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. 2022 May 1;79(5):498-508.
doi: 10.1001/jamaneurol.2022.0429.

Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases

Jun Y Oh  1   2 , Christine M Walsh  1 , Kamalini Ranasinghe  1 , Mihovil Mladinov  1 , Felipe L Pereira  1 , Cathrine Petersen  1 , Neus Falgàs  1   3 , Leslie Yack  4 , Tia Lamore  1 , Rakin Nasar  1 , Caroline Lew  1 , Song Li  1 , Thomas Metzler  4 , Quentin Coppola  1 , Natalie Pandher  1 , Michael Le  1 , Hilary W Heuer  1 , Helmut Heinsen  5 , Salvatore Spina  1 , William W Seeley  1 , Joel Kramer  1 , Gil D Rabinovici  1 , Adam L Boxer  1 , Bruce L Miller  1   3 , Keith Vossel  6 , Thomas C Neylan  1   4   7 , Lea T Grinberg  1   3   8   9
Affiliations

Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases

Jun Y Oh et al. JAMA Neurol. .

Abstract

Importance: Sleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena.

Objectives: To examine the correlation between the number of important subcortical wake-promoting neurons and clinical sleep phenotypes in patients with Alzheimer disease (AD) or progressive supranuclear palsy (PSP).

Design, setting, and participants: This longitudinal cohort study enrolled 33 patients with AD, 20 patients with PSP, and 32 healthy individuals from the Memory and Aging Center of the University of California, San Francisco, between August 22, 2008, and December 31, 2020. Participants received electroencephalographic and polysomnographic sleep assessments. Postmortem neuronal analyses of brainstem hypothalamic wake-promoting neurons were performed and were included in the clinicopathological correlation analysis. No eligible participants were excluded from the study.

Exposures: Electroencephalographic and polysomnographic assessment of sleep and postmortem immunohistological stereological analysis of 3 wake-promoting nuclei (noradrenergic locus coeruleus [LC], orexinergic lateral hypothalamic area [LHA], and histaminergic tuberomammillary nucleus [TMN]).

Main outcomes and measures: Nocturnal sleep variables, including total sleep time, sleep maintenance, rapid eye movement (REM) latency, and time spent in REM sleep and stages 1, 2, and 3 of non-REM (NREM1, NREM2, and NREM3, respectively) sleep, and wake after sleep onset. Neurotransmitter, tau, and total neuronal counts of LC, LHA, and TMN.

Results: Among 19 patients included in the clinicopathological correlation analysis, the mean (SD) age at death was 70.53 (7.75) years; 10 patients (52.6%) were female; and all patients were White. After adjusting for primary diagnosis, age, sex, and time between sleep analyses and death, greater numbers of LHA and TMN neurons were correlated with decreased homeostatic sleep drive, as observed by less total sleep time (LHA: r = -0.63; P = .009; TMN: r = -0.62; P = .008), lower sleep maintenance (LHA: r = -0.85; P < .001; TMN: r = -0.78; P < .001), and greater percentage of wake after sleep onset (LHA: r = 0.85; P < .001; TMN: r = 0.78; P < .001). In addition, greater numbers of LHA and TMN neurons were correlated with less NREM2 sleep (LHA: r = -0.76; P < .001; TMN: r = -0.73; P < .001). A greater number of TMN neurons was also correlated with less REM sleep (r = -0.61; P = .01). A greater number of LC neurons was mainly correlated with less total sleep time (r = -0.68; P = .008) and greater REM latency (r = 0.71; P = .006). The AD-predominant group had significantly greater sleep drive, including higher total sleep time (mean [SD], 0.49 [1.18] vs -1.09 [1.37]; P = .03), higher sleep maintenance (mean [SD], 0.18 [1.22] vs -1.53 [1.78]; P = .02), and lower percentage of wake after sleep onset during sleep period time (mean [SD], -0.18 [1.20] vs 1.49 [1.72]; P = .02) than the PSP-predominant group based on unbiased k-means clustering and principal component analyses.

Conclusions and relevance: In this cohort study, subcortical wake-promoting neurons were significantly correlated with sleep phenotypes in patients with AD and PSP, suggesting that the loss of wake-promoting neurons among patients with neurodegenerative conditions may disturb the control of sleep-wake homeostasis. These findings suggest that the subcortical system is a primary mechanism associated with sleep disturbances in the early stages of neurodegenerative diseases.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Yack reported receiving personal fees from the University of California, San Francisco, during the conduct of the study. Dr Coppola reported receiving grants from the National Institute on Aging, the Rainwater Charitable Foundation, and the Tau Consortium, during the conduct of the study. Dr Pandher reported receiving grants from the National Institutes of Health (NIH), the Rainwater Charitable Foundation, and the Tau Consortium during the conduct of the study. Dr Spina reported receiving consulting fees from Acsel Health, Precision Xtract, and Techspert.io outside the submitted work. Dr Rabinovici reported receiving grants from the NIH during the conduct of the study; grants from the Alzheimer's Association, the American College of Radiology, Genentech, and the NIH; personal fees from Eisai, Eli Lilly and Company, Genentech, Johnson & Johnson, and Roche; and being employed as an associate editor of JAMA Neurology outside the submitted work. Dr Boxer reported receiving grants from the NIH and the Rainwater Charitable Foundation during the conduct of the study; grants from Biogen, Eisai, and Regeneron Pharmaceuticals; personal fees from Denali Therapeutics, GlaxoSmithKline, Humana, Oligomerix, Oscotec, Roche, Transposon Therapeutics, and Wave Life Sciences; nonfinancial support from Eli Lilly and Company and Novartis; and owning stock options in Alector, Arvinas, AZTherapies, and TrueBinding outside the submitted work. Dr Miller reported receiving grants from the NIH; serving as an advisor for the Arizona Alzheimer's Disease Center, the Association for Frontotemporal Degeneration, the Bluefield Project to Cure FTD, the Buck Institute for Research on Aging, the John Douglas French Alzheimer’s Foundation, the Larry L. Hillblom Foundation, the Massachusetts Alzheimer’s Disease Research Center, the National Institute for Health Research Cambridge Biomedical Research Centre (and its subunit, the Biomedical Research Unit in Dementia), Stanford University, the Tau Consortium, the University of Southern California, and the University of Washington; serving as a director or codirector of the Bluefield Project to Cure FTD, the Global Brain Health Institute, and the Tau Consortium; and being employed as affiliated faculty at the Institute for Neurodegenerative Diseases outside the submitted work. Dr Vossel reported receiving grants from the Alzheimer's Association, the John Douglas French Alzheimer's Foundation, the NIH, and the S.D. Bechtel, Jr. Foundation during the conduct of the study. Dr Grinberg reported receiving grants from the NIH and the Rainwater Charitable Foundation during the conduct of the study and personal fees from CuraSen Therapeutics and the Simons Foundation outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Clinicopathological Sleep Study Flow Diagram
All participants were recruited from the Memory and Aging Center of the University of California, San Francisco. Among 32 healthy individuals in the control cohort, 18 followed the same sleep recording protocol as the progressive supranuclear palsy (PSP) cohort, and 14 followed the same sleep recording protocol as the Alzheimer disease (AD) cohort. In the PSP cohort, 20 participants met criteria for inclusion in the polysomnographic sleep study; of those, autopsy, neuropathological examination, and quantitative morphological analysis of the nuclei of interest were performed for 9 participants with a diagnosis of PSP. In the AD cohort, 33 participants met criteria for inclusion in the electroencephalographic sleep study; of those, autopsy, neuropathological examination, and quantitative morphological analysis of the nuclei of interest were performed in 10 participants with a diagnosis of AD. LC indicates locus coeruleus; LHA, lateral hypothalamic area; and TMN, tuberomammillary nucleus.
Figure 2.
Figure 2.. Correlations Between Clinical Sleep Measurements and Postmortem Stereological Neuronal Counts of 3 Wake-Promoting Nuclei
Darker blue indicates a stronger positive correlation and darker red a stronger negative correlation. Only statistically significant correlations are shown in color blocks. Sample sizes were 14 participants for correlations with locus coeruleus (LC) neurons, 16 participants for correlations with lateral hypothalamic area (LHA) neurons, and 17 participants for correlations with tuberomammillary nucleus (TMN) neurons. HDC indicates histidine decarboxylase; N1, stage 1 of non–rapid eye movement (REM) sleep; N2, stage 2 of non-REM sleep; N3, stage 3 of non-REM sleep; SPT, sleep period time; TH, tyrosine hydroxylase; TST, total sleep time; and WASO, wake after sleep onset.
Figure 3.
Figure 3.. Comparison of Alzheimer Disease–Predominant and Progressive Supranuclear Palsy–Predominant Groups
Self-generated from a k-means clustering algorithm using summative pathological variables of the 3 wake-promoting nuclei. z Scores were normalized to data from the healthy control cohort. The dots scattered around the graph represent the outlier values of each box plot. The horizontal line across the graph represents normalized z score 0 for all measures. The horizontal lines within individual boxes represent the median value of each group. The whiskers represent maximum and minimum. AD indicates Alzheimer disease; N1, stage 1 of non–rapid eye movement (REM) sleep; N2, stage 2 of non-REM sleep; N3, stage 3 of non-REM sleep; PSP, progressive supranuclear palsy; SPT, sleep period time; TST, total sleep time; and WASO, wake after sleep onset.
Figure 4.
Figure 4.. Principal Component Analysis of Clinical and Pathological Sleep Measurements
A, The overall summary of main variations in the first principal component (PC1) was associated with total sleep time (TST), sleep maintenance, wake after sleep onset (WASO), stage 2 of non–rapid eye movement (REM) sleep (N2), and stage 3 of non-REM sleep (N3). The arrows radiating from the center represent the directions of the covariance matrix (the principal component analysis eigenvectors). B, The overall summary of main variations in the PC1 was associated with total locus coeruleus (LC) neurons, total lateral hypothalamic area (LHA) neurons, total tuberomammillary nucleus (TMN) neurons, tau percentage of TMN neurons, and tau percentage of LHA neurons. The arrows radiating from the center represent the directions of the covariance matrix (the principal component analysis eigenvectors). Braak stage 0 indicates no cortical neurofibrillary tangles (NFTs); stages I-II, NFTs confined to transentorhinal region; stages III-IV, NFTs in limbic regions; and stages V-VI, NFTs in neocortical regions. C, The dots represent individual cases projected by the pathological PC1 (x-axis) and clinical PC1 (y-axis). The dashed line represents the linear regression projection, and the gray shadow represents the CI of the linear regression. AD indicates Alzheimer disease; HDC, histidine decarboxylase, N1, stage 1 of non-REM sleep; PC2, second principal component; PSP, progressive supranuclear palsy; pTau, pathological tau; SPT, sleep period time; and TH, tyrosine hydroxylase.
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