Background: Presymptomatic genetic testing should always involve a considered choice. Young adults are at a key life stage as they may be developing a career, forming partnerships and potentially becoming parents. Presymptomatic testing may therefore affect the future lives of consultands significantly when testing is undertaken in early adulthood. Aim: To explore presymptomatic testing for hereditary cancer in consultands aged 18-30 years with particular reference to psychosocial impact, the decision-making process and the consequent counselling needs. Methods: A mixed-methods sequential exploratory design was used, comprising a systematic review, a qualitative study and a quantitative study. Results of all phases were used to build a theoretical model regarding the process of presymptomatic testing in young adults. Findings: The systematic review indicated that many participants grew-up with little or no information concerning their genetic risk. The experience of genetic counselling was either reported as an opportunity for discussing problems or associated with feelings of disempowerment. Parents appeared to have exerted pressure on their children during the decision-making process. However, as a result of the qualitative study, the influence of other people and the decision-making process prior to counselling were identified as key factors. Further results from the quantitative phase underlined that parents felt they had control over the decisions their children made, while the majority of the young adults reported the request for the genetic test as their own decision. A new theoretical model of decision making and impact on young adults was built to synthesise the overarching experience of participants in this research project. Conclusion: Counselling approaches to this population may require modification both for young adults and their parents. Young adults may benefit from a multi-step approach to presymptomatic testing. Parents need to be more informed that genetic counselling is a forum where information can be obtained and young adults can talk about the testing decision, regardless of whether they want to be tested or not. The traditional ‘wait until they come to us’ approach by health services may be failing to meet the educational and emotional needs of this population.

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Les dégénérescences lobaires fronto-temporale (DLFT) sont des démences neurodégénératives rares. 30-50% des DLFT a une cause génétique, la plupart sont des mutations des gènes C9orf72 et progranuline (GRN). L'objectif de la thèse a été d'élargir le spectre mutationnel et phénotypique des mutations GRN. Nous avons identifié les premières délétions partielles du gène GRN chez des patients avec progranulinémie baisse (la progranulinémie est abaissée en cas de mutation), mais sans mutation détectée par séquençage. Nous avons contribué à élargir le spectre clinique de la maladie en décrivant un phénotype d'atrophie corticale postérieure et des lésions de la substance blanche cérébrale chez des patients GRN, caractéristique évocatrice de cette forme génétique. Enfin, nous avons étudié la phase présymptomatique de la maladie, alors que se développent les premiers essais thérapeutiques, par une approche longitudinale avec IRM et TEP-FDG. Le métabolisme cérébral est réduit dans le lobe temporal latéral gauche 20 ans avant l'apparition des symptômes et, après 20 mois, dans les régions frontales et l'épaisseur corticale dans les régions temporales gauche. Le lobe temporal latéral pourrait être donc l'"épicentre " de la maladie, et le processus lésionnel pourrait, secondairement, progresser vers les régions frontales. J'ai également contribué à définir les phénotypes associés aux mutations de gènes plus rares de DLFT/DLFT-SLA. TARDBP est associé à un large spectre phénotypique; TBK1 est caractérisé par une démence sémantique ou aphasie non fluent associés à l'atteinte de la corne antérieure. Cette étude importante souligne le rôle de ces mutations dans le spectre clinique des DLFT. / Frontotemporal lobar degeneration (FTLD) are rare neurodegenerative dementias. 30-50% of FTLD has a genetic cause, most are mutations in C9orf72 and in progranulin gene (GRN). The aim of the thesis was to expand the mutational and phenotypic spectrum of GRN mutations. We identified the first partial deletions of GRN gene in patients with low plasmatic progranulin (the plasmatic progranulin is low in case of mutation), but without mutation detected by sequencing. We contributed to expand the clinical spectrum of the disease by describing a posterior cortical atrophy phenotype and lesions of the cerebral white matter in GRN patients, evocative feature of this genetic form. Finally, we studied the presymptomatic stage of the disease, while the first clinical trials develop, for a longitudinal approach with MRI and FDG-PET. The cerebral metabolism is reduced in the left temporal lobe 20 years before clinical onset and, after 20 months, the metabolism is reduced in the frontal regions and the cortical thickness in the left temporal regions. The lateral temporal lobe could thus be the "epicenter" of the disease, and the lesional process could secondarily progress towards the frontal regions. I also contributed to define the phenotypes associated with rare gene mutations in FTLD/FTLD-ALS. TARDBP is associated with a wide phenotypic spectrum; TBK1 is characterized by semantic dementia or not fluent aphasia associated with involvement of the anterior horn. This important study highlights the role of these mutations in the clinical spectrum of FTLD.

Alzheimer’s disease (AD) is a major cause of the rapidly growing and crushing aging challenge that threatens to economically undermine today’s healthcare system. AD prevalence will grow to over 100 million cases in 2050. AD is incurable but can be prevented. Therefore, the most viable solution may be to detect very early signs of AD (presymptomatically) in citizens-at-risk and to intervene in time to reduce AD risk or prevent it entirely. The present project will refine and validate two breakthrough innovations for AD detection and AD prevention and commercialize them as a one-stop digital medical device, named ‘AD Detect & Prevent’. The first innovation is a highly sensitive cognitive assessment method recently pioneered by a group of researchers that has been shown to detect subtle presymptomatic stage cognitive decline specific to AD. This will be integrated with the second innovation – a digital AD prevention programme delivered on an award-winning computerized cognitive training and rehabilitation platform (app + web) that uses high intensity immersive and adaptive ‘neurogames’ and audio-based therapy for behavioural intervention, designed for strengthening core cognitive functions, building cognitive reserve, changing lifestyle and thus reducing the overall AD risk in individuals. The detection and prevention methods will undergo vigorous scientific validation, and the ambition is to create and become the global standard of care for precise presymptomatic detection of AD and effective AD prevention.

Les modèles murins de la Sclérose Latérale Amyotrophique (SLA) ont permis des avancées dans la compréhension des mécanismes pouvant conduire à la mort sélective et progressive des motoneurones (Mns) mais ils présentent des disparités dans la sévérité et le décours temporel de la maladie. Parmi les hypothèses avancées figurent des modifications des propriétés intrinsèques des motoneurones conduisant à des modifications de l’excitabilité et de l’homéostasie du calcium intracellulaire et à la mort du motoneurone.Nous avons donc étudié les propriétés électrophysiologiques des Mns lombaires de souris SOD1G85R et SOD1G93A, deux modèles à faible nombre de copies du gène humain muté, durant les deux premières semaines postnatales afin d’identifier d’éventuelles anomalies pré-symptomatiques précoces. Nos travaux ont été réalisés sur deux préparations in vitro de moelle entière isolée et de tranches de moelle épinière. Les Mns mutants présentent, sur les deux types de préparations, une altération des propriétés du potentiel d’action se traduisant par un allongement de la durée associée à une diminution des vitesses maximales de dépolarisation et repolarisation et une réduction d’amplitude. Ces altérations apparaissent entre P2-P5 dans les Mns SOD1G85R et entre P6-P10 dans les Mns SOD1G93A et suggèrent une diminution de la densité des canaux sodiques et potassiques associés au potentiel d’action. Nous avons aussi observé sur des tranches de moelle épinière entre P6-P10 que le gain de fréquence des Mns SOD1G85R diminue et celui des SOD1G93A augmente sans aucune modification des densités des courants entrants persistants sodiques et calciques. On note également que, sur tranches de moelle épinière, les Mns SOD1G93A présentent un potentiel de repos diminué. En présence d’une surcharge calcique extracellulaire, les propriétés membranaires des Mns SOD1G85R entre P6-P10 sont moins affectées que celles des Mns témoins. Les effets différentiels de cette surcharge peuvent être dus à des modifications différentes de la dépendance au voltage des canaux voltage-dépendants et/ou à la modulation de certains types de canaux activés par le calcium extracellulaire. Une arborisation dendritique plus ramifiée que celle de Mns témoins, comparable à celle précédemment décrite dans les Mns SOD1G85R, a été observée dans les Mns SOD1G93A à P8-P9 avec des altérations du potentiel d’action citées plus haut et une réduction de la rhéobase. Ces altérations morphologiques et électriques pourraient indiquer des modifications de cinétiques et/ou de densités de canaux sur des sites différents dans ces Mns. Nos travaux montrent donc, d’une part que les mutations SOD1G85R et SOD1G93A induisent dans ces deux modèles murins des altérations des propriétés des Mns lombaires comparables mais décalées dans le temps et d’autre part que certaines altérations semblent être spécifiques à une mutation SOD1 donnée. / The SOD1 murine models of Amyotrophic Lateral Sclerosis (ALS) allowed major progress in the understanding of mechanisms which could lead to a selective loss of motoneurons (Mns), but these models display differences in the severity and time course of the disease. Changes in intrinsic properties of motoneurons may induce changes in excitability and intracellular calcium homeostasis leading to motoneuron death.Therefore, we studied electrophysiological properties of lumbar Mns from SOD1G85R and SOD1G93A mice, low expressor lines, during the first two postnatal weeks in order to identify possible early presymptomatic abnormalities. Our studies were carried out on two in vitro preparations: the whole isolated spinal cord and acute spinal cord slices. Mutant Mns display, in the two preparations, a modified action potential characterized by an increased duration due to a decrease of the maximal speeds of depolarisation and repolarisation and a reduction of the spike amplitude. These alterations appeared between P2-P5 in SOD1G85R Mns and between P6-P10 in SOD1G93A Mns and suggest a decrease of the density of sodium and potassium channels related to action potential. We also showed on spinal cord slices between P6-P10 that the gain of frequency decreases for SOD1G85R Mns and increases for SOD1G93A Mns without any change in the density of persistent inward sodium or calcium currents in these different mutant Mns. We observed also that the resting membrane potential of SOD1G93A Mns on spinal cord slices is decreased. The membrane properties of SOD1G85R Mns between P6-P10 were less susceptible to changes in presence of an extracellular calcium overload. Differential effects of this extracellular calcium overload on membrane properties of WT and SOD1G85R Mns could be due to different alterations of the potential dependence of voltage-gated channels and/or to the modulation of some types of channels sensitive to extracellular calcium. An over-branching of dendritic arborization, similar to that previously described in SOD1G85R Mns, was observed in SOD1G93A at P8-P9 with the above-mentioned action potential alterations and a weak rheobasic current. These morphogical and electrical changes could indicate together alterations of kinetics and/or density of channels on different sites on these Mns. In conclusion, our work shows on one hand that SOD1G85R and SOD1G93A mutations induce similar alterations of lumbar Mns properties but time-shifted in these two murine models and on the other hand that some alterations seem to be specific to a given SOD1 mutation.