Mapping the Huntington's disease process using cerebrospinal fluid analysis

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a CAG-repeat expansion in the HTT-gene. Today there are no disease-modifying therapies (DMTs), but several promising clinical trials are underway, including therapies that reduce mutant huntingtin expression. Reliable biomarkers could empower such trials and guide the timing for initiation of future DMTs. Neurofilament light (NFL) and tau, which are cerebrospinal fluid markers of neuronal death, have been implicated as markers of disease progression. Increased levels of the inflammatory marker YKL-40 have also been reported in HD. The aim was to validate and compare the above biomarker candidates by targeted analyses, while explorative liquid chromatography-mass spectrometry (LC-MS) was used to identify new candidates. Clinically well-characterized HD patients, premanifest gene expansion carriers (pGECs), and controls were enrolled from Uppsala University Hospital in Sweden. In contrast to tau, NFL levels differed between all three groups and NFL had stronger correlations with symptom severity compared with total-tau and phospho-tau. Longitudinally, only NFL maintained intergroup differences and rose with disease progression. Soluble CD27, a marker of T cell-mediated inflammation, differed between all three groups, with the highest levels in manifest HD, and mostly undetectable levels in controls. YKL-40 showed a non-significant trend toward increase in manifest HD. We applied LC-MS metabolomics and discovered a metabolite signature unique to manifest HD, with deranged tyrosine metabolism including L-DOPA, dopamine, and thyroxine. Utilizing LC-MS we also identified altered proteins in manifest HD, including proenkephalin that was decreased and associated with symptom severity. In conclusion, NFL may be used as a pharmacodynamic marker in intervention trials. Interestingly, elevated sCD27 implies a role of adaptive immunity before disease onset, but validation is needed. YKL-40 is not suitable as an early marker in HD. The CSF metabolome constitutes a new compartment of potential biomarkers but challenges in metabolite identification should be addressed in future studies. Proenkephalin levels potentially reflect the remaining number of striatal medium spiny neurons and hold promise as a marker of disease progression.