ADEEPSLEEP · Focusing on deep sleep-wake brain regions in the context of Alzheimer's disease pathogenesis: a multi-modal, high-resolution neuroimaging approach

Focusing on deep sleep-wake brain regions in the context of Alzheimer's disease pathogenesis: a multi-modal, high-resolution neuroimaging approach

The longer average lifespan in our modern society is accompanied by a global increase in the prevalence of dementia, with Alzheimer’s disease (AD) being the most common cause. By 2050, the number of individuals with AD is expected to double in Europe and to triple worldwide reaching up to 153 million, highlighting the urgent need for developing effective treatment. AD is characterised by a slow pathological process during which amyloid-beta (Aβ) and tau proteins, the main neuropathophysiological hallmarks of the disease, start to accumulate in the brain two to three decades before the onset of cognitive symptoms. Confronted to the limited success of clinical trials targeting Aβ in the prodromal phase of AD, the research community has now moved toward alternate approaches revolving around the development of preventive actions in asymptomatic individuals to delay the AD pathological cascade. The long preclinical disease course is therefore considered as a critical window of opportunity for the implementation of early preventive strategies. In the worldwide effort to identify modifiable factors to delay the onset of AD, sleep has emerged as a promising candidate. Mounting evidence indicates that older individuals with sleep-related issues are at a ~1.5 increased risk of developing AD, and that an estimated 15% of AD in the population may be solely attributed to treatable sleep problems. Yet, our modern 24-7 society is overwhelmed by recurrent episodes of sleep deprivation and an increased prevalence of sleep complaints. As successful treatments for AD remain elusive, considering the role of sleep-wake regulation as a protective factor against early AD-related changes is therefore timely. At the neurobiological level, the regulation of sleep and wakefulness periods across the 24-h sleep-wake cycle is determined by the concerted (inter)actions of several neuromodulatory subcortical systems forming the so-called sleep-wake circuitry. Animal and postmortem studies demonstrated that these systems are directly involved in critical sleep macro- and micro-structural dimensions, and that they are also the first brain regions affected by tau pathology in AD, before any cortical deposition, leading to marked neurodegeneration within these nuclei as the disease unfolds. Even though landmark discoveries recently established that disruption of sleep constitutes a core mechanism of early AD pathogenesis, little attention has been given to the role of the neuromodulatory subcortical systems, leaving a major gap in understanding how sleep-wake disturbances relate to the initial AD pathophysiological processes. Together, these elements led to a novel framework shifting focus to these key sleep-wake nuclei as crucial nexus regions for the interplay between early sleep disruption and AD pathogenesis. To date, the number of experimental studies within this framework is limited because it is challenging to accurately identify these nuclei in vivo with standard imaging sequences and magnetic resonance imaging (MRI) scanners. Yet, advances in MRI methods at ultra-high field (≥ 7 Tesla (T)) and the recent availability of robust, unbiased segmentation algorithms now enables the precise investigation of these small brain structures in vivo in humans, creating unprecedented opportunities to assess their role in sleep-wake disruption in the earliest stages of AD. The overarching objective of this project is therefore to identify, for the first time in vivo in humans, the contributions of the structural and functional integrity of key sleep-wake brain regions, namely the brainstem locus coeruleus (LC), the postero-lateral hypothalamus (HTH), and the basal forebrain (BF), to sleep-wake phenotypes in the context of early AD-related processes in cognitively unimpaired individuals.

Data: CORDIS, © European Union