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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

Partial least square (PLS) analyses of NMR spectra of plasma samples from HD patients with no or little signs of the disease and controls.Three groups of presymptomatic, early and mildly affected HD patients were constituted on the basis of their UHDRS scores, as described in the methods. The first and second components in the X space (NMR spectrum) are denoted PC[1] and PC[2] respectively. PLS score plots (PC[1]/PC[2]) of pair-wise compared groups show the greater variation within the NMR spectrum according to a priori classification with UHDRS. There is a clear separation between presymptomatic and early HD patients (a), as well as between early and mildly affected HD patients (b). Despite some overlap, presymptomatic mutation carriers can also be distinguished from controls (c).
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pone-0000647-g001: Partial least square (PLS) analyses of NMR spectra of plasma samples from HD patients with no or little signs of the disease and controls.Three groups of presymptomatic, early and mildly affected HD patients were constituted on the basis of their UHDRS scores, as described in the methods. The first and second components in the X space (NMR spectrum) are denoted PC[1] and PC[2] respectively. PLS score plots (PC[1]/PC[2]) of pair-wise compared groups show the greater variation within the NMR spectrum according to a priori classification with UHDRS. There is a clear separation between presymptomatic and early HD patients (a), as well as between early and mildly affected HD patients (b). Despite some overlap, presymptomatic mutation carriers can also be distinguished from controls (c).

Mentions: PLS analyses distinguished HD individuals at different stages of the disease as shown in Figure 1. The difference between presymptomatic carriers and early HD is shown in Figure 1a. Early and mildly affected patients could be distinguished (Figure 1b), as could controls and presymptomatic carriers, despite some overlap (Figure 1c).


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)

Partial least square (PLS) analyses of NMR spectra of plasma samples from HD patients with no or little signs of the disease and controls.Three groups of presymptomatic, early and mildly affected HD patients were constituted on the basis of their UHDRS scores, as described in the methods. The first and second components in the X space (NMR spectrum) are denoted PC[1] and PC[2] respectively. PLS score plots (PC[1]/PC[2]) of pair-wise compared groups show the greater variation within the NMR spectrum according to a priori classification with UHDRS. There is a clear separation between presymptomatic and early HD patients (a), as well as between early and mildly affected HD patients (b). Despite some overlap, presymptomatic mutation carriers can also be distinguished from controls (c).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0000647-g001: Partial least square (PLS) analyses of NMR spectra of plasma samples from HD patients with no or little signs of the disease and controls.Three groups of presymptomatic, early and mildly affected HD patients were constituted on the basis of their UHDRS scores, as described in the methods. The first and second components in the X space (NMR spectrum) are denoted PC[1] and PC[2] respectively. PLS score plots (PC[1]/PC[2]) of pair-wise compared groups show the greater variation within the NMR spectrum according to a priori classification with UHDRS. There is a clear separation between presymptomatic and early HD patients (a), as well as between early and mildly affected HD patients (b). Despite some overlap, presymptomatic mutation carriers can also be distinguished from controls (c).
Mentions: PLS analyses distinguished HD individuals at different stages of the disease as shown in Figure 1. The difference between presymptomatic carriers and early HD is shown in Figure 1a. Early and mildly affected patients could be distinguished (Figure 1b), as could controls and presymptomatic carriers, despite some overlap (Figure 1c).

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