Cerebrospinal fluid biomarkers for assessing Huntington disease onset and severity

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 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 severity of Huntington disease. We conducted a hypothesis-driven analysis of 26 pre-specified protein analytes in CSF from sixteen 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 to 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 accuracy of disease-onset predictions, complement existing clinical and imaging biomarkers for monitoring severity of Huntington disease, and potentially for assessing therapeutic response in clinical trials. Additional studies with CSF from larger cohorts of Huntington disease mutation carriers are needed to replicate these exploratory findings.

Complementary insights into corticostriatal synapse loss and cognition in Huntington’s disease

“…In line with these data, an HD CSF biomarker exploration study showed unchanged expression of C1q subunits (C1qB and C1qC) across early-mid HD cohorts. 10 However, C1qB levels were substantially reduced in late-stage HD, which may reflect extreme loss of C1q-expressing neurons via phagocytosis as highlighted in the current study.…”

Molecular Biomarkers of Neurodegenerative Disorders: A Practical Guide to Their Appropriate Use and Interpretation in Clinical Practice

“…NfL has emerged as a promising HD biomarker, with elevated CSF levels associated with disease severity and progression. Furthermore, NfL levels in plasma have been associated with disease progression and can predict the onset of the disease in premanifest mutation carriers [112].…”

Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington’s Disease: Mechanisms and Potential Therapeutics

“…Landmark studies in multiple neurodegenerative fields have repeatedly demonstrated shared impairments of neurotrophin homeostasis in human subjects and rodent models. These impairments most often include the regional downregulation of BDNF expression in affected neural structures [ 49 , 50 ] or in cerebrospinal fluid (CSF) vs. controls [ 51 , 52 , 53 , 54 ]. This downregulation is often associated with the dysregulation of transcription and translation of the BDNF gene, but it may also exist as a result of disruption of the proteolysis of its precursor, proBDNF, or through the altered metabolism of its mature isoform [ 54 , 55 ].…”