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Disease progression and prognostic factors in multiple system atrophy: A prospective cohort study.
多系统萎缩的疾病进展和预后因素: 一项前瞻性队列研究。
- 影响因子:5.36
- DOI:10.1016/j.nbd.2020.104813
- 作者列表:"Foubert-Samier A","Traon AP","Guillet F","Le-Goff M","Helmer C","Tison F","Rascol O","Proust-Lima C","Meissner WG
- 发表时间:2020-02-19
Abstract
:Multiple system atrophy (MSA) is a rare neurodegenerative disease, with limited understanding of disease progression and prognostic factors. We leveraged the data of the largest prospective cohort of MSA to study both clinical progression and survival and assess their determinants. All consecutive patients seen at the French Reference Centre for MSA since 2007 were included in a prospective cohort with an annual follow-up including the Unified MSA Rating Scale (UMSARS). We used joint models to evaluate the risk of death, the mean trajectory of each UMSARS subscale and to determine the potential factors. Investigated factors included gender, age at baseline, MSA subtype, diagnosis certainty, type of first symptoms and the duration between symptom onset and the first visit. Among the 261 MSA patients included in our cohort, the median duration of clinical follow-up was 2.1 years (up to 10.3 years) and the median survival was 4.0 years since the first visit. Main factors for poor survival were the progression over time of UMSARS score (I + II and IV) and the severity of orthostatic hypotension. MSA subtype had no effect on progression or survival. The UMSARS I + II score progressed faster over time in subjects with autonomic dysfunction as the initial feature and in women. Despite a faster progression, women and men had similar survival. From this large MSA cohort, we confirm the rapid progression and poor prognosis of MSA. We provide additional evidence for a negative impact of early autonomic dysfunction and the severity of orthostatic hypotension on both disease progression and survival.
摘要
: 多系统萎缩 (MSA) 是一种罕见的神经退行性疾病,对疾病进展和预后因素的了解有限。我们利用最大的 MSA 前瞻性队列的数据来研究临床进展和生存率,并评估其决定因素。2007年在法国 MSA 参考中心就诊的所有连续患者均被纳入一项前瞻性队列,每年进行随访,包括统一 MSA 评定量表 (UMSARS)。我们使用联合模型评估死亡风险、每个 umsra 子量表的平均轨迹并确定潜在因素。调查因素包括性别、基线年龄、 MSA 亚型、诊断确定性、首发症状类型以及症状发作与初诊之间的持续时间。在纳入我们队列的 261 例 MSA 患者中,自首次就诊以来,临床随访的中位时间为 2.1 年 (最多 10.3 年),中位生存期为 4.0 年。生存不良的主要因素是随着时间的推移,umsra 评分 (i + ii 和 IV) 的进展和直立性低血压的严重程度。MSA 亚型对进展或生存无影响。以自主神经功能障碍为初始特征的受试者和女性的 UMSARS i + ii 评分随时间推移进展更快。尽管进展更快,但女性和男性的生存率相似。从这个大型 MSA 队列中,我们证实了 MSA 的快速进展和不良预后。我们提供了早期自主神经功能障碍和直立性低血压的严重程度对疾病进展和生存的负面影响的额外证据。
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METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.