Brain-Derived Neurotrophic Factor Levels ‘Unlikely’ as Valid Biomarker
Brain-derived neurotrophic factor (BDNF) may not be the biomarker for Huntington’s disease that it was previously thought to be, a recent study reported.
The progressive loss of BDNF, a factor that helps neurons grow and survive, associates with Huntington’s progression in mouse disease models, and past studies found it at reduced levels in patients. Because of this evidence, some experimental Huntington’s therapies target the BDNF pathway.
Scientists at University College London, however, recently found no difference in BDNF levels between presymptomatic and symptomatic Huntington’s patients, or those of healthy controls.
Their study, “Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington’s disease,” was published in the journal Scientific Reports.
Proposed as a blood biomarker for Huntington’s, BDNF has not yet been “successfully quantified” in patients’ cerebrospinal fluid or CSF, the fluid bathing the brain and spinal cord, the study reported.
If the progression of Huntington’s disease were to affect BDNF levels, they could serve as a means of measuring dysfunction, estimating likely outcomes (prognoses), and monitoring the effects of some therapies.
Previous reports of BDNF levels in the CSF of people with neurodegenerative diseases “have found concentrations below the linear range” of the assay used to test for them, the researchers wrote, “raising doubt as to the validity and accuracy of the reported disease differences.”
To provide a more quantitative measure of BDNF levels in the blood and CSF related to Huntington’s disease, the team took sensitive measurements of the protein from the plasma (blood without red blood cells) and CSF of 20 people with presymptomatic Huntington’s, 40 with evident Huntington’s symptoms, and 20 healthy controls over a two-year period.
Overall, the concentration of BDNF in participants’ CSF was below the limit of detection of a widely used, conventional test called an ELISA. A more sensitive assay was able to detect BDNF levels in all participants, but showed no appreciable difference between people carrying the Huntington’s-causing mutation and healthy individuals, both in the blood and CSF.
BDNF concentrations also did not associate with brain volume as measured by MRI — a standard means of assessing neurodegeneration — or with clinical disease measures. Researchers noted only plasma BDNF levels “weakly” correlated with the Verbal Fluency category scores on the Unified Huntington’s Disease Rating Scale.
Furthermore, BDNF concentrations in the CSF neither differed noticeably between patients at any of Huntington stages, nor provided enough information to accurately distinguish symptomatic and presymptomatic Huntington’s mutation carriers apart from controls.
One unexpected finding was that BDNF levels in frozen plasma appeared to decline the longer a sample was stored.
“This diminishes the utility of stored frozen samples for BDNF quantification in plasma and suggests time in storage should be controlled for in future biomarker studies,” the researchers wrote.
Prior to sampling participants’ blood and CSF, the investigators had compared different standard ELISA test kits and selected the one that proved to be most sensitive, meaning it was able to detect the smallest amount of BDNF. They also ruled out age, medications, and body mass index as potential factors influencing BDNF concentration.
“We conclude,” the researchers wrote, “that BDNF in CSF and plasma is unlikely to be a biomarker of [Huntington’s] progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.”
As an important caveat, however, they added that “it is important to note that even though we found BDNF to lack utility as a biomarker of [Huntington’s] in the natural history setting, it is still theoretically possible that a therapeutic intervention could produce detectable and meaningful changes in CSF or plasma BDNF.
“Our findings may be of value for the design of such trials in which BDNF would serve as a pharmacodynamic biomarker.”