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

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 utilised longitudinally collected samples from a well-characterised 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 the present study and as compared to previous reports in the literature. The magnitude of the mean disease effect over two 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.

A Glimpse of Molecular Biomarkers in Huntington’s Disease

“…Therefore, it is reasonable to apply transcriptomics’ approaches to the analysis of blood samples and skin fibroblasts from patients, which initially supported distinctive profiles between pre-symptomatic and symptomatic stages and identified potential biomarkers for measuring both disease progression and response to treatment (based on histone deacetylase inhibition) [ 109 , 110 , 111 , 112 ]. Using microarray and DeepSAGE technologies, several biomarkers have been proposed: AIM2 ; ANXA1 ; ANXA3 ; AQP9 ; ARFGEF2 ; BCL2L1 ; CAPZA1 ; CYSTM1 ; DAB2 ; DUSP1 ; EGR1 ; GOLGA8G ; H2AFY ; HIF1A ; HLA-DQA1 ; IER3 ; IL1B ; IL8 ; LPAR6 ; LTBR ; MARCHF7 ; MDX1 ; MLH3 ; NEAT1 ; NFKBIA ; P2RX1 ; PCNP ; PPIF ; PPP1R15A ; PROK2 ; ROCK1 ; SAP30; SF3B1 ; SP3 ; SUZ12 ; TAF7 ; TNF ; TNFRSF17 ; YPEL5 or ZNF238 [ 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 ]. However, even using the most updated transcriptomics technology based on next-generation sequencing (NGS) in the form of RNA-seq [ 118 ], there is a lack of replication across studies using peripheral blood as a biomaterial source.…”

“…However, even using the most updated transcriptomics technology based on next-generation sequencing (NGS) in the form of RNA-seq [ 118 ], there is a lack of replication across studies using peripheral blood as a biomaterial source. In addition, no clear association was observed with disease progression within 2 years of a longitudinal study [ 116 ]. In an effort to reconcile these studies, Andrade-Navarro, Priller and colleagues compared their own RNA-seq results with previous reports [ 119 ], suggesting that a HD blood signature may exist after all, as some overlaps were detected (e.g., ANXA3 , CYSTM1 , IL1B and PROK2 ).…”

“…Moreover, despite the expression of mHTT in blood cells [ 43 ], its impact on gene expression is not as profound as that in neurons. Thus, the reported differential expression in peripheral blood between HD manifest patients and healthy controls was limited to a few genes compared to brain structures (none or very few after FDR correction [ 116 , 118 , 120 ]). In the study by Hensman-Moss et al [ 118 ], the dysfunction of pathways rather than genes seems to be shared between brain and blood, an observation that is difficult to translate into the clinics.…”

Morphological classification and changes in dementia (Review)

“…From the terminal button of the presynaptic axon to the dendrite of the postsynaptic neuron, the axonal traffic of neurotransmitters suffers. Synaptic plasticity is low and glial cells cannot be compensated either (51,52).…”

Retinal affectation in Huntington’s disease mouse models concurs with a local innate immune response

“…Although the most prominent signs are derived from malfunctioning and degeneration of the basal ganglia and the corticostriatal circuitry 3 , the involvement of other brain areas and peripheral tissues/cells plays a substantial role in the decline of quality of life, extending the repertoire of HD symptoms [4][5][6][7][8] . However, our current toolbox of biomarkers to explain the large variability in the pleiotropic manifestation of symptoms with potential application in clinics is still limited [9][10][11] , and justifies the search for novel biomarkers with prognostic value in HD to enable the evaluation of therapeutic responses and to facilitate decision-making during clinical management.…”