Clinical and neuroimaging profiles to identify C9orf72-FTD patients and serum Neurofilament to monitor the progression and the severity of the disease

Background: The C9orf72 pathogenetic GGGGCC hexanucleotide repeat expansion is one of the most common causes of Frontotemporal Dementia (FTD), and early identification of this mutation is crucial for clinical and prognostic outcome. Although promising preclinical studies tried to evaluate the efficacy of biomarkers to identify C9orf72 expansion carriers, they have not been adequately assessed in humans. Aim: To identify clinical, neuroimaging, and biological features that could be used to identify FTD subjects eligible to genetic testing. Methods: This is a retrospective, case-control study of clinical, neuropsycological, biological, and neuroimaging data of C9orf72 expansion carriers compared with non-mutated FTD patients. Neurofilament light chain was evaluated by Quanterix Simoa essay. Results: The study revealed a set of peculiar characteristics in patients with C9orf72 expansion, compared with not expanded, as: lower age at onset, higher number of familial form and affected relatives, higher FTD-MND symptoms, frequent behavioral and motor disorders at onset, higher incidence of dysphagia, lower mnesic deficits and higher rate of “Average” and “Rapid” progression of the disease. Neuroimaging data reveled that C9orf72 subgroup patients showed a higher hypometabolism of the frontal lobes involving both cortical and subcortical regions. Moreover, in symptomatic C9orf72 patients, NfL concentration was strongly elevated compared with presymptomatic carriers, increasing after 1 year of follow-up. Conclusion: The metabolic signature combined with the clinical features could be a helpful tool to direct the genetic counseling. We confirmed that serum NfL evaluation could be a valid biomarker to monitor the disease severity and progression.