Increased levels of neurofilament light indicate risk for ALS
Click Here to Manage Email Alerts
Increased levels of neurofilament light in plasma samples correlated with a greater risk for ALS, according to findings from an analysis of plasma samples obtained within 5 years of an ALS diagnosis that was published in Neurology.
Samples obtained further from the diagnosis did not demonstrate such a relationship, the researchers noted.
“Despite efforts to create diagnostic criteria that increase the sensitivity and reduce time to diagnosis of the disease, the average time from the first symptom until diagnosis is still 12 months, a figure that has remained similar over the last decade,” the researchers wrote. “Neurofilament light chain (NfL), a sensitive and specific marker of neuroaxonal damage, has consistently been reported to be increased in ALS patients, suggesting that it could be a useful biomarker in ALS. However, most of these studies included patients well into the disease course, making it difficult to determine whether NfL is a reliable marker early in the disease.”
Kjetil Bjornevik, MD, PhD, a member of the neuroepidemiology research group at Harvard’s T.H. Chan School of Public Health, and colleagues aimed to determine whether NfL levels in plasma were elevated prior to ALS diagnosis and to examine whether these pre-diagnostic NfL levels corelated with metabolic changes. They performed a matched case-control study nested within three larger prospective U.S. cohorts, including the Nurses’ Health Study, the Health Professionals Follow-up Study and the Multiethnic Cohort Study. The researchers identified individuals who were diagnosed with ALS during follow-up and had plasma samples available from before the diagnosis.
Bjornevik and colleagues randomly selected control participants for each ALS case from those who were still alive at the time of the case diagnosis. The researchers matched these participants according to birth year, sex, race/ethnicity, fasting status, cohort and time of blood draw. They measured NfL in plasma samples and used conditional logistic regression to assess RRs and 95% CIs for ALS, adjusting for BMI, smoking, physical activity and urate levels.
Among more than 118,000 participants who provided blood samples in the three cohorts, the researchers identified 93 individuals who developed ALS (mean age, 64.4 years; 52.7% men). Of those patients, 84 had samples available from before their diagnosis.
The researchers found that increased NfL levels correlated with a greater risk for ALS in plasma samples obtained within 5 years of an ALS diagnosis (RR per 1 standard deviation [SD] increase = 2.68; 95% CI, 1.18-6.08). However, they did not observe this link in samples collected further away from the diagnosis, according to the study results (RR per 1 SD increase = 1.16; 95% CI, 0.78-1.73). Bjornevik and colleagues reported a multivariable-adjusted RR for ALS per 1 SD increase in pre-diagnostic NfL levels within 5 years of ALS diagnosis of 2.39 (95% CI, 1.08-5.29).
Analyses that compared NfL levels with the levels of 404 metabolites from ALS cases identified 21 metabolites with a “nominally significant” correlation with NfL. However, none of those associations remained significant after the researchers accounted for numerous comparisons.
“In our study, we found no association between NfL and ALS in samples obtained [5] years or longer before ALS diagnosis and observed that the biomarker levels only appeared to increase [12 to 24] months before the diagnosis. This suggests that ALS is characterized by a shorter pre-clinical phase than [Alzheimer’s disease], [Parkinson’s disease] and MS,” Bjornevik and colleagues wrote. “Still, the preclinical phase may be longer than suggested by our results, as our analyses were based on time of diagnosis, and symptom onset may start some time before the disease is diagnosed.”
The researchers noted that the inclusion of only 84 cases of ALS may have reduced the statistical power of their analyses and caused estimates to be “more prone” to random variation but added that “this challenge is inherent” in the difficulty of performing prospective studies in a rare disease state such as ALS.
“This study provides Class II evidence that plasma NfL levels are elevated in pre-diagnostic [patients with ALS],” Bjornevik and colleagues wrote.
Perspective
Back to Top
Prior studies identified elevated levels of neurofilament proteins (neurofilament light chain or neurofilament heavy chain) in the blood of asymptomatic mutation carriers 12 months to 24 months prior to ALS symptom onset. The current study by Bjornevik and colleagues used a case-control design using prospective plasma samples from over 100,000 individuals from three cohort studies to identify 84 participants who developed ALS during follow-up.
The researchers detected elevated NfL in the plasma of pre-diagnostic ALS patients within 12 months to 24 months before diagnosis, though NfL was not elevated more than 5 years before disease diagnosis. This study confirms and extends findings of prior studies to indicate neurofilament proteins increase in the blood before ALS diagnosis even for sporadic disease. The results also suggest a shorter pre-clinical phase for ALS than other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease and may provide a window into the timing of treatments that impact disease processes prior to clinical diagnosis.
Collapse
Read more about
Click Here to Manage Email Alerts