Detection of Huntington's disease decades before diagnosis: the Predict-HD study

Abstract

Objective:The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington’s disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis.Methods:We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor.Results:Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies.Conclusions:These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

“…The need for clinical trials close to disease onset has motivated a raft of observational studies (5,9,10). This provides the opportunity to investigate the relationship between onset and progression, whether they are influenced by the same biology, and permits the study of subjects before clinical onset.…”

Cortical Metabolites as Biomarkers in the R6/2 Model of Huntington's Disease

“…Since loss of striatal volume is the most welldocumented measure of prodromal changes in HD (Paulsen et al, 2008;Hobbs et al, 2010), MRIs were acquired in conjunction with MRS to document changes in mouse brain size (Figure 2; Supplementary Table 1). Between 4 and 8 weeks, increases in anterior brain, cortical, hypothalamic, and striatal volumes were observed in littermates but not in R6/ 2s.…”

“…Biomarkers for Huntington's disease (HD) are actively being sought for following progression from prodromal periods through manifest disease (Paulsen et al, 2008). Genomic, proteomic, and metabolomic panels as well as individual proteins or metabolites from peripheral tissues and fluids have been proposed as biomarkers (Sturrock et al, 2010;Zuccato et al, 2010).…”

Verbal episodic memory declines prior to diagnosis in Huntington's disease

“…Several studies have documented structural and functional brain changes in CAG-expanded individuals who have not yet been diagnosed (Aylward et al, 1996;Aylward et al, 2000;Aylward et al, 2004;Kipps et al, 2005;Paulsen et al, 2006b;Reading et al, 2004). Although relatively few studies have investigated the association between cognition and brain changes in HD, a recent study showed that cognitive task performance correlated with cerebral white matter and striatal volumes in early HD (Beglinger et al, 2005).…”