Sleep deprivation exhibits an age-dependent effect on infraslow global brain activity.

Total sleep deprivation (TSD) significantly increases infraslow global brain activity as measured by gBOLD signal amplitude.

• The study used a rigorously controlled in-laboratory total sleep deprivation protocol.
• gBOLD signal is defined as infraslow (<0.1 Hz) global brain activity quantified by the global mean blood-oxygenation-level-dependent signal in resting-state fMRI.
• TSD-induced increases in gBOLD amplitude were statistically significant across participants.
• The increase was interpreted as a compensatory mechanism potentially enhancing glymphatic clearance following acute sleep loss.

Total sleep deprivation significantly increases the coupling between gBOLD signal and cerebrospinal fluid (CSF) flow.

• CSF dynamics represent a key pathway for brain waste clearance implicated in neurodegenerative disorders such as Alzheimer's disease.
• The coupling between gBOLD and CSF flow was elevated after TSD.
• This enhanced coupling was interpreted as potentially facilitating glymphatic clearance after acute sleep loss.
• The coupling effect mirrors what is normally observed during sleep, suggesting TSD triggers a compensatory response.

TSD-induced enhancements in gBOLD amplitude and gBOLD-CSF coupling exhibit robust age dependency.

• Midlife adults aged 40 to 50 years showed markedly attenuated responses to TSD compared to other age groups.
• The compensatory increases in gBOLD signal and CSF coupling seen after TSD were significantly reduced in the midlife group.
• Age-dependent effects were described as 'robust,' indicating consistent findings across the sample.
• The attenuation in midlife was a primary distinguishing finding relative to younger participants.

The absence of TSD-induced compensatory gBOLD and CSF coupling responses in midlife adults may increase dementia susceptibility.

• Midlife adults (40 to 50 y) lacked the compensatory mechanism observed in younger adults following sleep deprivation.
• This absence may exacerbate age-related impairments in neurotoxic clearance.
• The authors suggest this offers mechanistic insights into the nexus between sleep disruption, aging, and neurodegeneration.
• The findings are discussed in the context of Alzheimer's disease risk, given the role of glymphatic clearance in removing neurotoxic waste.

Infraslow gBOLD activity is normally elevated during sleep and coupled to CSF dynamics as part of the glymphatic clearance pathway.

• gBOLD signal frequency range is defined as less than 0.1 Hz.
• The coupling of gBOLD to CSF flow during sleep is established as a key pathway for brain waste clearance.
• This sleep-dependent mechanism is implicated in protection against neurodegenerative disorders such as Alzheimer's disease.
• Prior to this study, the effect of sleep deprivation on gBOLD activity and its interaction with aging remained poorly understood.