title: 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: OBJECTIVE
  Patients with Huntington's disease (HD) show a high prevalence of sleep disorders that typically occur prior to the onset of motoric symptoms and neurodegeneration. Our understanding of the pathophysiological alterations in premanifest HD is limited, hindering the ability to measure disease modification in response to treatment. We used a full-length knock-in HD model to determine early changes in the electroencephalogram (EEG) and sleep that may predict the onset and progression of the disease.
  
  
  METHODS
  A 10-month longitudinal study was designed to determine the effect of the HD mutation on the EEG and sleep/wake changes in heterozygous (HET) and homozygous (HOM) zQ175 mice and wild-type (WT) littermates from 8 to 48 w of age. Mice were instrumented with tethered headmounts to record EEG/electromyography signals. Telemeters were implanted to continuously measure locomotor activity (LMA) and body temperature (Tb). Sleep deprivation (SDep) was performed at 8, 12, 16, 24, 32, and 48 w of age.
  
  
  RESULTS
  The HD mutation disrupted the EEG field potential from 8-12 w in an age- and mutant huntington dose-dependent manner, prior to changes in sleep/wake states, LMA, and Tb. Prominent effects of the HD mutation on the EEG included a progressive reduction in low frequency power, a slowing of rapid eye movement peak theta frequency, and the emergence of state-dependent beta/gamma oscillations. There was no effect of genotype on the relative increase in nonrapid eye movement delta power or sleep time in response to SDep.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fisher
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schwartz
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wurts-Black
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Alexia M
authors.initials: AM
authors.lastname: Thomas
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Tsui-Ming
authors.initials: TM
authors.lastname: Chen
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miller
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Jeremiah B
authors.initials: JB
authors.lastname: Palmerston
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Morairty
mesh_terms: D000375:Aging; D000818:Animals; D001831:Body Temperature; D058256:Brain Waves; D004195:Disease Models, Animal; D018450:Disease Progression; D004569:Electroencephalography; D004576:Electromyography; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D009043:Motor Activity; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D012892:Sleep Deprivation / Q000503:physiopathology; D012893:Sleep Wake Disorders / Q000150:complications* / Q000503:physiopathology*; D012895:Sleep, REM / Q000502:physiology; D014851:Wakefulness / Q000502:physiology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
keywords: EEG; Huntington's disease; biomarker; sleep; zQ175 mouse