Multimodal Imaging

Multimodal Imaging of Brain Pathologies (Dir : G. Chételat)

For more informations on Gaël Chetela’s team : www.gael-chetelat.fr

This new team will look at ways of using multimodality neuroimaging to detect and probe certain brain diseases. The ongoing “Multimodality Imaging of Early-stage Alzheimer’s Disease” (IMAP) programme is emblematic of all the studies that Team 3 is planning to undertake. This programme brings together different promising and complementary neuroimaging techniques in a bid to meet the three main objectives of current research on Alzheimer’s disease (AD), namely 1) finding the most cost-effective marker, or combination of markers, for predicting progression to AD at a predementia or even asymptomatic stage, 2) identifying sensitive and reliable indicators of the progression of this neurogedenerative disease that will make it possible to gauge the effects of new drug or nondrug treatments, and 3) studying the links (similarities, differences or correlations) between different types of imaging examinations that highlight different manifestations of the disease, in order to understand the underlying pathophysiological mechanisms more fully. To this end, the team will develop new 6 image processing techniques and procedures, which can then be applied to other brain pathologies investigated by Teams 1 and 3.

Imaging of Alzheimer’s disease at an early stage

Superposition of atrophy on a 3D view of the hippocampus: towards a better sensitivity to distinguish normal aging from Alzheimer's disease

Declared a national, Alzheimer’s disease (AD) is a major public health due to socio-economic weight it represents. The best way to fight against this disease is to identify a very early stage of its evolution and to intervene with appropriate treatments. So we need predictive markers of AD, and neuroimaging is a particularly promising. Develop techniques for more detailed analysis could improve the diagnostic efficacy of certain biomarkers, so study the hippocampal subfields rather than the hippocampus as a whole is a first track for future studies (Figure shown against).

The development of new radiotracers (eg GDP, AV-45, FDDNP), which, combined with PET to visualize pathological lesions characteristic of AD (ie amyloid deposits and neurofibrillary tangles – DNF) also offers an exceptional interest. These tracers are indeed considerable hope not only for early diagnosis but also to better understand the pathophysiology of the disease, the dynamic evolution of these lesions and their respective roles in the cascade responsible for the degeneration in order to ‘guide therapeutic developments to target the most appropriate. In this context, multi-modal studies are particularly important since they allow to study the links between the different manifestations of the disease (Figure shown against).

Interest of multi-modal studies: to better understand the pathophysiology of Alzheimer

Interest in longitudinal studies: identification of markers for monitoring

Finally, these therapeutic research, growing, it is crucial to have tracking markers, ie indices sensitive to changes in the degenerative process to test new drugs efficiently and economically. Longitudinal studies are therefore crucial for the identification of markers follow-up (Figure shown against).

The three main objectives of this project are i) to identify, compare and combine predictive markers of AD in a pre-dementia stage (or pre-symptomatic), ii) to make a significant contribution to the understanding of pathophysiological mechanisms responsible for AD, and iii) to study the ability of different neuroimaging techniques to monitor disease progression.

We have developed a program of large-scale research (IMAP for multimodal imaging of Alzheimer’s disease at an early stage) that combines all the key elements to address these issues: the study of the stages most early (pre-symptomatic and asymptomatic), a longitudinal reinforced (with imaging tests repeated at intervals), and use of complementary imaging techniques to study all the key biomarkers of AD at the time.

Examinations performed in the IMAP project

So healthy subjects and AD patients, as well as various categories of patients at risk of developing AD, receive clinical, neuropsychological and neuroimaging MRI combining structural, functional (at rest and activation), PET-FDG and PET-AV-45 (which marks the amyloid deposits) (Figure shown against). All examinations are repeated several times during a follow-up of 18 to 36 months (depending on the types of patients).

Other tests are performed, such as blood tests and an MRI acquisition of the hippocampus at high resolution with an original sequence (La Joie R, Fouquet M, Mézenge F, Landeau B, Villain N, Mevel K, Pélerin A, Eustache F, Desgranges B, Chételat G (2010). Differential effect of age on hippocampal subfields assessed using a new high-resolution 3T MR sequence. Neuroimage 53 : 506-514) (Figure shown against).

Results of the study IMAP: Study of hippocampal subfields with high-resolution MRI

Results of the study IMAP illustrating the interest of multimodality in AD: distribution and relative levels of different brain damage in Alzheimer

The data are analyzed by modality (comparing different groups of participants and examinations obtained at different times of the study), but also by comparing different modalities and studying their relationships (Figure below cons). Finally, it is a dynamic project that meets the constraints of a longitudinal study (repeat examinations in the same conditions as baseline) while retaining the flexibility to add, remove, improve or replace examinations according to changes in technology and knowledge. We plan to replace for example the PET-FDG by another imaging study of molecular neuropathological characteristics of AD and complementary to the AV-45.

Partners involved in IMAP

This project was financed by the ANR in the framework of the Longevity and Aging (LONGVIE 2007) and part of the explorations started in early 2008. Under the direction of Gael Chételat, technicians, engineers, PhD students and postdocs are involved in the acquisition and processing of these data and continue to be recruited under the project. Five partners with complementary skills working at different levels of the project (Figure below cons): 1) University Hospital of Lille (F Pasquier, a national expert center for the study of patients with early onset Alzheimer’s), 2) unit U930 (D Guilloteau, Tours) associated with the CIC-IT 806, and the Unit GDM-PET of CEA-CNRS UMR 6232 (L Barré, Caen) for synthesis and production of brand new PET radiotracers. Finally, the project will benefit from the expertise of the U919 (C Ali, Caen) for biomarkers, and U614 (D Hannequin and D Campion, Rouen) specialists in genetics and also appointed a national expert center for the study genetics of early onset Alzheimer’s. International collaborations fostered by the U1077, particularly in the field of molecular imaging, are also strengthening the network of expertise that feed the IMAP project.

People involved in the unit U1077 : G. Chételat, B. Desgranges, F. Eustache, C. Lalevée, B. Landeau, A. Perrotin, F. Mezenge, A. Pélerin, V. de la Sayette, F. Viader

Masters, Doctorants et Post-doctorants : M. Fouquet, R. La Joie, K. Mevel,N. Villain

Collaborations : consultations with all the CMRR of Lower Normandy, Rouen University Hospital and Rennes, the team of Louisa Barré Cyceron, Denis Guilloteau unit at Tours, and the unit to Denis Vivien Cyceron