Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis

Objective: To provide a detailed profile of the peripheral IGF system in the neurological conditions; amyotrophic lateral sclerosis (ALS), post polio syndrome (PPS) and multiple sclerosis (MS). To determine whether subsets of patients within the disease groups could be identified in whom one or more components of the IGF regulatory system are altered compared to healthy control subjects matched for age, sex and BMI. Design: Three cohorts of patients were recruited, 28 with ALS, 18 with PPS and 23 with MS. Patients were individually matched to a healthy control based on sex, age (±3yr), and BMI (±2.5 kg·m^-2). The concentration (ng/ml) of serum IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and acid-labile subunit (μg/ml) was determined by IRMA. Results: In ALS patients, there was an increase of 11% in [IGF_TOTAL] (p = 0.042) ([IGF_TOTAL] = [IGF-I] + [IGF-II]) and [IGFBP-1] was decreased by 34% (p = 0.050) compared to matched controls. In "surviving" ALS patients, defined as those ALS patients with long disease duration (+2 SD from the mean survival time for Irish patients post diagnosis), there was an increase in [IGF-I] 36% (p = 0.032) and a large decrease in [IGFBP-1] -58% (p = 0.020) compared to controls. These differences were not evident in pre-agonal ALS patients. The concentration of serum IGF-I was 38% (p = 0.018), acid-labile subunit 17% (p = 0.044) and IGFBP-2 43% (p = 0.035) higher in MS patients compared to controls. When stratified for interferon-beta (IFN-β) use, we observed an increase in serum [IGF-I] 52% (p = 0.013) and [IGF_TOTAL] 19% (p = 0.043) in MS patients undergoing IFN-β treatment, but MS patients not undergoing IFN-β treatment had similar IGF and IGFBP concentration to controls. Serum [IGFBP-3] 18% (p = 0.033), [IGFBP-2] 86% (p = 0.015) and (acid-labile subunit) 33% (p = 0.012) was also higher in IFN-β patients compared to controls. Stratified by stage of disease the most significant increase in components of the peripheral IGF system was attributed to relapsing-remitting MS patients treated with IFN-β. All components of the peripheral IGF system in PPS patients were similar to controls. Conclusions: The increase in circulating IGF-I and a reduction in regulatory binding protein IGFBP-1 in ALS patients with a "stable" disease profile suggest a potential change in peripheral IGF bioavailability in these subjects. In MS, we report a change in a number of components of the peripheral IGF system, the observed increase in IGF-I in patients treated with IFN-β being of most significance as a potential therapeutic biomarker.