Leuk ukocy cyte telomere leng ngth h is associ ciated d with h di disabi bility pr progression n in n mul ultipl ple scl clerosis inde ndepe pende ndent of chr chrono nological age Kristen Krysko, MD Neuroimmunology Clinical Research Fellow University of California, San Francisco Kristen M. Krysko, Roland G. Henry, Bruce Cree, Jue Lin, UCSF MS-EPIC Team, Stacy Caillier, Adam Santaniello, Chao Zhao, Refujia Gomez, Carolyn Bevan, Dana Smith, William Stern, Gina Kirkish, Stephen L. Hauser, Jorge R. Oksenberg, Jennifer S. Graves
Disclosur ures es This study was funded by the National Multiple Sclerosis Society (NMSS RG-1607-25103 PI J Graves). I am supported by a Sylvia Lawry award from the National Multiple Sclerosis Society and a Biogen MS fellowship grant. Dr. Graves has received recent grant and clinical trial support from the National MS Society, Race to Erase MS, UCSF CTSI RAP program, Biogen, and Genentech. She has received honoraria from Biogen, Novartis and Genzyme for education events.
Ba Backgrou ound: Ag Aging and MS MS prog ogression on • Factors leading to progression in MS are not fully understood • Older chronological age associated with faster time to disability milestones (Confavreux & Vukusic 2006; Freilich et al. 2017; Tutuncu et al. 2013; Scalfari et al. 2011) • Biological aging may contribute to neurodegeneration in MS • Decline in remyelination capacity (Chari et al. 2003; Sim et al 2002) • Altered immunologic response with age (Rawji et al 2016; Shaw et al 2013)
Ba Backgrou ound: Telome omeres • Telomeres contain proteins and nucleotide repeats at the ends of chromosomes that shorten with each cell division • Telomere shortening accelerated by oxidative stress and DNA damage (Blackburn, Epel, Lin 2015) • Shortened telomeres seen in: • Cardiovascular disease (Haycock et al 2014) • Dementia (Forero et al 2016) • Autoimmune disease (lupus, rheumatoid arthritis) (Georgin-Lavialle et al 2010) • Primary progressive multiple sclerosis (Guan J-Z et al 2015)
Ob Objective • To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume in MS independent of chronological age and disease duration Cumulative cell division over lifetime Telomerase activity Biological Aging: DNA Damage MS disability Telomere shortening Decreased repair Response accumulation Immune changes Environmental stress Genetic factors
Me Method ods: D : Design • Cohort study of adults with MS or CIS in the EPIC study at UCSF to evaluate cross-sectional and longitudinal associations • 516 of 517 in the original cohort were included (DNA available at baseline) • Nested case-control study to evaluate association of change in LTL with disability and MRI metrics longitudinally • 23 converting to SPMS during follow-up with DNA available • Matched 1:1 on baseline age, sex, disease duration, EDSS to those who remained with relapsing MS
Me Method ods: Me : Measures Leukocyte telomere Yearly: length (LTL) – T/S ratio - EDSS (primary outcome) - MSFC - MRI brain volumes Baseline Subset of 46 with LTL LTL LTL LTL measured at multiple timepoints
Me Method ods: St : Statistical An Analyses 1) Cross-sectional analysis of baseline data for association of LTL with EDSS and secondary outcomes (n=516) • Linear regression models 2) Analysis of 23 matched pairs • Mixed models to assess association of change in LTL with change in outcomes 3) Longitudinal analysis of entire cohort using baseline LTL as a predictor (n=516) • Mixed models with interaction term between LTL and visit
Ba Baseline Ch Characteri ristics (n=516) 516) Characteristic Cohort (n=516) Age, mean years (SD) 42.6 (9.8) Female sex, n (%) 354 (68.6) Disease duration, median years (range) 6 (0-45) Smoking status, n (%) Current 64 (12.4) Former 157 (30.5) Never 295 (57.2) MS subtype, n (%) RRMS 367 (71.1) CIS 80 (15.5) SPMS 47 (9.1) PPMS 17 (3.3) PRMS 4 (0.8) Unclear 1 (0.2) Leukocyte telomere length, mean T/S ratio (SD) 0.97 (0.18) EDSS, median (range) 1.5 (0.0-7.0)
An Analyses 1) Cross-sectional analysis of baseline data for association of LTL with EDSS and secondary outcomes (n=516) • Linear regression models 2) Analysis of 23 matched pairs • Mixed models to assess association of change in LTL with change in outcomes 3) Longitudinal analysis of entire cohort using baseline LTL as a predictor (n=516) • Mixed models with interaction term between LTL and visit
Ba Baseline Cr Cros oss-se sectional Analysi sis s (n (n=5 =516) Unadjusted Adjusted c Outcome a b b b b 95% CI p-value 95% CI p-value Disability score (EDSS) 0.41 0.27 to 0.56 <0.001 0.27 0.13 to 0.42 <0.001 MSFC z-score -0.09 -0.16 to -0.03 0.006 -0.05 -0.12 to 0.02 0.13 Total brain volume, mm 3 -22.3 -30.6 to -14.0 <0.001 -7.4 -14.7 to -0.10 0.047 Total WM volume, mm 3 -7.4 -11.5 to -3.3 <0.001 -4.0 -8.0 to -0.04 0.048 Total GM volume, mm 3 -14.7 -20.1 to -9.2 <0.001 -3.4 -7.8 to 1.0 0.13 Cortical GM volume, mm 3 -12.9 -17.5 to -8.3 <0.001 -3.1 -6.8 to 0.61 0.10 b linear regression coefficient; CI confidence interval; EDSS Expanded Disability Status Scale; MSFC multiple sclerosis functional composite; WM white matter; GM grey matter. a n=516 for EDSS, n=511 for MSFC and n=515 for all other outcomes. b Per 0.2 unit decrease in mean T/S ratio (leukocyte telomere length). c Adjusted for chronological age, sex, and disease duration.
An Analyses 1) Cross-sectional analysis of baseline data for association of LTL with EDSS and secondary outcomes (n=516) • Linear regression models 2) Analysis of 23 matched pairs • Mixed models to assess association of change in LTL with change in outcomes 3) Longitudinal analysis of entire cohort using baseline LTL as a predictor (n=516) • Mixed models with interaction term between LTL and visit
Lon Longitudinal A Analysis of of s subset of of 23 p 23 pairs with LTL TL measured over time (n=46) Unadjusted Adjusted c b b b b 95% CI p-value 95% CI p-value Outcome a Disability score (EDSS) 0.31 0.05 to 0.57 0.021 0.34 0.08 to 0.61 0.012 MSFC z-score 0.07 -0.03 to 0.17 0.15 0.08 -0.02 to 0.18 0.10 Total brain volume, mm 3 -9.1 -20.6 to 2.4 0.12 -6.2 -17.6 to 5.2 0.29 Total WM volume, mm 3 -3.4 -10.7 to 3.8 0.35 -2.4 -9.7 to 4.9 0.52 Total GM volume, mm 3 -4.4 -11.3 to 2.6 0.22 -2.7 -9.3 to 4.0 0.44 Cortical GM volume, mm 3 -0.55 -6.2 to 5.1 0.85 0.13 -5.4 to 5.7 0.96 b linear regression coefficient; CI confidence interval; EDSS Expanded Disability Status Scale; MSFC multiple sclerosis functional composite; WM white matter; GM grey matter. a n=46 b Per 0.2 unit decrease in mean T/S ratio (leukocyte telomere length). c Adjusted for baseline chronological age, sex, and disease duration.
An Analyses 1) Cross-sectional analysis of baseline data for association of LTL with EDSS and secondary outcomes (n=516) • Linear regression models 2) Analysis of 23 matched pairs • Mixed models to assess association of change in LTL with change in outcomes 3) Longitudinal analysis of entire cohort using baseline LTL as a predictor (n=516) • Mixed models with interaction term between LTL and visit
Predicted EDSS over time by baseline LTL TL (n=516) Baseline difference in EDSS by LTL p=0.001 LTL by year interaction p=0.09 Shaded areas represent 95% CI.
Su Summa mmary of of f findings • In cross-sectional study of >500 MS patients, LTL is associated with EDSS and total brain volume • Longitudinal changes in LTL are associated with changes in EDSS over time
St Strengths a and Li Limi mitation ons • Novel investigation of the ultimate biological clock on disability progression • Large cohort of well characterized patients • Cross-sectional and longitudinal analyses using robust statistical models • DNA availability limited ability to measure LTL in all individuals over time • Low power to detect associations in the subset of 46 individuals
Con Conclusion ons • Our marker of biological aging was associated with MS disability • Aging-related processes may contribute to MS progression • Oxidative stress, decline in remyelination capacity, altered immune function • Co-morbidities and lifestyle factors may contribute • Targeting aging-related processes may be a therapeutic strategy
Ac Acknowledgements UCSD/UCSF UCSF Neurology UCSF Thesis Committee Jennifer S Graves Jorge Oksenberg Emmanuelle Waubant Stephen L Hauser Ann Lazar Roland G Henry Charles McCulloch Blackburn Lab Bruce Cree Kristine Yaffe Elizabeth Blackburn Stacy Caillier Jue Lin Adam Santaniello Dana Smith Chao Zhao Refujia Gomez Carolyn Bevan William Stern Gina Kirkish UCSF EPIC Team Funded by National Multiple Sclerosis Society (NMSS RG-1607-25103 PI J Graves. Fellowship funded by the NMSS (FP-1605-08753 (Krysko)).
Th Thank you
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