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.

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  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 Heidi Jacobs

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