Affiliation:
1. Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia , Vancouver, BC V5Z 4H4 , Canada
2. Human Health Therapeutics Research Centre, National Research Council of Canada , Ottawa, ON K1A 0R6 , Canada
3. BC Children’s Hospital Research Institute, University of British Columbia , Vancouver, BC V5Z 4H4 , Canada
4. Division of Neuroscience, Oregon National Primate Research Center , Beaverton, OR 97006 , USA
5. Department of Behavioral Neuroscience, Oregon Health and Science University , Portland, OR 97239 , USA
Abstract
Abstract
The identification of molecular biomarkers in CSF from individuals affected by Huntington disease may help improve predictions of disease onset, better define disease progression and could facilitate the evaluation of potential therapies. The primary objective of our study was to investigate novel CSF protein candidates and replicate previously reported protein biomarker changes in CSF from Huntington disease mutation carriers and healthy controls. Our secondary objective was to compare the discriminatory potential of individual protein analytes and combinations of CSF protein markers for stratifying individuals based on the severity of Huntington disease. We conducted a hypothesis-driven analysis of 26 pre-specified protein analytes in CSF from 16 manifest Huntington disease subjects, eight premanifest Huntington disease mutation carriers and eight healthy control individuals using parallel-reaction monitoring mass spectrometry. In addition to reproducing reported changes in previously investigated CSF biomarkers (NEFL, PDYN, and PENK), we also identified novel exploratory CSF proteins (C1QB, CNR1, GNAL, IDO1, IGF2, and PPP1R1B) whose levels were altered in Huntington disease mutation carriers and/or across stages of disease. Moreover, we report strong associations of select CSF proteins with clinical measures of disease severity in manifest Huntington disease subjects (C1QB, CNR1, NEFL, PDYN, PPP1R1B, and TTR) and with years to predicted disease onset in premanifest Huntington disease mutation carriers (ALB, C4B, CTSD, IGHG1, and TTR). Using receiver operating characteristic curve analysis, we identified PENK as being the most discriminant CSF protein for stratifying Huntington disease mutation carriers from controls. We also identified exploratory multi-marker CSF protein panels that improved discrimination of premanifest Huntington disease mutation carriers from controls (PENK, ALB and NEFL), early/mid-stage Huntington disease from premanifest mutation carriers (PPP1R1B, TTR, CHI3L1, and CTSD), and late-stage from early/mid-stage Huntington disease (CNR1, PPP1R1B, BDNF, APOE, and IGHG1) compared with individual CSF proteins. In this study, we demonstrate that combinations of CSF proteins can outperform individual markers for stratifying individuals based on Huntington disease mutation status and disease severity. Moreover, we define exploratory multi-marker CSF protein panels that, if validated, may be used to improve the accuracy of disease-onset predictions, complement existing clinical and imaging biomarkers for monitoring the severity of Huntington disease, and potentially for assessing therapeutic response in clinical trials. Additional studies with CSF collected from larger cohorts of Huntington disease mutation carriers are needed to replicate these exploratory findings.
Funder
Huntington’s Disease Society of America (HDSA) Berman/Topper HD Career Development Fellowship
Huntington Society of Canada
Brain Canada Multi-Investigator Research Initiative
Collection of CSF
Cure Huntington’s Disease Initiative (CHDI) Foundation
Canadian Institutes of Health Research
Publisher
Oxford University Press (OUP)
Subject
Neurology,Cellular and Molecular Neuroscience,Biological Psychiatry,Psychiatry and Mental health