Preclinical progression of neurodegenerative diseases

Abstract

Neurodegenerative diseases are disorders that are characterized by a progressive decline of the motor and/or cognitive function caused by a selective loss of neurons within the central nervous system. Recent advancements in the translational research have facilitated extensive insights into the molecular pathophysiology of neurodegenerative diseases. Nonetheless, a myriad of compounds that suppressed the disease progression in cellular and animal models did not exhibit efficacy in clinical trials. Perhaps, various biological, medical, and methodological factors could be attributed to unfavorable results of clinical trials of such disease-modifying therapies. Primarily, the fact that pathological changes at molecular and cellular levels precede the clinical onset by several years underscores a pressing need for the initiation of interventions before the emergence of neurological symptoms. Using exquisite biomarkers, recent studies revealed the preclinical and prodromal progression of pathophysiology, as well as compensatory brain responses in several neurodegenerative diseases. This review aims to discuss the recent advancement of biomarker studies on presymptomatic subjects and the perspective on a preventive trial of disease-modifying therapies for devastating neurological disorders.

Keywords: biomarker; disease-modifying therapy; neurodegenerative disease; preclinical; preventive therapy; prodromal.

Fig. 1

Time course of neurodegeneration Accumulation of abnormal proteins instigates primary of molecular changes in neurons followed by secondary events such as glial alteration and neuroinflammation. Compensatory responses cope with neural dysfunction and maintain neurological function at an early stage, but breakdown of such defense machinery leads to manifestation of clinical symptoms. The definition of “preclinical” has not been fully established. It includes prodromal phase, when patients develop mild, auxiliary symptoms, in some studies, while other researches define preclinical as being free from any symptoms. In this review, we adopted the former definition.