2 markers for Huntington’s found to indicate disease progression

In a biomarker study, scientists in South Korea found that levels of two proteins — neurofilament light chain (NfL) and phosphorylated tau (p-Tau) — serve as markers to indicate disease progression in Huntington’s.

Their findings on p-Tau are novel, and show that levels of this protein — known to form toxic clumps in the brains of people with Alzheimer’s disease — are able to gauge the stages of Huntington’s disease severity.

Meanwhile, levels of NfL, a marker of nerve cell degeneration, were able to distinguish between people with presymptomatic and fully symptomatic Huntington’s disease, the study showed.

“This study supports plasma NfL being a biomarker for initial HD [Huntington’s disease] manifestation in [this] Korean cohort, and a novel suggestion of plasma p-Tau as a potential biomarker reflecting the clinical severity in full-manifest HD,” the researchers wrote.

The study, “Plasma neurofilament light-chain and phosphorylated tau as biomarkers of disease severity in Huntington’s disease: Korean cohort data,” was published in the Journal of the Neurological Sciences.

Biological markers needed for Huntington’s disease progression, severity

In Huntington’s disease, defects in the HTT gene produce an abnormally long huntingtin protein, which is thought to form toxic clumps in the brain and cause damage. Characteristic Huntington’s symptoms include uncontrolled jerking movements, walking difficulties, problems with speech and swallowing, and, in some cases, cognitive impairment.

While clinical and genetic tests can be used to diagnose Huntington’s, there is still a need for blood-based biological markers, or biomarkers, to assess disease progression and severity, and to monitor the impact of treatments.

NfL functions as a structural protein in nerve cell fibers, known as axons. When these cells are damaged, NfL is released into the bloodstream and can be detected in plasma, the non-cell part of blood.

According to the researchers, however, “the association of plasma NfL with clinical severity in full manifest HD patients has not been established.”

Additionally, tau protein plays an essential role in the function of nerve cells in the brain. While emerging evidence suggests tau clumps also may play a part in the development of Huntington’s, there are no studies investigating tau-based biomarkers, the researchers noted.

To learn more about both, the team assessed NfL and tau as potential biomarkers of disease severity in a group of 67 Korean Huntington’s patients, ages 28-52.

The participants were classified based on their Huntington’s stage: Six were at the preclinical stage, before the onset of overt motor symptoms, while 31 had mild disease (stages 1-2), and 30 moderate to severe disease (stages 3-5).

The team collected blood samples and measured the levels of NfL, total tau, and p-Tau — a modified form of tau that is a major component of disease-causing clumps.

The blood tests revealed that the mean plasma NfL level was more than eight times higher in Huntington’s patients compared with the reference values (41.3 vs. 4.94 picograms/mL). Likewise, p-Tau was significantly elevated in Huntington’s (2.72 vs. 1.36 picograms/mL), though total tau was not.

Both plasma markers were shown to indicate disease progression in [Huntington’s disease], but with different features across the functional stages of the disease.

Consistently, the mean levels of NfL and p-Tau tended to increase gradually from the preclinical stage to more severe disease stages.

While plasma NfL was significantly higher in those with mild disease than among preclinical patients (40.9 vs. 17.8 picograms/mL), no further increases were found between mild and moderate to severe cases.

Conversely, p-Tau showed no increases from the preclinical to the mild stage but was significantly higher in severe versus mild Huntington’s patients (3.39 vs. 2.2 picograms/mL).

“Both plasma markers were shown to indicate disease progression in HD, but with different features across the functional stages of the disease,” the team wrote.

Findings suggest p-Tau as new potential biomarker for progression

The researchers then compared NfL and p-Tau levels against standard clinical assessments, including the Unified Huntington’s Disease Rating Scale (UHDRS) for total motor score and total functional capacity. Cognitive status was assessed using the mini-mental status examination and the Montreal Cognitive Assessment.

Elevated plasma NfL levels significantly correlated with worse motor symptoms and functional abilities. NfL also correlated with worse scores from the mini-mental status examination and the Montreal cognitive assessment.

“Because the NfL reflects neuronal axonal damage and brain atrophy [shrinkage] in [Alzheimer’s disease] patients as well as in normal aging, it is possible that brain atrophy might be a substrate for the relationship between elevated NfL and reduced global cognition in our HD patients,” the researchers suggested.

After statically adjusting for factors that may influence the relationships, only mini-mental status examination scores were independently associated with plasma NfL levels.

These data indicated that “plasma NfL could serve as a biomarker for monitoring clinical onset in premanifest individuals, but its role may be limited for assessing the clinical severity and functional stages in full-manifest HD patients,” the scientists wrote.

In comparison, higher p-Tau levels significantly correlated with worse UHDRS functional abilities while showing a non-significant trend with worse scores from the Montreal cognitive assessment. Total tau was not related to any clinical factors.

“Thus, our findings suggest plasma p-Tau as a new feasible biomarker for HD progression and raise the possible role of tauopathy in HD-related neurodegeneration,” the team wrote.

According to the researchers, both of these proteins could serve as markers for disease progression in Huntington’s, albeit with different features.

The “plasma NfL might be a potential biomarker for disease onset and early-stage of the disease, while the plasma p-Tau might be a complementary marker for disease progression after full manifestation” of Huntington’s, the team concluded.