The role of neurofilament light in genetic frontotemporal lobar degeneration

Abstract

Genetic frontotemporal lobar degeneration caused by autosomal dominant gene mutations provides an opportunity for targeted drug development in a highly complex and clinically heterogeneous dementia. These neurodegenerative disorders can affect adults in their middle years, progress quickly relative to other dementias, are uniformly fatal, and have no approved disease modifying treatments. Frontotemporal dementia, caused by mutations in the GRN gene which encodes the protein progranulin, is an active area of interventional drug trials that are testing multiple strategies to restore progranulin protein deficiency. These and other trials are also examining neurofilament light as a potential biomarker of disease activity and disease progression, and as a therapeutic endpoint based on the assumption that cerebrospinal fluid and blood neurofilament light levels are a surrogate for neuroaxonal damage. Reports from genetic frontotemporal dementia longitudinal studies indicate that elevated concentrations of blood neurofilament light reflect disease severity and are associated with faster brain atrophy. To better inform patient stratification and treatment response in current and upcoming clinical trials, a more nuanced interpretation of neurofilament light as a biomarker of neurodegeneration is now required, one that takes into account its relationship to other pathophysiological and topographic biomarkers of disease progression from early presymptomatic to later clinically symptomatic stages.

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

“…NfL is a well-known clinical biomarker for many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), FTD and spinal muscular atrophy (SMA). Consistent with previous publications, our data showed NfL in CSF and plasma are increased in patients with all forms of FTD with the highest elevation observed in symptomatic GRN mutation carriers [ 53 , 23 , 32 , 33 ], and baseline levels correlate positively with the rate of disease progression [ 23 ]. In patients with dementia, the highest NfL levels are observed in patients with FTD as compared to other types of dementia such as AD, and NfL levels correlate with disease severity and survival, regardless of clinical diagnosis [ 54 , 23 ].…”

Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration

“…Finally, LGMN overexpression led to a 10-fold increase in plasma neurofilament light chain (NfL) (Fig. 7f), a biomarker for neuronal damage also used in clinical studies 46,47 . Taken together, these results suggest that…”

Neurofilaments Light Chain in Neurodegenerative Dementias: A Review of Imaging Correlates

“…However, we still need a deeper understanding of this marker’s role in each of these situations before it can become part of the clinical routine. Studying the correlation between NfLs and neuroimaging features may help to better understand their disease-specific features and underlying mechanisms [ 13 , 31 ]. The present scoping review is aimed at collecting findings on this topic to sum up the present knowledge in this field, allowing for a more systematic understanding that will help clinical interpretation.…”