We generated and tested 2 mutually nonexclusive hypotheses that may explain why sNFL correlates stronger with MS severity compared with cNFL: a) brain atrophy–associated MS progression leads to dilution of cNFL due to compensatory increase in CSF volume (Figure 4A) and b) spinal cord (SC) injury, associated with MS disability, such as injury to lower motor neurons or the autonomic nervous system, leads to release of NFL from axons of peripheral nerves into blood, bypassing the CSF (Figure 4D). Here, NEFL is linked to myeloid sarcoma.