Predict to Prevent PGRN Disease

Overview

Progranulin (GRN or PGRN) mutations are among the most common genetic causes of frontotemporal lobar degeneration (FTLD). With the advent of gene-specific therapeutic interventions, an accurate knowledge of the presymptomatic phase of the disease is of utmost importance. Increases of plasma neurofilament light chain (NfL) levels are good predictors of phenoconversion in presymptomatic carriers. However their increase rates remain partially elucidated insofar, with many confounding factors. Another point which deserves further precision is the definition of the biological onset of the disease, via the identification of markers of intraneuronal accumulation of TDP-43 protein. PREVENT-PGRN aims aims at studying the trajectory of plasma NfL changes in presymptomatic GRN mutation carriers in comparison with healthy controls, in partnership with the GENFI-QBS study. Additionally, other disease-related biomarkers, namely associated with TDP-43 pathology, will be investigated in this study, at the presymptomatic and clinical phase.

Despite several advances in the understanding of the presymptomatic phase of GRN-associated FTLD, some aspects concerning longitudinal biomarker changes and their capacity to predict phenoconversion have been only partially elucidated. Plasma NfL levels proved to be good tools for monitoring neurodegeneration in the years preceding phenoconversion, but thresholds for cross-sectional values and longitudinal increase rates need to be validated in international studies on large populations. In addition, numerous confounding factors (head trauma, epilepsy, metabolic disorders, etc.) may punctually impact plasma NfL dosages. This may suggest that several measurements spaced over time are best predictors of phenoconversion rather than a single assay. Whether cross-sectional NfL levels or their rate of change during follow-up are the best parameter for individual monitoring in the presymptomatic and clinical phases still has to be determined. This knowledge is an essential prerequisite for all current and future therapeutic trials designed for GRN carriers at the presymptomatic phase. To answer this question, this project aims to define the trajectory of plasma NfL levels as exactly as possible in carriers of GRN gene mutations during the presymptomatic and clinical phase. NfL dosages will be performed every 3 months over a 2-year period and carriers' trajectories will be compared with those measured in age-matched control individuals. This study takes place in the frame of the international collaborative project GENFI-QBS substudy (quarterly blood sampling), aiming at characterizing the evolution of plasma biomarkers in genetic FTLD by repeated assays every 3 months. Plasma samples will also allow complementary biomarker analyses, providing a broader biomarker panel to better elucidate the pathophysiological mechanisms of the disease. Notably, the validation of in vivo TDP-43 biomarkers and the tracking of the longitudinal progression of the proteinopathy represent other major challenges. Indeed, the advent of such a biomarker in asymptomatic GRN carriers would allow to establish the start of the lesional process (i.e., TDP-43 accumulation) and thus the appropriate moment to start preventive treatments. Therefore, this study will enrol 90 participants, including 10 patients with early-stage FTD (or other clinically defined syndromes within FTLD spectrum) carrying pathogenic GRN mutations and 80 asymptomatic at-risk individuals (i.e., first-degree relatives of individuals carrying a GRN mutation. These latter will thus be either presymptomatic GRN carriers (\~50% risk) or controls. The determination of the genetic status of asymptomatic participants will be done in research setting, and results will be blinded to participants and investigators. A part of study participants will be selected from Predict-PGRN (NCT04014673), a natural history study aiming at characterizing the presymptomatic phase of PGRN disease over 5-year follow-up. A comprehensive evaluation including neurological examination, cognitive and behavioral assessment, brain MRI, biological blood sampling and olfactory swab sampling will be performed at inclusion, at 12 months and at 24 months. Neuropsychological, behavioral and MRI data will allow to compare additional cognitive-behavioral and neuroimaging markers between carriers and non-carriers, providing further information on the clinical progression and the risk of phenoconversion of the former. As optional assays, upon participants' specific consent, CSF sampling and skin biopsy will be proposed at the same time-points, in order to provide additional substrates to look for biomarkers of TDP-43 accumulation, together with plasma and olfactory mucosa samples. Intermediate visits will be made every 3 months (at month 3, 6, 9, 15, 18 and 21), only for quick clinical follow-up and blood sampling. The purpose of these visits is to enable close monitoring of blood biomarkers, namely NfL, but also to document the occurrence of intercurrent events and to monitor participants' clinical status.