Contributions
Abstract: P749
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Introduction: Magnetization transfer ratio (MTR) and brain volumetric imaging are (semi-)quantitative MRI markers capturing demyelination (especially MTR), axonal degeneration and/or inflammation. Neuroprotective therapies represent an unmet clinical need while the genetic markers shaping variation in these MRI traits are largely unknown.
Aim: We explore whether variation in MTR and brain volumetric indices over time is primarily influenced by pre-existing inter-patient differences or by the ongoing disease process. Next, we evaluate how genetics can explain inter-patient differences in MRI traits.
Methods: We collected a longitudinal cohort of 33 multiple sclerosis (MS) patients and extended it cross-sectionally to 213 individuals. We measured MTR histogram measures (median, peak height) in lesions, normal appearing white matter (NAWM) and grey matter (NAGM) and total brain, grey matter, white matter and lesion volume. We performed a genome-wide association study (GWAS) with the individual MRI traits. Through implementation of a reverse regression approach, we additionally looked at genetic associations with MTR across multiple tissue classes.
Results: Longitudinally, differences in MRI measures at inclusion and changes occurring during follow-up explained at least 70% of variance (P ≤ 1.85 x 10-7). Inter-patient differences were the main determinant (≥ 99%). Age and gender explained much less (about 30%) of variation in total brain and grey matter volume. Age did only influence peak height MTR. Cross-sectionally, we observed a high correlation of median and peak height MTR across lesions, NAGM and NAWM implying a shared pathway. The genetic risk score of all known variants affecting MS susceptibility was not convincingly associated with MTR (P ≥ 0.02) or volumetric indices (P ≥ 0.23). Conversely, we identified two independent novel associations (P = 8.87 x 10-6 & P = 2.17 x 10-5) on chr8p23 near FDFT1 and CTSB with susceptibility to demyelination across three tissues (lower peak height MTR in NAWM, NAGM and lesions).
Conclusion: Our data suggest that MTR and volumetric traits reflect individual variation in biological processes rather than being proxies for disease activity or duration. Our GWAS points to a role for genetic variation near FDFT1 and CTSB, involved in cholesterol biosynthesis and/or the local inflammatory response, in de- and remyelination. These findings translate evidence from demyelination observed in animal models to humans.
Disclosure: BD has received consulting fees and/or funding from Bayer, Biogen Idec, Merck, Sanofi, Novartis and TEVA Pharma Nederland. AG has received funding from Novartis and Roche. IS, MM, MV, KH, VL, JD, KM, SS, PD and PVD have nothing to disclose.
Abstract: P749
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Introduction: Magnetization transfer ratio (MTR) and brain volumetric imaging are (semi-)quantitative MRI markers capturing demyelination (especially MTR), axonal degeneration and/or inflammation. Neuroprotective therapies represent an unmet clinical need while the genetic markers shaping variation in these MRI traits are largely unknown.
Aim: We explore whether variation in MTR and brain volumetric indices over time is primarily influenced by pre-existing inter-patient differences or by the ongoing disease process. Next, we evaluate how genetics can explain inter-patient differences in MRI traits.
Methods: We collected a longitudinal cohort of 33 multiple sclerosis (MS) patients and extended it cross-sectionally to 213 individuals. We measured MTR histogram measures (median, peak height) in lesions, normal appearing white matter (NAWM) and grey matter (NAGM) and total brain, grey matter, white matter and lesion volume. We performed a genome-wide association study (GWAS) with the individual MRI traits. Through implementation of a reverse regression approach, we additionally looked at genetic associations with MTR across multiple tissue classes.
Results: Longitudinally, differences in MRI measures at inclusion and changes occurring during follow-up explained at least 70% of variance (P ≤ 1.85 x 10-7). Inter-patient differences were the main determinant (≥ 99%). Age and gender explained much less (about 30%) of variation in total brain and grey matter volume. Age did only influence peak height MTR. Cross-sectionally, we observed a high correlation of median and peak height MTR across lesions, NAGM and NAWM implying a shared pathway. The genetic risk score of all known variants affecting MS susceptibility was not convincingly associated with MTR (P ≥ 0.02) or volumetric indices (P ≥ 0.23). Conversely, we identified two independent novel associations (P = 8.87 x 10-6 & P = 2.17 x 10-5) on chr8p23 near FDFT1 and CTSB with susceptibility to demyelination across three tissues (lower peak height MTR in NAWM, NAGM and lesions).
Conclusion: Our data suggest that MTR and volumetric traits reflect individual variation in biological processes rather than being proxies for disease activity or duration. Our GWAS points to a role for genetic variation near FDFT1 and CTSB, involved in cholesterol biosynthesis and/or the local inflammatory response, in de- and remyelination. These findings translate evidence from demyelination observed in animal models to humans.
Disclosure: BD has received consulting fees and/or funding from Bayer, Biogen Idec, Merck, Sanofi, Novartis and TEVA Pharma Nederland. AG has received funding from Novartis and Roche. IS, MM, MV, KH, VL, JD, KM, SS, PD and PVD have nothing to disclose.