Neurofilament relates to white matter microstructure in older adults

Abstract

Cerebrospinal fluid (CSF) neurofilament light (NFL) is a protein biomarker of axonal injury. To study whether NFL is associated with diffusion tensor imaging (DTI) measurements of white matter (WM) microstructure, Vanderbilt Memory & Aging Project participants with normal cognition (n = 77), early mild cognitive impairment (n = 15), and MCI (n = 55) underwent lumbar puncture to obtain CSF and 3T brain MRI. Voxel-wise analyses cross-sectionally related NFL to DTI metrics, adjusting for demographic and vascular risk factors. Increased NFL correlated with multiple DTI metrics (p-values < 0.05). An NFL × diagnosis interaction (excluding early mild cognitive impairment) on WM microstructure (p-values < 0.05) was detected, with associations strongest among MCI. Multiple NFL × CSF biomarker interactions were detected. Associations between NFL and worse WM metrics were strongest among amyloid-β-negative, tau-positive, and suspected nonamyloid pathology participants. Findings suggest increased NFL, a biomarker of axonal injury, is correlated with compromised WM microstructure. Results highlight the role of elevated NFL in predicting WM damage in cognitively impaired older adults who are amyloid-negative, tau-positive, or meet suspected nonamyloid pathology criteria.

Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences

“…Aβ 42 and APOE-ε4 may exert their influence early, prior to the onset of neurodegeneration, consistent with work showing Aβ 42 deposition plateaus between late MCI and AD development (Jack et al, 2013) and Aβ 42 status more closely associates with cognitive decline in earlier disease states (Landau et al, 2012). It is possible Aβ 42 deposition in temporal and frontal regions (Grothe et al, 2017) damages neuronal myelin sheaths (Moore et al, 2018) and disrupts functional connectivity (Yi et al, 2015), leading to cognitive decline prior to the neuroimaging gray matter alterations observed in more severe stages of impairment (Mattsson et al, 2015). Additionally, APOE-ε4 may exacerbate early Aβ 42 deposition (Risacher et al, 2013) via increased aggregation (Liu et al, 2017) or decreased clearance (Castellano et al, 2011), further modifying network connectivity (Wang et al, 2017) and contributing to a phenotype of middle MCI.…”

Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition

“…Such improved specificity may be due to neuroaxonal degradation occurring secondary to neuronal death during the onset and progression of AD‐related cortical atrophy. Furthermore, emerging evidence leveraging CSF Aβ42 and hyperphosphorylated tau have linked these core AD pathologies to white matter microstructural damage among aging adults [5] even in familial AD [27,28]. These findings suggest damage to the cerebral white matter (and underlying axons) may be more directly involved in the AD pathological cascade than previously recognized.…”

White Matter Disease and Outcomes of Mechanical Thrombectomy for Acute Ischemic Stroke

“…17,18 Common pathologic correlates of WMD include those commonly implicated in neurodegeneration, such as elevated markers of axonal damage, the presence of activated microglia, and disorganization of aquaporin-4 localization on vessel-associated astrocytes. [19][20][21][22] Mechanisms by which WMD may exert a negative effect on outcomes following an acute stroke are multifold. First, it is associated with disruption of endothelial function, resulting in damage to the microvascular integrity, and blood-brain barrier dysfunction, resulting in extravasation of blood products and hemorrhagic complications.…”