Combined FDG and raclopride PET study in a case of ALS with the R521C FUS gene mutation

Abstract

Mutations in the fused in sarcoma (FUS) gene have been associated with familial and apparently sporadic cases of amyotrophic lateral sclerosis (ALS) [8]. This study evaluated the cerebral glucose metabolism and postsynaptic dopaminergic function in the striatum using positron emission tomography (PET) in an ALS patient with a FUS gene mutation. The patient was a 25 year-old Japanese female who presented with difficulty in flexing her neck in the supine position. She developed difficulty in raising her arms 2 months later followed by swallowing difficulties. Her mother had been diagnosed with ALS at age 29 years and died 10 years later. An examination 10 months after the onset of the disease revealed symmetric weakness and atrophy of the proximal muscles including the upper limbs and neck flex muscles. There was neither atrophy nor fasciculation in her tongue. The lower limb reflexes were brisk, but she had absence of upper limbs reflexes and flexor planter responses. There was no sensory disturbance, extrapyramidal signs or cerebellar signs. Neuropsychological assessments revealed that her Mini-Mental State Examination score was 30 and her Frontal Assessment Battery score was 17, which was normal in comparison to age-matched normal subjects. Her verbal, performance, and full-scale scores of Wechsler Adult Intelligence Scale were, 86, 114, and 94, respectively. She achieved six sorting categories in the Nelson modification of the Wisconsin card sorting test. Magnetic resonance imaging (MRI) of the brain was normal (Fig. 1a). A genetic analysis revealed that she had a heterozygous R521C mutation in the FUS gene. Functional brain imaging was performed using [F]-fluorodeoxyglucose (FDG)-PET to measure the cerebral metabolic rate of glucose (CMRGlc) and [C] raclopride-PET for investigation of post synaptic dopaminergic neuronal activity. In addition the semi-quantitative regions of interest (ROIs)/cerebellum ratio was analyzed as described previously [6]. Analyses of the PET images showed that CMRGlc did not apparently decrease in either the cerebral cortices or basal ganglia (Table 1), while [C] raclopride binding decreased in the putamen (Table 1; Fig. 1b). Pathological studies of ALS patients with an R521C mutation showed cytoplasmic basophilic inclusions containing FUS to be distributed in the neurons in widespread brain areas including the frontotemporal cortex, the striatum, the substantia nigra, thalamus and cerebellum in addition to the upper and lower motor neurons [8, 9, 11]. Four ALS patients with an R521C mutation and one with a G156E mutation have been reported to present with parkinsonism or frontotemporal dementia (FTD) [1, 12, 13]. There have so far been few reports on functional brain imaging in ALS patients with FUS mutations. A SPECT study shows a decrease in cerebral blood flow in the frontotemporal cortex and striatum in an ALS patient with an R521C mutation who presented neither dementia nor parkinsonism [11]. The findings of a raclopride PET study in this patient showed postsynaptic dopaminergic dysfunction in the putamen, which may thus suggest that the S. Kono (&) T. Terada M. Suzuki H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp