Kjetil Bjornevik1, Eilis J O'Reilly2,3, Samantha Molsberry2, Laurence N Kolonel4, Loic Le Marchand4, Sabrina Paganoni5,6, Michael A Schwarzschild6,7, Pascal Benkert8, Jens Kuhle9, Alberto Ascherio2,10,11. 1. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA kbjorne@hsph.harvard.edu. 2. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 3. School of Public Health, College of Medicine, University College Cork, Ireland. 4. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. 5. Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital and Healey Center for ALS, Massachusetts General Hospital, Boston, Massachusetts, USA. 6. Harvard Medical School, Boston, Massachusetts, USA. 7. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA. 8. Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 9. Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 10. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 11. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Abstract
OBJECTIVE: To assess whether plasma neurofilament light chain (NfL) levels are elevated before ALS diagnosis and to evaluate whether pre-diagnostic NfL levels are associated with metabolic alterations. METHODS: We conducted a matched case-control study nested in three large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study), and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels. RESULTS: Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 standard deviation [SD] increase: 2.68, 95% CI: 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI: 0.78-1.73). A total of 21 metabolites were correlated with pre-diagnostic NfL levels in ALS cases (p < 0.05), but none of these remained significant after multiple comparison adjustments. CONCLUSIONS: Plasma NfL levels were elevated in pre-diagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma NfL levels are elevated in pre-diagnostic ALS patients.
OBJECTIVE: To assess whether plasma neurofilament light chain (NfL) levels are elevated before ALS diagnosis and to evaluate whether pre-diagnostic NfL levels are associated with metabolic alterations. METHODS: We conducted a matched case-control study nested in three large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study), and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels. RESULTS: Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 standard deviation [SD] increase: 2.68, 95% CI: 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI: 0.78-1.73). A total of 21 metabolites were correlated with pre-diagnostic NfL levels in ALS cases (p < 0.05), but none of these remained significant after multiple comparison adjustments. CONCLUSIONS: Plasma NfL levels were elevated in pre-diagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma NfL levels are elevated in pre-diagnostic ALS patients.
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