Nerve proteins may serve as biomarkers for SBMA progression
Study: Over 2 years, levels rose alongside further declines in functional ability
Adults with spinal and bulbar muscular atrophy (SBMA) have elevated levels of neurofilament light (NfL) chain and glial fibrillary acidic protein (GFAP), two biomarkers for nerve damage, in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord, according to a study.
Over two years, biomarker levels in SBMA patients rose alongside further declines in functional abilities, indicating ongoing neurodegeneration, the study found.
“These results indicate that SBMA is associated with progressive neurodegeneration and that either CSF, GFAP, or NfL may be useful for patient stratification and monitoring treatment effects in trials of disease-modifying therapies,” researchers wrote.
The study, “CSF and blood neuronal injury biomarkers in spinal bulbar muscular atrophy and amyotrophic lateral sclerosis 4,” was published in Brain Communications.
Study compares SMBA to ALS4
SBMA, or Kennedy’s disease, is a rare adult-onset form of spinal muscular atrophy. It’s caused by genetic defects in the AR gene that lead to the production of abnormal androgen receptor proteins, which are thought to form toxic clumps in motor neurons, the specialized nerve cells responsible for controlling muscle movement.
A slowly progressing condition, SBMA is characterized by weakness and wasting in the limbs and bulbar muscles of the face and throat. Even so, life expectancy in SBMA patients is near normal.
Because there are few biomarkers to assess SBMA progression and therapeutic response, a research team at the National Institute of Neurological Disorders and Stroke, in the U.S., designed an observational study (NCT04944940) to examine biomarkers of neurodegeneration in the bodily fluids of SBMA patients.
As a comparison, the team also studied people with amyotrophic lateral sclerosis type 4, or ALS4, a juvenile and slowly progressing form of ALS., in NCT04394871.
Caused by mutations in the SETX gene, which also lead to motor neuron degeneration, ALS4 is marked by muscle weakness that usually appears in late childhood or adolescence and slowly worsens over time. Life expectancy is unaffected in ALS4.
In CSF samples, GFAP was higher in SBMA patients than in controls
In total, 10 SBMA patients, seven ALS4 patients, and five healthy individuals who served as controls underwent sampling of blood and CSF. Six SBMA patients also underwent follow-up sampling for up to two years. The researchers then measured the levels of three markers of neurodegeneration: NfL, GFAP, and total-tau (T-tau).
Initial comparisons confirmed that the levels of NfL, GFAP, and T-tau in blood generally matched those in CSF.
In CSF samples, GFAP was significantly higher in SBMA patients than in controls, but not compared with ALS4 patients. NfL was also significantly higher in SBMA samples compared with both ALS4 and control samples. T-tau did not differ between the groups.
In blood samples, the levels of NfL or GFAP did not differ between SBMA, ALS4, or controls, but T-tau levels were significantly lower in SBMA than in controls.
NfL levels in CSF samples had the highest diagnostic accuracy in separating SBMA from controls and ALS4, with an area-under-the-curve (AUC) of 0.79 and 0.77, respectively. AUC is a number between zero and one that shows how well a test can distinguish between two conditions, with values closer to one reflecting better accuracy. The AUC for T-tau in blood samples to separate SBMA from controls was 0.94, and the AUC for SBMA versus ALS4 was 0.89.
The results suggest that SBMA patients have increased concentrations of CSF GFAP and NfL as compared to ALS4 and controls, and higher levels of these biomarkers are associated with disease severity.
Elevated levels of all three biomarkers in the CSF and blood correlated with a decline in several functional measures, including the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS), the timed up and go test, and the adult myopathy assessment tool. The strongest match was between GFAP in CSF and the TUG test, which measures the time it takes to rise from a chair, walk a short distance, turn around, and sit back down.
Over two years, the average SBMAFRS scores dropped by 0.83 points in SBMA patients. At the same time, GFAP rose by 1.40 times, NfL by 1.25 times, and T-tau by 1.16 times in CSF. T-tau in blood also increased by 1.2 times.
“The results suggest that SBMA patients have increased concentrations of CSF, GFA, and NfL as compared to ALS4 and controls, and higher levels of these biomarkers are associated with disease severity,” the researchers concluded. “Future directions include replication and validation of the CSF findings in a larger longitudinal cohort.”
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