Plasma Neurofilament Light Reflects White Matter Hyperintensity-Driven Neurodegeneration in Aging
Poster No:
201
Submission Type:
Abstract Submission
Authors:
Khalid Saifullah1, Gulam Mahfuz Chowdhury1, Arnold Evia2, David Bennett2, Julie Schneider2, Konstantinos Arfanakis2
Institutions:
1Illinois Institute of Technology, Chicago, IL, 2Rush University Medical Center, Chicago, IL
First Author:
Co-Author(s):
Introduction:
Neurofilament light chain (NfL), an axonal structural protein, has emerged as a promising blood biomarker for neurodegeneration and brain structural integrity (Coppens et al. 2023; Gaetani et al., 2019; Mattsson et al., 2017; Mattsson et al., 2019). However, its relationship with white matter hyperintensities (WMH), a marker of small vessel disease (Duering et al., 2018; Qu et al., 2021; van Gennip et al., 2024), and direct neurodegeneration measured through deformation-based morphometry (DBM) remains unclear in non-demented older adults. Understanding these associations is crucial, as it can provide insights into early neurodegenerative processes and vascular contributions to brain atrophy. This study aims to clarify the interplay between NfL, WMH, and neurodegeneration, with a specific focus on the role of vascular pathology as a mediator, potentially informing future diagnostic and therapeutic strategies.
Methods:
Participants and Data
This study included 202 non-demented community-dwelling older adults from four studies: the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and African American Clinical Core of the Rush Alzheimer's Disease Research Center (Barnes et al., 2012; Bennett et al., 2018) (Fig.1). Blood samples were collected from fasting participants and processed within 30 minutes. Plasma neurofilament light (NfL) was measured using EDTA-treated blood, which was processed and stored at -80°C before batch shipment to National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) for analysis on the Quanterix Simoa HD-X. Quality was maintained through control samples and pooled plasma references for consistency. Whole brain 3D T1w MPRAGE (1×1×1mm3) images were registered to the MIITRA-1mm atlas, calculating the log Jacobian (LogJ) of the deformation field for each voxel, with Gaussian smoothing applied (FWHM=4mm). WMH were segmented from T2w FLAIR (0.9×0.9×4mm3) and T1w images, generating a mask to calculate WMH volume. WMH level was expressed as a percentage of intracranial volume and log-transformed.
Statistical analysis
Voxel-wise linear regression was used to evaluate associations between log-transformed NfL levels and LogJ maps, indicative of neurodegeneration, as well as between WMH burden and LogJ maps. Additionally, the relationship between log-transformed NfL levels and WMH burden was analyzed. Finally we tested whether WMH mediates the relationship between NfL and neurodegeneration. All analyses adjusted for age, sex, education, time interval between blood sampling and MRI, and scanner type. Voxel-wise analyses were conducted in FSL PALM (Winkler et al., 2015) with 5000 permutations, family-wise error correction (p<0.05), and threshold-free cluster enhancement.
This study included 202 non-demented community-dwelling older adults from four studies: the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and African American Clinical Core of the Rush Alzheimer's Disease Research Center (Barnes et al., 2012; Bennett et al., 2018) (Fig.1). Blood samples were collected from fasting participants and processed within 30 minutes. Plasma neurofilament light (NfL) was measured using EDTA-treated blood, which was processed and stored at -80°C before batch shipment to National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) for analysis on the Quanterix Simoa HD-X. Quality was maintained through control samples and pooled plasma references for consistency. Whole brain 3D T1w MPRAGE (1×1×1mm3) images were registered to the MIITRA-1mm atlas, calculating the log Jacobian (LogJ) of the deformation field for each voxel, with Gaussian smoothing applied (FWHM=4mm). WMH were segmented from T2w FLAIR (0.9×0.9×4mm3) and T1w images, generating a mask to calculate WMH volume. WMH level was expressed as a percentage of intracranial volume and log-transformed.
Statistical analysis
Voxel-wise linear regression was used to evaluate associations between log-transformed NfL levels and LogJ maps, indicative of neurodegeneration, as well as between WMH burden and LogJ maps. Additionally, the relationship between log-transformed NfL levels and WMH burden was analyzed. Finally we tested whether WMH mediates the relationship between NfL and neurodegeneration. All analyses adjusted for age, sex, education, time interval between blood sampling and MRI, and scanner type. Voxel-wise analyses were conducted in FSL PALM (Winkler et al., 2015) with 5000 permutations, family-wise error correction (p<0.05), and threshold-free cluster enhancement.
Results:
NfL levels were significantly associated with neurodegeneration, evidenced by reduced brain tissue volume in key regions (Fig. 2a) and with ventricular enlargement (Fig. 2b). A positive association was also observed between NfL levels and WMH level (β = 0.0798, SE = 0.0436, p = 0.0344), even after adjusting for covariates. WMH burden itself was strongly associated with neurodegeneration (Fig. 2c and 2d). Notably, the association between NfL and neurodegeneration was no longer significant after adjusting for WMH, underscoring WMH as a critical mediator.
Conclusions:
These findings highlight NfL as a biomarker reflecting both neurodegenerative and vascular aspects of brain aging, with WMH burden emerging as a critical mediator of neurodegeneration. Addressing small vessel disease may offer a pathway to slow neurodegenerative processes, even in non-demented individuals, underscoring its significance for early intervention strategies.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Lifespan Development:
Aging 2
Modeling and Analysis Methods:
Multivariate Approaches
Keywords:
Aging
Blood
Cerebrovascular Disease
Degenerative Disease
MRI
Statistical Methods
STRUCTURAL MRI
White Matter
1|2Indicates the priority used for review
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