#ACTRIMS2019 – Leukocyte Telomere Length Shortening is Predictive of Disability Progression in MS, Study Shows

As the protective molecular caps of our genetic information — called telomeres — become shorter in certain immune cells, the extent of multiple sclerosis (MS) disability progression increases, regardless of age, researchers at the University of California, San Francisco (UCSF) reported.

The findings were presented at the annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019, in Dallas, Texas, on Feb. 28.

The presentation, given by Kristen Krysko, MD, from UCSF, was titled “Leukocyte Telomere Length Is Associated with Disability Progression in Multiple Sclerosis Independent of Chronological Age.” The study suggested that preserving telomere length can be a therapeutic or preventative strategy for MS.

Factors contributing to MS disease progression are not fully understood. Although older chronological age is a factor known to be associated with a faster time for a patient to reach certain disability milestones.

This suggests that aging-related mechanisms in cells, and damage to those that protect cells from aging, may contribute to the neurodegeneration underlying MS progression.

A process associated with aging is the shortening of the telomeres that protect the ends of chromosomes — long strings of DNA that contain genetic information. Telomeres shorten every time cells grow and divide, a naturally occurring biological aging process.

However, telomere shortening can be sped up by DNA-damaging factors, such as UV-rays. Also, several diseases have been linked to excessive telomere shortening, such as heart disease, dementia, autoimmune diseases, and also primary progressive MS.

Interestingly, the telomere length in leukocytes — immune cells involved in counteracting foreign substances and disease— has been linked with MS disease progression. However, how chronological aging, biological aging (as measured by leukocyte telomere length), and MS progression are associated is not known.

Researchers at UCSF dove into this question. They examined the possible links between leukocyte telomere length, chronological age, and disease duration with brain volume and clinical disability in MS patients.

To do so, researchers took advantage of UCSF’s EPIC cohort study — an intensive observational study of more than 500 MS patients who have been carefully followed since 2004 to gain a greater understanding of MS susceptibility and long-term progression.

In total, data from 356 women and 160 men were analyzed. Their average age at the start of the study was 43 years, a median disease duration of six years, and a median Expanded Disability Status Scale (EDSS) of 1.5 (range 0-7; the higher the EDSS score, the worse the patient’s disability).

To measure leukocyte telomere length, researchers analyzed patients’ DNA samples. Telomeres are made of repeated bits of DNA, and comparing these repeats to other bits of known unrepeated DNA gives an approximation of telomere length.

At the start of the study, researchers found that shorter leukocyte telomere lengths were strongly associated with a greater chronological age and longer disease duration. In addition, they saw that total brain volume decreased with a shortening of telomere length, independently of chronological age — meaning that patients whose telomeres were shorter, had more advanced disease regardless of how old they were.

When patients were followed over time, results showed that those with shorter leukocyte telomere lengths at the start of the trial had increased EDSS scores and lower brain volumes, over time, indicating accelerated disease progression.

The team also analyzed a subset of 23 patients who developed secondary progressive MS (SPMS) during the follow-up period. These patients were matched on age, sex, and disease duration to participants who remained with relapsing MS.

Results showed that, in these 23 matched pairs, a change in leukocyte telomere length was predictive of a change in disability (EDSS score) over 10 years — as leukocyte telomere length decreased, EDSS increased.

“Shorter telomere length was associated with disability in both cross-sectional and longitudinal analyses after adjustment for chronological age, suggesting biological aging may contribute to neurological injury in MS,” the researchers wrote.

Thus, “targeting aging-related processes may be a potential therapeutic strategy,” Krysko suggested.