Biomarkers Measured for Early Detection of Huntington's Disease

The 5' end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, which is repeated multiple times. Normal persons have a CAG repeat count of between seven and 35 repeats, while the mutated form of the gene has anywhere from 36 to 180 repeats. The mutant form of huntingtin is broken down into toxic peptides, which cause the loss of a type of brain cell called striatopallidal medium spiny projection neurons (MSNs). Destruction of these cells causes involuntary movements, problems with coordination, and, ultimately, in cognitive decline and depression. There is currently no treatment for this fatal disease.

Early detection of Huntington’s disease (HD) could help the development of effective therapeutic strategies to block or delay disease progression. Seeking a method for early diagnosis of HD, investigators at University College London (United Kingdom) tested samples of blood plasma and cerebrospinal fluid (CSF) for both neurofilament light (NfL) protein, which is often a product of nerve cell damage, and for concentration of the mutant huntingtin (mHTT) protein that causes the disease. They then compared these results to traditional clinical measurements such as brain area volumes from MRI scans and motor and cognitive tests.

Results revealed that among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over four to eight weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. Concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. Computational analysis further showed that alterations in circulating NfL and mHTT concentrations may be among the earliest detectable changes in HD.

These findings provided evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.

"Many people who develop Huntington's report subtle signs such as with mood or coordination, in what is called the prodromal stage before any changes can be detected by brain scans. We have found that blood testing could help identify groups of people with very early neurodegeneration to help us run clinical trials of drugs to prevent symptoms," said senior author Dr. Ed Wild, a principal investigator in the institute of neurology at University College London. "We were surprised to find the blood tests could pick up signs even before any evidence of neurodegeneration could be seen in brain scans."

The paper was published in the September 12, 2018, online edition of the journal Science Translational Medicine.

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