Neurofilament Light Chain as a Biomarker in Cerebral Small-Vessel Disease

Objective:To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.Methods:In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.Results:Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.Conclusions:Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.

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Reader response: Serum neurofilament light is sensitive to active cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000005672 ◽

2018 ◽

Vol 90 (24) ◽

pp. 1126.2-1126

Author(s):

Stefanie Schreiber ◽

Vincent Scheumann ◽

Valentina Perosa ◽

Stefan Vielhaber ◽

Anne Assmann

Keyword(s):

Reader Response ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Neurofilament Light ◽

Vessel Disease

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Serum Neurofilament Light Chain Is Associated with Incident Lacunes in Progressive Cerebral Small Vessel Disease

Journal of Stroke ◽

10.5853/jos.2019.02845 ◽

2020 ◽

Vol 22 (3) ◽

pp. 369-376

Author(s):

Nils Peters ◽

Esther van Leijsen ◽

Anil M. Tuladhar ◽

Christian Barro ◽

Marek J. Konieczny ◽

...

Keyword(s):

Cognitive Impairment ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Analysis Of Covariance ◽

Small Vessel ◽

Cognitive Measures ◽

Neurofilament Light ◽

Baseline Serum ◽

Vessel Disease

Background and Purpose Serum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) cross-sectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally.Methods From 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA).Results Serum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=–0.159; 95% confidence interval [CI], –0.242 to –0.068; P=0.001; executive function β=–0.095; 95% CI, –0.170 to –0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P<0.001), however not after adjusting for age.Conclusions Longitudinally, serum-NfL is associated with markers of SVD, especially with incident lacunes, and future cognitive impairment affecting various domains. NfL may potentially serve as an additional marker for disease monitoring and outcome in SVD, potentially capturing both vascular and neurodegenerative processes in the elderly.

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Editors' note: Serum neurofilament light is sensitive to active cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000005674 ◽

2018 ◽

Vol 90 (24) ◽

pp. 1126.1-1126

Author(s):

Megan Alcauskas ◽

Steven Galetta

Keyword(s):

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Neurofilament Light ◽

Vessel Disease

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Neurofilament light chain predicts future dementia risk in cerebral small vessel disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-325681 ◽

2021 ◽

pp. jnnp-2020-325681

Author(s):

Marco Egle ◽

Laurence Loubiere ◽

Aleksandra Maceski ◽

Jens Kuhle ◽

Nils Peters ◽

...

Keyword(s):

Clinical Trials ◽

Cognitive Decline ◽

Small Vessel Disease ◽

Surrogate Marker ◽

Cerebral Small Vessel Disease ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Vessel Disease ◽

Dementia Risk

ObjectivesSerum neurofilament light chain (NfL) has been proposed as prognostic markers in neurogenerative disease. A cross-sectional study in cerebral small vessel disease (SVD) reported an association with cognition and disability. If NfL is to be used to predict outcome, studies are required to demonstrate baseline NfL predicts future dementia risk. Furthermore, if it is to be used as a surrogate marker in clinical trials, change in NfL over time periods typical of a clinical trial must be linked to clinical progression. In a longitudinal study of patients with lacunar stroke and confluent white matter hyperintensities, we determined whether both baseline, and change, in NfL levels were linked to changes in MRI markers, cognitive decline and dementia risk.MethodsPatients underwent MRI, cognitive testing and blood taking at baseline and annually for 3 years. Clinical and cognitive follow-up continued for 5 years.ResultsNfL data were available for 113 subjects for baseline analysis, and 90 patients for the longitudinal analysis. Baseline NfL predicted cognitive decline (global cognition β=−0.335, SE=0.094, p=0.001) and risk of converting to dementia (HR=1.676 (95% CI 1.183 to 2.373), p=0.004). In contrast to imaging, there was no change in NfL values over the follow-up period.ConclusionsBaseline NfL predicts changes in MRI markers, cognitive decline and dementia rate over a 5 years follow-up period in SVD, suggesting NfL may be a useful prognostic marker. However, change in NfL values was not detected, and therefore NfL may not be a useful surrogate marker in clinical trials in SVD.

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