Abstract
BackgroundDisturbed sleep is associated with cognitive decline in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood.MethodsWe investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subjects over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Spectral power and sleep stages were measured from within the home cage environment using EEG electrodes. In addition, locomotor activity and performance during a T-maze task were measured.ResultsSpectral power in the delta and theta bands showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity in the dark phase significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks, rTG4510 mice had significant degeneration in the hippocampus and cortex whereas doxycycline-treated rTG4510 mice were protected. Pathology significantly correlated with sleep and EEG outcomes, in addition to locomotor and cognitive measures.ConclusionsWe show that reduced EEG spectral power precedes reductions in sleep and home cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behaviour and cognition, which suggest tau-related effects on sleep architecture in patients with neurodegenerative diseases.
Highlights
Alzheimer’s disease (AD) and other forms of dementia such as frontotemporal dementia (FTD) are characterised by progressive neurodegeneration resulting in progressive loss of cognitive function and memory [1, 2]
EEG spectral power declines over time in Repressible rTg(tet-o-TauP301L)4510 (rTg4510) mice We continuously measured EEG parameters for 1 week in every 4 weeks
We show that a model of tauopathy displays significant longitudinal neurological changes manifested by altered sleep architecture, decreased spectral power and decreases in spatial working memory
Summary
Alzheimer’s disease (AD) and other forms of dementia such as frontotemporal dementia (FTD) are characterised by progressive neurodegeneration resulting in progressive loss of cognitive function and memory [1, 2]. It is crucial to recognise and treat sleep problems in dementia patients since these are associated with cognitive and functional decline [6, 7] and worsening behavioural or psychological symptoms [8]. Both AD and FTD often present with desynchronisation of circadian rhythms, lower sleep efficiency, lower percentage of non-rapideye-movement (NREM) sleep and a greater frequency of arousals and awakenings [9,10,11,12,13]. The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood
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