CE17 - Recherche translationnelle en santé

PET-TAU MRI IN VARIANTS OF PROGRESSIVE SUPRANUCLEAR PALSY – PSP-TAU

Submission summary

Besides the classical Richardson form of the disease, Progressive Supranuclear Palsy (PSP) may have several other presentations defining PSP variants, which can be difficult to differentiate clinically from Parkinson’s disease (PD), especially at the early stage of the disease. In this project we propose to improve the differential diagnosis of the parkinsonian variant of PSP (PSP-P), a tauopathy, and the axial forms of PD, a synucleinopathy, using 18F-AV-1451 PET-tau imaging. We hypothesize that PSP-P patients have a tau-specific lesion load which will be different not only from that of healthy controls (HCs) and PD subjects but also from that of subjects with PSP-Richardson syndrome (PSP-RS). In addition, we assume that the lesion load measured by PET-tau will correlate with the anatomical and functional changes observed using morphological MRI, diffusion imaging and functional MRI.
We will explore the patterns and compare the distribution of tau depositions in patients with the probable form of PSP-RS and PSP-P and PD using PET-tau imaging, with the PET-tau 18F-AV-1451 tracer. In PSP-RS patients, we expect to observe specific patterns of 18F-AV-1451 uptake that would correspond to those found in the basal ganglia and the midbrain in neuropathological studies. In PSP-P patients, we expect to find a profile with a more focal uptake at the level of the basal ganglia.
We will investigate if this new PET tracer can differentiate between PSP-RS, PSP-P, PD and HCs. We expect that the fixation patterns of patients with PSP (RS and P) will differ from those of PD, which is a synucleinopathy and not tauopathy although some off-binding may be present.
We will determine whether PET-tau can improve the early diagnosis of PSP variants, differentiating them from PD. We will analyze the radioligand profile in patients with an uncertain diagnosis at early stage but with confirmation at follow-up, compared to those of the previously established groups to determine if their binding profile corresponds to that of PSP-P with positive binding or PD where no tauopathy is expected.
We will study by MRI the morphological, microstructural and functional modifications associated with Tau binding, since the link between PET-tau deposits and the underlying neural changes is poorly known. Using simultaneous PET and MRI acquisitions, we expect to find a relationship between the PET-tau depositions and the morphological, structural and functional connectivity changes in both PSP-RS and PSP-P.
Finally, we will analyze in PSP the relationship between the PET-MRI multimodal changes and clinical scores. We will look for a relationship between PET-tau binding, MRI changes and disease severity. We will include 100 subjects including 15 PSP-RS, 15 PSP-P, 15 PD, and 15 HC as well as 40 subjects with uncertain diagnosis between PSP-P and PD recruited in the movement disorders clinic of the Salpetriere hospital. Patients with uncertain diagnosis at baseline will have a clinical follow-up at 2 years to confirm the diagnosis.
Acquisitions will be performed using a 3T PET-MRI system. The topographic distribution and intensity of tau lesion load, the morphological, diffusion and functional MRI changes will be analyzed.
We expect to demonstrate the interest of PET-tau for the differential diagnosis of PSP variants and improve the early diagnosis of the PSP-P. Better knowledge of both the topographic distribution of lesions, but also of the correspondence between these lesions and the cerebral consequences may be useful to optimize therapeutic developments specific to this disease, in particular in the case of PSP-P patients who have a longer survival time than PSP-RS and could be good candidates for neuroprotective treatments. Having a pathophysiological biomarker of PSP relevant to atypical forms of the disease will allow more efficient selection of patients to be included in therapeutic trials.

Project coordination

Nadya Pyatigorskaya (INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE)

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

ICM INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE

Help of the ANR 390,402 euros
Beginning and duration of the scientific project: May 2021 - 48 Months

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