Larger intracranial volume affords reserve against disability in relapsing-remitting multiple sclerosis: Implications for clinical trial research (P6.130)

OBJECTIVE: We investigated maximal lifetime brain growth (MLBG, estimated with intracranial volume, ICV) as a marker of disability risk in patients with relapsing-remitting multiple sclerosis (RRMS). BACKGROUND: Disability varies widely across patients with RRMS, and it is difficult to identify which patients are at greatest risk for disability. This is an obstacle for early intervention research (including clinical trials) and clinical treatment planning. DESIGN/METHODS: Disability was evaluated in a cross-sectional sample of 235 RRMS patients with the Expanded Disability Status Scale (EDSS), Functional System Scores (FSS), Multiple Sclerosis Functional Composite (MSFC; 25-Foot-Walk, Nine-Hole-Peg-Test, PASAT, SDMT), and Finger-Tapping-Test. MRI measured MLBG (ICV, adjusted for sex), cerebral atrophy (normalized gray, white, deep gray, total brain volumes), T2 lesion volume. Regressions predicted disability outcomes: stepwise entry of demographics and disease burden (block one); MLBG (block two). We also investigated whether MLBG moderates disability progression (EDSS) over 4.5 years in an independent prospective sample of 22 RRMS patients. RESULTS: Larger MLBG independently predicted less disability on the EDSS (p=.007) and MSFC (p=.041), with specific links to better pyramidal (FSS-p, Nine-Hole-Peg-Test, Finger-Tapping-Test; Ps=.001 to .047) and cerebellar (FSS-c, 25-Foot-Walk; Ps=.013 to .029) functions, as well as cognitive status (PASAT, SDMT, Ps=.001 to .006). Larger MLBG attenuated disability progression within the prospective RRMS sample (p=.008). CONCLUSIONS: Larger MLBG provides reserve against physical and cognitive disability in RRMS. Consideration of MLBG (easily estimated with ICV) may help identify RRMS patients at greatest risk of disability (those with smaller MLBG), which is a critical step toward a science and clinical practice of early intervention / preventative medicine (including clinical trial research). This is also the first extension of the reserve hypothesis to physical disability. Study Supported by: Partial support provided by grants from the Ministry of Science, Republic of Serbia (175031) and the NIH (HD060765 to JFS).