WP5: Disease progression
Scientific background
Neuroimaging of prodromal PD
Prof. Dr Stéphane Lehéricy is head of the Center for NeuroImaging Research (CENIR), the imaging platform of the Paris Brain Institute (ICM), and co-head with Prof. Dr Marie Vidailhet of the Movement, Investigation and Therapeutics (MOVIT) team at the ICM. His main research focuses on the pathophysiology of PD and atypical Parkinsonism using multimodal imaging42 in relation to clinical signs (gait, sleep, autonomic and eye movement disorders) and the development of new neuroimaging markers41,43,44 that can be used for early diagnosis of the disease, differential diagnosis, characterization of groups of patients with homogeneous evolving profiles (with a view to personalized medicine), identification of predictive factors45, therapeutic monitoring and modeling of the progressive profile of the disease. He has contributed to the characterization of brain lesions in PD, particularly in the brainstem, in relation to motor and non-motor signs of the disease, the study of prodromal forms of the disease (idiopathic RBD - iRBD), the mathematical modeling of disease progression, and the differential
diagnosis and characterization of lesions in atypical parkinsonian syndromes. Together with Profs. Drs. Corvol, Vidailhet, and Arnulf, Lehéricy’s team is conducting the ICEBERG clinical trial, an on-going 5y prospective longitudinal study (to be completed by end of 2025) aiming at identifying and validating markers for predicting and monitoring the progression of brain lesions of PD from the prodromal phase to the clinical expression phase.
Working plan and methodology
PD patients, sleep and 7T MRI
We will study the progression of structural and functional abnormalities primarily in the SN, and then beyond, in patients in the prodromal stage of PD (iRBD) and in the early phase of the disease from two cohorts of patients: the established ICEBERG study and a new prospective study at 7T. Patient inclusion criteria comprise a clinical diagnosis of iRBD or PD performed by sleep neurologists and movement disorder specialists according to international criteria, 18–75y, minimal or no cognitive disturbances
(Mini-Mental State Examination score >26/30) and disease duration <4y for PD patients. The presence or absence of RBD will be confirmed using polysomnography. The ICEBERG study (ClinicalTrials.gov: NCT02305147) includes 170 PD, 58 iRBD, and 70 healthy control subjects with three time points separated by 2y each. Subjects have detailed clinical and biological information (DNA, clinical, behavioral, cognitive, sleep, MRI and (123)I-FP-CIT SPECT). Clinical examinations include the Hoehn and
Yahr scale, the MDS-UPDRS, the Mattis dementia rating scale, the Montréal cognitive assessment score, and Ardouin’s scale of behavior in PD. Sleep was evaluated at the baseline visit via a medical face-to-face assessment of sleep disorders, questionnaires including RBD questionnaire-Hong Kong and Epworth sleepiness scale, and all patients underwent night video-polysomnography. The recordings included three electroencephalogram channels, two electrooculograms, chin and bilateral tibialis anterior muscles electromyograms, electro-cardiogram, oronasal flow (via oronasal thermistor plus nasal pressure), respiratory thoracic and abdominal efforts (via plethysmography), transcutaneous oxyhemoglobin, position, infrared video, and sounds. Sleep neurologists scored sleep stages, arousals, periodic leg
movements and respiratory events according to international criteria. The presence of RBD was diagnosed through video-polysomnography by experienced raters and followed the international criteria. Sleep analyses will be conducted as described previously.
The MRI examinations were performed at 3T using three-dimensional T1w MP2RAGE, FLAIR and QSM imaging, and a 2D neuromelanin-sensitive sequence, resting state fMRI and multi-shell diffusion imaging. The volume and signal to noise ratio of the SN will be calculated using neuromelanin-sensitive imaging and deep-learning based automated software. Susceptibility maps and striatal binding ratios will be calculated as previously described.
The new 7T prospective study will include 30 new subjects in each of the PD, iRBD and control groups. Patients will be recruited using the same clinical criteria and clinical examinations. Images will be acquired using a 7T Terra.X Siemens scanner (delivered at ICM on June 9th, 2024) equipped with CE-marked multi-transmission and strong gradients and an 8Tx32Rx head coil (same scanner as in Leipzig). The MRI protocol will include the qMRI protocol developed by the consortium. Semi quantitative maps of iron and myelin will be analyzed using the segmentation algorithms and 3D multimodal atlases model developed in WP2 and quantitative biomarkers of nigral integrity developed in WP6 linking quantitative MRI parameters with tissue microstructure.
Using these two cohorts, we aim at quantifying the longitudinal changes in neuromelanin, iron deposition and diffusion MRI changes in the different compartments of the SN, including the nigrosomes, using qMRI acquisition techniques and the atlases developed by the consortium (WP2). WP1 with its biophysical modeling and qMRI developments will ensure harmonization of the qMRI data of both cohorts.
Team – Paris Brain Institute, Sorbonne Université
