Blood Neurofilament Light Chain Levels May Be Myelopathy Biomarker in ALD

Blood Neurofilament Light Chain Levels May Be Myelopathy Biomarker in ALD
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Elevated blood levels of a nerve cell-derived component known as neurofilament light chain (NfL) could be a potential biomarker for myelopathy — spinal cord degeneration — in patients with adrenoleukodystrophy (ALD), a study suggests.

The study, “Plasma NfL and GFAP as biomarkers of spinal cord degeneration in adrenoleukodystrophy,” was published in the journal Annals of Clinical and Translational Neurology.

All men with ALD, and about 80% of women with the genetic brain disorder, develop progressive myelopathy, which is characterized by the degeneration of the nerves running from the brain through the spinal cord.

Current treatments for myelopathy in ALD only relieve symptoms, but disease-modifying therapies are being developed. Yet, tools like molecular biomarkers of disease progression and of the therapies’ efficacy are missing.

Now, researchers at Amsterdam University Medical Centers, in the Netherlands, investigated the potential of two proteins — neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) — as biomarkers for myelopathy in ALD.

Both proteins are found in the cell body of nerve cells and astrocytes, which are cells that provide nutrients to neurons, repair nervous tissue following injury, and facilitate communication between nerve cells.

Upon damage to the cells and astrocytes, these proteins are released into the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord.

NfL and GFAP levels have been found to correlate with nerve tissue damage in other neurodegenerative diseases, like multiple sclerosis.

In total, the researchers analyzed 185 samples. These included 105 blood samples from 45 men with ALD, who had a mean age of 44. Of these samples, 45 were collected at the study’s start, and the other 60 after follow-up. Another 47 blood samples were collected, all at the start of the study, from 47 women with ALD, with a mean age of 54. Additionally, the researchers included 33 CSF samples from male patients, of which 20 were collected at baseline and 13 after follow-up.

The follow-up samples from 39 male patients were collected after one year, while those from 18 patients were taken after two years.

As controls, samples were included from 36 healthy men, with a mean age of 45.9 years, and 38 healthy women, whose mean age was 42.3 years. Men with ALD had a very similar age to the male control group. However, the female ALD patients were significantly older — mean 6.3 years older — than the women in the control group.

The researchers observed that age was a significant predictor of neurofilament light chain levels in both women and men.

After adjusting for age, the analysis showed that NfL and GFAP levels were significantly higher in men with ALD compared with male controls. A similar result was found between ALD women and female controls.

When researchers divided ALD patients as asymptomatic or symptomatic — those with signs and symptoms of myelopathy — they observed that both patient groups had significantly higher concentrations of NfL and GFAP compared with controls, with no significant differences between the two patient groups.

Specifically in men, the levels of NfL in the healthy controls were a mean of 6.2 picograms (pg)/mL compared with 8.9 pg/mL in asymptomatic patients and 13.4 pg/mL in those symptomatic. In women, healthy controls had a mean level of 6.5 pg/mL versus 8.9 pg/mL in asymptomatic and 14.2 pg/mL in symptomatic patients.

Regarding GFAP levels, its mean levels in men were 70.1 pg/mL in controls versus 76.5 in asymptomatic people and 99.4 pg/mL in those symptomatic. In women, while controls had mean levels of 71.9 pg/mL, asymptotic females had levels of 109.6 and symptomatic of 148.6.
Next, the researchers assessed how myelopathy severity parameters associated with NfL and GFAP levels.The severity of myelopathy was assessed using mainly three parameters: expanded disability status scale (EDSS) — the most widely accepted clinical disability scale — the severity scoring system for progressive myelopathy (SSPROM), and the timed up-and-go.EDSS scores range from zero (no disability) to 10 (death). Meanwhile, SSPROM measures the severity of myelopathy ranging from zero to 100, where lower scores indicate a higher degree of impairment. The timed up-and-go is a test used to evaluate walking function by recording the time that the patient takes to get up from an armchair, walk 3 meters, turn around, walk back, and sit again.

The results showed that the three parameters of disease severity and age significantly predicted the blood NfL levels in men with ALD. However, no correlation was found for GFAP.

In women with ALD, age strongly predicted NfL and GFAP levels, but none of the three disease severity parameters were able to predict the biomarkers levels.

Similarly to the levels detected in blood samples, the NfL levels in the CSF were higher in patients compared with controls. Moreover, a strong correlation was found between the levels of NfL in the blood and CSF.

The follow-up analysis demonstrated that EDSS, but not SSPROM and time up-and-go, increased slightly with time. No changes were seen for NfL or GFAP levels.

Overall, these findings indicated that NfL levels could have a greater potential to identify myelopathy in ALD. Moreover, since NfL is a marker of disease activity, it could be useful to assess the effects of “disease modifying treatment on a short term,” researchers wrote.

“Our study illustrates the potential of NfL as a biomarker of spinal cord degeneration in male ALD patients, while plasma GFAP seems less valuable,” they added.

“A longitudinal study demonstrating that elevated NfL levels lead to progression of myelopathy is needed to confirm our findings and is currently ongoing in this cohort,” the team concluded.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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