Quantitative Electroencephalographic Biomarkers in Preclinical and Human Studies of Huntington's Disease: Are They Fit-for-Purpose for Treatment Development?

Michael K Leuchter,Carlos Cepeda,Andrew F Leuchter,Aimee M Hunter,Ana María Estrada-Sánchez,Michael S Levine,Elissa J Donzis,Ian A Cook

doi:10.3389/fneur.2017.00091

Abstract

A major focus in development of novel therapies for Huntington’s disease (HD) is identification of treatments that reduce the burden of mutant huntingtin (mHTT) protein in the brain. In order to identify and test the efficacy of such therapies, it is essential to have biomarkers that are sensitive to the effects of mHTT on brain function to determine whether the intervention has been effective at preventing toxicity in target brain systems before onset of clinical symptoms. Ideally, such biomarkers should have a plausible physiologic basis for detecting the effects of mHTT, be measureable both in preclinical models and human studies, be practical to measure serially in clinical trials, and be reliably measurable in HD gene expansion carriers (HDGECs), among other features. Quantitative electroencephalography (qEEG) fulfills many of these basic criteria of a “fit-for-purpose” biomarker. qEEG measures brain oscillatory activity that is regulated by the brain structures that are affected by mHTT in premanifest and early symptom individuals. The technology is practical to implement in the laboratory and is well tolerated by humans in clinical trials. The biomarkers are measureable across animal models and humans, with findings that appear to be detectable in HDGECs and translate across species. We review here the literature on recent developments in both preclinical and human studies of the use of qEEG biomarkers in HD, and the evidence for their usefulness as biomarkers to help guide development of novel mHTT lowering treatments.

Highlights

Many current strategies for the treatment of Huntington’s disease (HD) are focused on development of agents to lower mutant huntingtin protein burden
The R6/2 mouse carries a fragment of exon 1 of the human mutant huntingtin (mHTT) gene with an expanded CAG-repeat segment that shows relatively early onset of rapidly progressive symptoms (10, 11)
The zQ175 knock-in (KI) mouse model, which expresses the mHTT gene within the mouse genomic context (13), allows for further examination over the course of a slower progression that more closely follows the course of human disease (13–16)

Summary

Introduction

Many current strategies for the treatment of Huntington’s disease (HD) are focused on development of agents to lower mutant huntingtin (mHTT) protein burden. The presence of mHTT adversely affects the function of multiple cell lines, neurons, from early human development through phenoconversion to the illness. Chronic reduction in the levels of mHTT prior to the onset of symptoms could presumably prevent the development or reduce the severity of many of the manifestations of HD. Biomarkers play a unique role in research aimed at mHTT reduction. In contrast to most degenerative diseases of the central nervous system, highly specific biomarkers for HD already exist: the genetic mutation that leads to production of mHTT (a trinucleotide repeat expansion) has been identified. It is already possible to identify individuals who will develop the illness based on the presence of the mutation, estimate their age of disease onset (by measuring length of the expansion), and to quantify levels of mHTT in a subject’s cerebrospinal fluid and body tissues

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Conclusion