Anna B. SZABO – PhD defense

PhD defense in english

Zoom link : https://univ-tlse3-fr.zoom.us/j/92029196377?pwd=aGY4aTRDV2lSYUw3MFp6cmM4amZWZz09

Team : REMEMBER

Supervisors : Lionel DAHAN (CRCA-CBI) / Luc VALTON (CerCo)

Committee members :

• Pr. Marc Dhenain, Rapporteur, Université Paris-Saclay, Fontenay-aux-Roses
• Dr. Pierre-Pascal Lenck-Santini, Rapporteur, Aix-Marseille Université, Marseille
• Dr. Laure Peter-Derex, Rapporteure, Université Claude Bernard Lyon 1, Lyon
• Pr. Marie Sarazin, Examinatrice, Sorbonne Université, Paris
• Pr. Maria-Eugénia Soto-Martin, Examinatrice, Université Paul Sabatier, Toulouse
• Pr. Agnès Trebuchon-Da Fonseca, Examinatrice, Aix-Marseille Université, Marseille
• Dr. Lionel Dahan, Supervisor, Université Paul Sabatier, CRCA-CBI, Team REMEMBER, Toulouse
• Dr. Luc Valton, Supervisor, CHU de Toulouse, Université Paul Sabatier, CerCo, Team DYNAMO, Toulouse

Abstract :

Previous research on murine models of Alzheimer’s disease (AD) highlighted the potential role of cerebral excitatory-inhibitory imbalance in the pathophysiology of AD. Clinical research has since reported that this imbalance may give rise to epileptic activities in as much as 50% of AD patients as well. However, these epileptic events may remain undetected due to their silent, mostly sleep-occurring nature. Using a translational approach, the aim of this thesis was to better understand the link between AD, epilepsy, sleep and memory.

First, in the framework of a preclinical study, I aimed at (I) characterizing epileptic activities over the sleep-wake cycle in the Tg2576 mouse model and (II) gaining better insight into the mechanistic underpinnings of these peculiar epileptic events. Epileptic activities were frequent, showed a predominance during REM sleep, and were locked to the phase of the theta cycle corresponding to the maximal firing probability of pyramidal cells. Furthermore, these events seemed to be counterbalanced by noradrenergic signalling via α1 adrenoreceptors during wakefulness and partially during SWS, but this effect would be lost during REM sleep when noradrenergic cells cease firing. Given the early degeneration of the locus coeruleus – the primary source of noradrenaline in the brain – in AD patients, this could have important clinical implications in the future.

In the second part of this thesis, the objective was to explore the prevalence and the distribution of epileptic activities during sleep in a cohort of 30 AD patients (selected as early AD, & without epilepsy) compared to a group of age-matched, healthy controls, and to understand the impact of these activities on cognitive decline and sleep-related memory consolidation. To this end, a full-night video-EEG combined with polysomnography was undertaken, together with a two-part neuropsychological test battery with pre-and post-sleep memory tests. These measures were combined with brain imaging (MRI), genetic analyses and the evaluation of lifestyle-related risk factors. The preliminary results with 25 participants per group that are presented hint at a risk ratio for EA occurrence five times higher in patients than controls. In contrast to the preclinical results, epileptic events are predominant during non-REM sleep. Importantly, other sleep-related deficits were also observed, including an increased percentages of superficial sleep in patients at the detriment of deeper ones and unexpectedly high prevalence of newly diagnosed Sleep Apnea Syndrome: 63% in AD patients and 50% in controls. While our sample size is currently insufficient to draw steady conclusions from our results, our preliminary models suggest a combined impact of sleep quantity, sleep apnoea, epileptic events and AD itself on memory consolidation, especially on episodic memory. We suggest that treating EAs, sleep apnoea and improving sleep quality could potentially slow down or lessen memory complaints in AD patients.