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. 2020 Oct 17;2(2):fcaa172.
doi: 10.1093/braincomms/fcaa172. eCollection 2020.

Longitudinal expression changes are weak correlates of disease progression in Huntington's disease

Christopher T Mitchell  1   2 , Irina Krier  3 , Jamshid Arjomand  4 , Beth Borowsky  4 , Sarah J Tabrizi  5 , Blair R Leavitt  6 ; TRACK-HD Investigators; Ruth Luthi-Carter  1   2
Affiliations

Longitudinal expression changes are weak correlates of disease progression in Huntington's disease

Christopher T Mitchell et al. Brain Commun. .

Abstract

Huntington's disease is a severe but slowly progressive hereditary illness for which only symptomatic treatments are presently available. Clinical measures of disease progression are somewhat subjective and may require years to detect significant change. There is a clear need to identify more sensitive, objective and consistent measures to detect disease progression in Huntington's disease clinical trials. Whereas Huntington's disease demonstrates a robust and consistent gene expression signature in the brain, previous studies of blood cell RNAs have lacked concordance with clinical disease stage. Here we utilized longitudinally collected samples from a well-characterized cohort of control, Huntington's disease-at-risk and Huntington's disease subjects to evaluate the possible correlation of gene expression and disease status within individuals. We interrogated these data in both cross-sectional and longitudinal analyses. A number of changes in gene expression showed consistency within this study and as compared to previous reports in the literature. The magnitude of the mean disease effect over 2 years' time was small, however, and did not track closely with motor symptom progression over the same time period. We therefore conclude that while blood-derived gene expression indicators can be of value in understanding Huntington's disease pathogenesis, they are insufficiently sensitive to be of use as state biomarkers.

Keywords: biomarker; expression profiling; microarray; neurodegenerative disease.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Gene expression of four probesets that showed the strongest evidence of differential expression in Huntington’s disease subjects compared to controls. Asterisks indicate nominal P < 0.05. Adjusted P-values >0.05 for all genes. Error bars represent SEM. Expression signals are unlogged for display purposes.
Figure 2
Figure 2
The four probesets with the strongest correlation between disease progression and differential expression over 2 years. These analyses are based on data from preHD B (n = 15; mean age at Year 3 ± SD: 39.9 ± 8.9 years; mean TMS change ± SD: 4.67 ± 4.47) and diagnosed Huntington’s disease subjects zHD stage 1 (n = 16; 50.0 ± 9.3 years; 6.56 ± 6.74) and zHD stage 2 (n = 16; 54.5 ± 6.6; 7.13 ± 6.16). Correlation calculated using Pearson’s correlation coefficient (r). When the significance of correlation was calculated and multiple testing correction performed, adjusted P > 0.05 in all probesets. (A) AQR: r = −0.61; nominal P = 4.3 × 10−6. (B) LMNA: r = +0.58; nominal P = 1.6 × 10−5. (C) ELAVL3: r = +0.58; nominal P = 2.3 × 10−5. (D) TMEM5: r = −0.56; nominal P = 4.9 × 10−5.
Figure 3
Figure 3
Probesets representing genes found to be dysregulated in previously transcriptomic Huntington’s disease blood studies that showed significant association between disease progression and differential expression in our longitudinal analysis. These analyses are based on data from preHD B (n = 15; mean age at Year 3 ± SD: 39.9 ± 8.9 years; mean TMS change ± SD: 4.67 ± 4.47) and diagnosed Huntington’s disease subjects zHD stage 1 (n = 16; 50.0 ± 9.3 years; 6.56 ± 6.74) and zHD stage 2 (n = 16; 54.5 ± 6.6; 7.13 ± 6.16). Correlation calculated using Pearson’s correlation coefficient (r). When the significance of correlation was calculated and multiple testing correction performed, adjusted P > 0.05 in all probesets. (A) ROCK1: r = +0.36; nominal P = 0.013. (B) SAP30: r = +0.35; nominal P = 0.017. (C) IL23A: r = −0.33; nominal P = 0.022. (D) LTBR: r = +0.29; nominal P = 0.049.
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