NfL a Better Prognostic Marker of Cognitive Decline?

Plasma levels of neurofilament light (NfL) are a better predictor of cognitive decline and changes on neuroimaging in comparison with total tau (T-tau), new research suggests.

In certain contexts, T-tau improves cross-sectional analyses of these outcomes, but adding T-tau measurements to NfL measurements does not improve the predictive power of NfL, results of a longitudinal analysis show.

Jordan Marks

“The major distinction, for cognition at least, was that NfL cross-sectionally was associated with most cognitive outcomes, and longitudinally, higher NfL at baseline was associated with cognitive decline in every domain,” study investigator Jordan Marks, an MD/PhD student at the Mayo Clinic, in Rochester, Minnesota, told Medscape Medical News.

The findings were presented at the virtual American Academy of Neurology (AAN) 2021 Annual Meeting.

New Tool for Dementia Diagnosis?

In recent years, researchers have studied NfL and T-tau as potential blood-based biomarkers of neurodegeneration. In cross-sectional and longitudinal studies, NfL and T-tau have been associated with worse cognition and with neuroimaging measures of cortical thickness, cortical atrophy, white-matter hyperintensity, and white-matter integrity. However, no previous research has directly compared the prognostic ability of these two biomarkers.

The study included 995 participants without dementia in the Mayo Clinic Study on Aging. All participants underwent measurement of NfL and T-tau and assessment of cognitive status, as well as neuroimaging.

The investigators measured NfL and T-tau on the Simoa HD-1 platform. They reexamined patients approximately every 15 months. The median follow-up time was 6.2 years.

To examine associations between baseline plasma NfL or T-tau and cognitive or neuroimaging outcomes, the researchers conducted data analyses using linear mixed effects models and adjusted the data for age, sex, and education. They replicated these analyses using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). For these analyses, they selected 387 participants without dementia who had been followed for a median of 3.0 years.

In all analyses, baseline plasma NfL was more strongly associated with cognitive and neuroimaging outcomes than T-tau.

“Baseline plasma NfL was associated with cognitive decline in all domains measured, while T-tau was not associated with cognitive decline,” said Marks.

Plasma NfL was more strongly associated with decreases in cortical thickness over time than T-tau was. NfL was also more strongly associated with declining hippocampal volume and white-matter changes.

However, in cross-sectional analysis, the combination of elevated NfL levels and elevated T-tau levels at baseline was more strongly associated with decreased global cognition and memory, compared with elevated NfL levels alone.

The combination also was more strongly associated with neuroimaging measures, such as temporal cortex thickness and increased number of infarcts. However, in longitudinal analyses, T-tau did not add to the predictive value of NfL.

The analyses using ADNI data yielded similar results. Overall, the results suggest that NfL is a better prognostic marker of neurodegeneration in general, said Marks.

These findings, he said, may have implications for screening and diagnosis.

“I’m definitely hopeful that NfL will be useful in a clinical setting to screen for those at risk of dementia and will be helpful, along with other modalities, like cognitive testing, for dementia diagnosis,” said Marks.

Future research should examine how changes in these biomarkers are associated with cognitive and neuroimaging outcomes over time.

“We used plasma levels at one point in time in this study, but we need a better sense of how to interpret, for example, what a rise in plasma NfL over a certain time period means for someone’s risk of developing neurodegenerative disease,” Marks added.

An “Exciting” Prospect

Commenting on the study for Medscape Medical News, Glen R. Finney, MD, director of the Memory and Cognition Program for Geisinger Health in Wilkes-Barre, Pennsylvania, and fellow of the AAN, said the findings add to neurologists’ ability to screen for brain diseases.

“Evidence of neurodegeneration is part of the modern diagnosis of several disorders. While brain imaging can also provide that and may be needed for other reasons, this could provide an easy, potentially inexpensive way to screen for damage to the brain, giving us an added tool,” said Finney.

The prospect of using blood plasma markers to explore disease of the brain is exciting, Finney added.

“I would like to see ongoing refinement of this approach and would like to see if there’s other markers in blood that could be used to find what specifically may be causing the damage,” he said.

The study was funded by the National Institutes of Health, the National Institute on Aging, and the GHR Foundation. Marks and Finney have disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2021 Annual Meeting: Presented April 18, 2021.

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