MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study

Abstract

Objective: To investigate the feasibility of microRNA (miRNA) levels in CSF as biomarkers for prodromal Huntington disease (HD).

Methods: miRNA levels were measured in CSF from 60 PREDICT-HD study participants using the HTG protocol. Using a CAG-Age Product score, 30 prodromal HD participants were selected based on estimated probability of imminent clinical diagnosis of HD (i.e., low, medium, high; n = 10/group). For comparison, participants already diagnosed (n = 15) and healthy controls (n = 15) were also selected.

Results: A total of 2,081 miRNAs were detected and 6 were significantly increased in the prodromal HD gene expansion carriers vs controls at false discovery rate q < 0.05 (miR-520f-3p, miR-135b-3p, miR-4317, miR-3928-5p, miR-8082, miR-140-5p). Evaluating the miRNA levels in each of the HD risk categories, all 6 revealed a pattern of increasing abundance from control to low risk, and from low risk to medium risk, which then leveled off from the medium to high risk and HD diagnosed groups.

Conclusions: This study reports miRNAs as CSF biomarkers of prodromal and diagnosed HD. Importantly, miRNAs were detected in the prodromal HD groups furthest from diagnosis where treatments are likely to be most consequential and meaningful. The identification of potential biomarkers in the disease prodrome may prove useful in evaluating treatments that may postpone disease onset.

Clinicaltrialsgov identifier: NCT00051324.

Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Hierarchal clustering of differentially expressed microRNAs (miRNAs)

Hierarchal clustering of 14 diagnosed Huntington disease cases and 14 controls presented on the X axis defined by the color at the top of the figure, using the top 25 most differentially expressed miRNAs presented on the Y axis (table 2). Samples and miRNAs have been clustered based on their normalized expression. Colors in this heatmap reflect miRNA-wise z score transformation of normalized expression where darker shades of red represent increased levels and darker shades of blue represent decreased levels.

Figure 2. Plots of microRNAs (miRNAs) across categories of control, prodromal, and diagnosed Huntington disease (HD)

Boxplots of the distribution of DESeq2/variance stabilized and batch-corrected expression among the 5 ordinal groups (risk of diagnosis of HD) for each of the 6 miRNAs differentially expressed between HD and control participants (table 2; A, 50f-3p; B, 135b-3p; C, 4317; D, 3928-5p; E, 8082; F, 140-5p). p Values and logFC values are the same as in table 3. The low-risk, medium-risk, high-risk, and diagnosed HD groups are synonymous with the far from onset, middle from onset, near onset, and symptomatic HD groups.