Neuronal correlates of sleep in neurodegenerative diseases

Abstract

Sleep plays a key role in the origination and progression of neurodegenerative diseases. We have recently shown that the key areas that regulate sleep and wakefulness in the subcortical nuclei are particularly vulnerable to tau-inclusion and neuronal loss even in the early stages in AD. Nevertheless, it remains uncertain whether the pathological lesion of specific nuclei directly contributes to the patient's clinical sleep impairment. Here, we correlate quantitative sleep measurements with post-mortem stereological neuronal analysis in neurodegenerative diseases.Twenty-two patients (50% female; mean age: 70.65 ± 1.54) completed overnight polysomnography and/or MEG at the Memory and Aging Center at UCSF. Of 22 patients, 12 were neuropathologically diagnosed with AD, and 10 were PSP (progressive supranuclear palsy)(Table 1). Locus coeruleus (LC), lateral hypothalamus (LHA), and tuberomammillary nuclei (TMN) were immunostained for their respective primary neurotransmitter (TH, orexin, or histamine) and tau inclusions, followed by stereological neuronal count and Spearman correlation analysis.The number of orexinergic and histaminergic neurons showed a significant correlation with the objective sleep measurements, including total sleep time (TST), wake-after sleep onset (WASO), sleep maintenance, NREM2 sleep, and REM sleep (Figure 1).Loss of neurons involved in the sleep-wake network may play a direct role in impairing sleep architecture and function in neurodegenerative disease. This is the first study to use a quantitative, systematic approach to correlate pathological lesions and sleep parameters in AD and PSP. Understanding the neuronal basis of sleep impairment in neurodegenerative diseases is crucial in designing the next generation of sleep medications and even slowing down the progress of neurodegenerative diseases through early inventions.