Natural History Characterization in Symptomatic and Asymptomatic Progranuline Gene Mutation Carriers (Predict-PGRN)

The purpose of this study is to investigate whether cognitive deficits, structural and functional changes can be detected before symptom onset in presymptomatic progranuline mutation carriers. The main objectives of the project are to identify novel cognitive, brain imaging markers and peripheral biomarkers for early diagnosis of FTLD, and to follow disease progression.

The project focuses on the progranulin (PGRN) gene mutation, one of the most frequent genetic forms of frontotemporal dementias (FTD, or frontotemporal lobar degeneration, FTLD). FTD is the second commonest cause of degenerative dementia in presenium after Alzheimer's disease. Behavioral and cognitive impairments progressively lead to dementia. Two major pathological subtypes are now defined in FTD, FTD-TDP and FTD-TAU. FTD is difficult to detect at an early stage, and no clinical, biological or imaging features can predict the underlying pathology in living patients. Therapeutic perspectives have emerged against tau aggregation, PGRN deficit and C9orf72 expansion. Presymptomatic carriers of genetic FTD would benefit, before onset of symptoms, from these therapeutics that would delay or prevent the disease. At this step, it becomes crucial to develop markers to know how many years before symptoms, the pathological process begins, to treat the patients at the earliest stage of the disease. Markers are also needed to predict the pathology (FTD-TDP/FTD-tau) in patients that will be eligible for trials targeting specific pathological lesion. The main objectives of the project are to identify novel cognitive, brain imaging markers and peripheral biomarkers for early diagnosis of FTLD, and to follow disease progression. Ninety participants including 8 patients and 82 'at-risk' individuals will be recruited and evaluated by clinical partners of the project (Paris, Lille, Rouen, Toulouse, Saint-Etienne, Marseille, Nantes). 'At-risk individuals' are the first- degree relatives of PGRN patients, who have a high a risk (50%) to carry the mutation. Brain structural changes will be evaluated by voxel-based morphometry (SPM12 software) to assess global brain atrophy in one with the evaluation of atypical shape patterns such as cortical thickness (Freesurfer software) and the study of the cortical sulci (BrainVISA/Morphologist software). Fluoro Deoxy DGlucose-Positron Emission Tomography (FDG-PET) will allow the identification of brain metabolic markers. Then voxel-based methods using Statistical Parametric Mapping software will be applied to compare different groups or analyze correlations between brain metabolism and cognitive deficits. The identification of peripheral biomarkers of disease onset and disease progression will take advantage from RNA sequencing, in order to study gene expression and RNA splicing alterations in lymphocytes of patients and 'at risk individuals'.

Change in cerebral metabolism by PET (metabolic markers by Fluoro-DeoxyDGlucose-Positron Emission Tomography (FDG-PET))

Correlations between cognitive and behavioral scores, MRI morphological criteria, cerebral metabolism by FDG-PET and transcriptome analysis in presymptomatic subjects and in symptomatic patients at early disease stage

Voxel-based methods using Statistical Parametric Mapping software will be applied to compare different groups or analyze correlations between brain atrophy/metabolism and cognitive deficits.

Differences in transcriptome analysis between symptomatic patients, asymptomatic carriers and controls.

Inclusion Criteria: Inclusion criteria for symptomatic patients: Age ≥ 18 Signed informed consent for genetic and clinical study To be carrier of a PGRN mutation - Diagnosis criteria of FTD To be affiliated to the social security scheme Inclusion criteria for 'at-risk' asymptomatic relatives: Age ≥ 18 To be first degree relative of a person carrying a PGRN mutation or first degree relative of FTD deceased patient whose PGRN mutation as been identified in the family Signed informed consent for genetic and clinical study To be affiliated to the social security scheme Exclusion Criteria: Exclusion criteria for symptomatic patients: Presence of one exclusion criteria from Diagnosis criteria of FTD. - Participation to another therapeutic trial. - Contra-indication to perform a brain MRI and/or PET-FDG Inability to lie one hour without moving Breastfeeding and pregnant women Presence of another intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....) Exclusion criteria for 'at-risk' asymptomatic relatives : Presence of neurological or neurodegenerative disease Clinical proven signs of FTD, language disorder, praxis disorder, mnemic, of parkinson's syndrome or amyotrophic lateral sclerosis Contra-indication to perform a brain MRI and/or PET-FDG Inability to lie one hour without moving Breastfeeding and pregnant women Severe vascular lesion , tumor or infectious brain imaging if an MRI was done previously

Caroppo P, Habert MO, Durrleman S, Funkiewiez A, Perlbarg V, Hahn V, Bertin H, Gaubert M, Routier A, Hannequin D, Deramecourt V, Pasquier F, Rivaud-Pechoux S, Vercelletto M, Edouart G, Valabregue R, Lejeune P, Didic M, Corvol JC, Benali H, Lehericy S, Dubois B, Colliot O, Brice A, Le Ber I; Predict-PGRN study group. Lateral Temporal Lobe: An Early Imaging Marker of the Presymptomatic GRN Disease? J Alzheimers Dis. 2015;47(3):751-9. doi: 10.3233/JAD-150270.

Saracino D, Dorgham K, Camuzat A, Rinaldi D, Rametti-Lacroux A, Houot M, Clot F, Martin-Hardy P, Jornea L, Azuar C, Migliaccio R, Pasquier F, Couratier P, Auriacombe S, Sauvee M, Boutoleau-Bretonniere C, Pariente J, Didic M, Hannequin D, Wallon D; French Research Network on FTD/FTD-ALS; PREV-DEMALS and Predict-PGRN study groups; Colliot O, Dubois B, Brice A, Levy R, Forlani S, Le Ber I. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications. J Neurol Neurosurg Psychiatry. 2021 Dec;92(12):1278-1288. doi: 10.1136/jnnp-2021-326914. Epub 2021 Aug 4.