In Alzheimer's, More ZZZs Once Wakefulness Neurons Die

Nighttime sleep disturbances plague people with neurodegenerative diseases. Scientists led by Lea Grinberg and Thomas Neylan at the University of California, San Francisco, suggest that losing neurons that control wakefulness might be responsible. In the April 4 JAMA Neurology, they reported that wake-promoting neurons degenerated in people with Alzheimer’s, allowing them to sleep longer at night. People with progressive supranuclear palsy (PSP), a tauopathy that leaves people sleep-deprived, slept less, in part because they retained these particular neurons, the authors claim. These findings highlight the role of wake-promoting neurons in neurodegenerative disease, though the focus has previously been on neurons that promote sleepiness.

  • Tauopathies can affect sleep patterns.
  • People with AD slept more than people with PSP.
  • They also have fewer wake-promoting neurons.

“This paper confirms that neurodegenerative disorders affect subcortical arousal circuits,” Luis de Lecea of Stanford University wrote to Alzforum. Sigrid Veasey, University of Pennsylvania, Philadelphia, agreed. She wondered if the sleep differences are caused by changes in neuron activity rather than loss. “We typically think of loss of neurons, loss of connectivity, and loss of function in neurodegenerative disorders, but another key component … may be dysfunction, and in some cases potentially hyperactivity of wake-promoting neurons,” Veasey wrote (comment below). Veasey thinks this might be the case in PSP. A recent paper from de Lecea suggested as much in mice, with old mice having fewer but overexcitable orexinergic neurons that fragmented their sleep (Li et al., 2022). Orexin is a major wake-promoting neuropeptide.

Neurons in three minuscule areas of the brain, the locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN), produce noradrenaline, orexin, and histamine, respectively. All three help keep people awake (see image below). In a postmortem study, Grinberg and colleagues had previously found that these neurons had degenerated in people who had had AD, but not in those who had had PSP (Oh et al., 2019). Just as the sleep cycle disturbances can begin before cognitive symptoms in AD, neural activity in these subcortical areas can change early in the disease, as well (reviewed by Musiek et al., 2015; Sep 2021 news).

Subcortical Stimuli. Neurons in the locus coeruleus (LC), lateral hypothalamic area (LHA), and tuberomammillary nucleus (TMN) keep people awake by pumping out noradrenaline, orexin, and histamine, respectively. [Courtesy of Oh et al., JAMA Neurology, 2022.]

In this latest study, Grinberg wanted to know if degeneration of these neurons contributed to sleepiness in AD. To find out, co-first authors Jun Oh and Christine Walsh correlated sleep disturbances with stereological neuron counts from 10 people who had had AD and nine, PSP. All had received care at USCF’s Memory and Aging Center. The average age at death was 70, about half were women. All were Caucasian.

On average 3.5 years before death, the researchers had used polysomnography and electroencephalography to measure the study participants' total sleep time and time spent awake or in each sleep stage for one night. For postmortem analysis, they counted the number of total and phospho-tau-positive neurons in the LC, LHA, and TMN, then adjusted neuron counts for age, sex, AD or PSP diagnosis, and time between the sleep study and death.

As the researchers had seen before, AD participants had fewer wake-promoting neurons in all three areas than did PSP participants. The former also slept an average of two hours more than the latter. “It is striking how strong the relationship is between wake-activated neuron counts and one sleep study from two to five years back in a relatively small population of subjects,” Veasey said.

Did the neuron loss correlate with sleep? A relationship emerged after the researchers combined sleep data and neuron counts into one algorithm based on principal component analysis. Overall, people with AD spent less time lying awake because they had fewer wake-promoting neurons in their LHA and TMN than did people with PSP, Grinberg et al propose.

How does tau play into this? Previous research showed that cognitively normal or very mildly impaired older people with tau tangles sleep longer at night and also nap during the day more than people without tangles (Jan 2019 news). Likewise, Oh and Walsh found that participants with more p-tau202-positive TMN neurons slept more than those with fewer.

Curiously, the two disorders differed in how wake-promoting neurons accumulated p-tau202 and perished. AD tissue had 2.5 times as many p-tau-positive neurons in the TMN and half as many in the LHA as did PSP tissue. The p-tau may have led to the neuron's demise, because people with AD had fewer TMN neurons with more of their remaining cells containing p-tau than people who'd had PSP.

Why would p-tau harm the TMN in AD but not PSP? Grinberg thinks specific neuron populations may be selectively vulnerable to the tau species unique to each disease (see Oct 2021 news). Tangles in AD comprise three-repeat and four-repeat tau isoforms, which include three or four microtubule-binding domain repeats, respectively, while PSP tangles are made exclusively from 4R isoforms.

Veasey agreed, pointing at amyloid pathology. “In Alzheimer’s, amyloid may induce tau-specific or tau-independent changes to promote neuron hypofunction and loss, while, in PSP, the different tau splice forms may enhance activity and provide partial protection,” she wrote. For his part, Clifford Saper, Harvard Medical School, Boston, attributed the differences to tau's tendency to accumulate in different nerve cell populations. “Tau tends to be deposited in neurons in AD, and predominantly in the limbic system, cerebral cortex, and cell groups that project there,” he wrote. Projection neurons include those of the TMN and the LC. “In PSP, tau tends to be deposited in glial cells more than neurons, and mainly in the brainstem.”

Overall, people with fewer wake-promoting neurons and a higher p-tau202 load in their lateral hypothalamic area slept more. Grinberg hopes that studying the role of these neurons in sleep disturbances of AD will motivate physicians to consider prescribing drugs that modulate the arousal system. Staying more alert during the day is a top priority for AD patients, she said. Suvorexant, which blocks the orexin receptor to reduce wakefulness and promote sleep, is approved to treat insomnia in AD.

This study did not measure daytime sleepiness. Saper isn’t convinced that loss of arousal neurons causes it in AD. “While it is certainly possible, I do not think one can draw that conclusion from this study,” he wrote. He suggested recording entire wake-sleep patterns over multiple days and comparing AD patients to controls, not to people with PSP.—Chelsea Weidman Burke

Comments

  1. This paper tested the hypothesis that sleep alterations associated with Alzheimer’s or PSP could be mediated by subcortical arousal nuclei. Sleep analysis of a small cohort of AD and PSP patients confirmed increased total sleep time in AD and increased arousal/decreased sleep in PSP. The authors found significant degeneration of Hcrt/orexin neurons in the lateral hypothalamus of AD patients, as well as reductions in noradrenergic locus coeruleus (LC) neurons and histaminergic neurons. In contrast, brains from PSP patients showed numbers of LC neurons comparable with, or even above, control averages, which is surprising. The clinical manifestations of sleep disorders correlate well with changes in neuronal cell numbers, but the paper's message that fewer arousal neurons leads to more sleep is oversimplistic.

    These findings are a logical extension of previous work from the Neylan and Grinberg labs. As the authors point out, it is unknown whether sleep-promoting neurons are affected, although it is easy to speculate that they will be, because at least some of them are intermingled with wake-promoting cells in the hypothalamus.

    Our group recently showed that Hcrt/orexin and LC neurons also decrease in the brains of healthy aged mice. However, the remaining Hcrt cells were significantly more active than in younger mice, which resulted in sleep fragmentation (Li et al., 2022). Since the hypothalamus is a well-conserved brain region across mammals, and the aging effects on sleep go in the same direction in mice and people, it is easy to speculate that a similar mechanism occurs in healthy people and AD patients.

    It will be interesting to test whether PSP patients also have overactive wake-promoting neurons. Overall, the manuscript confirms the fact that neurodegenerative disorders affect subcortical arousal circuits.

    References:

    Li SB, Damonte VM, Chen C, Wang GX, Kebschull JM, Yamaguchi H, Bian WJ, Purmann C, Pattni R, Urban AE, Mourrain P, Kauer JA, Scherrer G, de Lecea L. Hyperexcitable arousal circuits drive sleep instability during aging. Science. 2022 Feb 25;375(6583):eabh3021. PubMed.

    View all comments by Luis de Lecea

  2. There are several important observations in this study led by Dr. Lea Grinberg. First, it is striking how strong the relationships are between wake-activated neuron counts and one sleep analysis from two to five years back in a relatively small population of subjects. This suggests that sleep traits are either stable over time or changing in a predictable fashion across the groups. This relationship also suggests that wake-activated neurons sway sleep-wake behaviors in significant ways. That may make sense to many, but sleep scientists have examined sleep in animal models with either locus coeruleus neuron loss or locus coeruleus and histaminergic neuron loss and have found minimal differences in sleep wake behavior.

    In contrast, loss of orexinergic neurons can result in narcolepsy, manifesting as daytime sleepiness and nighttime sleeping difficulties. Thus, it is unlikely that the loss predicts the sleep/wake disturbance; it is more likely the greater number of neurons has an overall higher-than-normal activation, especially in PSP with short sleep. We typically think of loss of neurons, loss of connectivity, and loss of function in neurodegenerative disorders, but another key component in these disorders may be dysfunction, and in some cases potentially hyperactivity of wake-activated neurons.

    A phenomenon like this was recently described by Luis De Lecea’s team (Li et al., 2022). He found that aged mice had functional impairment in a specific potassium channel in orexinergic neurons that resulted in excitability and sleep disruption. Importantly, this hyperexcitability is evident with a reduced overall number of orexin neurons.

    Overexcitability in wake-activated neurons may be the case in the Grinberg study, particularly in PSP cases, and should be explored. In Alzheimer’s, where the injury to, and loss of, wake-activated neurons is more profound, the remaining wake-active neurons may either not be excitable or are not excited to the same degree as in PSP.

    One final point is that many studies have shown that chronic short sleep results in a loss of locus coeruleus neurons. However, PSP subjects with markedly less sleep had much less loss of wake-activated neurons than individuals with Alzheimer’s and better total sleep times. This raises the possibility that the particular degenerative process, and its effects of aggregated proteins, may influence wake-activated neuron survival and activity. Thereby, amyloid may induce tau-specific or tau-independent changes in locus coeruleus neurons, promoting neuron hypofunction and loss, while in PSP different tau splice forms may enhance activity and provide partial protection.

    References:

    Li SB, Damonte VM, Chen C, Wang GX, Kebschull JM, Yamaguchi H, Bian WJ, Purmann C, Pattni R, Urban AE, Mourrain P, Kauer JA, Scherrer G, de Lecea L. Hyperexcitable arousal circuits drive sleep instability during aging. Science. 2022 Feb 25;375(6583):eabh3021. PubMed.

    View all comments by Sigrid Veasey

  3. In the global endeavor to find new promising targets for the primary prevention of neurodegenerative diseases, the neuromodulatory subcortical systems have recently gained significant attention because of their early involvement in the disease course (Ehrenberg et al., 2018; Jacobs et al., 2021) and their important role in a multitude of brain functions, including sleep-wake regulation. Previous research reported associations between the integrity of specific sleep-wake brain regions, and subjective or actigraphy-derived sleep-wake dimensions in cognitively unimpaired older individuals and across the AD continuum (Lim et al., 2014; Wang et al., 2015; Elman et al., 2021; Van Egroo et al., 2021). This work by Oh et al. is the first to bridge clinical and preclinical work by combining antemortem sleep-EEG metrics with histological quantitative assessments of three major wake-active neuronal populations, the noradrenergic locus coeruleus (LC), the orexinergic lateral hypothalamic area (LHA), and the histaminergic tuberomammillary nucleus (TMN), in 10 Alzheimer’s disease (AD) and nine progressive supranuclear palsy (PSP) patients.

    This unique approach allows for a refined investigation of the relationships between neurophysiological measures of sleep-wake processes and degeneration of the underlying subcortical circuitry. Oh and colleagues found that across all patients, a higher number of neurons within the nuclei of interest was related to an overall lower sleep drive, as reflected by a shorter sleep duration and more frequent intrusion of wakefulness episodes during the night.

    While these findings may be considered counterintuitive, it should be noted that these observations are made within the groups of patients included in the study, and not relative to a control group. Oh and colleagues previously demonstrated that PSP patients exhibit relative loss of neurons in these nuclei compared to healthy controls, especially for the LC (Oh et al., 2019), which aligns with our findings that lower MRI-assessed LC integrity is associated with more frequent nocturnal awakenings in healthy older individuals with elevated tau burden (Van Egroo et al., 2021). It would thus be valuable in the future to compare these sleep-brain relationships not only within patients, but also with reference to a control group.

    Notably, Oh and colleagues were able to distinguish two robust clinical sleep phenotypes in which the PSP-predominant pattern exhibited a shorter and more fragmented sleep relative to an AD-predominant pattern of sleep-wake alteration. These clinical phenotypes also mapped to distinct neurobiological substrates, with a lower number of hypothalamic neurons and a higher tau burden in these neurons in the AD-predominant group. These findings provide critical insight into the distinct neurobiological substrates that may explain the opposing clinical sleep-wake phenotypes between AD and PSP patients, despite the common—and central—involvement of tau in these often-neglected subcortical systems in both diseases.

    This study constitutes a key step in the emerging effort to relate sleep-wake regulation processes to the integrity of the subcortical sleep-wake nuclei in the context of neurodegenerative diseases. Recent developments to image the locus coeruleus in vivo (Betts et al., 2019; Priovoulos et al., 2018) and parcellate the hypothalamic subregions (Billot et al., 2020), are now providing opportunities to replicate and possibly extend these findings in vivo, characterize sleep-wake imbalances during disease progression, and ultimately inform personalized prevention strategies.

    Studies such as this, combining clinical with postmortem observations, can provide important information for in vivo studies, where the biological source of the MRI signal is still under debate. This study emphasizes the clinical and fundamental urgency for research connecting early sleep-wake dysfunction to the brain regions that are first affected by pathology in neurodegenerative disorders.

    References:

    Ehrenberg AJ, Suemoto CK, França Resende EP, Petersen C, Leite RE, Rodriguez RD, Ferretti-Rebustini RE, You M, Oh J, Nitrini R, Pasqualucci CA, Jacob-Filho W, Kramer JH, Gatchel JR, Grinberg LT. Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease. J Alzheimers Dis. 2018;66(1):115-126. PubMed.

    Jacobs HI, Becker JA, Kwong K, Engels-Domínguez N, Prokopiou PC, Papp KV, Properzi M, Hampton OL, d'Oleire Uquillas F, Sanchez JS, Rentz DM, El Fakhri G, Normandin MD, Price JC, Bennett DA, Sperling RA, Johnson KA. In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer's disease pathology and cognitive decline. Sci Transl Med. 2021 Sep 22;13(612):eabj2511. PubMed.

    Lim AS, Ellison BA, Wang JL, Yu L, Schneider JA, Buchman AS, Bennett DA, Saper CB. Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. Brain. 2014 Oct;137(Pt 10):2847-61. Epub 2014 Aug 20 PubMed.

    Wang JL, Lim AS, Chiang WY, Hsieh WH, Lo MT, Schneider JA, Buchman AS, Bennett DA, Hu K, Saper CB. Suprachiasmatic neuron numbers and rest-activity circadian rhythms in older humans. Ann Neurol. 2015 Aug;78(2):317-22. Epub 2015 Jun 18 PubMed.

    Elman JA, Puckett OK, Beck A, Fennema-Notestine C, Cross LK, Dale AM, Eglit GM, Eyler LT, Gillespie NA, Granholm EL, Gustavson DE, Hagler DJ Jr, Hatton SN, Hauger R, Jak AJ, Logue MW, McEvoy LK, McKenzie RE, Neale MC, Panizzon MS, Reynolds CA, Sanderson-Cimino M, Toomey R, Tu XM, Whitsel N, Williams ME, Xian H, Lyons MJ, Franz CE, Kremen WS. MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction. Alzheimers Dement. 2021 Jun;17(6):1017-1025. Epub 2021 Feb 13 PubMed.

    Van Egroo M, van Hooren RW, Jacobs HI. Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer's disease plasma biomarkers: a 7T MRI study. Alzheimers Res Ther. 2021 Sep 24;13(1):159. PubMed.

    Oh J, Eser RA, Ehrenberg AJ, Morales D, Petersen C, Kudlacek J, Dunlop SR, Theofilas P, Resende ED, Cosme C, Alho EJ, Spina S, Walsh CM, Miller BL, Seeley WW, Bittencourt JC, Neylan TC, Heinsen H, Grinberg LT. Profound degeneration of wake-promoting neurons in Alzheimer's disease. Alzheimers Dement. 2019 Oct;15(10):1253-1263. Epub 2019 Aug 12 PubMed.

    Betts MJ, Kirilina E, Otaduy MC, Ivanov D, Acosta-Cabronero J, Callaghan MF, Lambert C, Cardenas-Blanco A, Pine K, Passamonti L, Loane C, Keuken MC, Trujillo P, Lüsebrink F, Mattern H, Liu KY, Priovoulos N, Fliessbach K, Dahl MJ, Maaß A, Madelung CF, Meder D, Ehrenberg AJ, Speck O, Weiskopf N, Dolan R, Inglis B, Tosun D, Morawski M, Zucca FA, Siebner HR, Mather M, Uludag K, Heinsen H, Poser BA, Howard R, Zecca L, Rowe JB, Grinberg LT, Jacobs HI, Düzel E, Hämmerer D. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain. 2019 Sep 1;142(9):2558-2571. PubMed.

    Priovoulos N, Jacobs HI, Ivanov D, Uludağ K, Verhey FR, Poser BA. High-resolution in vivo imaging of human locus coeruleus by magnetization transfer MRI at 3T and 7T. Neuroimage. 2018 Mar;168:427-436. Epub 2017 Jul 22 PubMed.

    Billot B, Bocchetta M, Todd E, Dalca AV, Rohrer JD, Iglesias JE. Automated segmentation of the hypothalamus and associated subunits in brain MRI. Neuroimage. 2020 Dec;223:117287. Epub 2020 Aug 25 PubMed.

    View all comments by Maxime Van Egroo View all comments by Heidi Jacobs

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Is a Waning Locus Coeruleus an Early Sign of Alzheimer’s Disease?
  2. Tau, More than Aβ, Affects Sleep Early in Alzheimer’s
  3. Flock of New Folds Fills in Tauopathy Family Tree

Therapeutics Citations

  1. Suvorexant

Paper Citations

  1. Li SB, Damonte VM, Chen C, Wang GX, Kebschull JM, Yamaguchi H, Bian WJ, Purmann C, Pattni R, Urban AE, Mourrain P, Kauer JA, Scherrer G, de Lecea L. Hyperexcitable arousal circuits drive sleep instability during aging. Science. 2022 Feb 25;375(6583):eabh3021. PubMed.
  2. Oh J, Eser RA, Ehrenberg AJ, Morales D, Petersen C, Kudlacek J, Dunlop SR, Theofilas P, Resende ED, Cosme C, Alho EJ, Spina S, Walsh CM, Miller BL, Seeley WW, Bittencourt JC, Neylan TC, Heinsen H, Grinberg LT. Profound degeneration of wake-promoting neurons in Alzheimer's disease. Alzheimers Dement. 2019 Oct;15(10):1253-1263. Epub 2019 Aug 12 PubMed.
  3. Musiek ES, Xiong DD, Holtzman DM. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med. 2015 Mar 13;47:e148. PubMed.

Further Reading

Primary Papers

  1. Oh JY, Walsh CM, Ranasinghe K, Mladinov M, Pereira FL, Petersen C, Falgàs N, Yack L, Lamore T, Nasar R, Lew C, Li S, Metzler T, Coppola Q, Pandher N, Le M, Heuer HW, Heinsen H, Spina S, Seeley WW, Kramer J, Rabinovici GD, Boxer AL, Miller BL, Vossel K, Neylan TC, Grinberg LT. Subcortical Neuronal Correlates of Sleep in Neurodegenerative Diseases. JAMA Neurol. 2022 May 1;79(5):498-508. PubMed.

Annotate

To make an annotation you must Login or Register.