Sleep Spindles and Fragmented Sleep as Prodromal Markers in a Preclinical Model of LRRK2-G2019S Parkinson's Disease

Lindsey M. Crown, Mitchell J. Bartlett, Jean Paul L. Wiegand, Allison J. Eby, Emily J. Monroe, Kathleen Gies, Luke Wohlford, Matthew J. Fell, Torsten Falk, Stephen Leigh Cowen

Research output: Contribution to journalArticle

Abstract

Sleep disturbances co-occur with and precede the onset of motor symptoms in Parkinson's disease (PD). We evaluated sleep fragmentation and thalamocortical sleep spindles in mice expressing the p.G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene, one of the most common genetic forms of PD. Thalamocortical sleep spindles are oscillatory events that occur during slow-wave sleep that are involved in memory consolidation. We acquired data from electrocorticography, sleep behavioral measures, and a rotarod-based motor enrichment task in 28 LRRK2-G2019S knock-in mice and 27 wild-type controls (8–10 month-old males). Sleep was more fragmented in LRRK2-G2019S mice; sleep bouts were shorter and more numerous, even though total sleep time was similar to controls. LRRK2-G2019S animals expressed more sleep spindles, and individual spindles were longer in duration than in controls. We then chronically administered the LRRK2-inhibitor MLi-2 in-diet to n = 12 LRRK2-G2019S and n = 15 wild-type mice for a within-subject analysis of the effects of kinase inhibition on sleep behavior and physiology. Treatment with MLi-2 did not impact these measures. The data indicate that the LRRK2-G2019S mutation could lead to reduced sleep quality and altered sleep spindle physiology. This suggests that sleep spindles in LRRK2-G2019S animals could serve as biomarkers for underlying alterations in sleep networks resulting from the LRRK2-G2019S mutation, and further evaluation in human LRRK2-G2019S carriers is therefore warranted.

Original languageEnglish (US)
Article number324
JournalFrontiers in Neurology
Volume11
DOIs
StatePublished - May 8 2020

Keywords

  • EEG
  • LRRK2
  • Parkinson's disease
  • biomarker
  • prodromal
  • sleep fragmentation
  • sleep spindles

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Crown, L. M., Bartlett, M. J., Wiegand, J. P. L., Eby, A. J., Monroe, E. J., Gies, K., Wohlford, L., Fell, M. J., Falk, T., & Cowen, S. L. (2020). Sleep Spindles and Fragmented Sleep as Prodromal Markers in a Preclinical Model of LRRK2-G2019S Parkinson's Disease. Frontiers in Neurology, 11, [324]. https://doi.org/10.3389/fneur.2020.00324