DS0404 - Innovation biomédicale

Therapeutic Lithium response in Bipolar Disorders and brain Lithium-7 NMR Spectroscopy Imaging at 7 Tesla – BIP-Li7

Submission summary

Bipolar disorder (BD) is an affective disorder with recurrent major depressive and manic episodes. It is the 7th most burdensome disorder in the global ratings of morbidity, mainly due the high risk of relapse and to a persistent functional impairment. Lithium (Li) is the leading treatment for relapse prevention with many patients remaining asymptomatic for several years (even decades). However, a significant subgroup of patients experience high relapse rates despite Li treatment and it remains difficult for clinicians to accurately predict which patients will respond without prescribing a lengthy Li trial. In addition, biomarkers predicting Li response are lacking and the mechanisms of Li action and transport across brain barriers remain poorly understood.
Based on recent animal studies and pilot studies in humans, it appears that the concentration of, and regional distribution of Li in the brain are associated with therapy success. Thus, the development of a technique to accurately determine concentrations and regional distribution of Li in the brain as well as to investigate the molecular determinants of Li diffusion across the different brain barriers will help to identify pharmacokinetic and imaging-based biomarkers to better predict treatment response.
Nuclear Magnetic Resonance (NMR) Imaging is a rapidly evolving imaging technology for the investigation of physiological and biochemical processes. Great opportunities have emerged using high magnetic fields to image low-gyromagnetic ratio nuclei such as Lithium-7 (7Li) with unprecedented sensitivity. NeuroSpin (CEA/DSV/I2BM) is an ultra-high field NMR facility and a leading research center in neurosciences dedicated to novel technologies to explore brain using NMR imaging with a strong emphasis on translational research and cognitive neurosciences.
To our knowledge, this is the first project to investigate brain Li content in Li-treated bipolar patients (n=30) using 7Li MR Spectroscopy (7Li-MRS) at 7 Tesla. Lithium response will be assessed using strict criteria of clinical improvement and quantification of confounders (Alda Scale). A secondary objective is to perform an exploratory association analysis of Li response and brain Li distribution. Patients with good response (n=15, Alda score>= 7) and partial response (n=15, Alda score <7) will be included. Two ‘Expert Centers’ involved in the assessment and management of BD cases will be responsible for the recruitment.
In parallel to these clinical studies, we will conduct two experimental studies: (1) a preclinical study in rat to help the interpretation of the results obtained in humans by: (i) correlating Li brain content measured by 7Li MRS and Li brain concentrations measured ex-vivo in different rat brain regions; (ii) investigating covariation of brain Li content with other routinely used psychotropic drugs in bipolar patients. (2) an in vitro study of the mechanisms controlling Li transport between the plasma and the brain parenchyma across the two main brain barriers, i.e the blood-brain barrier using an optimized model of hCMEC/D3 human brain endothelial cells and the blood-cerebrospinal fluid barrier using an optimized model of human choroid plexuses cells (HIBCPP).
Our consortium includes leading experts in the management of BD cases, Human and rat neuroimaging using high field MRS, assays to measure Li in various matrixes, preclinical models of Li-treated rats and in vitro models of brain barriers. This project is implemented in the era of the personalized medicine and the development of brain biomarkers that may help to better predict Li response in BD. Expected results are (i) improved understanding of the brain regions involved in Li response; (ii) directions for the design of a larger study to measure the predictive value of brain Li content in clinical response; and (iii) new evidence to better understand the mechanisms of transport and action of Li.

Project coordination

FRANK BELLIVIER (INSERM UMR-S1144 - VariaPsy Variability of the Response to Psychotropic Drugs)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM UMR-S1144 INSERM UMR-S1144 - VariaPsy Variability of the Response to Psychotropic Drugs
CEA-EA Commissariat à l'Energie Atomique et aux Energies Alternatives
APHP Assistance Publique - Hôpitaux de Paris
INSERM UMR-S1153 Institut national de la santé et de la recherche médicale
APHP Assistance Publique - Hôpitaux de Paris

Help of the ANR 384,187 euros
Beginning and duration of the scientific project: November 2014 - 45 Months

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