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Proposed ALS staging model (adapted from Benatar et al. 24 ) based on the dynamic of NF subunit and cryptic HDGFL2 accumulation in CSF of C9orf72 mutation carriers. While CSF NF levels rise during the prodromal phase and continue increasing during the first few years of symptomatic disease, CSF cryptic HDGFL2 may peak before symptom onset and decrease during symptomatic disease progression. Due to these temporal differences, we propose a staging scale whereby the ratio of CSF NfL:cryptic HDGFL2 or pNfH:cryptic HDGFL2 concentrations would be <1 during the presymptomatic stage of ALSFTD and increase to >1 during symptomatic disease.

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