In our final issue for 2014, the HD Insights team wanted to recognize the most influential papers in HD research in the 2013–2014 year. Our staff, Editorial Board, and leading HD researchers nominated the eleven papers below in three categories: lab research, clinical research, and imaging and biomarkers. The HD Insights Editorial Board then voted to select the three most influential papers, one in each category. The authors of the winning papers will present their research in a panel discussion at the Huntington Study Group meeting on November 7, 2014. Congratulations to all the nominees and winners!
Mutant huntingtin is present in neuronal grafts in Huntington’s disease patients
By: Cicchetti F, Lacroix S, Cisbani G, Vallières N, Saint-Pierre M, St-Amour I, Tolouei R, Skepper JN, Hauser RA, Mantovani D, Barker RA, Freeman TB (Summary by Francesca Cicchetti, PhD)
Mutant huntingtin (mHTT), which drives HD pathology, has long been thought to exert its effects in a cell-autonomous manner, where degeneration occurs within individual cells that carry the mutant gene. We investigated the hypothesis that mHTT is capable of spreading within cerebral tissue.
The brains of four HD patients who received genetically unrelated fetal neural allografts at least a decade earlier were examined postmortem. We found a number of mHTT protein aggregates located within intracerebral allografts of striatal tissue in three of these HD patients. No grafts survived in the fourth transplant recipient. The mHTT aggregates were observed in the extracellular matrix of the genetically unrelated transplanted tissue, while in the host brain they were localized in neurons, neuropil, extracellular matrix, and blood vessels. In addition, peripheral immune cells in separate HD patients contained mHTT. There are thus a number of non-cell autonomous mechanisms that could explain these observations, including trans-synaptic propagation and hematogenous transport of mHTT, among others.
This is the first in vivo demonstration of mHTT spread in patients with a monogenic neurodegenerative disorder of the CNS. These observations raise questions about the importance of non–cell-autonomous mechanisms of pathological protein spread, and provide new targets for the development of therapeutic strategies.
Deep brain stimulation for Huntington’s disease: long-term results of a prospective open-label study
By: Gonzalez V, Cif L, Biolsi B, Garcia-Ptacek S, Seychelles A, Sanrey E, Descours I, Coubes C, de Moura AM, Corlobe A, James S, Roujeau T, Coubes P (Summary by Victoria Gonzalez, MD, PhD)
The role of deep brain stimulation (DBS) in the clinical management of HD has not yet been validated, although promising case reports have shown its efficacy in the treatment of severe chorea. This study aimed to analyze long-term motor outcome of a cohort of HD patients treated with globus pallidus internus (GPi) DBS. Seven patients with pharmacologically resistant chorea were included in a prospective open-label study with a median follow-up of three years. The Unified HD Rating Scale motor section was the main outcome measure. GPi DBS led to significant reduction of chorea for all patients with a mean improvement of 58.3% at one-year visit and 59.8% at three-year visit (p<0.05). Switching OFF stimulation tests confirmed sustained therapeutic effect for chorea throughout the study period. Bradykinesia and dystonia showed a non-significant trend towards progressive worsening. Increased bradykinesia was partly induced by DBS settings, and improved after adjustment of stimulation parameters. GPi DBS may provide sustained reduction of chorea in selected HD patients, with transient benefit in physical aspects of quality of life before progression of behavioral and cognitive disorders. Further studies are needed to assess the impact of GPi DBS on quality of life and cognitive measures in HD.
PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease
By: Rosas HD, Doros G, Gevorkian S, Malarick K, Reuter M, Coutu JP, Triggs TD, Wilkens PJ, Matson W, Salat DH, Hersch SM (Summary by H. Diana Rosas, MD)
PRECREST, the first clinical trial of a drug intended to delay the onset of symptoms in individuals at risk for HD, enrolled sixty-four participants, of whom nineteen knew their gene status. Participants were randomized into two groups, regardless of gene status: one group to twice-daily oral doses of creatine, up to thirty grams per day, the other, placebo for six months.
Participants were followed for an additional twelve months on open-label creatine and assessed at regular study visits for adverse effects, and dosage levels were adjusted, if necessary, to reduce unpleasant side effects. Cognitive assessments, measurement of blood markers and MRI brain scans were conducted at the trial’s outset, at six months, and at the end of the study. Fifteen participants, including several who knew that they carried the HD mutant gene, discontinued taking creatine because of gastrointestinal discomfort, taste of the drug, inconvenience, or the stress of being constantly reminded of their HD risk. MRI scans at six months showed a slower rate of cortical and basal ganglia atrophy in gene-positive carriers who took creatine, compared to placebo. After twelve months, atrophy rates in those who crossed over to treatment were also slower than during the period of taking placebo. The results of the trial suggest that at-risk individuals can participate in clinical trials even if they do not want to learn their genetic status, and that useful biomarkers can be developed to help assess therapeutic benefits.