Levels of 3 metabolites in brain may mark Huntington’s progression
Study supports differences seen on scans of patients at varying disease stages
In Huntington’s disease (HD), progression is associated with metabolite changes in the brain that generally worsen as patients move from a presymptomatic stage to overt symptom onset, a review study reports.
Its scientists looked at data from published studies analyzing metabolic changes in the brain between people with Huntington’s and those without the disease, using a type of noninvasive imaging called proton magnetic resonance spectroscopy (H-MRS).
Specifically, levels of the metabolites N-acetyl aspartate (NAA) and creatine were found to be significantly reduced in the basal ganglia, a brain region severely affected by Huntington’s, before and, especially, after symptom onset.
Brain levels of another metabolite, called myo-inositol, were significantly lower in presymptomatic patients — a stage also known as pre-manifest disease — and significantly higher in those with manifest symptoms, relative to healthy controls. (Metabolites are the molecular byproducts of metabolism, the chemical reactions within cells providing energy and nutrients.)
Accordingly, findings highlight that “N-acetylaspartate and creatine in the basal ganglia are already sensitive at the preclinical stage and are promising biomarkers for tracking disease progression,” the researchers wrote, while myo-inositol could help in “distinguishing HD stages.”
Patients can go for decades without symptoms being evident
The review study, “Neurochemical changes in the progression of Huntington’s disease: A meta-analysis of in vivo 1H-MRS studies,” was published in Neurobiology of Disease.
Huntington’s is caused by excessive repeats of a sequence of three DNA building blocks – CAG – in the HTT gene, which provides instructions for producing the huntingtin protein. This increase in CAG repeats leads to abnormally long huntingtin proteins, which can form clumps that cause inflammation and nerve damage in the brain.
Patients can experience an array of disease symptoms — cognitive, behavioral, and those affecting movement or motor control — but there is “a decades-long asymptomatic stage before the onset of clinical symptoms (usually defined as motor signs),” the researchers wrote.
Identifying biomarkers that track disease-associated changes from before and after symptom onset, or that mark a specific disease stage, would allow for better predicting and monitoring of disease progression, helping to “determine the optimal window for future intervention, and develop personalized therapeutic strategies in different phases,” the researchers wrote.
Previous studies have pointed to metabolic changes in the brain, which can be measured using proton magnetic resonance spectroscopy, as being potential biomarkers.
However, “there has never been a comprehensive meta-analysis of … H-MRS studies” in Huntington’s disease, the team added.
Imaging has marked metabolic differences in the Huntington brain
Researchers in Germany systematically analyzed published studies up to December 2023 that reported on brain metabolic differences between Huntington’s patients at different disease stages and healthy people as a control group.
The goal was “to investigate neurochemical alterations in the common metabolites for Pre-HD [presymptomatic disease] and Symp-HD [symptomatic disease], that can help to further identify valid and specific biomarkers associated with progression and could be used to monitor treatment effects,” the researchers wrote.
A total of 16 studies were included in the meta-analysis: Nine compared data from 188 presymptomatic patients and 227 healthy controls, and 14 compared data from 306 symptomatic patients and 326 controls.
When brain regions were examined independently, only the basal ganglia, which is responsible for movement coordination and shows severe neurodegeneration in HD, exhibited significant changes.
Biomarkers seen to distinguish Huntington’s early, and disease stages
Across the studies, three metabolites emerged as promising biomarkers: N-acetyl aspartate, creatine, and myo-inositol. Changes in these and other metabolites, as well as in metabolite ratios, generally were more pronounced in symptomatic patients relative to patients without manifest symptoms.
Levels of NAA, a marker of neuronal health, in the basal ganglia was 8.41% lower among the presymptomatic group and 20.02% lower in symptomatic patients, relative to controls.
Basal ganglia levels of creatine, which is involved in energy production, also were diminished in both patient groups compared with controls: by 6.08% with presymptomatic Huntington’s and by 19.37% with symptomatic HD.
Myo-inositol, which is involved in nerve cell function and neuroinflammation, showed a unique pattern of dysregulation in the brains of patients in both groups.
Prior to the onset of detectable symptoms, patients showed 6.4% lower myo-inositol levels across all brain regions compared with controls. However, symptomatic patients had higher myo-inositol levels, by 17.24%, relative to controls.
Researchers suggested that myo-inositol could be used to distinguish between Huntington’s presymptomatic and symptomatic stages.
Study results indicate that “NAA and [creatine] in the basal ganglia have similar patterns of alterations in Pre-HD and Symp-HD, and seem to be sensitive and reliable in detecting early neuronal degeneration and … energy production deficits in Pre-HD,” the team wrote. “Besides, [myo-inositol] appears to be a specific marker for differentiating HD stages, as decreased in Pre-HD but increased in Symp-HD.”
Researchers also noted it is possible that metabolic changes beyond the basal ganglia were difficult to detect due to the small sample size. As such, “future studies need to pay more attention to the distribution of metabolites in other brain regions in the context of disease progression, which may provide more comprehensive mechanistic insights into HD [development],” they concluded.
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