Abstract
Alzheimer's disease (AD) and Parkinson's disease (PD) are the first and second most common neurodegenerative disorders, respectively. Both are proteinopathies with inexorable courses and no approved disease-modifying therapies. A substantial effort has been made to identify interventions that could slow down the progression of AD and PD; to date, with no success. The advances in biomarker research improved the identification of individuals at risk for these disorders before symptom onset, recognizing the pre-clinical stage, in which there is abnormal protein accumulation but no clinical symptoms of the disease, and the prodromal stage, in which mild symptoms are present but the clinical diagnostic criteria for disease cannot be fulfilled. The ability to detect pre-clinical and prodromal stages of these diseases has encouraged clinical trials for disease-modification at earlier phases, seeking to slow or prevent phenoconversion into clinical disease. Clinical trials at these stages have several challenges, such as the identification of the eligible population, the appropriate choice of biomarkers, the definition of clinical endpoints, the duration of follow-up, and the statistical analysis. This article aims to discuss some of the methodological challenges in the design of trials for pre-clinical and prodromal phases of AD and PD, to critically review the recent studies, and to discuss methodological approaches to mitigate these challenges in trial design.
Highlights
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the first and second most common neurodegenerative disorders, respectively
Several methodological challenges may arise in the design of such trials, including the identification of the eligible population, the appropriate choice of biomarkers for subject enrollment, the definition of clinical endpoints, the potential need for surrogate outcomes, the definition of patientreported outcomes, the duration of follow-up, and the statistical analysis [9]. Considering these challenges, this article aimed to discuss the methodological challenges in the design of randomized controlled trials (RCTs) for pre-clinical and prodromal phases of AD and PD, respectively; to critically review the recent RCTs performed for disease-modifying therapy (DMT); and to discuss potential methodological approaches to mitigate the issues in trial design
There is a crucial need for effective DMT in AD and PD
Summary
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the first and second most common neurodegenerative disorders, respectively. It is estimated that nearly 45 million people live with AD and related forms of dementia globally [1, 2], and that other 6.1 million live with PD [2]; both with prospects for an exponential increase in prevalence due to population growth and prolonged lifespan [3, 4]. While these are distinct disorders in terms of pathology, clinical presentation, and management, there are essential points in common: both are proteinopathies with an inexorable course and no definite disease-modifying therapy (DMT) [5, 6]. This is an intriguing situation, notably when experimental studies have unveiled so many promising drugs, which failed in human phase 2 or phase 3 clinical trials
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