Levels of KP Metabolites in Blood, CSF Unlikely as Disease Biomarkers
Metabolites seen as potential biomarkers of Huntington’s disease — called kynurenine pathway metabolites — showed little evidence of Huntington’s-specific activity in a recent study.
While researchers could not entirely rule out kynurenine pathway metabolites as possible treatment targets, their results suggest that the disease is not well represented by the levels of these molecules as found in patients’ blood and in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord.
The study, “Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington’s disease,” was published in the Journal of Neurochemistry.
The kynurenine pathway (KP) is the primary route for metabolizing the essential amino acid tryptophan, essential for the generation of cellular energy. Of note, amino acids are the building blocks of proteins, and metabolites are the intermediate products that derive from this metabolic reaction.
Imbalances in KP metabolites have been associated with several neurodegenerative and psychiatric disorders, as well as with cancer and autoimmune diseases.
Some past studies have found clues that KP metabolites are involved in Huntington’s, possibly by accumulating to toxic levels, but the evidence for this is limited. The few studies available predate the discovery of the Huntington genetic mutation, involve small numbers of patients, and often don’t control for things that could cause KP metabolite levels to vary, such as time of day or fasting.
The mutation underlying Huntington’s consists of copies of a DNA sequence, called a CAG repeat. The more this sequence is copied within the HTT gene, the earlier symptoms appear.
A team of researchers from the U.K. and the Netherlands sought to analyze differences in KP metabolites in the blood and CSF of Huntington’s patients and healthy controls.
“Quantifying KP metabolites in HD [Huntington’s disease] CSF remains desirable, both to study pathobiology [disease mechanisms and manifestations] in living human patients, and as a potential source of biomarkers to quantify pathway dysfunction and the biochemical impact of therapeutic interventions targeting its components,” the researchers wrote.
They recruited 80 adults between the ages of 18 and 75 to their study. Of these, 40 had manifest — early stage — Huntington’s, 20 had pre-manifest Huntington’s, and 20 were healthy individuals.
Although the levels of most KP molecules appeared to remain stable over the span of four to eight weeks within patient CSF, they showed no significant difference between the three groups, and associated with age, but not with the number CAG repeats, sex, or other key factors.
The researchers next evaluated the ratios between pairs of these molecules. Although the ratios of two pairs — 3-HK to KYNA and of KYNA to KYN — differed between manifest and pre-manifest patients, neither these nor any of the other ratios associated with CAG repeat count, age, sex, or other variables.
Additionally, none of the metabolites measured in the blood or CSF showed relevant associations with clinical or imaging measures as assessed on MRI scans.
“These findings suggest that the characteristics of KP metabolites make them less likely to be useful as diagnostic and monitoring biomarkers,” the researchers wrote.
Rather, the researchers suggested that the observed association between all measured KP metabolites and age might be one reason they appeared as altered in previous Huntington’s studies, as the disorder typically becomes evident in adulthood and develops slowly over time.
Ratios that did differ somewhat between manifest and pre-manifest individuals, they wrote, might reflect changes relevant to nerve damage, although further investigation is needed.
Despite the largely negative findings, the team points out that these results do not imply that KP metabolites are not valid therapeutic targets.
“It is possible that cell-specific or region-specific disease-related alterations in this pathway contribute substantially to the pathogenesis of [Huntington’s] and that pharmacologically correcting them could favourably modify the course of the disease,” the researchers wrote.
The small differences seen between manifest and pre-manifest patients might grow more significant when measured in larger patient groups, they added.
“Overall, however,” they concluded, “this study provides little support for a relevant alteration of KP function in [Huntington’s] that is biochemically detectable in accessible patient biofluids.”