A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers

Putaminal metabolites examined using cross‐sectional magnetic resonance spectroscopy (MRS) can distinguish pre‐manifest and early Huntington's Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was t...

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Published inMovement disorders Vol. 30; no. 3; pp. 393 - 401
Main Authors Sturrock, Aaron, Laule, Corree, Wyper, Katy, Milner, Ruth A., Decolongon, Joji, Santos, Rachelle Dar, Coleman, Allison J., Carter, Kimberley, Creighton, Susan, Bechtel, Natalie, Bohlen, Stefan, Reilmann, Ralf, Johnson, Hans J., Hayden, Michael R., Tabrizi, Sarah J., Mackay, Alex L., Leavitt, Blair R.
Format Journal Article
LanguageEnglish
Published United States Blackwell Publishing Ltd 01.03.2015
Wiley Subscription Services, Inc
Subjects
Adult
Analysis of Variance
Aspartic Acid - analogs & derivatives
Aspartic Acid - metabolism
Biomarkers - metabolism
Brain - metabolism
Cross-Sectional Studies
Female
Humans
Huntington Disease - metabolism
Huntington Disease - pathology
Huntington's disease
Inositol - metabolism
Longitudinal Studies
Magnetic Resonance Spectroscopy
Male
Middle Aged
Movement disorders
MRI
MRS
myo-inositol (MI)
N-acetyl aspartate (NAA)
Putamen - pathology
Statistics as Topic
Time Factors
White Matter - pathology
N-acetyl aspartate (NAA)
myo-inositol (MI)
Huntington's disease
MRI
MRS
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Summary:Putaminal metabolites examined using cross‐sectional magnetic resonance spectroscopy (MRS) can distinguish pre‐manifest and early Huntington's Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was to evaluate longitudinal in vivo brain metabolite profiles in HD over 24 months. Eighty‐four participants (30 controls, 25 pre‐manifest HD, 29 early HD) recruited as part of TRACK‐HD were imaged at baseline, 12 months, and 24 months using 3T MRS of left putamen. Automated putaminal volume measurement was performed simultaneously. To quantify partial volume effects, spectroscopy was performed in a second, white matter voxel adjacent to putamen in six subjects. Subjects underwent TRACK‐HD motor assessment. Statistical analyses included linear regression and one‐way analysis of variance (ANOVA). At all time‐points N‐acetyl aspartate and total N‐acetyl aspartate (NAA), neuronal integrity markers, were lower in early HD than in controls. Total NAA was lower in pre‐manifest HD than in controls, whereas the gliosis marker myo‐inositol (MI) was robustly elevated in early HD. Metabolites were stable over 24 months with no longitudinal change. Total NAA was not markedly different in adjacent white matter than putamen, arguing against partial volume confounding effects in cross‐sectional group differences. Total NAA correlations with disease burden score suggest that this metabolite may be useful in identifying neurochemical responses to therapeutic agents. We demonstrate almost consistent group differences in putaminal metabolites in HD‐affected individuals compared with controls over 24 months. Future work establishing spectroscopy as an HD biomarker should include multi‐site assessments in large, pathologically diverse cohorts. © 2015 International Parkinson and Movement Disorder Society
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ArticleID:MDS26118
Dr. Leavitt reports no financial disclosures. He receives research funding from CHDI, the Canadian Institutes of Health Research, and the Michael Smith Foundation.
Dr. Bohlen reports no disclosures.
Dr. Johnson reports no disclosures.
This study was privately sponsored by CHDI, a not‐for‐profit organization dedicated to finding treatments for Huntington's disease. NIH Grant Number; 20R‐03189.
Dr. MacKay's research program is supported by operating grants from the Natural Sciences and Engineering Research Council of Canada and the Multiple Sclerosis Society of Canada.
Dr. Hayden reports no financial disclosures. He receives funding from the Canadian Institutes of Health Research, Genome BC and CHDI.
Professor Sarah Tabrizi reports no financial disclosures. She receives funding from the Medical Research Council (MRC), The Wellcome Trust and CHDI.
Nothing to report.
Dr. Laule, Miss Wyper and Ms. Milner report no disclosures.
Funding agencies
Full financial disclosures and author roles may be found in the online version of this article.
Dr. Reilmann provided consulting services, advisory board functions, clinical trial services, quantitative motor analyses, and/or lectures for Novartis, Pfizer, Siena Bitoech, Neurosearch Inc., Ipsen, Teva, Lundbeck, Medivation, Wyeth, ISIS Pharma, Link Medicine, Prana Biotechnology, the Cure Huntington's Disease Initiative Foundation, MEDA Pharma, Temmler Pharma, AOP Orphan Pharmaceuticals AG. He received grant support from the Cure Huntington's Disease Initiative Foundation (CHDI), the Deutsche Forschungsgemeinschaft (DFG), the European Union (EU‐FP7 program) and the European Huntington's Disease Network (EHDN).
Ms. Decolongon, Miss Dar Santos and Miss Coleman are Clinical Research Co‐ordinators. Miss Carter was a research assistant. Each receive(d) a portion of their funding from CHDI.
Dr. Bechtel has received travel grants from the “Deutsche Gesellschaft für Neurologie” and the European Huntington's Disease Network (EHDN).
Dr Sturrock was formerly a full‐time Clinical Research Fellow on the TRACK‐HD study. He received funding from CHDI.
Relevant conflicts of interest/financial disclosures
Ms Creighton reports no disclosures.
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ISSN:0885-3185
1531-8257
1531-8257
DOI:10.1002/mds.26118