A systems-level "misunderstanding": the plasma metabolome in Huntington's disease.
OBJECTIVE
Huntington's disease (HD) is a rare neurodegenerative disease caused by the expansion of an N-terminal repeat in the huntingtin protein. The protein is expressed in all cells in the body; hence, peripheral tissues, such as blood, may recapitulate processes in the brain. The plasma metabolome may provide a window into active processes that influence brain health and a unique opportunity to noninvasively identify processes that may contribute to neurodegeneration. Alterations in metabolic pathways in brain have been shown to profoundly impact HD. Therefore, identification and quantification of critical metabolomic perturbations could provide novel biomarkers for disease onset and disease progression.


METHODS
We analyzed the plasma metabolomic profiles from 52 premanifest (PHD), 102 early symptomatic HD, and 140 healthy controls (NC) using liquid chromatography coupled with a highly sensitive electrochemical detection platform.


RESULTS
Alterations in tryptophan, tyrosine, purine, and antioxidant pathways were identified, including many related to energetic and oxidative stress and derived from the gut microbiome. Multivariate statistical modeling demonstrated mutually distinct metabolomic profiles, suggesting that the processes that determine onset were likely distinct from those that determine progression. Gut microbiome-derived metabolites particularly differentiated the PHD metabolome, while the symptomatic HD metabolome was increasingly influenced by metabolites that may reflect mutant huntingtin toxicity and neurodegeneration.


CONCLUSIONS
Understanding the complex changes in the delicate balance of the metabolome and the gut microbiome in HD, and how they relate to disease onset, progression, and phenotypic variability in HD are critical questions for future research.
Department of Neurology Boston, Massachusetts ; Center for Neuro-imaging of Aging and Neurodegenerative Diseases Boston, Massachusetts ; Athinoula A. Martinos Center for Biomedical Imaging Charlestown, Massachusetts ; Radiology, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts.
Herminia D
HD
Rosas
Department of Biostatistics, School of Public Health, Boston University Boston, Massachusetts.
Gheorghe
G
Doros
Edith Nourse Rogers Memorial Veterans Hospital Bedford, Massachusetts.
Swati
S
Bhasin
Edith Nourse Rogers Memorial Veterans Hospital Bedford, Massachusetts.
Beena
B
Thomas
Department of Neurology Boston, Massachusetts ; Center for Neuro-imaging of Aging and Neurodegenerative Diseases Boston, Massachusetts ; Athinoula A. Martinos Center for Biomedical Imaging Charlestown, Massachusetts.
Sona
S
Gevorkian
Department of Neurology Boston, Massachusetts ; Center for Neuro-imaging of Aging and Neurodegenerative Diseases Boston, Massachusetts ; Athinoula A. Martinos Center for Biomedical Imaging Charlestown, Massachusetts.
Keith
K
Malarick
Edith Nourse Rogers Memorial Veterans Hospital Bedford, Massachusetts.
Wayne
W
Matson
Department of Neurology Boston, Massachusetts ; MassGeneral Institutes for Neurodegenerative Disease, Laboratory of Neurodegeneration and Neurotherapeutics, Boston University Boston, Massachusetts.
Steven M
SM
Hersch