Sleep disorders and late-onset epilepsy of unknown origin: Understanding new trajectories to brain amyloidopathy
Introduction
Beta-amyloid (Aß) is a soluble, physiologically secreted protein produced by the cleavage of amyloid-precurson-protein (APP) after the activity of ß- and γ- secretases (Selkoe, 2001; Boespflug and Iliff, 2018). Among the different isoforms of Aß currently identified, Aß40 is the most abundant isoform produced, but the main attention has been focused on the Aß42 isoform since it is the primary component of amyloid plaques, resulting from the aggregation into oligomeric and fibrillary forms of this peptide (Boespflug and Iliff, 2018). Aggregation and accumulation of Aß is an hallmark of Alzheimer’s Disease (AD) pathology, and the documentation of Aß plaques in the brain tissue is pathognomonic of AD (Hardy and Selkoe, 2002). The chain of events leading to the cerebral deposition of Aß into plaques starts with the release into the interstitial-fluid (ISF) of Aß42, which aggregates due to its high solubility and tends to precipitate thus producing amyloid plaques (Iwatsubo et al., 1994; Boespflug and Iliff, 2018). Therefore, the trajectory of CSF Aß42 levels during this pathological process can be briefly described in the following steps: i) a first very early event featured by cerebrospinal-fluid (CSF) Aß42 concentration increase as effect of reduced catabolism or increased production of Aß; ii) aggregation of Aß42 into amyloid plaques with the progressive reduction in the CSF to pathological levels; iii) stable dramatic lowering of CSF Aß42 concentration and widely diffused amyloid plaques deposition. How and why Aß42 cerebral metabolism pathologically changes at the beginning of AD pathology has not yet completely understood; but several hypotheses have been built and different risk factors have been identified. Notably, the modification of brain Aß42 CSF and ISF levels not always corresponds to AD pathology, since the alteration of cerebral Aß metabolism has been associated with different neurological disorders (Smid et al., 2013; Liguori et al., 2016a; Costa et al., 2016; Jennum et al., 2017; Chen et al., 2018). Among the neurological disorders associated with the modification of CSF Aß42, sleep disorders and epilepsy recently emerged. On the one hand, both insomnia and sleep-disordered breathing (SDB) have been associated with changes in Aß brain cascade, featured by pathological modification of CSF Aß42 levels (Plog and Nedergaard, 2018; Liguori et al., 2017a, 2019b). This evidence rises from the documentation that sleep presents a beneficial effect on brain health since it cleans from toxic substrates (such as Aß42) the ISF under the action of the glymphatic system (Plog and Nedergaard, 2018). Therefore, sleep deprivation and sleep fragmentation may induce Aß42 pathology. On the other hand, late-onset epilepsy of unknown origin (LOEU) has been associated with cognitive deterioration and cerebral Aß modifications; thereafter, these pathological changes resulted in the increased epileptogenic activity, clinically producing epileptic seizures (Costa et al., 2016; Liguori et al., 2019a). In both animal model and clinical studies, the dysregulation of Aß42 (ISF and CSF levels, respectively) has been associated with epileptic activity and the development of AD at the longitudinal analysis (Gurevicius et al., 2013; Costa et al., 2016; Kam et al., 2016; Lam et al., 2017; Costa et al., 2019; Gureviciene et al., 2019; Brunetti et al., 2020). Moreover, sleep and epilepsy have been bidirectionally linked, since sleep deprivation may induce epileptic activity and epileptic activity may fragment and impair sleep (Wang et al., 2018).
Therefore, all these findings provide motivation to understand further the relationship between sleep, Aß, and epilepsy. In this review, we focused on the interconnections between modifications in cerebral Aß42 dynamics and both sleep dysregulation and epileptic activity, respectively. Moreover, we hypothesize a complex model linking sleep impairment, brain cortical hyperexcitability and epilepsy to Aß pathology in aging brains.
Section snippets
Sleep disorders and Aß dynamic changes
Cerebral soluble form of Aß changes with sleep-wake cycle showing circadian physiological fluctuations featured by diurnal increase and nocturnal decrease of its CSF levels (Kang et al., 2009). The correlation between sleep and Aß dynamics suggests that modification of the sleep-wake activity, such as sleep deprivation or sleep enhancement, can change cerebral Aß levels (Lucey, 2020). Mice model studies identified that sleep deprivation increases ISF Aß concentrations and tends to provoke Aß
Late-onset epilepsy, seizures preceding cognitive decline, and Aß dynamic changes
The accumulation of Aβ has been shown to be an early event in the course of AD, a primer that consistently drives the way to neurodegeneration and tau accumulation (Qiang et al., 2017; Hardy and Higgins, 1992). Even when accumulating in patients with normal cognitive function, Aβ represents a critical risk factor for the progression to AD dementia, therefore justifying the identification of Aβ as a main target for dementia prevention and treatment. (Roberts et al., 2018).
Despite the
The possibly interplay between sleep, LOEU, and Aß
Recent studies have revealed increased epileptic activity, including spontaneous seizures, occurring concomitant with Aβ-pathology either in animal models or in experimental studies performed in humans (Gurevicius et al., 2013; Costa et al., 2016; Hazra et al., 2016; Kam et al., 2016; Lam et al., 2017; Costa et al., 2018; Gureviciene et al., 2019). Aβ has been considered as a putative risk factor for seizure generation in APP transgenic mice and in patients with AD (Minkeviciene et al., 2009;
Future perspectives
The intertwining between amyloid pathology, seizures and sleep impairment mediating cognitive decline seems to emerge transversally from available literature, with a consistent association independently from the study design. However, several issues remain incomplete and need further investigations. First, although one might argue on the potential epileptogenicity of Aβ, it is difficult to understand the mechanism with which some patients develop seizures before AD while other progress to MCI
Conclusion
LOEU and sleep-wake disorders are increased condition in the adult-elderly population and can have enormous consequences on the trajectories of cognitive impairment, although it is a relatively under-appreciated area of research with only a recent interest for the scientific community. In this mini-review, we have explored different aspects of Aß neuropathology, such as epileptic activity and sleep problems. The link between sleep and epilepsy has been widely established, emphasizing that these
Acknowledgements
Authors have no conflict of interests or financial disclosures.
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2021, Epilepsy and BehaviorCitation Excerpt :The accumulation of beta amyloid in the brain is also associated with seizures, as well as sleep disturbances such as obstructive sleep apnea. This suggests there may be a complex relationship between beta amyloid, sleep disturbances, dementia and new-onset epilepsy in older adults [53,54]. Our models suggest increased hazard of death related to age, presence of dementia, eFI and CCI scores at baseline epilepsy diagnosis.