Leading researchers report on the elusive search for biomarkers in Huntington's disease

While Huntington's disease (HD) is currently incurable, the HD research community anticipates that new disease-modifying therapies in development may slow or minimize disease progression. The success of HD research depends upon the identification of reliable and sensitive biomarkers to track disease and evaluate therapies, and these biomarkers may eventually be used as outcome measures in clinical trials. Biomarkers could be especially helpful to monitor changes during the time prior to diagnosis and appearance of overt symptomatology. Three reports in the current issue of the Journal of Huntington's Disease explore the potential of neuroimaging, proteomic analysis of brain tissue, and plasma inflammatory markers as biomarkers for Huntington's disease.

"Characteristics of an ideal biomarker include quantification which is reliable, reproducible across sites, minimally invasive and widely available. The biomarker should show low variability in the normal population and change linearly with disease progression, ideally over short time intervals. Finally, the biomarker should respond predictably to an intervention which modifies the disease," says Elin Rees, researcher at UCL Institute of Neurology, London.

In the first report, Rees and colleagues explore the use of neuroimaging biomarkers. She says they are strong candidates as outcome measures in future clinical trials because of their clear relevance to the neuropathology of disease and their increased precision and sensitivity compared with some standard functional measures. This review looks at results from longitudinal imaging studies, focusing on the most widely available imaging modalities: structural MRI (volumetric and diffusion), functional MRI, and PET.

"All imaging modalities are logistically complicated and expensive compared with standard clinical or cognitive end-points and their sensitivity is generally reduced in individuals with later stage HD due to movement," says Rees. "Nevertheless, imaging has several advantages including the ability to track progression in the pre-manifest stage before any detectable clinical or cognitive change."

Current evidence suggests that the best neuroimaging biomarkers are structural MRI and PET using [11C] raclopride (RACLO-PET) as the tracer, in order to assess changes in the basal ganglia, especially the caudate.

A study led by Garth J.S. Cooper, PhD, professor of Biochemistry and Clinical Biochemistry at the School of Biological Sciences and the Department of Medicine at the University of Auckland, used comparative proteome analysis to identify how protein expression might correlate with Huntington's neurodegeneration in two regions of human brain: the middle frontal gyrus (MFG) and the visual cortex (VC). The investigators studied post mortem human brain tissue from seven HD brains and eight matched controls. They found that the MFG of HD brains differentially expressed 22 proteins compared to controls, while only seven were different in the VC. Several of these proteins had not been linked to HD previous. Investigators categorized these proteins into six general functional categories: stress response, apoptosis, glycolysis, vesicular trafficking, and endocytosis. They determined that there is a common thread in the degenerative processes associated with HD, Alzheimer's disease, and diabetes.