Narcolepsy type 1 (NT1) is a disabling orphan disorder characterized by excessive daytime sleepiness and cataplexy, often associated with hypnagogic hallucinations, sleep paralysis, nighttime sleep disruption and weight gain. NT1 is a chronic disorder, and in the large majority of patients it is a sporadic disorder with the main peak of disease onset at 16 years of age. We showed in 2000 that NT1 is due to the specific loss of hypocretin (orexin) neurons within the hypothalamus. Although the etiology of the disease, the reason why the hypocretin neurons die is still obscure, it is clear that both genetic and environmental factors are important. A main specific genetic susceptibility marker is known since more than 95% of patients carry the human leukocyte antigen DQB1*06:02 allele. Increasing evidence argue for an autoimmune pathogenesis with epidemiological studies underlying a strong association between H1N1 influenza virus vaccination and narcolepsy following the 2009 vaccination campaign. The mechanisms underlying such association remain unclear and may involve either a specific immune response to H1N1 with potential molecular mimicry or a large non-specific stimulation of the immune system with increased brain inflammation/blood-brain permeability, allowing the autoimmune process to reach hypocretin neurons resulting in NT1. Recently we have provided evidence supporting the autoimmune hypothesis. We have generated a mouse model in which an induced and targeted neuro-inflammation was able to kill specifically hypocretin neurons and provoke sleep fragmentation and cataplexy episodes, thus an autoimmune mouse model for NT1. We have also reported an immune signature in NT1, alteration in P2RY11 signaling, and revealed the release of several cytokines and growth factors in the sera of NT1 patients. Now, our goal is to use a variety of complementary approaches to test realistic hypotheses regarding the immune mechanisms that could induce NT1. Our project is based on a translational approach using both human and animal models. Altogether preclinical and clinical research studies within this project have the objectives to decipher the autoimmune mechanisms able to destroy hypocretin-producing neurons and investigate how environmental factors such as infection or vaccination trigger an autoimmune response against CNS neurons. Our approaches include the in-depth study of cases of early-diagnosed NT1, induced or not by H1N1 vaccination, and the use of original animal models to test the different immunological pathways that could lead to NT1. The strong position of the 3 academic partners in the domain of sleep, sleep disorders and neuro-immunology, their real and efficient synergy and the access to the biobank of the French reference national center for narcolepsy in Montpellier are major advantages for the success of the project and will contribute to the scientific valorization of the results. New treatment strategies could emerge from the identification of the precise immunological alteration, especially early after disease onset when the potential immune process targeting hypocretin neurons is not too advanced and could be reverted. Our results may lead to new ways to treat such pathologies by opening up a new field of therapy potentially exploitable in public health politics, and leading to new patentable molecules.

The evidence of the effects of air pollution on cognitive function in adults is scare. Furthermore, most of the previous studies did not have individual measures of air pollution, using aggregated data, did not have a comprehensive set of confounding variables, did not have standardized cognitive tests but used registry-based diagnosis of disease, only contained one measurement of cognitive function, only included older adults and had small sample size. In summary, the study of the effects of air pollution on cognition still has many questions to answer and presents several methodological challenges, but we will overcome most of them in this project. Our project aims to evaluate the association between air pollution exposure and cognitive function in a large cohort of adults living all over France. Our overarching hypothesis is that air pollution, even at low levels of exposure, is a potential determinant for cognitive outcomes in adults. A secondary objective is to assess if exposure to heavy metals (HM) from air pollution, and which ones, are associated with cognitive outcomes in adults. Our project is based on the CONSTANCES cohort which is a large population-based cohort launched in late 2012, aiming to include 200,000 participants. The cohort is designed as a randomly selected sample of French adults aged 18-69 years at inception, living in different regions throughout France. At inclusion, the selected subjects are invited to fill a questionnaire and to attend a comprehensive health examination. The follow-up includes an annual questionnaire, a health examination every 5 years and the linkage to health national databases (“SNIIRAM” and the national mortality database). A large range of data is collected on social and demographic characteristics, socioeconomic status, life events, behaviours, and occupational factors; the health data cover a wide spectrum. A unique feature of CONSTANCES is the inclusion of a comprehensive set of cognitive tests exploring global cognitive performances, attention and executive functioning, verbal fluency, memory, and psychomotor speed starting as young as 45 years, earlier in life than most of the available population-based cohorts studying cognitive impairment or decline. Air pollution exposure will be assessed individually at the home address using three complementary maps of exposure. First, for classic pollutants, we will use a dispersion models that gives annual concentrations of PM10, PM2.5, NO2, SO2, C6H6 and O3 and a Europe-wide LUR model that gives annual concentrations of NO2, PM10 and PM2.5. Then we will assess exposure to atmospheric heavy metals using the data from the BRAMM network, a moss-biomonitoring database over France. Four trans-disciplinary partners are involved in the project, including researchers with a strong background in environmental epidemiology, in cohorts management, in cognition and in ecology and bio-monitoring. In conclusion, we will assess air pollution effects on cognitive function in a large cohort of adults in whom we performed cognitive tests from the age of 45, an earlier age than of the majority of other cohorts, allowing to identify accelerated decline in cognitive functions in early stages. Furthermore we will have three different fine scale models of air pollution exposure, all covering all the French territory, allowing for exposure assessment at individual level at the residential address. Two models will give exposure for classic pollutants and one very novel as it uses mosses that will allow assessing exposure to atmospheric HM. Our project will contribute to the knowledge of cognition impairment and its environmental determinants. Such knowledge can benefit public health and the society in general, by providing facts to policy makers to handle air pollution and trying to reduce population exposure to the air pollutants highlighted by our proposal.