Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood

Highly quantitative biomarkers of neurodegenerative disease remain an important need in the urgent quest for disease-modifying therapies. For Huntington's disease (HD), a genetic test is available (trait marker), but necessary state markers are still in development. In this report, we describe a large battery of transcriptomic tests explored as state biomarker candidates. In an attempt to exploit the known neuroinflammatory and transcriptional perturbations of disease, we measured relevant mRNAs in peripheral blood cells. The performance of these potential markers was weak overall, with only one mRNA, immediate early response 3 (IER3), showing a modest but significant increase of 32% in HD samples compared with controls. No statistically significant differences were found for any other mRNAs tested, including a panel of 12 RNA biomarkers identified in a previous report [Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, et al. (2005) Proc Natl Acad Sci USA 102:11023–11028]. The present results may nonetheless inform the future design and testing of HD biomarker strategies.

[1]  S. Fahn,et al.  Huntington disease , 1979, Neurology.

[2]  Jane S. Paulsen,et al.  Preparing for preventive clinical trials: the Predict-HD study. , 2006, Archives of neurology.

[3]  S. Tabrizi,et al.  Predict-HD and the future of therapeutic trials , 2006, The Lancet Neurology.

[4]  S. Hunot,et al.  Neuroinflammatory processes in Parkinson's disease , 2003, Annals of neurology.

[5]  P G Bhide,et al.  Early and Progressive Accumulation of Reactive Microglia in the Huntington Disease Brain , 2001, Journal of neuropathology and experimental neurology.

[6]  Sarah J Tabrizi,et al.  Gene expression in Huntington's disease skeletal muscle: a potential biomarker. , 2005, Human molecular genetics.

[7]  Jane S. Paulsen,et al.  Unified Huntington's disease rating scale: Reliability and consistency , 1996, Movement disorders : official journal of the Movement Disorder Society.

[8]  I. Heuser,et al.  The limbic-hypothalamic-pituitary-adrenal axis in Huntington's disease , 1991, Biological Psychiatry.

[9]  Å. Petersén,et al.  Hypothalamic–endocrine aspects in Huntington's disease , 2006, The European journal of neuroscience.

[10]  D. Bonifati,et al.  Role of complement in neurodegeneration and neuroinflammation. , 2007, Molecular immunology.

[11]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[12]  S. Tabrizi,et al.  Biomarkers for neurodegenerative diseases , 2005, Current opinion in neurology.

[13]  Ash A. Alizadeh,et al.  Individuality and variation in gene expression patterns in human blood , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Charles Kooperberg,et al.  Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. , 2002, Human molecular genetics.

[15]  Jane S. Paulsen,et al.  Unified Huntington's disease rating scale: Reliability and consistency , 1996, Movement disorders : official journal of the Movement Disorder Society.

[16]  A. Böyum,et al.  Isolation of leucocytes from human blood. A two-phase system for removal of red cells with methylcellulose as erythrocyte-aggregating agent. , 1968, Scandinavian journal of clinical and laboratory investigation. Supplementum.

[17]  J. Olson,et al.  Regional and cellular gene expression changes in human Huntington's disease brain. , 2006, Human molecular genetics.

[18]  F. Leblhuber,et al.  Activated Immune System in Patients with Huntington's Disease , 1998, Clinical Chemistry and Laboratory Medicine.

[19]  R V Jensen,et al.  Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Beal,et al.  Experimental therapeutics in transgenic mouse models of Huntington's disease , 2004, Nature Reviews Neuroscience.

[21]  I. Shoulson,et al.  Huntington disease , 1981, Neurology.

[22]  D J Brooks,et al.  Microglial activation correlates with severity in Huntington disease , 2006, Neurology.

[23]  P. Gasque,et al.  Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington's Disease , 1999, Experimental Neurology.

[24]  Benjamin M. Bolstad,et al.  affy - analysis of Affymetrix GeneChip data at the probe level , 2004, Bioinform..

[25]  G. Bates,et al.  Histone deacetylase inhibitors as therapeutics for polyglutamine disorders , 2006, Nature Reviews Neuroscience.

[26]  A. Young,et al.  Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1. , 2005, Human molecular genetics.

[27]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..