Plasma neurofilament light as a biomarker for vascular contributions to cognitive impairment and dementia

Abstract Background The MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort. Method Plasma NfL was measured using HD‐X and HD‐1 Simoa instruments. Samples from the MarkVCID consortium were used to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL in MarkVCID with general cognitive function (GCF) as the primary outcome (n=331). In secondary analyses we assessed NfL associations with white matter hyperintensities (WMH). Models were adjusted for potential confounders, including eGFR as renal function influences NfL clearance. We replicated our findings using cohorts from the CHARGE consortium (CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196). Result We found the Quanterix Simoa platform to be reliable with low coefficients of variation (average CV<12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in test‐retest samples drawn within 30 days (ICC=0.968). There was strong consistency across Quanterix instruments (HD‐X and HD‐1; R 2 ≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in MarkVCID (β=‐0.23; [95% CI ‐0.41; ‐0.01), CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.17; ‐0.06]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in MarkVCID (when controlled for eGFR), CHARGE, and the UCD ADRC. Conclusion We have found that NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH in MarkVCID and across independent samples, providing evidence that it can be a useful biomarker for stratification in VCID trials.

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Journal
Alzheimer s & Dementia
Published
2024-12-01
DOI
https://doi.org/10.1002/alz.086587
Citations
1
Primary Topic
Circadian rhythm and melatonin
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article
Field-Weighted Citation Impact
0.27
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article

Plasma neurofilament light as a biomarker for vascular contributions to cognitive impairment and dementia

Vilmundur Guðnason, Bruce M. Psaty, Charles DeCarli, Mitzi M. Gonzales et al.
1 citations
Alzheimer s & Dementia
Circadian rhythm and melatonin
0.27
article

Plasma neurofilament light as a biomarker for vascular contributions to cognitive impairment and dementia

Vilmundur Guðnason, Bruce M. Psaty, Charles DeCarli, Mitzi M. Gonzales, Chen‐Pin Wang, Donna M. Wilcock, Sudha S. Seshadri, Abhay P. Sagare, Lenore J. Launer, Julia J Mathews, Lee‐Way Jin, Joel H. Kramer, Tiffany L. Sudduth, Tiffany F. Kautz, Hugo J. Aparicio, Russell P. Tracy, Djass Mbangdadji, Danielle Parent, Pauline Maillard, Gary A. Rosenberg, Kristin Schwab, Steven Mark Greenberg, Danny J.J. Wang, Herpreet Singh, Thomas H. Mosley, Pia Kivisäkk, Saptaparni Ghosh, Qianqian Liu, Myriam Fornage, Josh Bis, Claudia Liliana Satizábal, Rebecca Bernal, Hanzhang Lu, Karl Helmer, Alexa S. Beiser
article en
1 citations

Abstract

Abstract Background The MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort. Method Plasma NfL was measured using HD‐X and HD‐1 Simoa instruments. Samples from the MarkVCID consortium were used to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL in MarkVCID with general cognitive function (GCF) as the primary outcome (n=331). In secondary analyses we assessed NfL associations with white matter hyperintensities (WMH). Models were adjusted for potential confounders, including eGFR as renal function influences NfL clearance. We replicated our findings using cohorts from the CHARGE consortium (CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196). Result We found the Quanterix Simoa platform to be reliable with low coefficients of variation (average CV<12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in test‐retest samples drawn within 30 days (ICC=0.968). There was strong consistency across Quanterix instruments (HD‐X and HD‐1; R 2 ≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in MarkVCID (β=‐0.23; [95% CI ‐0.41; ‐0.01), CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.17; ‐0.06]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in MarkVCID (when controlled for eGFR), CHARGE, and the UCD ADRC. Conclusion We have found that NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH in MarkVCID and across independent samples, providing evidence that it can be a useful biomarker for stratification in VCID trials.

Alzheimer s & DementiaVol. 20(S2)
Boston University (US), University of Vermont (US), University of Southern California (US), Cedars-Sinai Medical Center (US), Harvard University (US), University of Kentucky (US), Johns Hopkins University (US), The University of Texas at San Antonio Health Science Center (US), University of New Mexico (US), University of California, San Francisco (US), University of Washington (US), Johns Hopkins Medicine (US), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Massachusetts General Hospital (US), University Memory and Aging Center (US), Geriatric Research Education and Clinical Center (US), Institute for Neurodegenerative Disorders (US), National Institute on Aging (US), South Texas Veterans Health Care System (US), Icelandic Heart Association (IS), University of California Davis Medical Center (US), Indiana University – Purdue University Indianapolis (US), University of California, Davis (US), The University of Texas Health Science Center at Houston (US)
Openalex Percentile: Top 41%
Circadian rhythm and melatonin
0.27
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