Abstract
Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol metabolism in murine HD models and patients' tissues have been recently identified. On these grounds, and with the aim of identifying putative biomarkers in HD, we studied cholesterol metabolism through the analysis in vivo of plasma 24OHC and cholesterol in two independent cohorts of controls and patients of Italian and British origin. We analysed a total of 62 controls, 96 HD symptomatic patients at different disease stages (stage 1-3), and 33 HD gene-positive pre-manifest subjects [pre-manifest HD (pre-HD)]. Cholesterol and 24OHC plasma levels were comparable in both the British and Italian subjects, and were not influenced by fasting or post-meal status. Cholesterol levels did not show differences between controls, pre-HD subjects and HD patients. In contrast, the plasma levels of 24OHC were significantly higher in controls than in HD patients at all disease stages (P <0.001). Interestingly, in pre-HD subjects plasma 24OHC concentrations were similar to those of controls, and thus significantly greater than those of HD patients at any disease stage (P <0.001). As expected, significant differences in caudate volumes between stage 1-2 HD patients and pre-HD subjects, and pre-HD subjects and controls were found. The pre-HD cohort of subjects was heterogeneous as to 24OHC levels, since subjects closer to predicted development of motor signs of disease had lower 24OHC levels than those far from onset. Our data indicate that the brain-generated cholesterol metabolite 24OHC measured in plasma was significantly depleted in HD patients at any disease stage, and it could discriminate pre-manifest subjects from patients with overt motor disease. However, 24OHC levels failed to mark further disease progression in patients with manifest HD. Overall, we demonstrate that 24OHC levels parallel the large decrease in caudate volumes observed in gene-positive subjects from pre-manifest to HD stage 1, thus reflecting a critical phase characterized by neuronal loss. We conclude that that 24OHC levels complement MRI morphometry as a valuable tool to follow neurodegenerative changes in the early stages of Huntington disease.
| Original language | English |
|---|---|
| Pages (from-to) | 2851-2859 |
| Number of pages | 9 |
| Journal | Brain |
| Volume | 131 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2008 |
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Keywords
- 24S-hydroxycholesterol
- Biomarker
- Caudate volume
- Gas chromatography-mass spectrometry
- MRI
- Oxysterol
ASJC Scopus subject areas
- Clinical Neurology
Cite this
Plasma 24S-hydroxycholesterol and caudate MRI in pre-manifest and early Huntington's disease. / Leoni, Valerio; Mariotti, Caterina; Tabrizi, Sarah J.; Valenza, Marta; Wild, Edward J.; Henley, Susie M D; Hobbs, Nicola Z.; Mandelli, Maria Luisa; Grisoli, Marina; Björkhem, Ingemar; Cattaneo, Elena; Di Donato, Stefano.
In: Brain, Vol. 131, No. 11, 11.2008, p. 2851-2859.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Plasma 24S-hydroxycholesterol and caudate MRI in pre-manifest and early Huntington's disease
AU - Leoni, Valerio
AU - Mariotti, Caterina
AU - Tabrizi, Sarah J.
AU - Valenza, Marta
AU - Wild, Edward J.
AU - Henley, Susie M D
AU - Hobbs, Nicola Z.
AU - Mandelli, Maria Luisa
AU - Grisoli, Marina
AU - Björkhem, Ingemar
AU - Cattaneo, Elena
AU - Di Donato, Stefano
PY - 2008/11
Y1 - 2008/11
N2 - Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol metabolism in murine HD models and patients' tissues have been recently identified. On these grounds, and with the aim of identifying putative biomarkers in HD, we studied cholesterol metabolism through the analysis in vivo of plasma 24OHC and cholesterol in two independent cohorts of controls and patients of Italian and British origin. We analysed a total of 62 controls, 96 HD symptomatic patients at different disease stages (stage 1-3), and 33 HD gene-positive pre-manifest subjects [pre-manifest HD (pre-HD)]. Cholesterol and 24OHC plasma levels were comparable in both the British and Italian subjects, and were not influenced by fasting or post-meal status. Cholesterol levels did not show differences between controls, pre-HD subjects and HD patients. In contrast, the plasma levels of 24OHC were significantly higher in controls than in HD patients at all disease stages (P <0.001). Interestingly, in pre-HD subjects plasma 24OHC concentrations were similar to those of controls, and thus significantly greater than those of HD patients at any disease stage (P <0.001). As expected, significant differences in caudate volumes between stage 1-2 HD patients and pre-HD subjects, and pre-HD subjects and controls were found. The pre-HD cohort of subjects was heterogeneous as to 24OHC levels, since subjects closer to predicted development of motor signs of disease had lower 24OHC levels than those far from onset. Our data indicate that the brain-generated cholesterol metabolite 24OHC measured in plasma was significantly depleted in HD patients at any disease stage, and it could discriminate pre-manifest subjects from patients with overt motor disease. However, 24OHC levels failed to mark further disease progression in patients with manifest HD. Overall, we demonstrate that 24OHC levels parallel the large decrease in caudate volumes observed in gene-positive subjects from pre-manifest to HD stage 1, thus reflecting a critical phase characterized by neuronal loss. We conclude that that 24OHC levels complement MRI morphometry as a valuable tool to follow neurodegenerative changes in the early stages of Huntington disease.
AB - Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol metabolism in murine HD models and patients' tissues have been recently identified. On these grounds, and with the aim of identifying putative biomarkers in HD, we studied cholesterol metabolism through the analysis in vivo of plasma 24OHC and cholesterol in two independent cohorts of controls and patients of Italian and British origin. We analysed a total of 62 controls, 96 HD symptomatic patients at different disease stages (stage 1-3), and 33 HD gene-positive pre-manifest subjects [pre-manifest HD (pre-HD)]. Cholesterol and 24OHC plasma levels were comparable in both the British and Italian subjects, and were not influenced by fasting or post-meal status. Cholesterol levels did not show differences between controls, pre-HD subjects and HD patients. In contrast, the plasma levels of 24OHC were significantly higher in controls than in HD patients at all disease stages (P <0.001). Interestingly, in pre-HD subjects plasma 24OHC concentrations were similar to those of controls, and thus significantly greater than those of HD patients at any disease stage (P <0.001). As expected, significant differences in caudate volumes between stage 1-2 HD patients and pre-HD subjects, and pre-HD subjects and controls were found. The pre-HD cohort of subjects was heterogeneous as to 24OHC levels, since subjects closer to predicted development of motor signs of disease had lower 24OHC levels than those far from onset. Our data indicate that the brain-generated cholesterol metabolite 24OHC measured in plasma was significantly depleted in HD patients at any disease stage, and it could discriminate pre-manifest subjects from patients with overt motor disease. However, 24OHC levels failed to mark further disease progression in patients with manifest HD. Overall, we demonstrate that 24OHC levels parallel the large decrease in caudate volumes observed in gene-positive subjects from pre-manifest to HD stage 1, thus reflecting a critical phase characterized by neuronal loss. We conclude that that 24OHC levels complement MRI morphometry as a valuable tool to follow neurodegenerative changes in the early stages of Huntington disease.
KW - 24S-hydroxycholesterol
KW - Biomarker
KW - Caudate volume
KW - Gas chromatography-mass spectrometry
KW - MRI
KW - Oxysterol
UR - http://www.scopus.com/inward/record.url?scp=55749085638&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55749085638&partnerID=8YFLogxK
U2 - 10.1093/brain/awn212
DO - 10.1093/brain/awn212
M3 - Article
C2 - 18772220
AN - SCOPUS:55749085638
VL - 131
SP - 2851
EP - 2859
JO - Brain
JF - Brain
SN - 0006-8950
IS - 11
ER -