NEUROBIOLOGICAL BASIS OF SLEEP AND WAKE DYSFUNCTION IN AD AND OTHER TAUOPATHIES: THE ROLE OF THE NEUROMODULATORY SYSTEM

Abstract

Wake, sleep and circadian disturbances are common occurrences in Alzheimer’ disease (AD) and other tauopathies often preceding disease-defining symptoms. Clinical data point to a divergent sleep-wake behavior profiles among tauopathies which probably reflects their differential pattern of neuronal vulnerability and spread and thus, have implications for developing symptomatic and disease-modifying treatments. Although some aspects of the neurobiological basis of sleep disturbances in neurodegenerative diseases have been studied, including the bidirectional relationship between sleep apnea and beta-amyloid levels and more recent a possible impact of lack of sleep in tau levels, other aspects remain underexplored. The neuromodulatory system is brainstem, diencephalons and basal forebrain hosts numerous nuclei involved in wake, sleep and circadian controls. Although some these nuclei show tau-involvement in AD and tauopathies, they are seldom included in models explaining sleep dysfunction in neurodegenerative diseases in humans. Literature review and presentation of new data based on quantitative and multidimensional neuropathological investigation the neurobiological basis of sleep dysfunction in well-characterized AD and tauopathy cases, with emphasis on the neuromodulatory systems. This presentation will have two parts: 1) brief review of the anatomy of sleep, wake and circadian circuits in humans 2) discussion on the major neuropathological findings, including substantial unpublished data, in such nuclei in different tauopathies and their relationship with clinical outcomes and possible therapeutic strategies. Among the findings, we will show quantitative neuropathological data on the relationship between tau burden, neuronal dysfunction and neuronal loss in distinct wake and sleep promoting subcortical circuits and how these results are harmonized or not with clinical observations. Differential involvement of neuromodulatory systems in AD and tauopathies provides a good framework of explain clinical sleep signatures in these different diseases involving tau protein. Inclusion of pattern of degeneration of these systems in sleep/wake models may open avenues for better symptoms management and understanding of interaction between tau and neuronal dysfunction.