1. Movement disorders

In this project, teams from GHPS (Neurology department, Inserm U679, U678, U610, CNRS -UPR 640, CENIR) and NeuroSpin will focus on the use of ultra high field techniques for investigating the structural disorders of the brainstem and of the central deep nuclei in the field of Parkinsonian syndrome. This work aims at isolating biomarkers of the pathology by taking benefit from the last developments in the domain of ultra high fields and from the last high image processing innovations in the field of diffusion imaging based on high angular resolution models. Determining the biomarkers of the various forms of parkinsonian syndromes using ultra high field systems (7T) will surely open the way for developing new diagnosis tools at lower field. Therefore, the developments performed at 7T will be transferred to a clinical MR system (3T) that can be used for routine clinical applications.

The first aim of this project is to use very high field MR systems to deliver high resolution images of deep brain nuclei using the new contrasts mechanisms that have recently been discovered at ≥ 7T.

The second aim of this project is to characterize the cytarchitectonics of deep brain nuclei and the fiber pathways involved in the Parkinsonian syndromes using high angular resolution diffusion imaging.

The third aim of this project is to provide a statistical tool for isolating the biomarkers of Parkinsonian syndromes and to create a diagnosis tool of the pathology. We will develop computer-aided diagnostic tools for parkinsonian syndromes. Database of patients and healthy volunteers will be collected to be able to compare statistically the different populations.

2. Alzheimer’s disease and aging

Alzheimer’s disease (AD) and neurodegenerative dementias are growing health problems, since populations are constantly aging. The diagnosis of neurodegenerative diseases is therefore a challenge for modern neuroimaging techniques that extends beyond its traditional role of excluding other conditions such as neurosurgical lesions. Early diagnosis would also allow early treatment using currently available therapies, such as cholinesterase inhibitors that improve or stabilize cognition more efficiently when administered in the early stages of the disease, or using disease-modifying therapies in the future. Early diagnosis includes recognition of the pre-demented conditions, such as identification of MCI patients with prodromal AD or with high risk of developing AD. Imaging provides biomarkers that can be used for diagnosis, prognosis, understanding the pathophysiology of the disease as well as to evaluate new therapeutics in clinical or preclinical studies in animals.

The main objective of the project is to integrate new methodological developments from the different teams of the IFR49 (GHPS : Memory clinic, Inserm U610, U678, CNRS -UPR 640, CENIR, NeuroSpin, MIRCen, URA2210) to promote clinical and pathophysiological research on neurodegenerative dementias and particularly Alzheimer’s disease.

A better organization and structuring of research efforts and teams as well as new research collaborations will be promoted to develop collaboration between methodological, preclinical, and clinical research teams at UPMC and NeuroSpin/MIRCen.

Research projects will be pursued in three main directions :

1. physiopathology of the disease and the relationship between cognitive deficit and histological lesions (senile plaques and neurofibrillary tangles) ;
2. new diagnostic and prognostic strategies in prodromal AD ;
3. development of imaging markers to evaluate new drugs. More specifically, these projects will encompass the following.

Teams participating in the project have complementary expertise encompassing preclinical models in animals, cognitive neuroscience and neuropsychology, neurology, image acquisition and analysis. Complementary expertise allow addressing important clinical questions using up to date neuroimaging methods : MRI at high and very high field strength, structural imaging and high resolution diffusion tensor imaging, functional imaging and connectivity, software development for computer-aided diagnosis.

2a. Development of new imaging methods and algorithms

Imaging approaches will use existing structural, diffusion tensor imaging, relaxometry, and markers of functional connectivity and development of algorithms (SVM classification approach) and software (SACHA). We plan to evaluate the diagnostic strategies in prodromal AD using large series of patients from ongoing studies in France (Hippocampus study 200 prodromal AD, PHRC PredictMA : 100 MCI not prodromal AD and 100 controls), future studies (ISALP : SPECT and PET study of 350 subjects with memory complaint) as well as ADNI images.

Imaging methods will be developed, including dedicated contrast agents to evaluate lesion burden (amyloid plaques and NFT) in animals and humans. We will investigate the use of MR microscopy at very high field (7 Teslas) of the medial temporal lobe (methodological development and validation clinical, macro and microstructural imaging, imaging of the perforant path). Last, we will study functional connectivity using combined methods (MRI, SPECT, PET, MEG and EEG) and their relationship with cognitive deficits.

2b. Creation of a new Centre for large database, data analysis and processing

This encompasses 1) the constitution of an imaging database of patients and controls and 2) data analysis and processing on large series of subjects.

2c. Improved knowledge of the pathophysiology of the disease

Another line of research is to study the natural history of cognitive deficits and relationships between cognitive deficits and lesions using structural, microscopic, and functional imaging. Effects of treatments on the natural history of the disease will also be evaluated.

2d. Development of new markers for therapeutic evaluation

The development of new imaging markers should help to evaluate new therapeutics. Such markers will be used in human studies, but also at a preclinical stage to optimize the choice of products that will go through clinical trials. The constitution of a database of healthy volunteers carefully evaluated for cognitive functions for comparative studies in pharmacological trials is an essential part of this project.

The preclinical part of the project will be performed on transgenic and Primates (mouse lemurs and macaques) models of Alzheimer’s disease (MIRCen, URA2210, NeuroSpin). The models will be used to develop new imaging methods and evaluate the efficiency of experimental treatments. Reflexions to optimize the transfer of imaging methods developed in animals to humans will be conducted.

The clinical part of the project will benefit from the large recruitment of patients of the memory clinic in Salpetriere Hospital and the French network that was successfully created to gather MRI scans from about 30 imaging centres in France. In the IFR49, patients will be scanned with the MR scanners available in the IFR49 at CENIR and NeuroSpin, and SPECT or PET scanners in Orsay and Pitie-Salpetriere Hospital.

3. Psychiatric disorders

Projections suggest both unipolar depression and alcohol abuse will increase, and rank respectively first and fourth causes of burden of disease measured in disability adjusted life years (DALYs) in high-income countries. Changes in brain anatomy and function will be evaluated with MRI and PET in patients suffering of these psychiatric disorders and during treatments along two main research directions :

3a. Development & vulnerability

Since some mental disorders might be linked with measurable changes in brain structure development, investigations will focus on young subjects with autism spectrum disorder, or with risk for affective disorders, or for addictions (e.g.alcohol). This will be pursued through joint research projects with teams experienced in genomics or epidemiology, in order to tackle relationships between brain imaging and genetic variables. The characterization of young subjects and patients will be synergistic with an effort to constitute a large multimodal european database of adolescents in Neurospin, within the framework of an EU integrated project. Also, innovation regarding molecular brain imaging should usefully apply to metabolism diseases revealed by neuropsychiatric symptoms.

3.b. Drugs & treatments

Objective brain markers of drug effects will be extracted from both PET and MRI. Based on our acquired experience within the IFR of controlled therapeutic trials involving imaging in patients with depression or schizophrenia, new projects will aim at investigating the brain effects of a catecholamine reuptake inhibitor, a controlled trial for cocaine detoxification, and of medications used in current therapeutic settings. Research will involve both Neurospin and SHFJ platforms and clinical (pediatric and adult) departments in Paris Hospitals (University Paris Descartes, Paris Diderot, Paris Sud) and in Orsay hospital. Methodological developments in image analysis provided by Neurospin teams will be used to process these patient images.