Neuronal Protein Could Be a Blood Biomarker of MS

LONDON—Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis (RRMS) than in healthy subjects in a proof-of-concept study reported at the 32nd Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 and 12.5 pg/mL, respectively, and were also found to be higher in patients with RRMS with greater disease activity seen on MRI.

As the number of gadolinium-enhancing (Gd+) lesions increased, so did the blood concentration of NfL, which was 23.9 pg/mL in patients with no Gd+ lesions, 26.7 pg/mL in those with one Gd+ lesion, 33.4 pg/mL in those with two to three Gd+ lesions, and 55.9 pg/mL in those with more than three Gd+ lesions.

“These findings support a role for NfL as a peripheral biomarker for MS,” said Jens Kuhle, MD, of University Hospital Basel in Switzerland. “There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials.

“NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF, and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS.

Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity. In the current study, Dr. Kuhle and colleagues used a Single Molecule Array Immunoassay (Quanterix). This test is based on an enzyme-linked immunoassay with more than 280,000 wells and was developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood,” when compared with conventional enzyme-linked immunosorbent assay (ELISA) or electrochemiluminescence.

Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.

Patients with two or more relapses in the previous 24 months had significantly higher NfL levels than those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.

Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at six months being highly predictive of brain volume changes at 24 months.

And, in this preliminary dataset, patients who had been treated with fingolimod versus placebo during the FREEDOMS trial had lower NfL levels at six, 12, and 24 months. Dr. Kuhle observed that the findings of this study were corroborated by other study data presented at the ECTRIMS meeting.

The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle received research support and consulting fees from Biogen, Novartis, and Protagen. He also disclosed receiving speaker fees and travel expenses from Novartis and several other pharmaceutical companies. Several of Dr. Kuhle’s coinvestigators were employees of Novartis.

—Sara Freeman

LONDON—Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis (RRMS) than in healthy subjects in a proof-of-concept study reported at the 32nd Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 and 12.5 pg/mL, respectively, and were also found to be higher in patients with RRMS with greater disease activity seen on MRI.

As the number of gadolinium-enhancing (Gd+) lesions increased, so did the blood concentration of NfL, which was 23.9 pg/mL in patients with no Gd+ lesions, 26.7 pg/mL in those with one Gd+ lesion, 33.4 pg/mL in those with two to three Gd+ lesions, and 55.9 pg/mL in those with more than three Gd+ lesions.

“These findings support a role for NfL as a peripheral biomarker for MS,” said Jens Kuhle, MD, of University Hospital Basel in Switzerland. “There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials.

“NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF, and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS.

Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity. In the current study, Dr. Kuhle and colleagues used a Single Molecule Array Immunoassay (Quanterix). This test is based on an enzyme-linked immunoassay with more than 280,000 wells and was developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood,” when compared with conventional enzyme-linked immunosorbent assay (ELISA) or electrochemiluminescence.

Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.

Patients with two or more relapses in the previous 24 months had significantly higher NfL levels than those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.

Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at six months being highly predictive of brain volume changes at 24 months.

And, in this preliminary dataset, patients who had been treated with fingolimod versus placebo during the FREEDOMS trial had lower NfL levels at six, 12, and 24 months. Dr. Kuhle observed that the findings of this study were corroborated by other study data presented at the ECTRIMS meeting.

The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle received research support and consulting fees from Biogen, Novartis, and Protagen. He also disclosed receiving speaker fees and travel expenses from Novartis and several other pharmaceutical companies. Several of Dr. Kuhle’s coinvestigators were employees of Novartis.

—Sara Freeman

LONDON—Higher levels of a neuronal protein were found in the blood of patients with relapsing-remitting multiple sclerosis (RRMS) than in healthy subjects in a proof-of-concept study reported at the 32nd Annual Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Blood levels of neurofilament light chain (NfL) were 28.1 and 12.5 pg/mL, respectively, and were also found to be higher in patients with RRMS with greater disease activity seen on MRI.

As the number of gadolinium-enhancing (Gd+) lesions increased, so did the blood concentration of NfL, which was 23.9 pg/mL in patients with no Gd+ lesions, 26.7 pg/mL in those with one Gd+ lesion, 33.4 pg/mL in those with two to three Gd+ lesions, and 55.9 pg/mL in those with more than three Gd+ lesions.

“These findings support a role for NfL as a peripheral biomarker for MS,” said Jens Kuhle, MD, of University Hospital Basel in Switzerland. “There is an urgent unmet need for reliable biomarkers of neurodegeneration, besides efforts that are being done in MRI, optical coherence tomography, and evoked potentials.

“NfL is an exclusively neuronal protein. It is expressed in the cytosol of neurons, it is released upon cell injury into the CSF, and obviously it also appears in the blood circulation.” NfL in the CSF thus reflects nerve damage and had been seen in patients with MS and several other neurologic diseases, including Alzheimer’s disease, Parkinson’s disease, and ALS.

Until recently, however, it was not possible to detect NfL in the blood, as levels are around 50 to 100 times lower than in the CSF, but Dr. Kuhle and his associates have shown that an electrochemiluminescence immunoassay could detect increasing NfL levels with increasing disease activity. In the current study, Dr. Kuhle and colleagues used a Single Molecule Array Immunoassay (Quanterix). This test is based on an enzyme-linked immunoassay with more than 280,000 wells and was developed to be an ultrasensitive diagnostic platform to measure minute quantities of individual proteins. Dr. Kuhle noted that it had “significantly increased sensitivity to measure NfL in blood,” when compared with conventional enzyme-linked immunosorbent assay (ELISA) or electrochemiluminescence.

Two to three consecutive blood samples taken from 149 patients with RRMS participating in the phase III FREEDOMS trial were obtained and compared with samples from 29 similarly aged healthy individuals without MS obtained from a separate biobank.

Patients with two or more relapses in the previous 24 months had significantly higher NfL levels than those with one relapse or no relapses. Serum NfL also significantly increased with the Expanded Disability Status Scale score recorded at the time the blood samples were taken.

Furthermore, “blood NfL levels predicted subsequent brain atrophy rates,” Dr. Kuhle reported, with NfL levels at six months being highly predictive of brain volume changes at 24 months.

And, in this preliminary dataset, patients who had been treated with fingolimod versus placebo during the FREEDOMS trial had lower NfL levels at six, 12, and 24 months. Dr. Kuhle observed that the findings of this study were corroborated by other study data presented at the ECTRIMS meeting.

The FREEDOMS trial was sponsored by Novartis. Dr. Kuhle received research support and consulting fees from Biogen, Novartis, and Protagen. He also disclosed receiving speaker fees and travel expenses from Novartis and several other pharmaceutical companies. Several of Dr. Kuhle’s coinvestigators were employees of Novartis.

—Sara Freeman