer Disease/drug therapy , Alzheimer Disease/epidemiology , COVID-19/complications , Dementia/drug therapy , Dementia/epidemiology , Humans
7.
Molecules ; 25(22)2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-917015

ABSTRACT

Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.


Subject(s)
Flavonoids/chemistry , Flavonoids/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/prevention & control , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cardiovascular System/drug effects , Flavonoids/economics , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Nervous System/drug effects , Neurons/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Plant Leaves/chemistry , Plants/chemistry , Polyphenols/chemistry , Polyphenols/pharmacology , Quercetin/chemistry , Quercetin/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Stroke/drug therapy , Stroke/prevention & control
13.
Am J Manag Care ; 26(8 Suppl): S167-S176, 2020 08.
Article in English | MEDLINE | ID: covidwho-946633

ABSTRACT

The burden of Alzheimer disease (AD) on the US healthcare system is substantial and increasing. AD progresses along a continuum from preclinical disease characterized by normal cognition and abnormal brain biomarkers to mild cognitive impairment and then clinically apparent dementia. Diagnosis early in the AD continuum has benefits for patients and caregivers and appears cost-effective, but often, the clinical diagnosis of AD may be delayed. Currently available biomarkers include ß-amyloid positron emission tomography and cerebrospinal fluid tests. Collectively, they are expensive, may lead to adverse effects, are not widely available, and are not suited for primary care. Currently available treatment options, cholinesterase inhibitors and memantine, do not alter disease progression, but can help with some symptoms. Benefits of currently available treatments on cognition are difficult to quantify and are offset by a burden of adverse effects that often go unrecognized. More accurate diagnostic biomarkers and disease-modifying drug therapies are critical unmet needs of patients with AD despite decades of clinical research. Because many phase 3 clinical trials that enrolled patients with symptomatic AD have failed, researchers believe that disease-modifying treatment is more likely to demonstrate benefit when utilized early in the disease continuum. Within the past few years, significant achievements that will advance clinical trials in early AD include the Research Framework to define and stage the AD continuum, FDA guidance on study design in early AD, and development of scales to measure cognition that are suitable for early AD. In October 2019, the AD community was re-invigorated by unexpected news that a Biologics License Application will be submitted for aducanumab to treat AD. This article explores the current state of biomarker-driven drug development across the AD continuum and reviews investigational drugs in phase 2/3 clinical development for AD.


Subject(s)
Alzheimer Disease , Alzheimer Disease/diagnosis , Alzheimer Disease/drug therapy , Biomarkers , Brain , Early Diagnosis , Humans , Positron-Emission Tomography
14.
J Pineal Res ; 70(2): e12702, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-894785

ABSTRACT

Melatonin was discovered more than 60 years ago. Since then, several seminal discoveries have allowed us to define its function as a neuroendocrine hormone and its molecular targets in mammals and many other species. However, many fundamental issues have not yet been solved such as the subcellular localization of melatonin synthesis and the full spectrum of its molecular targets. In addition, a considerable number of controversies persist in the field, mainly concerning how many functions melatonin has. Altogether, this illustrates how "immature" the field still is. The intention of this opinion article is to note the controversies and limitations in the field, to initiate a discussion and to make proposals/guidelines to overcome them and move the field forward.


Subject(s)
Melatonin , Alzheimer Disease/drug therapy , Animals , Antioxidants , COVID-19/drug therapy , Humans
15.
ACS Chem Neurosci ; 11(15): 2145-2148, 2020 08 05.
Article in English | MEDLINE | ID: covidwho-646274

ABSTRACT

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer's dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aß) protein, the hallmark of Alzheimer's dementia. Reversely, deposition of Aß is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer's disease (AD) as well as have shown inhibition in various virus infections.


Subject(s)
Alzheimer Disease/drug therapy , Betacoronavirus , Calcium Channel Blockers/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/psychology , COVID-19 , Calcium/metabolism , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Coronavirus Infections/metabolism , Coronavirus Infections/psychology , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/psychology , SARS-CoV-2 , Treatment Outcome
17.
Travel Med Infect Dis ; 36: 101812, 2020.
Article in English | MEDLINE | ID: covidwho-633889

ABSTRACT

BACKGROUND: Hydroxychloroquine (HCQ) is currently being examined for COVID-19. No previous meta-analysis has evaluated its side effects versus placebo. We conducted this meta-analysis to compare the safety of HCQ versus placebo. METHODS: Two authors independently searched PubMed and EMBASE databases for randomized controlled trials (RCTs) of adults comparing the adverse events (AEs) of HCQ versus placebo for any indication. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were calculated based on random-effects models. The heterogeneity (I2) was assessed using Cochran's Q test. RESULTS: Nine RCTs (eight were double-blind) with a total of 916 patients were included. HCQ caused significantly more skin pigmentation than placebo (Peto OR, 4.64; 95% CI, 1.13 to 19.00; P-value = 0.033; I2 = 0%). The increase in other AEs did not reach statistical significance: rash (Peto OR, 1.11; 95% CI, 0.3 to 3.77; P-value = 0.03; I2 = 0%); gastrointestinal AEs (Peto OR, 1.43; 95% CI, 0.55 to 3.72; P-value = 0.46; I2 = 15.17%); headache (Peto OR, 1.94; 95% CI, 0.65 to 5.78; P-value = 0.23; I2 = 9.99%); dizziness (Peto OR, 1.32; 95% CI, 0.49 to 3.52; P-value = 0.58; I2 = 0%); fatigue (Peto OR, 2.13; 95% CI, 0.76 to 5.98; P-value = 0.15; I2 = 0%); and visual AEs (Peto OR, 1.61; 95% CI, 0.76 to 3.41; P-value = 0.22; I2 = 0%). Cardiac toxicity was not reported. CONCLUSIONS: This meta-analysis of RCTs found a significantly higher risk of skin pigmentation in HCQ users versus placebo. More data are needed to evaluate HCQ in the context of COVID-19 treatment.


Subject(s)
Alzheimer Disease/drug therapy , Antirheumatic Agents/adverse effects , Chronic Urticaria/drug therapy , Glomerulonephritis, IGA/drug therapy , HIV Infections/drug therapy , Hydroxychloroquine/adverse effects , Hyperpigmentation/chemically induced , Rheumatic Diseases/drug therapy , Arthritis, Rheumatoid/drug therapy , Asymptomatic Infections , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Dizziness/chemically induced , Exanthema/chemically induced , Fatigue/chemically induced , Gastrointestinal Diseases/chemically induced , Headache/chemically induced , Humans , Lupus Erythematosus, Cutaneous/drug therapy , Lupus Erythematosus, Systemic/drug therapy , Osteoarthritis/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Randomized Controlled Trials as Topic , SARS-CoV-2
19.
Am J Geriatr Psychiatry ; 28(9): 913-920, 2020 09.
Article in English | MEDLINE | ID: covidwho-305911

ABSTRACT

Advances in treating and preventing Alzheimer disease and other neurocognitive disorders of aging arise from rigorous preclinical and clinical research, with randomized controlled treatment trials as the last and definitive test. The COVID-19 pandemic has greatly disrupted ongoing interventional studies and researchers are scrambling to find ways to safely continue this critical work amidst rapidly shifting guidelines from sponsors, institutions, and state and federal guidelines. Here the authors describe novel approaches and work-flow adaptations to study visits, drug delivery and interim and endpoint safety and outcomes assessments to avoid sacrificing years of preparation and substantial financial investments, to work in the best interest of participants and their caregivers, and to continue on the path toward discovering disease-modifying treatments for the millions of individuals impacted by major neurocognitive disorders.


Subject(s)
Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Coronavirus Infections/prevention & control , Neurocognitive Disorders/drug therapy , Neurocognitive Disorders/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Aged , Alzheimer Disease/drug therapy , Alzheimer Disease/prevention & control , Betacoronavirus , COVID-19 , Guidelines as Topic , Humans , SARS-CoV-2
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