A Review of Biomarkers for Neurodegenerative Disease: Will They Swing Us Across the Valley?

Abstract

Measures of the severity of cognitive impairment or parkinsonism are the usual endpoints in clinical trials for Alzheimer’s disease (AD) and Parkinson’s disease (PD), but are critically hampered by their lack of disease sensitivity and specificity. Due to the high failure rate of clinical trials, the rate of regulatory approval for efficacious new drugs has stagnated in the past few decades, with the gap between basic science discovery and clinical application metaphorically termed the “Valley of Death”. While the causes for this are probably multiple and complex, the usage of biomarkers as surrogate endpoints, particularly when they are molecularly-specific for the disease, has achieved some success in cancer trials, and it is likely that neurodegenerative disease trials would benefit from the same approach. As dementia and parkinsonism are not disease-specific clinical syndromes, both AD and PD trials have been flawed by reliance on clinical diagnosis and clinical endpoints. Clinical improvement has been a requirement for regulatory approval, but molecularly-specific biomarkers should improve both diagnostic accuracy and tracking of disease progression, allowing quicker screening of drug candidates. However, even when a molecularly-specific biomarker is found, such as amyloid imaging for AD, it may not reflect the entire extant molecular disease repertoire and may not serve equally well in the different roles of preclinical detection, diagnostic confirmation and surrogate endpoint, necessitating the usage of two, three or more biomarkers, deployed in series or in parallel.

The technical reliability and biotemporal stability of cerebrospinal fluid biomarkers for profiling multiple pathophysiologies in Alzheimer’s disease

“…While the core amyloid-β (Aβ) and tau biomarkers of AD [ 16 , 17 ] are highly associated with the presence of signature plaque and tangle pathological hallmarks of AD in the brain [ 16 ], they do not assess other fundamental biochemical aspects of the disease, such as non-amyloid and non-tau neurodegeneration or metabolic, immune, and neurovascular dysfunction [ 18 – 21 ]. A panel of robust biomarkers that directly reflect these concomitant pathophysiologies may prove a better indicator of disease diagnosis [ 22 , 23 ], subtypes, staging, and activity, as well as treatment-specific target engagement.…”

Empowering phase II clinical trials to reduce phase III failures

“…Fleming and Powers provide a precise definition of what a surrogate endpoint is and also give several examples. In recent literature, the adoption of biomarkers as surrogate endpoints has been argued within neurodegenerative diseases and cancer trials, and it has even been suggested that these techniques be applied to other clinical fields . Unfortunately, we found no data on success rates in trials in which surrogate endpoints have been used.…”

Part Two: Extracellular Vesicles as a Risk Factor in Neurodegenerative Diseases

“…It is presumed that exosomes play an important role by facilitating the interneuronal transport of the proteins [114]. As well, there is a critical need in finding accessible biomarkers that can diagnose a neurodegenerative disease in the asymptomatic stage [115]. Dosing certain free proteins in biofluids can be an option, but several problems are experienced because of their low concentrations [115].…”

“…As well, there is a critical need in finding accessible biomarkers that can diagnose a neurodegenerative disease in the asymptomatic stage [115]. Dosing certain free proteins in biofluids can be an option, but several problems are experienced because of their low concentrations [115]. Therefore, a new approach is being attempted consisting in finding the proteins encapsulated in extracellular vesicles [116].…”