Quantitative Electroencephalographic Analysis Provides an Early-Stage Indicator of Disease Onset and Progression in the zQ175 Knock-In Mouse Model of Huntington's Disease

Abstract

The expression of the Huntington's disease (HD) mutation results in complex EEG alterations that occur prior to deficits in behavioral measures and are one of the earliest phenotypes uncovered in this mouse model. Despite these EEG changes, homeostatic responses to sleep loss were preserved in HET and HOM zQ175 mice. Greater insight into the localization and response of these EEG alterations to novel therapies may enable early intervention and improve outcomes for patients with HD.

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

“…However, the zQ175 Het model in this study showed no symptoms of disease onset, motor or otherwise, beyond the change in body weight (16). The EEG disturbances observed in the Het mice suggest HD pathology, but the link to phenoconversion remains unclear.…”

“…Current studies frequently utilize R6/2 mice with a CAG repeat length of 250 (12). 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). The resulting neural circuitry disruptions are observable through qEEG.…”

“…Fisher and colleagues (16) performed a follow-up to their earlier R6/2 study in which they examined both heterozygous (Het) and homozygous (Hom) zQ175 mouse models (16). Findings in the Hom zQ175 model were similar to those reported earlier in R6/2 mice although with later onset of diurnal disturbances (24 vs. 13 weeks) and core temperature regulation (16 vs. 13 weeks).…”

Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington’s Disease

“…A range of circadian deficits in the mouse models of HD have been reported, detailing the impact on rhythms in behavior and physiology (Bourne et al, 2006; Ciammola et al, 2006; Grimbergen et al, 2008; Cuturic et al, 2009; Kuljis et al, 2012; Fisher et al, 2016). The findings suggest that the most common sleep-related clinical complaints of HD patients (i.e., difficulty falling asleep, frequent awakenings during sleep, and difficulty staying awake during the active cycle) are due, at least in part, to the disease-induced dysfunction in the circadian system.…”

“…Recently, a detailed RNA-seq analysis of striatum, cortex, and liver of the Q175 line has been published (Langfelder et al, 2016); therefore, we have a good understanding of the transcriptional changes that occur with age in this model. Finally, recent work has carefully characterized age-related changes in the electroencephalogram (EEG) in both Hom and Het Q175 (Fisher et al, 2016). This wealth of data makes the Het Q175 an ideal preclinical model to examine the impact of circadian interventions on disease trajectory.…”