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Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression.

Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Le Bouc Y, Gervais C, Carcelain G, Vassault A, Feingold J, Rabier D, Durr A - PLoS ONE (2007)

Bottom Line: Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment.Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group.The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Hôpital de la Salpêtrière, UMR 679, Paris, France.

ABSTRACT
Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1)H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

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Related in: MedlinePlus

Differences in the relative concentrations of branched chain amino acids in plasma are responsible for the differences among the HD groups.PLS-contribution plots allow comparison of plasma metabolic profiles in early affected HD patients and presymptomatic carriers. NMR variables that have the greatest weight (w*1; scaled in units of standard deviation), therefore contributing most to the separation between HD groups, are decreased concentrations (>2SD) of metabolites located between 0.85 and 1.0 ppm: valine, leucine and isoleucine. A similar contribution plot was obtained when plasma metabolic profiles from mildly affected HD patients were compared to early HD patients (data not shown).
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pone-0000647-g002: Differences in the relative concentrations of branched chain amino acids in plasma are responsible for the differences among the HD groups.PLS-contribution plots allow comparison of plasma metabolic profiles in early affected HD patients and presymptomatic carriers. NMR variables that have the greatest weight (w*1; scaled in units of standard deviation), therefore contributing most to the separation between HD groups, are decreased concentrations (>2SD) of metabolites located between 0.85 and 1.0 ppm: valine, leucine and isoleucine. A similar contribution plot was obtained when plasma metabolic profiles from mildly affected HD patients were compared to early HD patients (data not shown).

Mentions: Metabolic profiles of plasma from early affected HD patients were then compared to those of presymptomatic carriers, those of mildly affected HD patients to early HD patients. The spectral region that contributed to differences among the HD groups determined from PLS contribution plots is shown in Figure 2. There was a significant (>2SD) decrease along with disease progression in the plasma concentrations of a group of variables from the buckets located between 0.85 to 1.0 ppm on the NMR spectrum. These peaks correspond to the branched chain amino acids (BCAA), valine, leucine and isoleucine. No other significant differences among the groups were detected in the spectra even though very small buckets (0.02 ppm) were analyzed.


Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression.

Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Le Bouc Y, Gervais C, Carcelain G, Vassault A, Feingold J, Rabier D, Durr A - PLoS ONE (2007)

Differences in the relative concentrations of branched chain amino acids in plasma are responsible for the differences among the HD groups.PLS-contribution plots allow comparison of plasma metabolic profiles in early affected HD patients and presymptomatic carriers. NMR variables that have the greatest weight (w*1; scaled in units of standard deviation), therefore contributing most to the separation between HD groups, are decreased concentrations (>2SD) of metabolites located between 0.85 and 1.0 ppm: valine, leucine and isoleucine. A similar contribution plot was obtained when plasma metabolic profiles from mildly affected HD patients were compared to early HD patients (data not shown).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1919424&req=5

pone-0000647-g002: Differences in the relative concentrations of branched chain amino acids in plasma are responsible for the differences among the HD groups.PLS-contribution plots allow comparison of plasma metabolic profiles in early affected HD patients and presymptomatic carriers. NMR variables that have the greatest weight (w*1; scaled in units of standard deviation), therefore contributing most to the separation between HD groups, are decreased concentrations (>2SD) of metabolites located between 0.85 and 1.0 ppm: valine, leucine and isoleucine. A similar contribution plot was obtained when plasma metabolic profiles from mildly affected HD patients were compared to early HD patients (data not shown).
Mentions: Metabolic profiles of plasma from early affected HD patients were then compared to those of presymptomatic carriers, those of mildly affected HD patients to early HD patients. The spectral region that contributed to differences among the HD groups determined from PLS contribution plots is shown in Figure 2. There was a significant (>2SD) decrease along with disease progression in the plasma concentrations of a group of variables from the buckets located between 0.85 to 1.0 ppm on the NMR spectrum. These peaks correspond to the branched chain amino acids (BCAA), valine, leucine and isoleucine. No other significant differences among the groups were detected in the spectra even though very small buckets (0.02 ppm) were analyzed.

Bottom Line: Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment.Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group.The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Hôpital de la Salpêtrière, UMR 679, Paris, France.

ABSTRACT
Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1)H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

Show MeSH
Related in: MedlinePlus