帕金森病及相关疾病中突触功能障碍的脑脊液生物标志物发生改变。

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders.

作者信息

Nilsson Johanna, Constantinescu Julius, Nellgård Bengt, Jakobsson Protik, Brum Wagner S, Gobom Johan, Forsgren Lars, Dalla Keti, Constantinescu Radu, Zetterberg Henrik, Hansson Oskar, Blennow Kaj, Bäckström David, Brinkmalm Ann

机构信息

Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Department of Neurology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

出版信息

Mov Disord. 2023 Feb;38(2):267-277. doi: 10.1002/mds.29287. Epub 2022 Dec 12.

DOI:10.1002/mds.29287

PMID:36504237

Abstract

BACKGROUND

Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects.

OBJECTIVE

To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.

METHODS

Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n = 51, n = 101), corticobasal degeneration (CBD) (n = 11, n = 3), progressive supranuclear palsy (PSP) (n = 22, n = 21), multiple system atrophy (MSA) (n = 31, n = 26), and healthy control (HC) (n = 48, n = 30) participants, as well as Alzheimer's disease (AD) (n = 23) patients in the second cohort.

RESULTS

Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25-0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate = -0.025 to -0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate = 0.32, P = 0.021).

CONCLUSIONS

These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

摘要

背景

突触功能障碍和退化是帕金森病相关疾病发病机制和进展的核心因素。因此，迫切需要识别和验证反映病理性突触改变的生物标志物，这些生物标志物可用于预后评估和监测治疗效果。

目的

探索帕金森病（PD）及相关疾病中突触功能障碍的候选生物标志物。

方法

采用质谱法对两个临床脑脊液（CSF）队列中的15种突触蛋白进行定量分析，其中包括PD患者（n = 51，n = 101）、皮质基底节变性（CBD）患者（n = 11，n = 3）、进行性核上性麻痹（PSP）患者（n = 22，n = 21）、多系统萎缩（MSA）患者（n = 31，n = 26）、健康对照（HC）参与者（n = 48，n = 30），以及第二个队列中的阿尔茨海默病（AD）患者（n = 23）。

结果

在两个队列中，与HC相比，PD、MSA和PSP患者的神经元五聚体蛋白（NPTX；1、2和受体）水平较低。在MSA和PSP患者中，与HC相比，神经颗粒素、AP2B1和突触结合蛋白-2水平较低。在AD患者中，与帕金森病相关疾病相比，14-3-3 ζ/δ、β-和γ-突触核蛋白水平较高。PD患者中较低的五聚体蛋白水平与简易精神状态检查表评分和特定认知缺陷相关（NPTX2；rho = 0.25 - 0.32，P < 0.05），并且与DaTSCAN测量的多巴胺能突触前完整性降低相关（NPTX2；rho = 0.29，P = 0.023）。此外，较低水平与姿势不平衡和步态困难症状的进展相关（所有NPTX；β估计值 = -0.025至 -0.038，P < 0.05）以及认知衰退相关（NPTX2；β估计值 = 0.32，P = 0.021）。