Prodromal Stage of Neurodegenerative Proteinopathies: From Bench to Bedside

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Background

Neurodegenerative proteinopathies like Parkinson’s disease (PD) and Alzheimer’s diseases (AD) are preceded by a long period of prodromal stage. The pathologic changes of both PD and AD can start decades before the appearance of the debilitating cardinal symptoms, at which point they are eventually diagnosed. For instance, numerous prospective longitudinal studies have now proven that REM sleep behavior disorder, hyposmia, and dysautonomia start up to 20 years before any motor symptom manifests in synucleinopathy. Brain imaging, serum, and cerebrospinal fluid (CSF) biomarkers, as well as subtle mild cognitive impairment (MCI), have been discovered to assist in the timely and accurate screening of AD during early prodromal stages. More studies are indeed required to clarify the prodromal stage of TDP-43 proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.

Although no neuroprotective or disease-modifying agent has been discovered for PD, AD, or other neurodegenerative proteinopathies so far, enhancing our knowledge on various aspects of the prodromal stage is essential for the diagnosis and future clinical trials and eventual provision of neuroprotective therapy in the early stages of neurodegenerative proteinopathies. It is speculated that one major reason for the failure of numerous clinical trials in neurodegenerative disorders is targeting the pathologic process in the later stage since by the time of diagnosis the majority of the neurons in the functional system of interest have already been irreversibly damaged. There is a recent shift, however, in the design of such clinical trials by recruiting participants within the prodromal stage of neurodegeneration hoping for a timely intervention. Furthermore, there is a dearth of knowledge on practical biomarkers to monitor disease trajectory during the prodromal stage, and/or accurately predict phenoconversion to a full-blown neurodegenerative disorder. Relentless basic science research is needed to discover early disease biomarkers and potential neuroprotective agents targeting the responsible pathologic process to stop or slow down neurodegeneration during the prodromal stage when a functional amount of neurons and their connectors are still alive.

This Research Topic aims to report recent discoveries on various aspects of the prodromal stage of neurodegenerative proteinopathies, such as AD and PD. Original research articles, review articles (narrative and systematic), and brief communications will be considered for publication.

This Research Topic will cover the following aspects:
- Original articles that describe the evolution of prodromal stage in various neurodegenerative proteinopathies
- Big data analysis on trajectories of prodromal features in neurodegenerative conditions
- Original articles (basic science, clinical, or translational studies) that report on the development, analytical validation, and clinical performance of new biomarkers covering all aspects of the prodromal stage of neurodegenerative conditions
- Original articles that describe new methods and technologies for translational novel biomarkers and disease-modifying agents discovery and development
- Animal work models neurodegenerative disease progression, monitors disease severity, assesses therapeutic efficacies
- Clinical trials or basic science contributions on novel potential neuroprotective agents to slow down the neurodegenerative process in the prodromal stage
- Review and perspective articles that discuss recent advances, potential contexts of use, and future perspectives of knowledge in prodromal neurodegenerative state
- Expert opinion on moral and ethical aspects of screening individuals with a prodromal neurodegenerative state decades before phenoconversion

Keywords: Parkinson’s disease, Alzheimer's disease, Prodromal stage, Proteinopathy, Phenoconversion, MCI

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