Skip to main content
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging 12/2016

28.06.2016 | Original Article

Striatal hypometabolism in premanifest and manifest Huntington’s disease patients

verfasst von: Diego Alfonso López-Mora, Valle Camacho, Jesús Pérez-Pérez, Saül Martínez-Horta, Alejandro Fernández, Frederic Sampedro, Alberto Montes, Gloria Andrea Lozano-Martínez, Beatriz Gómez-Anson, Jaime Kulisevsky, Ignasi Carrió

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 12/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

To assess metabolic changes in cerebral 18F-FDG PET/CT in premanifest and manifest Huntington’s disease (HD) subjects compared to a control group and to correlate 18F-FDG uptake patterns with different disease stages.

Materials and methods

Thirty-three gene-expanded carriers (Eight males; mean age: 43 y/o; CAG > 39) were prospectively included. Based on the Unified Huntington’s Disease Rating Scale Total Motor Score and the Total Functional Capacity, subjects were classified as premanifest (preHD = 15) and manifest (mHD = 18). Estimated time disease-onset was calculated using the Langbehn formula, which allowed classifying preHD as far-to (preHD-A) and close-to (PreHD-B) disease-onset. Eighteen properly matched participants were included as a control group (CG). All subjects underwent brain 18F-FDG PET/CT and MRI. 18F-FDG PET/CT were initially assessed by two nuclear medicine physicians identifying qualitative metabolic changes in the striatum. Quantitative analysis was performed using SPM8 with gray matter atrophy correction using the BPM toolbox.

Results

Visual analysis showed a marked striatal hypometabolism in mHD. A normal striatal distribution of 18F-FDG uptake was observed for most of the preHD subjects. Quantitative analysis showed a significant striatal hypometabolism in mHD subjects compared to CG (p < 0.001 uncorrected, k = 50 voxels). In both preHD groups we observed a significant striatal hypometabolism with respect to CG (p < 0.001 uncorrected, k = 50 voxels). In mHD subjects we observed a significant striatal hypometabolism with respect to both preHD groups (p < 0.001 uncorrected, k = 50 voxels).

Conclusion

18F-FDG PET/CT might be a helpful tool to identify patterns of glucose metabolism in the striatum across the stages of HD and might be relevant in assessing the clinical status of gene-expanded HD carriers due to the fact that dysfunctional glucose metabolism begins at early preHD stages of the disease. 18F-FDG PET/CT appears as a promising method to monitor the response to disease-modifying therapies even if applied in premanifest subjects.
Literatur
1.
Zurück zum Zitat Huntington Study Group. Unified Huntington’s disease rating scale: reliability and consistency. Mov Disord. 1996;11(2):136–42. Huntington Study Group. Unified Huntington’s disease rating scale: reliability and consistency. Mov Disord. 1996;11(2):136–42.
2.
Zurück zum Zitat The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72(6):971–83. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72(6):971–83.
3.
Zurück zum Zitat Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc Natl Acad Sci U S A. 1999;96(8):4604–9.CrossRefPubMedPubMedCentral Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc Natl Acad Sci U S A. 1999;96(8):4604–9.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, et al. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med. 2006;47(2):215–22.PubMed Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, et al. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med. 2006;47(2):215–22.PubMed
5.
Zurück zum Zitat Politis M, Piccini P. Positron emission tomography imaging in neurological disorders. J Neurol. 2012;259(9):1769–80.CrossRefPubMed Politis M, Piccini P. Positron emission tomography imaging in neurological disorders. J Neurol. 2012;259(9):1769–80.CrossRefPubMed
6.
Zurück zum Zitat Kuwert T, Lange HW, Langen KJ, Herzog H, Aulich A, Feinendegen LE. Cortical and subcortical glucose consumption measured by PET in patients with Huntington’s disease. Brain. 1990;113(5):1405–23.CrossRefPubMed Kuwert T, Lange HW, Langen KJ, Herzog H, Aulich A, Feinendegen LE. Cortical and subcortical glucose consumption measured by PET in patients with Huntington’s disease. Brain. 1990;113(5):1405–23.CrossRefPubMed
7.
Zurück zum Zitat Andrews TC, Weeks RA, Turjanski N, Gunn RN, Watkins LH, Sahakian B, et al. Huntington’s disease progression. PET and clinical observations. Brain. 1999;122(1):2353–63.CrossRefPubMed Andrews TC, Weeks RA, Turjanski N, Gunn RN, Watkins LH, Sahakian B, et al. Huntington’s disease progression. PET and clinical observations. Brain. 1999;122(1):2353–63.CrossRefPubMed
8.
9.
Zurück zum Zitat Kuhl DE, Phelps ME, Markham CH, Metter EJ, Riege WH, Winter J. Cerebral metabolism and atrophy in Huntington’s disease determined by 18FDG and computed tomographic scan. Ann Neurol. 1982;12(5):425–34.CrossRefPubMed Kuhl DE, Phelps ME, Markham CH, Metter EJ, Riege WH, Winter J. Cerebral metabolism and atrophy in Huntington’s disease determined by 18FDG and computed tomographic scan. Ann Neurol. 1982;12(5):425–34.CrossRefPubMed
10.
Zurück zum Zitat Young AB, Penney JB, Starosta-Rubinstein S, Markel DS, Berent S, Giordani B, et al. PET scan investigations of Huntington’s disease: cerebral metabolic correlates of neurological features and functional decline. Ann Neurol. 1986;20(3):296–303.CrossRefPubMed Young AB, Penney JB, Starosta-Rubinstein S, Markel DS, Berent S, Giordani B, et al. PET scan investigations of Huntington’s disease: cerebral metabolic correlates of neurological features and functional decline. Ann Neurol. 1986;20(3):296–303.CrossRefPubMed
11.
Zurück zum Zitat Hayden MR, Martin WR, Stoessl AJ, Clark C, Hollenberg S, Adam MJ, et al. Positron emission tomography in the early diagnosis of Huntington’s disease. Neurology. 1986;36(7):888–94.CrossRefPubMed Hayden MR, Martin WR, Stoessl AJ, Clark C, Hollenberg S, Adam MJ, et al. Positron emission tomography in the early diagnosis of Huntington’s disease. Neurology. 1986;36(7):888–94.CrossRefPubMed
12.
Zurück zum Zitat Young AB, Penney JB, Starosta-Rubinstein S, Markel D, Berent S, Rothley J, et al. Normal caudate glucose metabolism in persons at risk for Huntington’s disease. Arch Neurol. 1987;44(3):254–7.CrossRefPubMed Young AB, Penney JB, Starosta-Rubinstein S, Markel D, Berent S, Rothley J, et al. Normal caudate glucose metabolism in persons at risk for Huntington’s disease. Arch Neurol. 1987;44(3):254–7.CrossRefPubMed
13.
Zurück zum Zitat Hayden MR, Hewitt J, Stoessl AJ, Clark C, Ammann W, Martin WR. The combined use of positron emission tomography and DNA polymorphisms for preclinical detection of Huntington’s disease. Neurology. 1987;37(9):1441–7.CrossRefPubMed Hayden MR, Hewitt J, Stoessl AJ, Clark C, Ammann W, Martin WR. The combined use of positron emission tomography and DNA polymorphisms for preclinical detection of Huntington’s disease. Neurology. 1987;37(9):1441–7.CrossRefPubMed
14.
Zurück zum Zitat Mazziotta JC, Phelps ME, Pahl JJ, Huang SC, Baxter LR, Riege WH, et al. Reduced cerebral glucose metabolism in asymptomatic subjects at risk for Huntington’s disease. N Engl J Med. 1987;316(7):357–62.CrossRefPubMed Mazziotta JC, Phelps ME, Pahl JJ, Huang SC, Baxter LR, Riege WH, et al. Reduced cerebral glucose metabolism in asymptomatic subjects at risk for Huntington’s disease. N Engl J Med. 1987;316(7):357–62.CrossRefPubMed
15.
Zurück zum Zitat Kuwert T, Ganslandt T, Jansen P, Jülicher F, Lange H, Herzog H, et al. Influence of size of regions of interest on PET evaluation of caudate glucose consumption. J Comput Assist Tomogr. 1992;16(5):789–94.CrossRefPubMed Kuwert T, Ganslandt T, Jansen P, Jülicher F, Lange H, Herzog H, et al. Influence of size of regions of interest on PET evaluation of caudate glucose consumption. J Comput Assist Tomogr. 1992;16(5):789–94.CrossRefPubMed
16.
Zurück zum Zitat Antonini A, Leenders KL, Spiegel R, Meier D, Vontobel P, Weigell-Weber M, et al. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain. 1996;119(6):2085–95.CrossRefPubMed Antonini A, Leenders KL, Spiegel R, Meier D, Vontobel P, Weigell-Weber M, et al. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain. 1996;119(6):2085–95.CrossRefPubMed
17.
Zurück zum Zitat Ciarmiello A, Giovacchini G, Orobello S, Bruselli L, Elifani F, Squitieri F. 18F-FDG PET uptake in the pre-Huntington disease caudate affects the time-to-onset independently of CAG expansion size. Eur J Nucl Med Mol Imaging. 2012;39(6):1030–6.CrossRefPubMed Ciarmiello A, Giovacchini G, Orobello S, Bruselli L, Elifani F, Squitieri F. 18F-FDG PET uptake in the pre-Huntington disease caudate affects the time-to-onset independently of CAG expansion size. Eur J Nucl Med Mol Imaging. 2012;39(6):1030–6.CrossRefPubMed
18.
Zurück zum Zitat Huntington Study Group. Unified Huntington’s disease rating scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996;11:136–42.CrossRef Huntington Study Group. Unified Huntington’s disease rating scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996;11:136–42.CrossRef
19.
Zurück zum Zitat Feigin A, Kieburtz K, Bordwell K, Como P, Steinberg K, Sotack J, et al. Functional decline in Huntington’s disease. Mov Disord. 1995;10:211–4.CrossRefPubMed Feigin A, Kieburtz K, Bordwell K, Como P, Steinberg K, Sotack J, et al. Functional decline in Huntington’s disease. Mov Disord. 1995;10:211–4.CrossRefPubMed
20.
Zurück zum Zitat Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RAC, Durr A, Craufurd D, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8(9):791–801.CrossRefPubMedPubMedCentral Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RAC, Durr A, Craufurd D, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8(9):791–801.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet. 2004;65(4):267–77.CrossRefPubMed Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet. 2004;65(4):267–77.CrossRefPubMed
22.
Zurück zum Zitat Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RA, Durr A, Craufurd D, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8:791–801.CrossRefPubMedPubMedCentral Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RA, Durr A, Craufurd D, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8:791–801.CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Varrone A, Asenbaum S, Vander Borght T, Booij J, Nobili F, Någren K, et al. EANM procedure guidelines for PET brain imaging using [18F] FDG, version 2. Eur J Nucl Med Mol Imaging. 2009;36(12):2103–10.CrossRefPubMed Varrone A, Asenbaum S, Vander Borght T, Booij J, Nobili F, Någren K, et al. EANM procedure guidelines for PET brain imaging using [18F] FDG, version 2. Eur J Nucl Med Mol Imaging. 2009;36(12):2103–10.CrossRefPubMed
24.
Zurück zum Zitat Lange C, Suppa P, Frings L, Brenner W, Spies L, Buchert R. Optimization of statistical single subject analysis of brain FDG PET for the prognosis of mild cognitive impairment-to-Alzheimer’s disease conversion. J Alzheimers Dis. 2015;49(4):945–59.CrossRefPubMed Lange C, Suppa P, Frings L, Brenner W, Spies L, Buchert R. Optimization of statistical single subject analysis of brain FDG PET for the prognosis of mild cognitive impairment-to-Alzheimer’s disease conversion. J Alzheimers Dis. 2015;49(4):945–59.CrossRefPubMed
25.
Zurück zum Zitat Casanova R, Srikanth R, Baer A, Laurienti PJ, Burdette JH, Hayasaka S, et al. Biological parametric mapping: a statistical toolbox for multimodality brain image analysis. Neuroimage. 2007;34(1):137–43.CrossRefPubMed Casanova R, Srikanth R, Baer A, Laurienti PJ, Burdette JH, Hayasaka S, et al. Biological parametric mapping: a statistical toolbox for multimodality brain image analysis. Neuroimage. 2007;34(1):137–43.CrossRefPubMed
26.
Zurück zum Zitat Shin H, Kim MH, Lee SJ, Lee K-H, Kim M-J, Kim JS, et al. Decreased metabolism in the cerebral cortex in early-stage Huntington’s disease: a possible biomarker of disease progression? J Clin Neurol. 2013;9(1):21–5.CrossRefPubMedPubMedCentral Shin H, Kim MH, Lee SJ, Lee K-H, Kim M-J, Kim JS, et al. Decreased metabolism in the cerebral cortex in early-stage Huntington’s disease: a possible biomarker of disease progression? J Clin Neurol. 2013;9(1):21–5.CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Feigin A, Leenders KL, Moeller JR, Missimer J, Kuenig G, Spetsieris P, et al. Metabolic network abnormalities in early Huntington’s disease: an [18F]FDG PET study. J Nucl Med. 2001;42(11):1591–5.PubMed Feigin A, Leenders KL, Moeller JR, Missimer J, Kuenig G, Spetsieris P, et al. Metabolic network abnormalities in early Huntington’s disease: an [18F]FDG PET study. J Nucl Med. 2001;42(11):1591–5.PubMed
28.
29.
Zurück zum Zitat Feigin A, Tang C, Ma Y, Mattis P, Zgaljardic D, Guttman M, et al. Thalamic metabolism and symptom onset in preclinical Huntington’s disease. Brain. 2007;130(11):2858–67.CrossRefPubMedPubMedCentral Feigin A, Tang C, Ma Y, Mattis P, Zgaljardic D, Guttman M, et al. Thalamic metabolism and symptom onset in preclinical Huntington’s disease. Brain. 2007;130(11):2858–67.CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Aylward EH, Codori AM, Barta PE, Pearlson GD, Harris GJ, Brandt J. Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. Arch Neurol. 1996;53(12):1293–6.CrossRefPubMed Aylward EH, Codori AM, Barta PE, Pearlson GD, Harris GJ, Brandt J. Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. Arch Neurol. 1996;53(12):1293–6.CrossRefPubMed
31.
Zurück zum Zitat Antonini A, Leenders KL, Eidelberg D. [11C]raclopride-PET studies of the Huntington’s disease rate of progression: relevance of the trinucleotide repeat length. Ann Neurol. 1998;43(2):253–5.CrossRefPubMed Antonini A, Leenders KL, Eidelberg D. [11C]raclopride-PET studies of the Huntington’s disease rate of progression: relevance of the trinucleotide repeat length. Ann Neurol. 1998;43(2):253–5.CrossRefPubMed
32.
Zurück zum Zitat Panov AV, Gutekunst C-A, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci. 2002;5(8):731–6.PubMed Panov AV, Gutekunst C-A, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci. 2002;5(8):731–6.PubMed
33.
Zurück zum Zitat Beal MF. Energetics in the pathogenesis of neurodegenrative diseases. Trends Neurosci. 2000;23:298–304.CrossRefPubMed Beal MF. Energetics in the pathogenesis of neurodegenrative diseases. Trends Neurosci. 2000;23:298–304.CrossRefPubMed
34.
Zurück zum Zitat Squitieri F, Orobello S, Cannella M, Martino T, Romanelli P, Giovacchini G, et al. Riluzole protects Huntington disease patients from brain glucose hypometabolism and grey matter volume loss and increases production of neurotrophins. Eur J Nucl Med Mol Imaging. 2009;36(7):1113–20.CrossRefPubMed Squitieri F, Orobello S, Cannella M, Martino T, Romanelli P, Giovacchini G, et al. Riluzole protects Huntington disease patients from brain glucose hypometabolism and grey matter volume loss and increases production of neurotrophins. Eur J Nucl Med Mol Imaging. 2009;36(7):1113–20.CrossRefPubMed
35.
Zurück zum Zitat Aylward EH. Changes in MRI striatal volumes as a biomarker in preclinical Huntigton’s disease. Brain Res Bull. 2007;72:152–8.CrossRefPubMed Aylward EH. Changes in MRI striatal volumes as a biomarker in preclinical Huntigton’s disease. Brain Res Bull. 2007;72:152–8.CrossRefPubMed
36.
Zurück zum Zitat Paulsen JS, Nopoulos PC, Aylward E, Ross CA, Johnson H, Magnotta VA, et al. Striatal and white matter predictors of estimated diagnosis for Huntington disease. Brain Res Bull. 2010;82(3–4):201–7.CrossRefPubMedPubMedCentral Paulsen JS, Nopoulos PC, Aylward E, Ross CA, Johnson H, Magnotta VA, et al. Striatal and white matter predictors of estimated diagnosis for Huntington disease. Brain Res Bull. 2010;82(3–4):201–7.CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Aylward EH, Codori AM, Rosenblatt A, Sherr M, Brandt J, Stine OC, et al. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington’s disease. Mov Disord. 2000;15(3):552–60.CrossRefPubMed Aylward EH, Codori AM, Rosenblatt A, Sherr M, Brandt J, Stine OC, et al. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington’s disease. Mov Disord. 2000;15(3):552–60.CrossRefPubMed
38.
Zurück zum Zitat Berent S, Giordani B, Lehtinen S, Markel D, Penney JB, Buchtel HA, et al. Positron emission tomographic scan investigations of Huntington’s disease: cerebral metabolic correlates of cognitive function. Ann Neurol. 1988;23:541–6.CrossRefPubMed Berent S, Giordani B, Lehtinen S, Markel D, Penney JB, Buchtel HA, et al. Positron emission tomographic scan investigations of Huntington’s disease: cerebral metabolic correlates of cognitive function. Ann Neurol. 1988;23:541–6.CrossRefPubMed
Metadaten
Titel
Striatal hypometabolism in premanifest and manifest Huntington’s disease patients
verfasst von
Diego Alfonso López-Mora
Valle Camacho
Jesús Pérez-Pérez
Saül Martínez-Horta
Alejandro Fernández
Frederic Sampedro
Alberto Montes
Gloria Andrea Lozano-Martínez
Beatriz Gómez-Anson
Jaime Kulisevsky
Ignasi Carrió
Publikationsdatum
28.06.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 12/2016
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-016-3445-y

Weitere Artikel der Ausgabe 12/2016

European Journal of Nuclear Medicine and Molecular Imaging 12/2016 Zur Ausgabe