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. 2022 Jul 11:14:930315.
doi: 10.3389/fnagi.2022.930315. eCollection 2022.

Sleepiness in Cognitively Unimpaired Older Adults Is Associated With CSF Biomarkers of Inflammation and Axonal Integrity

Diego Z Carvalho  1   2 , Erik K St Louis  1   2 , Scott A Przybelski  3 , Timothy I Morgenthaler  2 , Mary M Machulda  4 , Bradley F Boeve  1   2 , Ronald C Petersen  1   3 , Clifford R Jack Jr  5 , Jonathan Graff-Radford  1 , Prashanthi Vemuri  5 , Michelle M Mielke  1   3   6
Affiliations

Sleepiness in Cognitively Unimpaired Older Adults Is Associated With CSF Biomarkers of Inflammation and Axonal Integrity

Diego Z Carvalho et al. Front Aging Neurosci. .

Abstract

Introduction: Sleepiness has been associated with cognitive decline and dementia in the elderly. Older adults with excessive daytime sleepiness appear to be more vulnerable to longitudinal amyloid PET accumulation before the onset of the dementia. However, it remains unclear whether sleepiness is similarly associated with other biomarkers of Alzheimer's disease (AD), axonal integrity, and inflammation, which may also contribute to neurodegeneration and cognitive decline.

Methods: In this cross-sectional analysis, we identified 260 cognitively unimpaired adults (>60 years) from the Mayo Clinic Study of Aging, a population-based cohort from Olmsted County (MN), who underwent CSF quantification of AD biomarkers (Aβ42, p-tau, p-tau/Aβ42) in addition to at least one of the following biomarkers [neurofilament light chain (NfL) interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α)]. We fit linear regression models to assess associations between sleepiness, as measured by the Epworth Sleepiness Scale (ESS), and CSF biomarkers, controlling for age, sex, APOε4 status, body mass index, hypertension, dyslipidemia, and prior diagnosis of obstructive sleep apnea.

Results: Higher ESS scores were associated with higher CSF IL-6 and NfL, but not with the other CSF biomarkers. For every ESS score point increase, there was a 0.009 ([95% CI 0.001-0.016], p = 0.033) increase in the log of IL-6 and 0.01 ([95% CI 0.002-0.018], p = 0.016) increase in the log of NfL. A sensitivity analysis showed an association between ESS scores and log of p-tau/Aβ42 only in participants with an abnormal ratio (>0.023), highly predictive of amyloid positivity. For every ESS score point increase, there was a 0.006 ([95% CI 0.001-0.012], p = 0.021) increase in the log of CSF p-tau/Aβ42.

Conclusion: Sleepiness was associated with greater CSF IL-6 and NfL levels, which could contribute to neurodegeneration or alternatively cause sleepiness. Higher NfL levels may result from sleep disruption and/or contribute to sleepiness via disturbed connectivity or damage to wake-promoting centers. Associations between sleepiness and p-tau/Aβ42 in participants with abnormal ratio suggest that amyloid positivity contributes to vulnerability to sleep disturbance, which may further amyloid accumulation in a feed-forward loop process. Prospective studies of these markers are needed to determine cause-effect relationships between these associations.

Keywords: Alzheimer’s disease; axonal integrity; inflammation; interleukin-6 (IL-6); neurofilament light chain (NfL); sleep disturbance; sleepiness.

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Conflict of interest statement

ES has received research support from Mayo Clinic CCaTS, NIH, the Michael J. Fox Foundation, and Sunovion, Inc. MaM receives research funding from the NIH. BB has served as an investigator for clinical trials sponsored by Alector and Biogen. He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH the Mangurian Foundation, the Little Family Foundation, and the Ted Turner and Family Foundation. RP consults for Roche, Inc., Merck, Inc., Genentech, Inc., and Biogen, Inc., GE Healthcare and receives royalties from Oxford University Press for the publication of Mild Cognitive Impairment. CJ consults for Lily and serves on an independent data monitoring board for Roche but he receives no personal compensation from any commercial entity. JG-R receives research funding from NIH and serves on the editorial board of Neurology. PV receives research funding from NIH (NIA and NINDS). MiM served as a consultant to Biogen, Brain Protection Company, and LabCorp and receives research support from the NIH and DOD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Scatterplot shows associations between ESS scores and log of CSF IL-6 (A) and log of NfL (B). Best fit line is displayed, with the Pearson correlation coefficient and its p-value.
FIGURE 2
FIGURE 2
Scatterplot shows an association between ESS scores and log of CSF p-tau/Aβ42 in participants with abnormal ratio (amyloid positive). Best fit line is displayed, with the Spearman’s correlation coefficient and its p-value.
See this image and copyright information in PMC

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