Article In Brief
New findings suggest that neurofilament light chain in the cerebrospinal fluid may be an important biomarker indicating measurable abnormalities for Huntington's disease more than 20 years prior to the emergence of clinical symptoms.
Changes related to Huntington's disease (HD) can be detected more than two decades before predicted clinical onset, according to new findings recently published in The Lancet Neurology.
The findings—from a group of mostly European researchers, led by investigators at the University College London—point to neurofilament light chain (NfL) in the cerebrospinal fluid (CSF) as an important biomarker able to show measurable abnormalities extremely early in people destined to get the disease. The changes in the biomarker make it a potentially crucial metric that could aid clinical trials of therapies that could be disease-modifying, investigators said. And the findings suggest that 24 years before onset is a reasonable time to begin assessments, they said.
Treatment may prevent clinical onset of the disease, which involves movement, cognitive and behavioral abnormalities that usually emerge between the fourth and sixth decades of life.
“By going back earlier in the disease course, we have identified a time, approximately 24 years from predicted clinical onset, when there is no apparent functional impairment in HD gene carriers,” said Sarah Tabrizi, PhD, principal investigator and director of the Huntington's Disease Center at University College London, and Paul Zeun, BMBS, co-first author and researcher at the same center, in joint responses to questions.
“Yet there is a subtle detectable rise in select measures of neurodegeneration. So interventions at this stage could offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment.”
The findings come from 64 young adults who were HD gene carriers (pre-HD) and 67 controls who were matched for age, education and sex. The controls either had a family history of HD but a negative genetic test or had no known family history of HD. Participants were 29 years old in both groups, and those in the pre-HD group were 23.6 years from predicted onset of disease on average.
Pre-HD subjects, with an average CAG repeat length of 42, had no significant cognitive or psychiatric impairments compared with controls, according to neuropsychological testing and a battery that tested executive function, processing speed, memory, emotion, motivation, impulsivity and social cognition, researchers said.
Levels of NfL in the CSF, NfL in plasma, and CSF YKL-40, an astrocytic marker, were all elevated [false discovery rates (FDR)< 0.0001, =0.01, and =0.03, respectively] but the only marker that was more likely to be elevated in those closer to their expected clinical onset was CSF NfL (FDS, 0.001), researchers reported.
“CSF NfL appears to show good potential for tracking the very earliest neurodegenerative changes given its very close relationship with predicted years to onset,” Drs. Tabrizi and Zeun said.
There was no difference in total huntingtin protein between pre-HD subjects and controls. Researchers said it was the first time that total huntingtin was studied in a human population and that it was interesting that having the HD mutation doesn't seem to affect the amount of total huntingtin that's produced. Mutant huntingtin protein was detected in the pre-HD participants, but most of the time it was seen at a level that was too small to be reliably quantified.
There were no structural brain differences between the groups, except for a slightly smaller putamen volume in the pre-HD group. But that didn't appear linked to the predicted time to onset.
Researchers acknowledged that using plasma NfL as a biomarker would be preferable in terms of cost and practicality: While trials of huntingtin-lowering therapies delivered intrathecally allow for CSF collection, non-intrathecal treatment approaches would “add cost and complexity,” they said.
But far ahead of disease onset, CSF NfL appears to be the superior marker, they said. Forty-seven percent of the gene carriers had levels of CSF NfL above the control range, compared to only 13 percent for plasma NfL.
“Plasma NfL looks set to be a very useful tool to monitor progression and treatment effects in those close to predicted onset or early stage manifest disease—however, in our cohort who are much earlier in the disease process, CSF NfL appears to clearly outperform plasma NfL as a marker of disease,” Drs. Tabrizi and Zeun said.
The reliability of CSF NfL has to be explored further, they said, noting that early data from an antisense oligonucleotide huntingtin-lowering trial reported increased CSF NfL that was transient.
“We will develop a better understanding of NfL's response to therapeutic interventions as its performance in numerous clinical trial programs becomes apparent, alongside the performance of each therapy,” they said.
Researchers are planning to reassess the participants in a few years to evaluate how these measures change over time and to further understand which factors lead to faster progression in the early disease course.
Sandra Kostyk, MD, PhD, associate professor of neuroscience and neurology at the Ohio State University Wexner Medical Center, said it's an “intriguing study that contributes highly to the literature.”
The researchers, Dr.Kostyk said, make a strong case for NfL in the CSF as a strong candidate for use as a marker for the start of disease onset from a biological point of view, which can be used as a biomarker following the impact of any of interventions. But the marker needs to be validated across larger groups and over a longer period of time, she said.
Dr. Kostyk cautioned that the study population was carefully selected—a study strength —to include the average range of CAG repeats seen in HD patients, but doesn't cover the entire range of symptomatic repeat lengths. She noted that about 10 percent of patients have clinical onset below age 30 and about 10 percent above age 60. This variable range in the time of presentation of HD might present a logistical challenge to the potential value of CSF NfL in knowing when to begin interventional therapy.
“If you had a repeat size of 40, but you didn't have symptom onset until you were in your 70s or 80s, do you want to spent 30 years or 20 years getting repeated LPs (lumbar punctures) to see if your CSF marker is increasing?” she said.
“Still, the findings are an important step in understanding the time course involved in HD biology,” Dr. Kostyk said. “It emphasizes the opportunity we have in our research about deciding when to begin and how to begin future pre-symptomatic trials to slow or stop the disease. So I found that a very important aspect of this paper.”
Steven M. Hersch, MD, PhD, professor of neurology at Harvard, said, “The findings fill in knowledge about the trajectory of NfL and other markers in HD patients. But the lack of neurologic, cognitive and neuroimaging findings do not make them a compelling population for clinical trials, since there is no possibility of showing a clinical benefit and no supporting biomarkers or clinical signs to substantiate that a therapeutic effect on NfL might have a reasonable likelihood of predicting a benefit.”
Were a disease-modifying treatment to be found in symptomatic patients, the next step would likely be to study it in a prodromal population with more evidence for active disease, he said.
“Using CSF NfL measurements in conjunction with age and CAG repeat length in the setting of a clinical trial may prove to be useful as an enrichment marker to help increase the likelihood of seeing measurable change over the time frame of the trial.”
—DR. WAYNE MARTIN
Wayne Martin, MD, professor emeritus of neurology at the University of Alberta, said that findings offer further evidence that objective brain changes precede clinical onset of HD.
“Using CSF NfL measurements in conjunction with age and CAG repeat length in the setting of a clinical trial may prove to be useful as an enrichment marker to help increase the likelihood of seeing measurable change over the time frame of the trial,” he said. “Further studies regarding specificity and sensitivity of the NfL measurement are important.”
“I think the key question,” Dr. Martin said, “is whether NfL correlates directly with disease severity and progression. The goal in the search for an effective HD therapy is to alter disease progression, thereby stabilizing—or, ideally, improving—patient function and not merely to alter the expression of a biomarker that may be remote from the evolving clinical disease. These results provide a first step in answering this question.”
Drs. Tabrizi has received fees for consulting and serving on scientific advisory boards for Alnylam Pharmaceuticals Inc., Annexon Inc., DDF Discovery Ltd, F. Hoffmann-La Roche Ltd, Genentech, PTC Bio, Novartis Pharma, Takeda Pharmaceuticals Ltd, Triplet Therapeutics, UCB Pharma S.A., University College Irvine and Vertex Pharmaceuticals Incorporated. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. Drs. Hersch, Kostyk, and Martin had no relevant disclosures.