Functional brain activity constrained by structural connectivity reveals cohort-specific features for serum neurofilament light chain

• Published in: Communications medicine Vol. 2; no. 1; pp. 8 - 14
• Main Authors: Sihag, Saurabh, Naze, Sébastien, Taghdiri, Foad, Gumus, Melisa, Tator, Charles, Green, Robin, Colella, Brenda, Blennow, Kaj, Zetterberg, Henrik, Dominguez, Luis Garcia, Wennberg, Richard, Mikulis, David J., Tartaglia, Maria C., Kozloski, James R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2022; Nature Portfolio
• Subjects: 59/36; 59/57; 631/114/116/2393; 631/1647; Medicine; Medicine & Public Health; Neurosciences; Neurovetenskaper; Dynamical systems; Biological techniques
• ISSN: 2730-664X; 2730-664X
• DOI: 10.1038/s43856-021-00065-5

Background Neuro-axonal brain damage releases neurofilament light chain (NfL) proteins, which enter the blood. Serum NfL has recently emerged as a promising biomarker for grading axonal damage, monitoring treatment responses, and prognosis in neurological diseases. Importantly, serum NfL levels also increase with aging, and the interpretation of serum NfL levels in neurological diseases is incomplete due to lack of a reliable model for age-related variation in serum NfL levels in healthy subjects. Methods Graph signal processing (GSP) provides analytical tools, such as graph Fourier transform (GFT), to produce measures from functional dynamics of brain activity constrained by white matter anatomy. Here, we leveraged a set of features using GFT that quantified the coupling between blood oxygen level dependent signals and structural connectome to investigate their associations with serum NfL levels collected from healthy subjects and former athletes with history of concussions. Results Here we show that GSP feature from isthmus cingulate in the right hemisphere (r-iCg) is strongly linked with serum NfL in healthy controls. In contrast, GSP features from temporal lobe and lingual areas in the left hemisphere and posterior cingulate in the right hemisphere are the most associated with serum NfL in former athletes. Additional analysis reveals that the GSP feature from r-iCg is associated with behavioral and structural measures that predict aggressive behavior in healthy controls and former athletes. Conclusions Our results suggest that GSP-derived brain features may be included in models of baseline variance when evaluating NfL as a biomarker of neurological diseases and studying their impact on personality traits. Plain language summary Neurofilament light chain (NfL) is a marker released into the blood as a result of central nervous system damage or neurodegeneration. However, we know little about how NfL levels relate to brain structure and activity. Here, we use imaging data and advanced statistical methods to look at the relationship between brain activity and structure in healthy people and former athletes with a history of multiple concussions, and determine whether these can predict NfL levels in the blood. We find the relationship between brain activity and structure and NfL levels is different between the two groups. Our findings help us to understand how brain injury might impact NfL levels and their relationship with brain activity, and could guide how NfL and imaging data are used as tools in research and in the clinic. Sihag et al. analyse brain imaging data, circulating neurofilament light chain levels and personality scores in a cohort of former athletes with a history of concussions. The authors use graph signal processing to identify brain structural and connectivity features associated with neurofilament levels and with aggressive behaviour.