Maple-Grødem Jodi, Chung Janete, Lunde Kristin Aaser, Tzoulis Charalampos, Tysnes Ole-Bjørn, Pedersen Kenn Freddy, Alves Guido
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Centre for Organelle Research, University of Stavanger, Stavanger, Norway.
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Neurosci Lett. 2018 May 1;674:123-126. doi: 10.1016/j.neulet.2018.03.036. Epub 2018 Mar 19.
Dementia in Parkinson disease (PD) is a common occurrence, and shows a marked overlap at a clinical and pathological level with Alzheimer's disease (AD), suggesting they share underlying disease mechanisms. Genetic variants in SORL1 have been identified in patients with AD, but a possible role in other dementias is unknown. The aim of this study was to investigate whether common polymorphisms in SORL1 affect the risk of developing dementia in a population-based cohort of patients with incident PD.
One common, nonsynonymous SORL1 variant (rs2298813; A528T) was identified in whole exome sequencing data from 185 patients with PD from the Norwegian ParkWest study, who had been followed up to the 7-year visit after diagnosis. A528T was tested for association with PD risk, the development of dementia, and in a subset of patients (n = 103) for associations with established AD cerebrospinal fluid (CSF) biomarkers measured at the time of PD diagnosis.
We found an association of A528T carrier status with increased risk of developing PD dementia (HR 2.31; 95% CI 1.09-4.90; p = 0.03) compared to non-carriers. Additionally, A528T carrier status was associated with a reduced ratio of CSF β-amyloid 42 to p-Tau (p = 0.014) but no alterations in absolute AD marker levels (all p > 0.05) at the time of PD diagnosis.
Our results show the first association of the AD risk factor SORL1 with incident dementia in PD, providing new evidence that AD related disease mechanisms may contribute to dementia in a subset of patients with PD. Finding support for a shared etiology for AD and PD dementia provides new directions for research into treatments for these diseases.
帕金森病（PD）中的痴呆很常见，在临床和病理水平上与阿尔茨海默病（AD）有明显重叠，提示它们有共同的潜在疾病机制。已在AD患者中鉴定出SORL1的基因变异，但在其他痴呆中的可能作用尚不清楚。本研究的目的是调查SORL1中的常见多态性是否会影响基于人群的新发PD患者队列中发生痴呆的风险。
在挪威ParkWest研究的185例PD患者的全外显子测序数据中鉴定出一种常见的非同义SORL1变异（rs2298813；A528T），这些患者在诊断后随访至7年。对A528T进行了与PD风险、痴呆发生的关联测试，并在一部分患者（n = 103）中测试了与PD诊断时测定的已确定的AD脑脊液（CSF）生物标志物的关联。
与非携带者相比，我们发现A528T携带者状态与发生PD痴呆的风险增加相关（HR 2.31；95%CI 1.09 - 4.90；p = 0.03）。此外，A528T携带者状态与PD诊断时CSFβ-淀粉样蛋白42与磷酸化tau蛋白的比值降低相关（p = 0.014），但绝对AD标志物水平无变化（所有p > 0.05）。
我们的结果首次显示AD风险因素SORL1与PD中的新发痴呆相关，提供了新的证据表明AD相关疾病机制可能导致一部分PD患者发生痴呆。为AD和PD痴呆的共同病因找到支持为这些疾病的治疗研究提供了新方向。
