Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease

Abstract

We identified 322 mRNAs that showed significantly altered expression in HD blood samples, compared with controls (P < 0.0005), on two different microarray platforms. A subset of up-regulated mRNAs selected from this group was able to distinguish controls, presymptomatic individuals carrying the HD mutation, and symptomatic HD patients. In addition, early presymptomatic subjects showed gene expression profiles similar to those of controls, whereas late presymptomatic subjects showed altered expression that resembled that of symptomatic HD patients. These elevated mRNAs were significantly reduced in HD patients involved in a dose-finding study of the histone deacetylase inhibitor sodium phenylbutyrate. Furthermore, expression of the marker genes was significantly up-regulated in postmortem HD caudate, suggesting that alterations in blood mRNAs may reflect disease mechanisms observed in HD brain. In conclusion, we identified changes in blood mRNAs that clearly distinguish HD patients from controls. These alterations in mRNA expression correlate with disease progression and response to experimental treatment. Such markers may provide clues to the state of HD and may be of predictive value in clinical trials. microarrays ͉ neurodegeneration ͉ polyglutamine diseases

Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients

“…Additionally, glucocorticoids have effects on peripheral blood cells and the hypothalamus-pituitary adrenal (HPA) axis, which is perturbed during depressive episodes of many patients (Gladkevich et al, 2004). Transcriptional profiling in whole blood has been used in the search for biomarkers for patients with neurological and other psychiatric disorders including patients with Parkinson's (Scherzer et al, 2007) and Huntington's disease (Borovecki et al, 2005), post-traumatic stress disorder Segman et al, 2005;Yehuda et al, 2009), schizophrenia (Kurian et al, 2011), bipolar disorder (Le-Niculescu et al, 2009;Padmos et al, 2008) and major depression (Segman et al, 2010;Spijker et al, 2010). Most of these studies have analyzed baseline gene expression profiles.…”

ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease

“…12 It has been reported that ATRX expression levels are elevated in the white blood cells of presymptomatic (1.6-fold) and symptomatic HD (2-fold) patients compared with the controls. 24 Given that deregulation of nucleosomal dynamics contributes to the HD pathogenesis and that ATRX expression is elevated in the peripheral blood of HD, it is reasonable to suggest that ATRX could have a role in chromatin remodeling and neurodegeneration in HD. Indeed, we found that ATRX is transcriptionally induced by mtHtt through activation of Cdx2.…”

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

“…All existing information, however, suggests that most of these individuals experience a period of apparent clinical and biological normalcy before entering a prodromal period in which there is active underlying disease without any evident clinical or functional consequences. Current evidence indicates that the causative processes involved in HD are present for at least 10 to 20 years before HD can be diagnosed clinically [21][22][23][24][25][26][27][28] on the basis of the unequivocal presence of the movement disorder.…”

“…21,28,30 Subtle cognitive, motor, psychiatric, [31][32][33] and metabolic abnormalities 34,35 are detectable in premanifest HD, and biochemical alterations are beginning to be detected in blood. 24,36 It is unknown whether the HD prodrome represents a stable condition until some decompensation causes manifest HD to emerge, or whether it is a continuum in which clinically silent neurodegeneration gradually accumulates sufficiently to cause unequivocal symptoms. The pace of the disease process can certainly vary over time, or can be accelerated by other stresses.…”