Brain-specific proteins in multiple sclerosis
Brain–specific proteins (BSP) are each relatively specific for particular cell–types within the nervous system. The BSP studied were glial fibrillary acidic protein (GFAP) and S100B for the astrocyte, ferritin for microglia and neurofilaments (Nf) for the axon. BSP are released into the extracellular fluid (ECF) following cellular destruction and during phases of high cellular activity such as astrocytic or microglial activation. ECF BSP equilibrate with those in the cerebrospinal fluid (CSF). This allows us to quantify BSP from the CSF and estimate the overall average of axonal damage (CSF Nf), astrocytic and microglia activation (respectively CSF S100B, CSF ferritin) and astrogliosis (CSF GFAP). New enzyme linked immunoabsorbant assays (ELISA) have been developed for measuring Nf and GFAP in the CSF. Previously established ELISAs have been used to measure S100B and ferritin. It has been shown that spinal cord atrophy in a mouse model of autoimmune encephalomyelitis (EAE) was paralleled by a decrease of Nf indicating loss of axons, and an increase in GFAP indicating astrogliosis. These findings have been confirmed and extended in a human post–mortem study where BSP levels were quantified in multiple sclerosis (MS) lesions of different age and activity. S100B and Nf were associated with acute lesions, ferritin was elevated in all lesion types, while GFAP was increased in both acute and chronic lesions. CSF BSP levels were then quantified in a cross–sectional study of MS patients with the aim of distinguishing clinical subgroups, such as relapsing remitting (RR), primary progressive (PP) and secondary progressive (SP) disease. In addition an attempt was made to relate CSF BSP levels to grades of disability using clinical scales including Kurtzke’s EDSS, an ambulation index (AI) and the 9–hole PEG test (9HPT). It was shown that CSF S100B was higher in RR MS while CSF ferritin was elevated in PP MS patients. The S100B:ferritin ratio emphasised the distinction between the MS subtypes. CSF GFAP was higher in poorly ambulating (AI) and severely disabled (EDSS) patients. CSF GFAP correlated with the EDSS in SP MS patients. This suggests that gliosis is an important feature in SP MS. CSF Nf levels were quantified in a longitudinal study at baseline and at 3–year follow–up. It was shown that more SP/PP than RR MS patients experienced an increase in CSF Nf levels over this time, suggesting cumulative axonal damage in this subgroup. RR MS patients who had elevated CSF Nf levels at baseline had a worse clinical course, suggesting that initial high CSF Nf levels in RR MS patients are a poor prognostic sign. CSF Nf levels at follow–up correlated with the EDSS, AI and 9HPT suggesting that axonal pathology in MS is a dynamic process possibly balancing features of de- and regenerative activities.