Potential Huntington’s Disease Biomarker Identified with fMRI Scans

Potential Huntington’s Disease Biomarker Identified with fMRI Scans

A team of researchers at Johns Hopkins Medicine have identified a possible non-invasive biomarker for testing new therapies to treat Huntington’s disease patients that have yet to show symptoms of the disease.

Huntington’s disease is a neurodegenerative disease caused by a mutation in the huntingtin gene (HTT) on chromosome 4. The mutated gene causes the progressive breakdown of nerve cells in the brain, resulting in movement, cognitive, and psychiatric disorders.

The disease is mostly an inherited disease, although around 10% of cases are caused by new mutations. Symptoms of the disease typically first appear when people are in their 30s or 40s. There are no treatments that can cure Huntington’s disease, although there are medications that can slow the progression of the disease. The disease is usually fatal after a period of 20 years following the onset of symptoms.

Patients with Huntington’s disease show dramatic decreases in the brain’s arterial blood volume, which results in progressive neuronal deterioration from low oxygen as the disease progresses.

The researchers conducted a study on mice engineered to carry the Huntingtin gene and mapped blood flow trajectory in the small blood vessels in the brain using blood volume to measure oxygen supply.

“What’s exciting about this study is the opportunity to identify a reliable biomarker that can track the potential success of genetic therapies before patients start manifesting symptoms,” said Wenzhen Duan, M.D., Ph.D., director of the translational neurobiology laboratory and psychiatry and behavior sciences professor at Johns Hopkins School of Medicine. “Such a biomarker could facilitate the development of new treatments and help us determine the best time to begin them.”

The researchers suppressed the Huntingtin gene and assessed the trajectory of arteriolar blood volumes at three, six, and nine months to identify abnormalities between the Huntington’s mice and the control group.

In the Huntington’s mice, the researchers identified a possible vascular response to decreased neuronal brain function and found that smaller blood vessels had a reduced diameter and increased density, which suggested compromised vascular structure could lead to lower blood volumes and a decreased ability to compensate for the loss during the symptomatic stage of the disease.

The researchers investigated whether it was possible to prevent the onset of symptoms by introducing an altered huntingtin gene into the mice prior to the onset of symptoms at two months of age and found that after 3 months the cerebral arteriolar blood volume observed through fMRI scans was equivalent to that of the control group of mice. The researchers also observed significant changes in arteriolar cerebral blood volume through fMRIs which begin prior to the onset of symptoms and the degeneration of neurons.

“Overall, our data suggest that the cerebral arteriolar blood volume measure may be a promising non-invasive biomarker for testing new therapies in patients with Huntington’s who are yet to show symptoms of the disease,” said Duan. “Introducing treatment in this early stage may have long-lasting benefits.” The next step will be to conduct clinical trials to validate the findings of their research.

You can read more about the study in the paper – Huntingtin silencing delays onset and slows progression of Huntington’s disease: a biomarker study – which was recently published in Brain. DOI: 10.1093/brain/awab190