Subcortical Wake-Promoting Neurons Significantly Correlated With Sleep Phenotype

Lea Grinberg, MD, PhD

Using quantitative postmortem neuronal analysis, newly published research in JAMA Neurology found significant correlations between subcortical wake-promoting neurons and sleep phenotypes in patients with Alzheimer disease (AD) and progressive supranuclear palsy (PSP), suggesting that the loss of wake-promoting neurons among those with neurodegenerative conditions may disturb the control of sleep-wake homeostasis.¹

The longitudinal cohort study included 33 patients with AD, 20 patients with PSP, and 32 healthy controls (HCs) who underwent electroencephalographic and polysomnographic sleep assessments. Senior investigator Lea Grinberg, MD, PhD, professor of neurology, University of California, San Francisco, and colleagues focused on a highly interconnected and interdependent subcortical system involving noradrenergic locus coeruleus (LC), orexinergic lateral hypothalamic area (LHA), and histaminergic tuberomammillary nucleus (TMN).

Postmortem neuronal analysis of brainstem hypothalamic wake-promoting neurons was performed for 10 patients with AD and 9 patients with PSP, and the data were included in the clinicopathological correlation analysis. Grinberg et al examined 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.

The mean age at death of those included in the clinicopathological correlation analysis was 70.53 (SD, 7.75) years. Notably, all patients were White. Using a Spearman correlation coefficient plot, a greater number of LHA or TMN wake-promoting neurons were correlated with decreased sleep drive, including shorter 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 during the sleep period time (LHA: r = 0.85, P <.001; TMN: r = 0.78, P <.001).

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A greater percentage of tau+ TMN neurons were positively correlated with total sleep time (r = 0.51; P = .04), and a greater number of LC neurons were associated with shorter total sleep time (r = –0.68; P = .008) and greater REM latency (r = 0.71; P = .006). Using the same approach, investigators found that a greater number of LHA neurons were correlated with lower percentage of time in NREM2 sleep during the sleep period time (r = –0.76; P <.001) and lower percentage of time in NREM3 sleep during the sleep period time (r = –0.62; P = .01).

Between patients with AD and PSP, the AD-predominant group had significantly greater sleep drive, including higher total sleep time (mean, 0.49 [SD, 1.18]; vs –1.09 [SD, 1.37]; P = .03), higher sleep maintenance (mean, 0.18 [SD, 1.22] vs –1.53 [SD, 1.78]; P = .02), and lower percentage of wake after sleep onset during the sleep period (mean, –0.18 [SD, 1.20] vs 1.49 [SD, 1.72]; P = .02). Regarding sleep architecture, the AD-predominant group exhibited a higher percentage of time in NREM2 sleep during the sleep period time (mean, 0.32 [SD, 1.05] vs –1.06 [SD, 1.26]; P = .003) than the PSP-predominant group. REM latency or percentage of time in NREM1, NREM3, or REM sleep during the sleep period time did not differ between the groups.

"The study’s findings may bring renewed attention to the neuromodulatory subcortical system as a primary mechanism in sleep disturbances among patients with neurodegenerative diseases,” Grinberg et al wrote.¹ "Further research on the specific patterns of neurodegeneration within the subcortical network, including sleep-promoting nuclei and the circadian system, may inform tailored treatment strategies for sleep disturbances and early symptoms of neurodegenerative diseases, which may help to slow overall disease progression."

A principal component analysis (PCA), a multivariate analysis that maximized variance, was conducted twice using clinical or pathological measurements. The first principal component (PC1), which represented the overall summary of the main variations, was most associated with total sleep time (11.38%), sleep maintenance (22.82%), percentage of wake after sleep onset (20.55%), percentage of time in NREM2 sleep (18.35%) and percentage of time in NREM3 sleep (10.71%). The PC1 composition of pathological PCA was most associated with total LC (18.74%), LHA (17.74%), and TMN neurons (18.77%).

REFERENCE
1. Oh JY, Walsh CM, Ranasinghe K, et al. Subcortical neuronal correlates of sleep in neurodegenerative diseases. JAMA Neurol. Published online April 4, 2022. doi:10.1001/jamaneurol.2022.0429