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13 HD Insights, Vol. 12 We report here on our work using a combination of approaches to show that the cerebrovasculature is compromised at four different levels in the context of HD. We show that: 1) mHTT protein aggregates are found in all compartments of the neurovascular unit 2) blood vessels are more dense but smaller in size 3) this change in size and density is accompanied by an increased blood-brain barrier permeability that leads to peripheral blood cell infiltration, and 4) there are mHTT aggregates in transcytotic vesicles. These observations appeared on MRI and in postmortem tissue in both the R6/2 mouse model and HD patients (Figure). These findings raise critical questions regarding the impact of vascular alterations on neuronal network activity and degeneration in HD, and could indicate a more significant crosstalk between elements of the blood and the CNS than originally thought. This could in turn create an increased inflammatory response as a result of immune cell infiltration to the brain and facilitate mHTT accumulation due to the leaky blood-brain barrier. We aim to further elucidate the contribution of blood-brain barrier compromise, and the resulting presence of inflammatory elements, to the pathophysiology and progression of HD. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression By: Southwell AL, Smith SE, Davis TR, Caron NS, Villanueva EB, Xie Y, Collins JA, Li Ye M, Sturrock A, Leavitt BR, Schrum AG, Hayden MR (Summary by Amber L. Southwell, PhD) The lack of quantitative, robust, and reliable biomarkers for use in early subclinical diagnosis is a major obstacle for development of disease- modifying therapies for HD. Such markers are needed to assist in monitoring disease progression, patient stratification, and evaluating efficacy of therapeutics in the clinic. The Hayden lab at the University of British Columbia (UBC) has collaborated with colleagues at UBC and the Mayo Clinic to develop an ultrasensitive method of measuring mHTT in the cerebrospinal fluid (CSF) of HD patients and model mice, called microbead-based immunoprecipitation and flow cytometry (IP-FCM), that could meet these needs. See Figure for a schematic that summarizes the method. Using IP-FCM, we have shown that mHTT in the CSF originates in the brain and is released by injured or dying brain cells. Levels of mHTT in the CSF increase with worsening HD symptoms, suggesting that this approach will be useful as a measure of disease progression. Additionally, lowering mHTT in the brain using gene- silencing treatments results in a measurable reduction of mHTT in the CSF, indicating that this method could be used to verify and quantify changes in brain mHTT levels in response to experimental therapies. This advance is clinically relevant and will enable more rigorous assessment of important endpoints in evaluating therapies for HD. Copyright © Huntington Study Group 2015. All rights reserved. Research Round-Up: Insights, cont... Most influential paper In imaging and biomarkers… Cerebrovascular and blood-brain barrier impairments in Huntington's disease: potential implications for its pathophysiology By: Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagacé M, Kuan WL, Saint-Pierre M, Dury RJ, Alata W, St-Amour I, Mason SL, Calon F, Lacroix S, Gowland PA, Francis ST, Barker RA, Cicchetti F (Summary by Janelle Drouin-Ouellet, PhD) H D I N S I G H T S Figure: The main cerebrovascular compromise in HD patients and in an HD mouse model of the disease, comprised of mhtt expression in cell types associated with blood vessels, the alteration of blood vessel morphology and an increase in blood-brain barrier permeability Figure: Schematic of detection of mHTT in CSF by immunoprecipitation and flow cytometry Drouin-Ouellet J, Sawiak SJ, Cisbani G, et al. Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology. Ann Neurol. 2015 Aug;78(2):160-77. doi: 10.1002/ana. 24406. Epub 2015 Apr 9. Southwell AL, Smith SE, Davis TR, et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep. 2015 Jul 15;5:12166. doi: 10.1038/srep12166. Most influential paper