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Progression and prognosis in multiple system atrophy presenting with REM behavior disorder.

表现为 REM 行为障碍的多系统萎缩的进展和预后。

  • 影响因子:3.85
  • DOI:10.1212/WNL.0000000000009372
  • 作者列表:"Giannini G","Mastrangelo V","Provini F","Droghini A","Cecere A","Barletta G","Mignani F","Guaraldi P","Cortelli P","Calandra-Buonaura G
  • 发表时间:2020-03-31
Abstract

OBJECTIVES:To investigate (1) the prevalence of REM sleep behavior disorder (RBD) as mode of disease onset in a cohort of patients with multiple system atrophy (MSA) and (2) disease progression and prognosis in patients with MSA with RBD predating (pre-RBD) and following (post-RBD) disease onset. METHODS:We retrospectively identified all patients with a clinical diagnosis of MSA evaluated at least once a year during the disease course. Type of onset was defined by the first reported motor or autonomic symptom/sign related to MSA. The occurrence of symptoms/signs and milestone of disease progression, and their latency from disease onset, were collected. Survival data were calculated. RBD was confirmed by video-polysomnography. RESULTS:Of a total of 158 patients, pre-RBD represented the mode of disease onset in 27% of patients, preceding disease onset according to the international criteria with a median of 3 (2-5) years. Comparing pre-RBD and post-RBD patients, the first group showed an increased prevalence of autonomic onset of disease, a reduced prevalence of parkinsonism, an earlier onset of stridor, pyramidal signs, symptomatic orthostatic hypotension, urinary dysfunction, severe dysphagia, and wheelchair dependency. The risk of death was higher in patients with pre-RBD. CONCLUSIONS:In our MSA cohort, RBD represented the most frequent mode of disease presentation. A more rapid progression of disease was observed in the pre-RBD group. These findings suggested a careful assessment of sleep disorders to early recognize RBD and a closer follow-up of autonomic dysfunction and stridor in patients with pre-RBD.

摘要

目的: 调查 (1) 多系统萎缩 (MSA) 患者队列中快速眼动睡眠行为障碍 (RBD) 作为发病模式的患病率 (2) RBD 发病前 (pre-RBD) 和发病后 (post-RBD) MSA 患者的疾病进展和预后。 方法: 我们回顾性确定了所有临床诊断为 MSA 的患者,在病程中每年至少评估一次。发病类型由首次报告的与 MSA 相关的运动或自主神经症状/体征定义。收集疾病进展的症状/体征和里程碑的发生情况,以及疾病发作的潜伏期。计算生存数据。RBD 通过视频多导睡眠图确诊。 结果: 在总共 158 例患者中,pre-RBD 代表了 27% 患者的发病模式,根据国际标准在疾病发作前,中位数为 3 (2-5) 年。比较 RBD 前和 RBD 后患者,第一组显示自主发病患病率增加,帕金森综合征患病率降低,喘鸣、锥体束征发病较早,症状性直立性低血压、排尿功能障碍、严重吞咽困难和轮椅依赖。RBD 前期患者的死亡风险较高。 结论: 在我们的 MSA 队列中,RBD 代表了最常见的疾病表现模式。在 RBD 前组中观察到疾病进展更快。这些发现建议仔细评估睡眠障碍以早期识别 RBD,并对 RBD 前期患者的自主神经功能障碍和喘鸣进行更密切的随访。

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DOI:10.1111/bpa.12761
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METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

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