Serum neurofilament light is increased in multiple system atrophy of cerebellar type and in repeat-expansion spinocerebellar ataxias: a pilot study

Abstract

Blood biomarkers in degenerative ataxias are still largely missing. Here, we aimed to provide piloting proof-of-concept that serum Neurofilament light (NfL) could offer a promising peripheral blood biomarker in degenerative ataxias. Specifically, as a marker of neuronal damage, NfL might (1) help to differentiate multiple system atrophy of cerebellar type (MSA-C) from sporadic adult-onset ataxia (SAOA), and (2) show increases in repeat-expansion spinocerebellar ataxias (SCAs) which might be amenable to treatment in the future. To explore these two hypotheses, we measured serum NfL levels by single-molecule array (Simoa) technique in 115 subjects, comprising patients with MSA-C (n = 25), SAOA (n = 25), the most frequent repeat-expansion SCAs (SCA 1, 2, 3 and 6) (n = 20), and age-matched controls (n = 45). Compared to controls, NfL was significantly increased in MSA-C, with levels significantly higher than in SAOA (AUC = 0.74 (0.59-0.89), mean and 95% confidence interval, p = .004). NfL was also significantly increased in SCA patients as compared to controls (AUC = 0.91 (0.81-1.00), p < .001), including NfL increases in SCA1 and SCA3. These findings provide first proof-of-concept that NfL might provide a promising peripheral biomarker in degenerative ataxias, e.g. supporting the differentiation of MSA-C from SAOA, and indicating neuronal damage in repeat-expansion SCAs.

NfL and pNfH are increased in Friedreich’s ataxia

“…Moreover, we explored possible age effects and could show that NfL levels are an excellent classifier for younger, but not for older patients. The difference we found in the amount of detected NfL between Friedreichs's ataxia patients and controls compares well with other slowly progressing neurodegenerative diseases such as hereditary spastic paraplegia, Alzheimer's disease, and spinocerebellar ataxia [17][18][19]. Levels are lower than in rapidly progressing neurodegenerative diseases such as ALS, FTD, CJD or ALSP [4][5][6][7]9], most likely reflecting the slower decay of axons, with less neurofilament liberated into CSF and peripheral blood per unit of time.…”

Serum Neurofilament Light Is Elevated Differentially in Older Adults with Uncomplicated Mild Traumatic Brain Injuries

“…Our results are consistent with past studies showing that serum levels of NF-L are higher in people with diverse neurological and neurodegenerative conditions. Researchers have reported that serum levels of NF-L are higher in people with multiple sclerosis (Kuhle et al, 2016;Disanto et al, 2017;Kuhle et al, 2017;Novakova et al, 2017), acute ischemic stroke (De Marchis et al, 2018), active cerebral small vessel disease (Gattringer et al, 2017), familial Alzheimer's disease (Mattsson et al, 2017;Weston et al, 2017), Huntington's disease (Byrne et al, 2017), frontotemporal dementia (Rohrer et al, 2016), Creutzfeldt-Jakob disease (Thompson et al, 2018), Parkinsonian disorders (Hansson et al, 2017), other degenerative ataxias such as multiple system atrophy (Wilke et al, 2018) and amyotrophic lateral sclerosis (Feneberg et al, 2018).…”

“…Because older adults are more likely to have neurological conditions prior to brain injury, NF-L might be elevated differentially in older adults, compared to middle-aged or younger adults, following mild traumatic brain injury (MTBI). A number of studies indicate that serum NF-L levels are higher in people with diverse neurological and neurodegenerative diseases (Kuhle et al, 2016;Rohrer et al, 2016;Byrne et al, 2017;Disanto et al, 2017;Gattringer et al, 2017;Hansson et al, 2017;Kuhle et al, 2017;Mattsson et al, 2017;Novakova et al, 2017;Weston et al, 2017;De Marchis et al, 2018;Feneberg et al, 2018;Thompson et al, 2018;Wilke et al, 2018). Therefore, as a potential diagnostic or prognostic biomarker for neurotrauma, it is important to determine whether there is an association between age and NF-L levels in individuals who sustain MTBIs.…”

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

“…Fluid biomarkers may serve to the same end and can be differentiated into two classes: (1) generic biomarkers of neurodegeneration that are not specific to the disease process but still allow the capture of the neuronal damage. For example, neurofilament light chain (NfL) reflects neuronal turnover in many neurodegenerative diseases, including first-promise studies in cerebellar ataxias, and can be accessed in blood with close correlation to CSF levels (Wilke et al, 2018). (2) Disease-specific markers that are closely related to pathophysiology and reflect early steps in pathogenesis may capture the direct target engagement of a compound and its efficacy.…”