Regular articleNeurofilament relates to white matter microstructure in older adults
Introduction
One rapidly emerging biomarker in abnormal cognitive aging and Alzheimer's disease is neurofilament light (NFL), a support protein within large, myelinated axons specifically within the cerebral white matter (WM) (Bergman et al., 2016, Friede and Samorajski, 1970, Skillback et al., 2014, Yates et al., 2009). Increased cerebrospinal fluid (CSF) NFL concentrations are thought to reflect breakdown of large caliber axons (Friede and Samorajski, 1970, Menke et al., 2015), thus compromising WM microstructure with cognitive consequences (Menke et al., 2015, Skillback et al., 2014). Elevated CSF NFL correlates with MRI T1-weighted WM hypointensities, reflecting WM macrostructural damage, particularly among older adults with mild cognitive impairment (MCI) and Alzheimer's disease (Zetterberg et al., 2016). Prior studies have yielded limited and inconsistent associations between CSF NFL and WM microstructure assessed by diffusion imaging among middle aged and older individuals with normal cognition (NC) (Melah et al., 2016, Racine et al., 2017) and more severe traumatic brain injury (Al Nimer et al., 2015). Therefore, it is unknown if CSF NFL relates to more sensitive measures of the WM specific to the microstructure of fiber bundles, among older adults with and without cognitive impairment.
The present study sought to examine the association between CSF NFL obtained in vivo and diffusion tensor imaging (DTI) measures of WM microstructure among older individuals with NC and MCI, a prodromal stage of Alzheimer's disease. Given prior research linking CSF NFL, axonal injury, and WM integrity in murine models (Friede and Samorajski, 1970) and motor neuron disease (Menke et al., 2015), we hypothesized that increased CSF NFL concentrations would correlate with compromised WM microstructure. We also hypothesized effect modification by cognitive diagnosis with associations stronger in MCI, where compromised axonal integrity may underlie clinical signs of cognitive impairment (Nir et al., 2013) and a greater range of WM degeneration is present (Huang et al., 2007). In post hoc analyses, NFL and WM microstructure associations were tested for interactions with established Alzheimer's disease biomarkers, including CSF Aβ42 and t-tau to determine if underlying Alzheimer's disease pathology was driving any significant observations.
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Study cohort
The Vanderbilt Memory & Aging Project (Jefferson et al., 2016) is a longitudinal observational study investigating vascular health and brain aging, enriched with older adults with MCI. Cohort inclusion criteria required participants to be at least 60 years of age, speak English, have adequate auditory and visual acuity for testing, and have a reliable study partner. At eligibility, participants underwent a comprehensive assessment and were excluded for a cognitive diagnosis other than NC, early
Participant characteristics
For all participants (n = 147, 72 ± 6 years, 68% males, 93% non-Hispanic white), CSF NFL concentrations ranged 268–3617 pg/mL, CSF Aβ42 concentrations ranged 289–1195 pg/mL, and CSF t-tau concentrations ranged 107–1542 pg/mL. NFL was not correlated with Aβ42 (r = −0.05, p = 0.55) and was correlated with t-tau (r = 0.42, p < 0.001). No collinearity was found between the CSF variables (Variation Inflation Index < 2.9 for all variables in all models). Mean time between brain MRI and lumbar
Discussion
Among community-dwelling older adults without a clinical history of stroke or dementia, higher CSF concentrations of NFL were associated with compromised WM microstructure measured with DTI. Specifically, NFL was negatively associated with FA and positively associated with mean, radial, and axial diffusivity. Diagnostic interactions revealed findings were strongest in the MCI participants. Biomarker interactions including both NC and MCI participants further indicated that findings were
Conclusions
The present study demonstrates a novel association between NFL and WM microstructure, which is modified by cognitive diagnosis (MCI) and biomarkers of Alzheimer's disease (Aβ42) and neurodegeneration (t-tau). Many older adults have comorbid pathologies present in late life (Schneider et al., 2007), and Alzheimer's disease therapies may be less effective when additional pathologies are present (Weekman et al., 2016). Therefore, the modified associations reported here between NFL and DTI in the
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgments
The authors would like to thank the dedicated Vanderbilt Memory & Aging Project participants, their loved ones, and the devoted staff and trainees who contributed to recruitment, screening, and enrollment of the baseline cohort. The authors would also like to thank the dedicated and skilled laboratory technicians at the Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital, Sweden, who performed all the CSF analyses.
Funding: This research was supported by Alzheimer's Association
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