以嗅覺測驗、黑質超音波影像和多巴胺系統核子影像[18F]-dopa PET作為巴金森氏病運動前期診斷工具來檢測LRRK2 G2385R變異帶因者之病例對照研究

Abstract

Parkinson’s disease(PD) is a relentlessly progressive neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra(SN). It is characterized by motor symptoms of bradykinesia, rest tremor and rigidity. Mutations in the gene leucine-rich repeat kinase 2 (LRRK2), located on chromosome 12p11.2-q13, are the most frequent causes of familial autosomal dominant PD. Recently genetic association studies identified LRRK2 G2385R variant is a common risk polymorphism for sporadic PD in the Chinese population. In vitro studies of transfected cells have proved that G2385R variant iss more vulnerable to oxidative stress and associated with a higher rate of apoptosis. Pathological studies have shown that at the time when PD motor symptoms appear, a significant amount with approximate 60% of dompaminergic neurons in the SN has already occurred. In the clinical aspects, hyposmia is considered as premotor sign of PD. Degeneration in the olfactory system has been also proved pathologically to be early in the stage of this degenerative disease. Moreover, based on in vivo PET and SPECT imaging of the dopaminergic system, the onset of dopaminergic neuronal loss antedates the motor symptoms of PD by approximately 4 to 6 years. Recently increased echogenicity of SN detected by transcranial sonography has been related to a functional impairment of the nigrostriatal system. It has also been proved to be a susceptibility marker for the development nigral injury that can be detected early in life prior to the onset of motor symptoms. These facts signify the importance of early diagnosis of PD in the premotor phase, in which neuroprotective measures can possibly intervene. With this background, we conducted this case-control cohort study in a hospital based cohort. We intended to evaluate various tools of premotor diagnosis with olfactory test, 18F-dopa PET and transcranial sonography of SN in the healthy subjects carrying LRRK2 G2385R variant, which has been proved to be specific for ethnic Han Chinese population. 526 healthy subjects were recruited from the PD center of National Taiwan University hospital for genetic screening of LRRK2 G2385R polymophism. Twenty four of them are G2385R variants. The prevalence rate of G2385R polymophism in our study group is 4.6%, which is similar to previous studies. Fifteen G2385R variants fulfilling the criteria of our study were then included for premotor diagnosis study. Meanwhile, fifteen aged and sex matched non-variants were included as control group. In the study of 18F-dopa PET, G2385R variants manifested a non-significant tendency to have decreased 18F-dopa uptake in the striatum, particularly in bilateral putamens. Our study has also proved that putaminal indicator of 18F-dopa PET imaging is a more sensitive indictor than the caudate indicator in terms of both clinical diagnosis and premotor diagnosis of PD. Furthermore, the G2385R variants did not show hyposmia or SN hyperechogenicity in comparison to the control group. It suggested that these two aforementioned premotor signs of PD seemed not related to LRRK G2385R polymophism. We should further follow particular subjects in this study, who presented with hyposmia, dopaminergic dysfunction shown by 18F-dopa PET, or SN hyperechoenicity to see if motor symptoms merge in the future and take in-time therapeutic intervention if PD is once diagnosed.