Pattern of degeneration of sleep‐wake nuclei correlates with objective sleep measurements in progressive supranuclear palsy: A quantitative clinicopathological study: Human neuropathology: Non‐AD neurodegenerative disease neuropathology. (7th December 2020)

• Record Type: Journal Article
• Authors: Oh, Jun Yeop; Walsh, Christine M.; Mladinov, Mihovil; Petersen, Catherine; Ruoff, Leslie; Robbins, Claire M.; Eser, Rana A.; Li, Song; Lew, Caroline; Varbel, Jonathan; Heuer, Hilary W.; Boxer, Adam L.; Seeley, William W.; Miller, Bruce L.; Neylan, Thomas; Grinberg, Lea Tenenholz
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.038015
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Individuals with progressive supranuclear palsy (PSP), a form of 4‐repeat tauopathy, show an extreme sleep phenotype featuring a short sleep duration. This is likely due to tau‐associated lesions in the subcortical sleep‐wake network. Nevertheless, it is unknown how the pathological lesions in the brainstem and hypothalamus relate to sleep phenotypes in PSP because detailed clinicopathological studies focusing on sleep are lacking. To elucidate this mechanism, here we correlate objective sleep‐wake measurements with quantitative pathological findings in the key sleep‐wake network in PSP for the first time. Method: Participants with a diagnosis of probable PSP based on the Litvan criteria were recruited at the Memory and Aging Center, UCSF from 2013 to 2019. Twenty participants (68% male; mean age: 70.95 ± 5.3) were asked to complete overnight polysomnography (PSG) and multiple sleep latency tests (MSLT) the subsequent day. Measures of interest on the PSG and MSLT are indicated in Figure 1. Of these individuals, 13 have undergone an autopsy, neurotransmitter and tau immunohistochemistry staining, and neuronal quantification using unbiased stereology in the following nuclei: noradrenergic Locus Coeruleus (LC), orexinergic lateral hypothalamic area (LHA), and histaminergic tuberomammillary nuclei (TMN). Result: Sleep parameters and pathological parameters (nuclei neuronal number, neurotransmitter expression, and tau burden), show significant and variable correlations (Figure 1). Conclusion: Neuronal loss and tau burden in the key neuromodulatory systems may explain clinical sleep signatures in PSP. For instance, shorter MSLT correlated with fewer histaminergic neurons which suggest that impaired histaminergic wake‐promoting system may lead to a higher tendency to fall asleep. Altogether, our preliminary data highlights the importance of clinicopathological study combining objective sleep measurements with unbiased postmortem evaluation in clarifying the contribution of subcortical tau pathology to sleep‐wake disturbances in tauopathies.