Changes in brain metabolites may be biomarkers for CLN3 disease
Markers of disease severity may be useful in clinical trials: Study
Changes in the levels of certain metabolites in the brain among people with juvenile Batten disease, also called CLN3 disease, are significantly associated with multiple measures of disease severity, a study showed.
Age accounted for many of these metabolite changes. Still, the levels of some brain metabolites — the byproducts of brain metabolism — were strongly associated with disease severity regardless of age.
As such, the researchers recommended that brain metabolite levels, as measured by non-invasive magnetic resonance spectroscopy (MRS), similar to an MRI, may be useful in future studies as surrogate measures of treatment responses.
“[Our] findings support use of these MRS-based measures of disease state in clinical trials,” the researchers wrote.
The MRS study, “Brain proton MR spectroscopy measurements in CLN3 disease,” was published in the journal Molecular Genetics and Metabolism.
The goal: Finding much-needed biomarkers of CLN3 disease severity
Batten disease is the result of inherited mutations that hinder the proper functioning of lysosomes, the recycling hubs within cells. As a result, accumulated waste materials build up to toxic levels, leading to tissue damage, particularly in nerve cells. The form of Batten known as CLN3 disease is caused by mutations in both copies of the CLN3 gene.
Signs of CLN3 disease typically start at about 4-6 years of age, with visual impairment as the first symptom, followed by cognitive decline, motor disabilities, and seizures.
To identify much-needed biomarkers of CLN3 disease, a team of researchers in the U.S. looked for potential associations between brain levels of metabolites that are markers of neuronal health or inflammation and disease severity in juvenile Batten patients.
The team examined MRS-scan and disease severity data collected from 27 patients, ages 6-21. The data came from when these individuals first enrolled in an ongoing natural history study (NCT03307304) sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, in Maryland.
A group of 38 healthy adults and children without symptoms, ages 1-42, were included as controls to compare normal age-related changes in metabolite levels.
A dozen patients carried a common disease-causing mutation, called 966-bp deletion, in both CLN3 gene copies (966-bp deletion homozygous). Another 10 carried this mutation in one gene copy and a different variant in the other copy (966-bp deletion heterozygous). Five patients had mutations other than the 966-bp deletion.
Two brain regions were investigated: the grey matter of the parietal lobe, near the upper back of the brain, and the left centrum semiovale (LCSO), an area of white matter within the brain. Grey matter comprises nerve cell bodies, while white matter mainly consists of nerve cell fibers.
Four primary brain metabolites were measured, including creatine, myoinositol, choline-containing compounds (choline), the combination of N-acetyl aspartate and N-acetyl aspartyl glutamate (NAA), and combined glutamate, glutamine, and gamma-aminobutyric acid (Glx).
Levels of 2 brain metabolites most closely tied to worse disease severity
The results showed that patients had lower levels of NAA, Glx, and creatine in the parietal grey matter than controls and that these differences increased with age. LCSO white matter scans also found NAA deficits that increased with age and trends toward increasing levels of creatine and choline.
Age-related decreases in myoinositol levels in white matter were seen in 966-bp deletion homozygous patients. By contrast, increasing LCSO myoinositol occurred in those who were 966-bp deletion heterozygous. All other metabolites were similar, regardless of genetic defect.
The team then assessed potential relationships between metabolite level differences and clinical assessments made at the study’s start.
Assessment tools included the Unified Batten Disease Rating Scale (UBDRS), a measure of CLN3 disease severity, focusing on scores for physical ability, capability, and a clinician’s global impression of change. The verbal IQ and Vineland Adaptive Behavior Composite (ABC) also were used to assess developmental abilities.
Within the LCSO white matter, excess creatine and NAA deficit most robustly correlated with disease severity, as measured by all three assessment tools (UBDRS, verbal IQ, and ABC).
However, age-related changes accounted for most of these metabolite differences, except for an excess of LCSO myoinositol, which remained associated with the UBDRS physical scores. Moreover, excess LCSO myoinositol was linked to lower UBDRS physical scores in homozygous patients, with a direct opposite effect in heterozygous patients.
“These correlations account for the same contribution made by considering the age of the participants,” the team wrote, “therefore, age seems to be the dominant variable predicting disease severity in the population.”
Within the parietal grey matter, lower levels of NAA and Glx most strongly correlated with all three severity measures. Across all cases, greater NAA or Glx deficits were associated with worse severity. As in the white matter region, most correlations between metabolites and severity were accounted for by age.
Of the MRS-visible metabolites measured, the cross-sectional results support the validity of measuring levels of NAA and Glx … as promising quantitative markers of disease state in CLN3 disease.
After adjusting for age and genetic defect, however, choline levels in the parietal grey matter were significantly associated with worse scores on verbal IQ, ABC, and UBDRS clinicians’ global impression of change, reflecting more severe disease.
“Of the MRS-visible metabolites measured, the cross-sectional results support the validity of measuring levels of NAA and Glx … as promising quantitative markers of disease state in CLN3 disease,” the researchers wrote, adding that “in a clinical trial, divergence of the MRS measurements and clinical severity markers from age may be useful as surrogate measures for treatment responses.”
About the Author
