Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases

Oh, Jun Yeop; Walsh, Christine M.; Ranasinghe, Kamalini G.; Mladinov, Mihovil; Pereira, Felipe Luiz; Petersen, Cathrine; Falgàs, Neus; Yack, Leslie; LaMore, Tia; Nasar, Rakin; Lew, Caroline; Li, Song; Metzler, Thomas J.; Coppola, Quentin; Pandher, Natalie; Le, Michael M.; Heuer, Hilary W.; Heinsen, Helmut; Spina, Salvatore; Seeley, William W.; Kramer, Joel H.; Rabinovici, Gil D.; Boxer, Adam L.; Miller, Bruce L.; Vossel, Keith A.; Neylan, Thomas C.; Grinberg, Lea T.

doi:10.1001/jamaneurol.2022.0429

Cited by 32 publications

(52 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relationship between NfL and parameters of hypoxemia in OSA patients suggest a different mechanism, potentially via increased oxidative stress and neuroinflammation causing neurodegeneration ( Daulatzai, 2015 ; Snyder et al, 2017 ) and white matter disease ( Rostampour et al, 2020 ; Zacharias et al, 2021 ), which may contribute to sleepiness ( Xiong et al, 2017 ). Although tau-related neurodegeneration of wake-promoting neurons can start in pre-clinical stages of AD ( Braak et al, 2011 ; Stratmann et al, 2016 ), and could contribute to sleepiness ( Oh et al, 2022 ), it is unknown whether it could be associated with higher NfL levels. We have shown that CU late middle-aged and older adults with EDS have decreased cortical thickness ( Carvalho et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…This feed-forward loop hypothesis is corroborated by another study that showed that severity of OSA was associated with greater brain amyloid PET deposition only in amyloid positive participants ( Sharma et al, 2018 ). Additionally, participants with higher amyloid levels are more likely to have increased tau pathology affecting wake-promoting neurons ( Stratmann et al, 2016 ; Oh et al, 2019 , 2022 ), which could also contribute to sleepiness.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Carvalho

Louis

Przybelski

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

IntroductionSleepiness 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.MethodsIn 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.ResultsHigher 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.ConclusionSleepiness 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Carvalho

Louis

Przybelski

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…A more severe neuronal loss of several arousal‐promoting brain nuclei, including Hcrt neurons, LC NA neurons, tuberomamillary nucleus (TMN) histaminergic neurons, in post‐mortem brains of AD patients with tauopathy has been observed 16 . In a longitudinal clinical cohort study, more surviving Hcrt and TMN neurons correlated with decreased homeostatic sleep drive, shorter sleep bout duration, and greater percentage of wakefulness after sleep onset, 17 indicating an upregulation of excitability in these neurons. The glymphatic system promotes movement of cerebrospinal fluid into the brain and clears metabolic waste with a more efficient clearance during sleep 18 .…”

Section: Figurementioning

confidence: 99%

The brake matters: Hyperexcitable arousal circuits in sleep fragmentation with age

Lecea

2022

Clinical & Translational Med

View full text Add to dashboard Cite

“…More tau- Tau Modulation by Circadian Rhythm positive neurons were found in sleep-regulating brainstem regions in parallel with the depletion of the total quantity of sleep and slow-wave activity during sleep [11]. The extension of tau pathology and neurodegeneration into the core circadian regions like the suprachiasmatic nucleus and its connecting regions, including the hypothalamus and brainstem, is regarded as a primary mechanism of circadian dysregulation in tauopathies [10,12]. In the viewpoint that circadian oscillation affects many brain functions and the impairment of the sleep-wake cycle increases the risk of neurodegenerative disease [13], the scenario in a reverse direction, circadian disruption gives an impact on tauopathies, is also possible.…”

Section: Introductionmentioning

confidence: 99%

“…From the very early stage of AD, instability in circadian rhythms reveals deficient slow-wave activity during the deep-sleep stage, and it seems to be strongly associated with tau pathology on tau-PET and tau levels in cerebrospinal fluid [ 9 ]. A recent postmortem study demonstrated an increased number of tau-positive and pTau-positive neurons in the subcortical wake-promoting area was significantly correlated with the disturbances in sleep variables in AD patients [ 10 ]. Similar results have been reported in the animal model, P301S tau transgenic mice presenting tau pathology.…”

Section: Introductionmentioning

confidence: 99%

The Change in Circadian Rhythms in P301S Transgenic Mice is Linked to Variability in Hsp70-related Tau Disaggregation

et al. 2022

View full text Add to dashboard Cite

Circadian disruption often involves a neurodegenerative disorder, such as Alzheimer' s disease or frontotemporal dementia, which are characterized by intraneuronal tau accumulations. The altered sleep pattern and diurnal rhythms in these disorders are the results of tau pathology. The circadian disturbance in reverse is thought to develop and potentially aggravate the condition. However, the underlying mechanism is not fully understood. In this study, perturbed oscillations in BMAL1, the core clock gene, were observed in P301S tau transgenic mice. Tau fractionation analysis of the hippocampus revealed profound fluctuations in soluble and insoluble tau protein levels that were in opposite directions to each other according to zeitgeber time. Interestingly, a diurnal oscillation was detected in the heat shock 70 kDa protein 1A (Hsp70) chaperone that was in-phase with soluble tau but out-of-phase with insoluble tau. Tau protein levels decreased in the soluble and insoluble fractions when Hsp70 was overexpressed in HEK293T cells. Transfection of the BMAL1 carrying vector was continual with the increase in Hsp70 expression and diminished tau protein levels, and it was effectively attenuated by the knockdown of Hsp70, suggesting that Bmal1 could modulate tau protein by Hsp70. Our results suggest that altered circadian oscillations affect tau status and solubility by modulating Hsp70 expression in an experimental model of tau pathology. These findings suggest Hsp70 as a possible pathogenic link between circadian disruption and aggravations of tau pathology.

show abstract

Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases

Cited by 32 publications

References 59 publications

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

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

The brake matters: Hyperexcitable arousal circuits in sleep fragmentation with age

The Change in Circadian Rhythms in P301S Transgenic Mice is Linked to Variability in Hsp70-related Tau Disaggregation

Contact Info

Product

Resources

About