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Mapping the Huntington's disease process using cerebrospinal fluid analysis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (landtblom)ORCID iD: 0000-0002-2576-9938
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

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. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1608
Keywords [en]
Neurodegeneration, Huntingtons disease, Neurogenetics, Neuroinflammation, Neurofilament light, tau, Proenkephalin
National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-393256ISBN: 978-91-513-0795-4 (print)OAI: oai:DiVA.org:uu-393256DiVA, id: diva2:1365221
Public defence
2019-12-12, Gunnesalen, ing.10 Akademiska sjukhuset, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-11-19 Created: 2019-10-23 Last updated: 2019-11-19
List of papers
1. Tau or neurofilament light - Which is the more suitable biomarker for Huntington’s disease?
Open this publication in new window or tab >>Tau or neurofilament light - Which is the more suitable biomarker for Huntington’s disease?
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0172762Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Previous studies have suggested cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and total tau are elevated in Huntington's disease (HD) and may be used as markers of disease stage. Biomarkers are needed due to the slow disease progression and the limitations of clinical assessment. This study aims to validate the role of NFL and tau as biomarkers in HD.

METHODS: CSF was obtained from a cohort of HD patients and premanifest HD-mutation carriers. Unified Huntington's Disease Rating Scale (UHDRS) testing was performed on all subjects at the time of sampling. NFL and tau concentrations were determined by ELISA. Spearman correlations were calculated with R version 3.2.3.

RESULTS: 11 premanifest HD and 12 manifest HD subjects were enrolled. NFL and tau levels were correlated. NFL showed strong correlations with all items included in the clinical assessment (for example the total functional capacity (TFC) (r = - 0.70 p < 0.01) and total motor score (TMS) (r = 0.83p < 0.01). Tau showed slightly weaker correlations (eg. TMS (r = 0.67 p < 0.01); TFC (r = - 0.59 p < 0.01)). NFL was significantly correlated with 5-year probability of disease onset, whereas tau was not.

CONCLUSION: This study strengthens the case for NFL as a useful biomarker of disease stage. NFL was strongly correlated to all evaluated items in the UHDRS assessment. Tau also has a potential for use as a biomarker but correlations to clinical tests are weaker in this study. We suggest that NFL and possibly tau be used in clinical drug trials as biomarkers of disease progression that are potentially influenced by future disease-modifying therapies.

Keywords
Huntingtons disease
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-317298 (URN)10.1371/journal.pone.0172762 (DOI)000395934400040 ()28241046 (PubMedID)
Projects
https://www.researchgate.net/project/Mapping-the-Huntingtons-disease-process-by-analyses-of-cerebrospinal-fluid
Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2019-10-23Bibliographically approved
2. Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease
Open this publication in new window or tab >>Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease
Show others...
2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0193492Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need further clarification.

METHODS: A clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau).

RESULTS: 52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age-adjustment.

CONCLUSION: Increased sCD27 in premanifest HD is a sign of T cell-mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-342996 (URN)10.1371/journal.pone.0193492 (DOI)000426049500119 ()29474427 (PubMedID)
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2019-10-23Bibliographically approved
3. Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
Open this publication in new window or tab >>Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
Show others...
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4129Article in journal (Refereed) Published
Abstract [en]

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-379886 (URN)10.1038/s41598-019-40186-5 (DOI)000460754600020 ()30858393 (PubMedID)
Funder
Åke Wiberg FoundationEU, Horizon 2020, 654241
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-10-23Bibliographically approved
4. CSF Proenkephalin decreases with the progression of Huntington's disease
Open this publication in new window or tab >>CSF Proenkephalin decreases with the progression of Huntington's disease
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 presymptomatic gene expansion carriers (pGEC) and 38 controls. In ManHD compared to pGEC 10 proteins were downregulated, and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin along with upregulated proteins (VASN, STC2, SGCE and C7) were all closely linked to HD symptom severity. The decreased PENK levels were replicated in a separate cohort of 23 ManHD and 23 controls where absolute quantitation was performed. We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK, and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD.   

Keywords
Proteomics, Mass spectrometry, Neurodegeneration, Cerebrospinal fluid, Huntington's disease
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-395606 (URN)
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23

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