Abstract
Imaging of type 1 metabotropic glutamate receptor (mGluR1) has recently become possible using positron emission tomography (PET). We aimed to examine the relationship between mGluR1 and cerebellar ataxia. Families with spinocerebellar ataxia type 19/22 (SCA19/22) and SCA6, six patients with sporadic SCA, and 26 healthy subjects underwent PET using an mGluR1 radiotracer. Volumes-of-interest were placed on the anterior and posterior lobes and vermis. The binding potential (BPND) was calculated to estimate mGluR1 availability. A partial volume correction was applied to the BPND values. The Scale for the Assessment and Rating of Ataxia (SARA) score were measured. In each patient with SCA19/22 and SCA6, the anterior lobe showed the highest decrease rates in the BPND values, compared with healthy subjects. In the families with SCA19/22 and SCA6, the disease durations and SARA scores were shorter and lower, respectively, in the offspring, compared with the parents. However, the offspring paradoxically showed lower BPND values, especially in the anterior lobe, compared with the parents. The patients with sporadic SCA showed significantly lower BPND values in all subregions than healthy subjects. The BPND values significantly correlated with the SARA scores in all participants. In conclusion, these results showed a decrease in mGluR1 availability in patients with hereditary and sporadic SCA, a correlation between mGluR1 availability and degree of cerebellar ataxia, and paradoxical findings in two families. These results suggest the potential use of mGluR1 imaging as a specific biomarker of cerebellar ataxia.
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Toyohara J, Sakata M, Fujinaga M, Yamasaki T, Oda K, Ishii K, Zhang MR, Moriguchi Jeckel CM, Ishiwata K (2013) Preclinical and the first clinical studies on [11C]ITMM for mapping metabotropic glutamate receptor subtype 1 by positron emission tomography. Nucl Med Biol 40(2):214–220. doi:10.1016/j.nucmedbio.2012.11.008
Toyohara J, Sakata M, Oda K, Ishii K, Ito K, Hiura M, Fujinaga M, Yamasaki T, Zhang MR, Ishiwata K (2013) Initial human PET studies of metabotropic glutamate receptor type 1 ligand 11C-ITMM. J Nucl Med 54(8):1302–1307. doi:10.2967/jnumed.113.119891
Martin LJ, Blackstone CD, Huganir RL, Price DL (1992) Cellular localization of a metabotropic glutamate receptor in rat brain. Neuron 9(2):259–270
Shigemoto R, Nakanishi S, Mizuno N (1992) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: an in situ hybridization study in adult and developing rat. J Comp Neurol 322(1):121–135. doi:10.1002/cne.903220110
Baude A, Nusser Z, Roberts JD, Mulvihill E, McIlhinney RA, Somogyi P (1993) The metabotropic glutamate receptor (mGluR1 alpha) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11(4):771–787
Yamasaki T, Maeda J, Fujinaga M, Nagai Y, Hatori A, Yui J, Xie L, Nengaki N, Zhang MR (2014) PET brain kinetics studies of (11)C-ITMM and (11)C-ITDM, radioprobes for metabotropic glutamate receptor type 1, in a nonhuman primate. Am J Nucl Med Mol Imaging 4(3):260–269
Yamasaki T, Fujinaga M, Maeda J, Kawamura K, Yui J, Hatori A, Yoshida Y, Nagai Y, Tokunaga M, Higuchi M, Suhara T, Fukumura T, Zhang MR (2012) Imaging for metabotropic glutamate receptor subtype 1 in rat and monkey brains using PET with [18F]FITM. Eur J Nucl Med Mol Imaging 39(4):632–641. doi:10.1007/s00259-011-1995-6
Li S, Huang Y (2014) In vivo imaging of the metabotropic glutamate receptor 1 (mGluR1) with positron emission tomography: recent advance and perspective. Curr Med Chem 21(1):113–123
Ferraguti F, Crepaldi L, Nicoletti F (2008) Metabotropic glutamate 1 receptor: current concepts and perspectives. Pharmacol Rev 60(4):536–581. doi:10.1124/pr.108.000166
Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, Zwingman TA, Tonegawa S (1994) Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell 79(2):377–388
Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, Coesmans M, Jaarsma D, Henzen-Logmans S, Vecht C, De Zeeuw C, Sekiyama N, Nakanishi S, Shigemoto R (2000) Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 342(1):21–27. doi:10.1056/NEJM200001063420104
Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R, Katsuki M, Aiba A (2000) mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288(5472):1832–1835
Notartomaso S, Zappulla C, Biagioni F, Cannella M, Bucci D, Mascio G, Scarselli P, Fazio F, Weisz F, Lionetto L, Simmaco M, Gradini R, Battaglia G, Signore M, Puliti A, Nicoletti F (2013) Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1. Mol Brain 6:48. doi:10.1186/1756-6606-6-48
Ishibashi K, Miura Y, Ishikawa K, Ishii K, Ishiwata K (2015) Decreased metabotropic glutamate receptor type 1 availability in a patient with spinocerebellar ataxia type 6: a (11)C-ITMM PET study. J Neurol Sci 355(1–2):202–205. doi:10.1016/j.jns.2015.05.041
Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Schols L, Szymanski S, van de Warrenburg BP, Durr A, Klockgether T, Fancellu R (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66(11):1717–1720. doi:10.1212/01.wnl.0000219042.60538.92
Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, Tsai PC, Ichikawa Y, Goto J, Monin ML, Li JZ, Chung MY, Mundwiller E, Shakkottai V, Liu TT, Tesson C, Lu YC, Brice A, Tsuji S, Burmeister M, Stevanin G, Soong BW (2012) Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol 72(6):859–869. doi:10.1002/ana.23701
Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4(3 Pt 1):153–158. doi:10.1006/nimg.1996.0066
Wu Y, Carson RE (2002) Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 22(12):1440–1452. doi:10.1097/00004647-200212000-00004
Meltzer CC, Leal JP, Mayberg HS, Wagner HN Jr, Frost JJ (1990) Correction of PET data for partial volume effects in human cerebral cortex by MR imaging. J Comput Assist Tomogr 14(4):561–570
Raz N, Gunning-Dixon F, Head D, Williamson A, Acker JD (2001) Age and sex differences in the cerebellum and the ventral pons: a prospective MR study of healthy adults. AJNR Am J Neuroradiol 22(6):1161–1167
Waite LM, Broe GA, Creasey H, Grayson D, Edelbrock D, O’Toole B (1996) Neurological signs, aging, and the neurodegenerative syndromes. Arch Neurol 53(6):498–502
Andersen BB, Gundersen HJ, Pakkenberg B (2003) Aging of the human cerebellum: a stereological study. J Comp Neurol 466(3):356–365. doi:10.1002/cne.10884
Verbeek DS, Schelhaas JH, Ippel EF, Beemer FA, Pearson PL, Sinke RJ (2002) Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21. Hum Genet 111(4–5):388–393. doi:10.1007/s00439-002-0782-7
Schelhaas HJ, Verbeek DS, Van de Warrenburg BP, Sinke RJ (2004) SCA19 and SCA22: evidence for one locus with a worldwide distribution. Brain J Neurol 127 (Pt 1):E6. doi:10.1093/brain/awh036 (author reply E7)
Chung MY, Lu YC, Cheng NC, Soong BW (2003) A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23. Brain J Neurol 126(Pt 6):1293–1299
Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, van Dijk F, Verschuuren-Bemelmans C, Hageman G, van de Vlies P, Kusters B, van de Warrenburg BP, Kremer B, Wijmenga C, Sinke RJ, Swertz MA, Kampinga HH, Boddeke E, Verbeek DS (2012) Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol 72(6):870–880. doi:10.1002/ana.23700
Seidel K, Kusters B, den Dunnen WF, Bouzrou M, Hageman G, Korf HW, Schelhaas HJ, Verbeek D, Rub U (2014) First patho-anatomical investigation of the brain of a SCA19 patient. Neuropathol Appl Neurobiol 40(5):640–644. doi:10.1111/nan.12128
Schelhaas HJ, van de Warrenburg BP (2005) Clinical, psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19). Cerebellum 4(1):51–54. doi:10.1080/14734220510007888
Rub U, Schols L, Paulson H, Auburger G, Kermer P, Jen JC, Seidel K, Korf HW, Deller T (2013) Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog Neurobiol 104:38–66. doi:10.1016/j.pneurobio.2013.01.001
Ishikawa K, Watanabe M, Yoshizawa K, Fujita T, Iwamoto H, Yoshizawa T, Harada K, Nakamagoe K, Komatsuzaki Y, Satoh A, Doi M, Ogata T, Kanazawa I, Shoji S, Mizusawa H (1999) Clinical, neuropathological, and molecular study in two families with spinocerebellar ataxia type 6 (SCA6). J Neurol Neurosurg Psychiatry 67(1):86–89
Gomez CM, Thompson RM, Gammack JT, Perlman SL, Dobyns WB, Truwit CL, Zee DS, Clark HB, Anderson JH (1997) Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol 42(6):933–950. doi:10.1002/ana.410420616
Kato T, Tanaka F, Yamamoto M, Yosida E, Indo T, Watanabe H, Yoshiwara T, Doyu M, Sobue G (2000) Sisters homozygous for the spinocerebellar ataxia type 6 (SCA6)/CACNA1A gene associated with different clinical phenotypes. Clin Genet 58(1):69–73
Takahashi H, Ishikawa K, Tsutsumi T, Fujigasaki H, Kawata A, Okiyama R, Fujita T, Yoshizawa K, Yamaguchi S, Tomiyasu H, Yoshii F, Mitani K, Shimizu N, Yamazaki M, Miyamoto T, Orimo T, Shoji S, Kitamura K, Mizusawa H (2004) A clinical and genetic study in a large cohort of patients with spinocerebellar ataxia type 6. J Hum Genet 49(5):256–264. doi:10.1007/s10038-004-0142-7
Klockgether T (2010) Sporadic ataxia with adult onset: classification and diagnostic criteria. Lancet Neurol 9(1):94–104. doi:10.1016/S1474-4422(09)70305-9
Stoodley CJ, Schmahmann JD (2009) Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. NeuroImage 44(2):489–501. doi:10.1016/j.neuroimage.2008.08.039
Acknowledgments
This study was supported by a Grant-in-Aid for Young Scientists (B) no. 15K19503 to KIshibashi and for Scientific Research (B) no. 24390298 to KIshiwata from the Japan Society for the Promotion of Science. The authors thank the people of Research Team for Neuroimaging at the Tokyo Metropolitan Institute of Gerontology.
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The study was approved by the Ethics Committee of the Tokyo Metropolitan Institute of Gerontology (H26-49).
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Ishibashi, K., Miura, Y., Ishikawa, K. et al. Relationship between type 1 metabotropic glutamate receptors and cerebellar ataxia. J Neurol 263, 2179–2187 (2016). https://doi.org/10.1007/s00415-016-8248-3
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DOI: https://doi.org/10.1007/s00415-016-8248-3