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Decreased metabotropic glutamate receptor type 1 availability in a patient with spinocerebellar ataxia type 6: A 11C-ITMM PET study

https://doi.org/10.1016/j.jns.2015.05.041Get rights and content

Highlights

  • We present the initial mGluR1 imaging in a patient with SCA6.

  • The expression of mGluR1 is exclusively localized in the cerebellar cortex.

  • The mGluR1 availability of the cerebellar subregions was 51.0 to 68.3% of controls.

  • The volume of the whole cerebellum was 72.6% of controls.

  • Imaging of mGluR1 can be a superior marker for estimation of cerebellar function.

Abstract

Objective

Imaging of metabotropic glutamate receptor type 1 (mGluR1), localized exclusively in the cerebellar Purkinje cells and related to cerebellar function, has recently become possible using positron emission tomography (PET). We report the initial mGluR1 imaging in a 74-year-old woman with spinocerebellar ataxia type 6 (SCA6).

Methods

The patient and 9 age-matched healthy controls underwent PET scanning with a mGluR1 radiotracer, N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl] -4-11C-methoxy-N-methylbenzamide. Volumes-of-interest were placed on the anterior and posterior lobes, vermis, and flocculus. Binding potential (BPND) was calculated to estimate mGluR1 availability using the simplified reference tissue model. A partial volume correction was applied to the BPND values. Additionally, the volume of the whole cerebellum was measured using MRI.

Results

The corrected BPND values of the cerebellar subregions and the volume of the whole cerebellum in the patient were 51.0% to 68.3% and 72.6%, respectively, of the controls. Thus, the magnitude of reduced BPND values was relatively larger than the magnitude of cerebellar atrophy in the patient.

Conclusion

These findings suggest that the measurement of mGluR1 availability is more sensitive than morphological measurements by MRI to detect reduced cerebellar function. Thus, imaging of mGluR1, probably reflecting the number and distribution of Purkinje cells, can be a specific and sensitive marker for estimation of cerebellar function.

Introduction

Metabotropic glutamate receptor type 1 (mGluR1) is involved in excitatory neurotransmission [1]. The regulation of mGluR1 is important in the pathophysiology of several neurological and psychiatric disorders. Imaging of mGluR1 in living human brains has recently been made possible using positron emission tomography (PET) along with the finding that mGluR1 in healthy subjects is exclusively localized to the cerebellar cortex [2]. As the expression of mGluR1 predominates postsynaptically in the cerebellar Purkinje cells and is involved in the regulation of cerebellar function [1], in vivo imaging of mGluR1 may provide crucial information for understanding the pathophysiology in cerebellar disorders. Spinocerebellar ataxia type 6 (SCA6) is one of the inherited cerebellar disorders, demonstrating relatively pure cerebellar symptoms due to selective Purkinje cell degeneration [3], [4]. Here we show the initial mGluR1 imaging in a patient with SCA6 and discuss its usefulness.

Section snippets

Research participants

The Ethics Committee of the Tokyo Metropolitan Institute of Gerontology approved the study protocol and written informed consent was obtained from all participants. The subjects comprised a patient with SCA6 and 9 age-matched healthy controls [3 men and 6 women; 71.6 ± 5.0 years (mean age ± SD)]. All participants underwent PET and magnetic resonance imaging (MRI) scans.

Characteristics of the patient with spinocerebellar ataxia type 6

The patient was a 74-year-old woman. She experienced dizziness during her middle 50s, developed imbalance in her 60s, and visited

Results

The BPND values before and after the partial volume correction in the patient were 38.1% to 65.2% and 51.0% to 68.3%, respectively, of the controls (Table 1). Of the cerebellar subregions, relatively reduced values of BPND were found in the vermis and flocculus. The volume of the whole cerebellum in the patient (Fig. 2A) was 72.6% of the controls. The BPND maps in the patient are displayed in native space (Fig. 2B and C). The BPND maps in 9 healthy controls were averaged in MNI space after they

Discussion

We present the initial imaging of mGluR1 in a patient with SCA6. SCA6 is clinically characterized by late-onset and slowly progressive pure cerebellar symptoms. Neurodegeneration in SCA6 is usually confined to the cerebellum and is less severe in other brain regions. Histologically, cerebellar atrophy is particularly seen in the vermis due to the selective loss of Purkinje cells [3], [4]. The mGluR1 expression is abundant in the dendritic arbors of Purkinje cells facing synaptic terminals of

Disclosure

None of the authors has any conflict of interest to disclose.

Acknowledgments

The authors thank Ms. Hatsumi Endo and Mr. Kunpei Hayashi for their technical assistance. This study was supported by a Grant-in-Aid for Scientific Research (B) No. 24390298 from the Japan Society for the Promotion of Science.

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    The rank order of VT values corresponds well to the estimated mGluR1 density in the human brain (Toyohara et al., 2013b). A recent case report study with 11C-ITMM in patients with spinocerebellar ataxia type 6 suggests that the magnitude of mGluR1 density reduction in the cerebellum is larger than the volumetric changes observed with magnetic resonance imaging (MRI; Ishibashi et al., 2015). Although these findings are promising, no information has been published regarding age and gender effects of mGluR1 density in healthy participants.

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    The cerebellar ataxia group consisted of 3 patients with SCA6, 3 patients with SCA19/22, and 6 patients with sporadic SCA (2 men and 4 women; aged 70.3 ± 13.3 years). Their clinical characteristics are described elsewhere [7,9]. Briefly, the patients with SCA6 were a 31-year-old man, a 68-year-old woman, and a 74-year-old woman with the SARA scores of 2, 21, and 6.5, respectively.

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