Leuk ukocy cyte telomere leng ngth h is associ ciated d with h - - PowerPoint PPT Presentation

▶
leuk ukocy cyte telomere leng ngth h is associ ciated d
SMART_READER_LITE
LIVE PREVIEW

Leuk ukocy cyte telomere leng ngth h is associ ciated d with h - - PowerPoint PPT Presentation

Nov 16, 2022 257 likes •523 views

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

slide-1
SLIDE 1

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

slide-2
SLIDE 2

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.

slide-3
SLIDE 3

Ba Backgrou

  • und: Ag

Aging and MS MS prog

  • gression
  • n
  • 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)
slide-4
SLIDE 4

Ba Backgrou

  • und: Telome
  • meres
  • 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)
slide-5
SLIDE 5

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

Telomere shortening DNA Damage Response Biological Aging: Decreased repair Immune changes MS disability accumulation Telomerase activity Genetic factors Cumulative cell division

  • ver lifetime

Environmental stress

slide-6
SLIDE 6

Me Method

  • ds: 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

slide-7
SLIDE 7

Me Method

  • ds: Me

: Measures

Baseline

Leukocyte telomere length (LTL) – T/S ratio

Yearly:

  • EDSS (primary outcome)
  • MSFC
  • MRI brain volumes

Subset of 46 with LTL measured at multiple timepoints

LTL LTL LTL

slide-8
SLIDE 8

Me Method

  • ds: 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
slide-9
SLIDE 9

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 Former Never 64 (12.4) 157 (30.5) 295 (57.2) MS subtype, n (%) RRMS CIS SPMS PPMS PRMS Unclear 367 (71.1) 80 (15.5) 47 (9.1) 17 (3.3) 4 (0.8) 1 (0.2) Leukocyte telomere length, mean T/S ratio (SD) 0.97 (0.18) EDSS, median (range) 1.5 (0.0-7.0)

slide-10
SLIDE 10

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
slide-11
SLIDE 11

Ba Baseline Cr Cros

  • ss-se

sectional Analysi sis s (n (n=5 =516)

Outcomea Unadjusted Adjustedc bb 95% CI p-value bb 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, mm3

  • 22.3
  • 30.6 to -14.0

<0.001

  • 7.4
  • 14.7 to -0.10

0.047 Total WM volume, mm3

  • 7.4
  • 11.5 to -3.3

<0.001

  • 4.0
  • 8.0 to -0.04

0.048 Total GM volume, mm3

  • 14.7
  • 20.1 to -9.2

<0.001

  • 3.4
  • 7.8 to 1.0

0.13 Cortical GM volume, mm3 -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.

an=516 for EDSS, n=511 for MSFC and n=515 for all other outcomes. bPer 0.2 unit decrease in mean T/S ratio (leukocyte telomere length). cAdjusted for chronological age, sex, and disease duration.

slide-12
SLIDE 12

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
slide-13
SLIDE 13

Lon Longitudinal A Analysis of

  • f s

subset of

  • f 23 p

23 pairs with LTL TL measured over time (n=46)

b linear regression coefficient; CI confidence interval; EDSS Expanded Disability Status Scale; MSFC multiple sclerosis functional composite; WM white matter; GM grey matter.

an=46 bPer 0.2 unit decrease in mean T/S ratio (leukocyte telomere length). cAdjusted for baseline chronological age, sex, and disease duration.

Outcomea Unadjusted Adjustedc bb 95% CI p-value bb 95% CI p-value 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, mm3

  • 9.1
  • 20.6 to 2.4

0.12

  • 6.2
  • 17.6 to 5.2

0.29 Total WM volume, mm3

  • 3.4
  • 10.7 to 3.8

0.35

  • 2.4
  • 9.7 to 4.9

0.52 Total GM volume, mm3

  • 4.4
  • 11.3 to 2.6

0.22

  • 2.7
  • 9.3 to 4.0

0.44 Cortical GM volume, mm3

  • 0.55
  • 6.2 to 5.1

0.85 0.13

  • 5.4 to 5.7

0.96

slide-14
SLIDE 14

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
slide-15
SLIDE 15

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.

slide-16
SLIDE 16

Su Summa mmary of

  • f 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
  • ver time
slide-17
SLIDE 17

St Strengths a and Li Limi mitation

  • ns
  • 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
slide-18
SLIDE 18

Con Conclusion

  • ns
  • 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
slide-19
SLIDE 19

Ac Acknowledgements

Funded by National Multiple Sclerosis Society (NMSS RG-1607-25103 PI J Graves. Fellowship funded by the NMSS (FP-1605-08753 (Krysko)).

UCSD/UCSF Jennifer S Graves Blackburn Lab Elizabeth Blackburn Jue Lin Dana Smith UCSF Neurology Jorge Oksenberg Stephen L Hauser Roland G Henry Bruce Cree Stacy Caillier Adam Santaniello Chao Zhao Refujia Gomez Carolyn Bevan William Stern Gina Kirkish UCSF EPIC Team UCSF Thesis Committee Emmanuelle Waubant Ann Lazar Charles McCulloch Kristine Yaffe

slide-20
SLIDE 20

Th Thank you

slide-21
SLIDE 21

Re References

Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain J Neurol. 2006;129(Pt 3):595-605. Freilich J, Manouchehrinia A, Trusheim M, et al. Characterization of annual disease progression of multiple sclerosis patients: A population-based

  • study. Mult Scler Houndmills Basingstoke Engl. May 2017:1352458517706252.

Tutuncu M, Tang J, Zeid NA, et al. Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2013;19(2):188-198. Scalfari A, Neuhaus A, Daumer M, Ebers GC, Muraro PA. Age and disability accumulation in multiple sclerosis. Neurology. 2011;77(13):1246-1252. Chari DM, Crang AJ, Blakemore WF. Decline in rate of colonization of oligodendrocyte progenitor cell (OPC)-depleted tissue by adult OPCs with

  • age. J Neuropathol Exp Neurol. 2003;62(9):908-916.

Sim FJ, Zhao C, Penderis J, Franklin RJM. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both

  • ligodendrocyte progenitor recruitment and differentiation. J Neurosci Off J Soc Neurosci. 2002;22(7):2451-2459.

Rawji KS, Mishra MK, Michaels NJ, Rivest S, Stys PK, Yong VW. Immunosenescence of microglia and macrophages: impact on the ageing central nervous system. Brain. 2016;139(3):653-661. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol. 2013;13(12):875-887. Blackburn EH, Epel ES, Lin J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science. 2015;350(6265):1193-1198. Haycock PC, Heydon EE, Kaptoge S, Butterworth AS, Thompson A, Willeit P. Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ. 2014;349:g4227. Forero DA, González-Giraldo Y, López-Quintero C, Castro-Vega LJ, Barreto GE, Perry G. Meta-analysis of Telomere Length in Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci. 2016;71(8):1069-1073. Georgin-Lavialle S, Aouba A, Mouthon L, et al. The telomere/telomerase system in autoimmune and systemic immune-mediated diseases. Autoimmun Rev. 2010;9(10):646-651. Guan J-Z, Guan W-P, Maeda T, Guoqing X, GuangZhi W, Makino N. Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening. Mol Cell Biochem. 2015;400(1-2):183-187.

slide-22
SLIDE 22

Ex Extra sl slide des

slide-23
SLIDE 23

Leukocyte Telomere Length (LTL) Biological Age MS disability Chronological Age Sex Disease duration

Evaluated as potential confounders: Smoking, HLA-DRB1*15:01 status

slide-24
SLIDE 24

Lon Longitudinal A Analysis of

  • f e

entire c coh

  • hort
  • rt u

using baseline LTL TL as a predictor (n=516)

b linear regression coefficient at visit 1; CI confidence interval; EDSS Expanded Disability Status Scale; MSFC multiple sclerosis functional composite; WM white matter; GM grey matter.

an=516 for EDSS and brain volume metrics, n=514 for MSFC. bPer 0.2 unit decrease in mean T/S ratio (leukocyte telomere length). cAdjusted for baseline chronological age, sex, and disease duration.

Outcomea Unadjusted Adjustedc Interaction Interaction Disability score (EDSS) 0.41 0.27 to 0.56 <0.001 0.09 0.25 0.11 to 0.39 0.001 0.09 MSFC z-score

  • 0.09
  • 0.16 to -0.02

0.008 0.44

  • 0.05
  • 0.12 to 0.02

0.15 0.42 Total brain volume, mm3

  • 22.5
  • 31.1 to -14.0

<0.001 0.58

  • 10.5
  • 18.0 to -3.0

0.006 0.60 Total WM volume, mm3

  • 7.5
  • 11.8 to -3.2

0.001 0.71

  • 4.3
  • 8.4 to -0.14

0.043 0.71 Total GM volume, mm3

  • 14.8
  • 20.3 to -9.2

<0.001 0.19

  • 6.4
  • 11.0 to -1.9

0.006 0.21 Cortical GM volume, mm3

  • 12.9
  • 17.7 to -8.2

<0.001 0.02

  • 5.9
  • 9.8 to -2.1

0.003 0.02

slide-25
SLIDE 25

Predicted MRI brain volume over time by baseline LTL TL (n (n=5 =516)

Baseline difference in brain volume by LTL p=0.006 LTL by year interaction p=0.60