GFAP may be Huntington’s disease progression biomarker: Study
Protein levels in cerebrospinal fluid increase as disease progresses
Levels of glial fibrillary acidic protein (GFAP), a marker of damage to specific neuron-supporting cells, in the fluid surrounding the brain and spinal cord increase with the progression of Huntington’s disease, a study showed.
Higher GFAP levels in the cerebrospinal fluid (CSF) were also significantly associated with more severe disease and with a higher risk of disease onset within five years among carriers of Huntington’s-causing mutations who were not yet showing symptoms.
The findings point to GFAP as “a potential biomarker of progression in HD [Huntington’s disease],” the researchers wrote, although they emphasized that larger studies are needed to confirm its utility.
The study, “Cerebrospinal fluid glial fibrillary acidic protein, in contrast to amyloid beta protein, is associated with disease symptoms in Huntington’s disease,” was published in The Journal of the Neurological Sciences.
Huntington’s is caused by excessive repeats of a sequence of three DNA building blocks, known collectively as CAG, in the HTT gene. This leads to the production of an abnormal huntingtin protein that forms toxic aggregates that accumulate inside neurons in the brain, eventually causing their death.
Searching for potential biomarkers
Huntington’s is diagnosed with the onset of hallmark motor symptoms, classified as manifest disease. However, some people may experience subtle changes in cognitive function, behavior, and fine motor skills before overt motor symptoms emerge. This is a preclinical stage referred as premanifest.
While levels of neurofilament light chain (NfL), a marker of nerve cell damage, in both the blood and CSF have shown biomarker potential for Huntington’s onset and clinical severity, “there is a need to develop biomarkers that reflect various aspects of disease mechanisms in HD,” the researchers wrote.
The team of researchers in three Huntington’s clinics in Sweden evaluated whether CSF levels of amyloid beta 42 and GFAP could be biomarkers of Huntington’s onset and progression.
Aggregation of amyloid beta 42 into toxic clumps is a hallmark of Alzheimer’s disease, and lower levels of the protein have been reported in people with neurodegenerative diseases.
GFAP is a marker of damage to astrocytes, the star-shaped cells that support neurons in the brain and whose dysfunction has been implicated in Huntington’s. Higher GFAP levels have been associated with certain neurodegenerative conditions.
The study looked at CSF samples from 59 adults, ranging in age from 20 to 78. Thirteen of them had premanifest Huntington’s, 27 had manifest Huntington’s, and 29 without signs of neurological disease, who served as controls.
Amyloid beta 42 levels were measured in all participants, while GFAP was measured in 47 participants: 13 with premanifest disease, 26 with manifest Huntington’s, and eight controls. The low number of controls was due to lack of remaining liquid from CSF samples, the team noted.
The researchers found a significant association between age and CSF levels of GFAP, but not amyloid beta 42. Given that the premanifest group was much younger than the manifest group (mean age 37.2 vs. about 55), analyses for both proteins were adjusted for age.
Analyses were also adjusted to reflect conditions at the centers at which samples were collected, as there were differences among centers in terms of storage time and protein levels in samples.
Adjusted analyses showed that there were no significant differences in CSF amyloid beta 42 levels among any of the three groups.
Higher GFAP, higher disease burden
CSF GFAP levels were significantly higher in manifest patients (mean 424 nanograms/L) than in premanifest patients (mean 266 nanograms/L) and healthy controls (208 nanograms/L). No significant differences were seen between the premanifest and control groups.
Among Huntington’s patients, higher GFAP levels in the CSF were significantly associated with a higher disease burden score (DBS), which considers the number of CAG repeats and age, with higher scores indicating worse disease burden.
There was also a significant link between higher levels of GFAP and lower scores in the total functional capacity (TFC) and the composite Unified Huntington’s disease rating scale (cUHDRS), indicating worse disability. cUHDRS accounts for cognitive function, motor skills, and the ability to function independently in daily life — assessed with the TFC.
The higher the GFAP levels, the higher the risk of experiencing disease onset within five years among those with premanifest Huntington’s.
No significant associations were observed between CSF amyloid beta 42 levels and DBS, TFC, cUHDRS, or five-year risk of onset among premanifest patients.
“To the best of our knowledge, this exploratory study is the first to assess the role of CSF [amyloid beta] and GFAP as potential biomarkers before and after clinical onset in HD,” the researchers wrote. “We provide preliminary evidence that indicates CSF [amyloid beta 42] has limited potential as a biomarker for HD,” but CSF GFAP levels “may have a role in assessing the severity of HD, and could potentially serve as a surrogate [outcome measure] in clinical trials,” the team concluded.
About the Author
