Huntington’s disease brains had widespread differences in metal levels compared with controls, post-mortem data showed.
Decreases in selenium levels were seen in 11 of 11 investigated brain regions in Huntington’s disease, reported Melissa Scholefield, PhD, of the University of Manchester, England, and co-authors. Selenium level risk ratios ranged from 2.3 to 9.0, and effect sizes were 0.7 to 1.9, the researchers wrote in eBioMedicine.
Increased sodium/potassium ratios were observed in every brain region studied (with risk ratios ranging from 2.5 to 8.0, and effect sizes from 1.2 to 5.8), except the substantia nigra. Several brain regions had increased calcium or zinc levels. Localized decreases in iron, copper, and manganese were seen in the globus pallidus, cerebellum, and substantia nigra, respectively.
These changes in metal levels could contribute to several pathogenic mechanisms, including mitochondrial dysfunction, oxidative stress, and blood-brain barrier dysfunction, Scholefield noted.
Huntington’s disease is a neurodegenerative disorder caused by an autosomal dominant mutation in the HTT gene that leads to the production of mutated huntingtin protein. It is characterized by progressive motor, psychiatric, and cognitive deterioration.
“Despite all the research that has been performed on Huntington’s disease, we still currently have no treatments that can stop, slow, or reverse its symptoms,” Scholefield told MedPage Today. “We hope this new discovery, with further research, could potentially lead to a new drug target in the future.”
Earlier evidence suggested blood selenium levels in Huntington’s disease were increased, which is one reason why patients should not self-medicate with supplements, she cautioned.
“Any over-the-counter supplements may, in fact, cause harm by further increasing blood selenium levels without having any benefit on brain selenium levels,” Scholefield said. “Further studies are needed to determine the best method of delivery and dose for any potential selenium supplementation to ensure it’s both safe and effective in targeting selenium levels in the brain itself.”
Scholefield and colleagues aimed to investigate whether changes in metal levels could be seen in end-stage post-mortem Huntington’s brains using inductively-coupled plasma mass spectrometry.
They obtained brain tissues from nine Huntington’s disease cases and nine controls, focusing on 11 brain regions: the cerebellum, substantia nigra, motor cortex, middle frontal gyrus, middle temporal gyrus, sensory cortex, cingulate gyrus, hippocampus, entorhinal cortex, globus pallidus, and putamen.
The researchers then measured the concentrations of eight essential metals — sodium, potassium, magnesium, calcium, iron, zinc, copper, and manganese — and the metalloid selenium in brain tissues.
All cases had genetically confirmed Huntington’s disease and were clinically manifest at the time of death. Both case and control groups included three females and six males. Mean age was 67.4 among cases and 65.2 among controls. The most common cause of death in Huntington’s cases was bronchopneumonia; in controls, it was ischemic heart disease.
The most striking finding was the deficiency of selenium in every part of the brain studied, the researchers emphasized. But several steps need to be performed before this information could be used to help patients, Scholefield observed.
“First, we must validate our results by using a larger study size with more participants,” she said. “Second, we must determine how selenium contributes to symptoms in Huntington’s disease.”
“Third, we would want to determine whether selenium supplementation may help alleviate, delay, or slow the development of symptoms — what dose is needed, is it safe, can it cross from the bloodstream into the brain, what is the best method of administering the selenium, etc.,” she continued.
“We are, at this point, in a very early stage,” Scholefield said. “We will not know the answers to any of these questions until further studies have been performed.”
This study was supported by the Lee Trust, the Endocore Research Trust, Cure Huntington’s Disease Initiative, the Oakley Mental Health Research Foundation, the Medical Research Council, the New Zealand Neurological Foundation, and others.
A patent disclosing selenium treatment for Huntington’s disease has been submitted to the U.S. Patent and Trade Office for examination by Scholefield and a co-author; the patent will be owned by the University of Manchester and the authors have no duality of interest. Scholefield has received travel support from Alzheimer’s Research U.K., Guarantors of Brain, and the British Neuroscience Association. Co-authors declare had nothing to disclose.
Source Reference: Scholefield M, et al “Widespread selenium deficiency in the brain of cases with Huntington’s disease presents a new potential therapeutic target” eBioMedicine 2023; DOI: 10.1016/j.ebiom.2023.104824.