Blood test to measure NfL may predict Huntington’s onset early
Greater NfL increases predict more severe motor, cognitive problems
Blood levels of neurofilament light protein (NfL) in people who carry Huntington’s disease-causing mutations, but aren’t showing symptoms, can identify those who will develop the disease in the next decade.
These are the findings of a 14-year study that also showed that greater increases in blood NfL levels, a marker of nerve damage, predict more severe motor and cognitive problems.
Also, while NfL levels rose relatively slowly during the early presymptomatic phase, when there are no overt symptoms, they increased rapidly immediately before their onset.
The study, “A 14-year longitudinal study of neurofilament light chain dynamics in premanifest and transitional Huntington’s disease,” was published in the Journal of Neurology.
Huntington’s is a neurodegenerative disorder caused by excessive repeats of three DNA building blocks — C, A, and G — in the HTT gene. While the gene normally contains 10-35 repeats, people with 40 or more repeats almost always develop Huntington’s. The more CAG repeats a person has, the earlier they tend to develop Huntington’s symptoms.
Because obvious motor symptoms typically emerge between ages 30 to 50, people carrying excessive CAG repeats in HTT, who are also known as carriers, have a prolonged presymptomatic phase.
Despite extensive research efforts to identify biomarkers to predict the onset of Huntington’s, current methods remain limited.
The potential of NfL as Huntington’s biomarker
Levels of NfL in blood and spinal fluid have shown potential for being biomarkers of Huntington’s onset and clinical severity. However, the few studies to measure NfL level changes in presymptomatic carriers are limited to three years.
Here, a team led by researchers at the University of Cambridge in the U.K. examined changes in blood NfL levels over 14 years, along with NfL levels’ predictive value for Huntington’s onset, in 21 Huntington’s carriers and 14 healthy people, who. served as controls.
All were participating in the Cambridge Huntington’s Sleep Study, where they underwent blood sampling at four time points between 2009 and 2023: baseline (2009-2010), time 2 (2011-2012), time 3 (2013-2014), and time 4 (2022-2023). The participants also underwent motor assessments at each point and completed a battery of cognitive tests at baseline and time 4.
Carriers had at least 38 CAG repeats in the HTT gene and weren’t having symptoms at the start of the study, and remained without symptoms until time 2. By the end of the study, up to 14 years later, six had begun to show subtle symptoms, a stage called prodromal Huntington’s, and eight developed full, or manifest, Huntington’s. Seven remained without symptoms, called nonconverters, while 14 had progressed to prodromal or manifest Huntington’s, that is, converters.
At the last assessment, NfL levels were significantly higher in converters than in nonconverters, who showed levels similar to healthy controls. Higher NfL levels were also significantly linked to more severe motor symptoms, as assessed by the Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-TMS), and poorer scores on four cognitive tests.
Converters’ NfL levels, while higher at baseline, showed an increase similar to that observed in healthy people in the early presymptomatic phase and a greater increase during late presymptomatic and conversion stages.
“A similar pattern has been observed in a number of other neurodegenerative conditions, with steepest increases in NfL seen during transition to symptomatic disease, followed by a plateau during subsequent progression,” the researchers wrote.
Further statistical analyses demonstrated that an NfL cutoff level of 24.06 picograms per mL of blood (pg/mL) at baseline could discriminate converters from those who didn’t develop symptoms after 14 years with an accuracy of 100%.
Although the annual rate of NfL change showed a much lower conversion predictability, of 64.3%, such annual changes significantly predicted more severe motor and cognitive impairment at last assessment.
When the researchers applied the 24.06 pg/ml baseline cutoff value to separate participants into high and low NfL groups, they found that UHDRS-TMS score trajectories significantly diverged over time. The high NfL group had a faster worsening in their motor functions than those with low NfL levels.
Lastly, the researchers compared data between the five carriers who converted to manifest Huntington’s and in whom the precise timing of conversion was known and the the seven who remained presymptomatic. They found that having baseline NfL levels above the cutoff increased the risk of converting by more than 12 times, a significant measure. This carrier group with high NfL levels at baseline converted after a mean of nine years.
“Baseline NfL concentrations showed excellent ability to discriminate those who underwent symptomatic conversion to manifest/prodromal disease during the 14-year study period from those who did not, and the rate of change of NfL was predictive of a number of more severe motor and cognitive clinical outcomes,” the researchers wrote. “We anticipate that both baseline and rate of change in NfL … are likely to provide best prognostic guidance.”
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