Cerebrospinal Fluid Biomarkers for Target Engagement and Efficacy in Clinical Trials for Alzheimer's and Parkinson's Diseases.

BACKGROUND: Cerebrospinal fluid (CSF) is increasingly being used to detect biochemical changes that occur in different neurological conditions. In Alzheimer's disease (AD), three CSF biomarkers (Aβ42, total tau, and phosphorylated tau) are used in clinical practice to support the diagnosis in the prodromal stages of the disease. In Parkinson's disease (PD), the investigation is following the pathway of AD research and some promising markers have been identified, with the main aim to favor an early diagnosis, i.e. in the premotor phase. Some of these CSF markers have also been incorporated in AD and PD clinical trials to demonstrate target engagement of the drug and/or to enrich the patient populations. In this chapter, we will review the main CSF biomarkers for AD and PD and their potential application to clinical trials.
SUMMARY: In clinical trials assessing the efficacy of disease-modifying agents for AD, CSF biomarkers are currently used both as a diagnostic criterion for inclusion and for monitoring the biochemical impact of the drug on the upstream neurodegenerative mechanisms. Accordingly, recent trials devoted to PD are following such a procedure, although in this neurodegenerative disorder CSF biomarkers are not ready yet for routine clinical use. KEY MESSAGES: AD and PD are neurodegenerative disorders that share a long asymptomatic/prodromal phase in which neurodegenerative phenomena already take place in the brain. Clinical trials assessing the efficacy of disease-modifying agents should include the CSF measurement of related biomarkers as biochemical proof of the underlying pathology as well as of the impact of the drug on these pathogenic mechanisms.