Confounding effect of blood volume and body mass index on blood neurofilament light chain levels
Open accessAbstract
Blood Neurofilament light chain (NfL) has been suggested as a promising biomarker in several neurological conditions. Since blood NfL is the consequence of leaked NfL from the cerebrospinal fluid, differences in individuals’ Body Mass Index (BMI) or blood volume (BV) might affect its correlation to other biomarkers and disease outcomes. Here, we investigated the correlation between plasma NfL, BMI, and BV in 662 controls and 2,586 multiple sclerosis cases. We found a significant negative correlation between plasma NfL, BMI/BV in both groups. Our results highlight the potential confounding effect of BMI/BV on associations between blood NfL and disease outcomes.
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Levels of NfL and GFAP vary with demographic and physiologic factors such as age, BMI, renal function, and hemoglobin A1C.
“Levels vary with demographic and physiologic factors such as age, body mass index (BMI), renal function, and hemoglobin A1C.9–11”
From Establishing demographic-based normative values for neurofilament light chain and glial fibrillary acidic protein in serum and plasma samples (2026) · cites this paper as [10]
The Results report an association between BMI and plasma NfL in controls and multiple sclerosis cases, and the Introduction describes NfL expression as age-dependent. The paper does not address GFAP, renal function, or hemoglobin A1C, and it does not establish an age association specifically for blood NfL. (LLM, conf=0.89)
Experimental — accuracy not yet measuredRegression models were adjusted for age, sex, and body mass index.
“adjusted for age, sex, and body mass index (31)”
From A Method to Combine Neurofilament Light Measurements From Blood Serum and Plasma in Clinical and Population-Based Studies (2022) · cites this paper as [31]
The Materials and Methods passage says the multiple linear regression models were adjusted for sex and age at sampling, with BMI assessed as a predictor. It separately describes analyses controlling for BMI, but does not establish that those regression models were adjusted for age, sex, and BMI together. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAssociations between serum NfL and renal function were investigated using linear or logistic regression models adjusted for age, sex, and body mass index.
“Associations between serum NfL and renal function (serum creatinine, glomerular filtration rate estimated via the CKD-EPI equation (30), and glomerular filtration rate ≤ 60 mL/min/1.73 m2 as indicator of kidney disease) were investigated using linear or logistic regression models [adjusted for age, sex, and body mass index (31)], respectively.”
From A Method to Combine Neurofilament Light Measurements From Blood Serum and Plasma in Clinical and Population-Based Studies (2022) · cites this paper as [31]
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Cites
Monitoring disease activity in multiple sclerosis using serum neurofilament light protein
Novakova, L., Zetterberg, H., Sundström, P., Axelsson, M., Khademi, M., Gunnarsson, M., Malmeström, C., Svenningsson, A., Olsson, T., Piehl, F., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000004683 · Cited by 426 · see citing works
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Research works printed but not linked: 6
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- [3]Kuhle J, Gaiottino J, Leppert D, et al. Serum neurofilament light chain is a biomarker of human spinal cord injury severity and outcome. J Neurol Neurosurg Psychiatry 2015; 86: 273– 279. 10.1136/jnnp-2013-307454 24935984 · DOI
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- [8]Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery 1962; 51: 224– 232. http://www.ncbi.nlm.nih.gov/pubmed/21936146. Accessed August 27, 2019. 21936146
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Blood neurofilament light: a critical review of its application to neurologic disease
Barro, C., Chitnis, T., & Weiner, H. L. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51234 · Cited by 296 · see citing works
Pichet Binette, A., Janelidze, S., Cullen, N., Dage, J. L., Bateman, R. J., Zetterberg, H., Blennow, K., Stomrud, E., Mattsson‐Carlgren, N., & Hansson, O. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12787 · Cited by 226 · see citing works
Picca, A., Guerra, F., Calvani, R., Romano, R., Coelho-Júnior, H. J., Bucci, C., & Marzetti, E. (2021) · Biomolecules · doi:10.3390/biom11101508 · Cited by 189 · see citing works
Rübsamen, N., Willemse, E. A. J., Leppert, D., Wiendl, H., Nauck, M., Karch, A., Kuhle, J., & Berger, K. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.894119 · Cited by 27 · see citing works
“73 m2 as indicator of kidney disease) were investigated using linear or logistic regression models [adjusted for age, sex, and body mass index (31)], respectively.”
MethodSheth, U., Öijerstedt, L., Heckman, M. G., White, L. J., Heuer, H. W., Lario Lago, A., Forsberg, L. K., Faber, K. M., Foroud, T. M., Rademakers, R., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00821-4 · Cited by 20 · see citing works
Neurofilament light level correlates with brain atrophy, and cognitive and motor performance
Kartau, M., Melkas, S., Kartau, J., Arola, A., Laakso, H., Pitkänen, J., Lempiäinen, J., Koikkalainen, J., Lötjönen, J., Korvenoja, A., et al. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.939155 · Cited by 16 · see citing works
Foshati, S., Poursadeghfard, M., Heidari, Z., & Amani, R. (2023) · Food & Function · doi:10.1039/d3fo00167a · Cited by 12 · see citing works
Borko, T. L., Ritchie, A., Selva, S., Sillau, S., Engebretson, E., Wolf, A. B., Alvarez, E., Gross, R., Gutierrez, E., Corboy, J., et al. (2026) · Multiple Sclerosis Journal – Experimental, Translational and Clinical · doi:10.1177/20552173261466440 · Cited by 1 · see citing works
- Authors
- Manouchehrinia, A., Piehl, F., Hillert, J., Kuhle, J., Alfredsson, L., Olsson, T., & Kockum, I.
- Affiliations
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Departments of Medicine, Biomedicine, and Clinical Research Neurologic Clinic and Policlinic University Hospital Basel University of Basel Basel Switzerland
- Corresponding author
- Manouchehrinia, Ali
- Venue
- Annals of Clinical and Translational Neurology
- Publisher
- Wiley
- Published
- 2020-01
- Volume
- 7
- Issue
- 1
- Pages
- 139-143
- ISSN
- 2328-9503 (ISSN-L)
- PMC
- PMC6952306
- OpenAlex
- W2998102810
- Cited by
- 249
- References
- 1
- Citations by year
- 2026: 33 · 2025: 40 · 2024: 57 · 2023: 33 · 2022: 47 · 2021: 30 · 2020: 9
- FWCI
- 19.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Annals of Clinical and Translational Neurology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Novartis
- Biogen
- Vetenskapsrådet
- AFA Försäkring
- Genzyme
- Hjärnfonden
- Korea National University of Transportation
- Sanofi
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- body mass index, blood volume, multiple sclerosis, confounding, biomarkers, cerebrospinal fluid leak, disease outcome
- MeSH terms
- Adult, Blood Volume, Female, Humans, Male, Middle Aged, Multiple Sclerosis, Biomarkers, Body Mass Index, Neurofilament Proteins
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