Blood Biomarker Predicts Dementia in Cerebral Small Vessel Disease

Serum neurofilament light chain (NfL), a marker of axonal damage, predicted future dementia risk in cerebral small vessel disease (SVD), a small longitudinal study suggested.

Baseline NfL predicted cognitive decline (global cognition β = -0.335 ± 0.094, P=0.001) and risk of converting to dementia (HR 1.676, 95% CI 1.183-2.373, P=0.004) over up to 5 years, reported Marco Egle, MSc, and Hugh Markus, MD, of the University of Cambridge in England, and co-authors in the Journal of Neurology, Neurosurgery, and Psychiatry.

“Our results demonstrate that NfL may be a useful marker to predict dementia risk in patients with lacunar stroke and SVD, and our analyses showed that it added extra prediction to simple clinical and demographic markers,” Egle told MedPage Today.

While some patients with cerebral small vessel disease will develop dementia, others remain dementia-free, Egle noted. “Magnetic imaging resonance techniques provide radiological markers of SVD, which do allow some prediction. However, this is an expensive technique and is not available to all patients with this small vessel disease,” he said.

Increased levels of NfL occur in neurodegenerative disorders, including Alzheimer’s disease. NfL has been linked to cognition and disability in a cross-sectional study of SVD, but few studies have looked at whether it can predict cognitive changes over time. “The novelty of our study was its prospective design,” Egle said.

The researchers used baseline and follow-up data from 121 patients with moderate-to-severe SVD in the St. George’s Cognition and Neuroimaging in Stroke (SCANS) study. Participants were followed annually for 5 years.

Average baseline age was 70, and 74% of participants were men. MRI was performed at baseline and after 1, 2, and 3 years; blood samples also were collected then. Cognition was evaluated annually. Disability was assessed using the modified Rankin score (mRS). The study began in January 2008 and ended in October 2013; all assays were performed in 2019-2020. Six incidences of strokes were recorded over the 5-year follow-up period, four lacunar strokes and two intracerebral haemorrhages.

Baseline serum NfL levels averaged 36.51 pg/mL. Cross-sectional analyses showed NfL levels were inversely associated with global cognitive function, executive function, and processing speed. They also were negatively correlated with disability. Higher NfL levels were positively associated with lacune count, cerebral microbleed count, white matter hyperintensities, and diffusion tensor imaging (DTI) measures, and were negatively associated with normalized brain volume.

Over 5 years, both global cognition and processing speed declined significantly. Higher NfL at baseline predicted lower function in global cognition independently of clinical markers and baseline cognition.

A total of 107 participants had complete baseline DTI and NfL data; 19 of them converted to dementia over time. Higher baseline NfL predicted not only dementia, but changes in lacune count, microbleed count, and brain volume, independently of initial MRI baseline values and patient age.

In contrast to imaging, there was no change in NfL values during follow-up. A potential application of NfL might be in clinical trials of SVD where it could be used to assess treatment effect, Egle noted. “We assessed this use by measuring NfL levels on repeated blood testing over a 3-year period to see if changes in levels predicted dementia,” he said. “However, we were unable to detect any significant changes in NfL levels over this time, demonstrating that they are unlikely to be a useful marker in a clinical trial in SVD.”

The study had several limitations, the researchers noted. Sample sizes were small and NfL levels at more than one time point were not available for all participants. Other research showed that participants who dropped out of the SCANS study had worse cognitive function than those who remained, which may have led to cognitive, MRI, and NfL changes over time being underestimated. Larger studies are needed to confirm the findings.

Last Updated February 12, 2021