Paracelsus-Elena-Klinik, Kassel, Germany.
Lancet Neurol. 2011 Mar;10(3):230-40. doi: 10.1016/S1474-4422(11)70014-X.
Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are brain disorders characterised by intracellular α-synuclein deposits. We aimed to assess whether reduction of α-synuclein concentrations in CSF was a marker for α-synuclein deposition in the brain, and therefore diagnostic of synucleinopathies.
We assessed potential extracellular-fluid markers of α-synuclein deposition in the brain (total α-synuclein and total tau in CSF, and total α-synuclein in serum) in three cohorts: a cross-sectional training cohort of people with Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders; a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders (CSF specimens were drawn ante mortem during clinical investigations); and a validation cohort of patients who between January, 2003, and December, 2006, were referred to a specialised movement disorder hospital for routine inpatient admission under the working diagnosis of parkinsonism. CSF and serum samples were assessed by ELISA, and clinical diagnoses were made according to internationally established criteria. Mean differences in biomarkers between diagnostic groups were assessed with conventional parametric and non-parametric statistics.
In our training set, people with Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies had lower CSF α-synuclein concentrations than patients with Alzheimer's disease and other neurological disorders. CSF α-synuclein and tau values separated participants with synucleinopathies well from those with other disorders (p<0·0001; area under the receiver operating characteristic curve [AUC]=0·908). In the autopsy-confirmed cases, CSF α-synuclein discriminated between dementia with Lewy bodies and Alzheimer's disease (p=0·0190; AUC=0·687); in the validation cohort, CSF α-synuclein discriminated Parkinson's disease and dementia with Lewy bodies versus progressive supranuclear palsy, normal-pressure hydrocephalus, and other neurological disorders (p<0·0001; AUC=0·711). Other predictor variables tested in this cohort included CSF tau (p=0·0798), serum α-synuclein (p=0·0502), and age (p=0·0335). CSF α-synuclein concentrations of 1·6 pg/μL or lower showed 70·72% sensitivity (95% CI 65·3-76·1%) and 52·83% specificity (39·4-66·3%) for the diagnosis of Parkinson's disease. At this cutoff, the positive predictive value for any synucleinopathy was 90·7% (95% CI 87·3-94·2%) and the negative predictive value was 20·4% (13·7-27·2%).
Mean CSF α-synuclein concentrations as measured by ELISA are significantly lower in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy than in other neurological diseases. Although specificity was low, the high positive predictive value of CSF α-synuclein concentrations in patients presenting with synucleinopathy-type parkinsonism might be useful in stratification of patients in future clinical trials.
American Parkinson Disease Association, Stifterverband für die Deutsche Wissenschaft, Michael J Fox Foundation for Parkinson's Research, National Institutes of Health, Parkinson Research Consortium Ottawa, and the Government of Canada.
帕金森病、路易体痴呆和多系统萎缩是由细胞内α-突触核蛋白沉积引起的脑部疾病。我们旨在评估脑脊液中α-突触核蛋白浓度的降低是否是脑内α-突触核蛋白沉积的标志物，因此是否可以诊断突触核蛋白病。
我们评估了三种队列中脑内α-突触核蛋白沉积的潜在细胞外液标志物（脑脊液中的总α-突触核蛋白和总tau 以及血清中的总α-突触核蛋白）：一组患有帕金森病、多系统萎缩、路易体痴呆、阿尔茨海默病或其他神经疾病的患者；一组经尸检证实患有路易体痴呆、阿尔茨海默病或其他神经疾病的患者（在临床研究期间，在生前抽取脑脊液标本）；以及一组在 2003 年 1 月至 2006 年 12 月期间因帕金森病样症状被转诊至专门的运动障碍医院接受常规住院治疗的患者。采用 ELISA 法检测 CSF 和血清样本，根据国际公认的标准进行临床诊断。采用常规参数和非参数统计方法评估诊断组之间生物标志物的差异。
在我们的训练集中，帕金森病、多系统萎缩和路易体痴呆患者的脑脊液α-突触核蛋白浓度低于阿尔茨海默病和其他神经疾病患者。脑脊液α-突触核蛋白和 tau 值很好地区分了突触核蛋白病患者和其他疾病患者（p<0·0001；接受者操作特征曲线下面积[AUC]为 0·908）。在经尸检证实的病例中，脑脊液α-突触核蛋白可区分路易体痴呆和阿尔茨海默病（p=0·0190；AUC=0·687）；在验证队列中，脑脊液α-突触核蛋白可区分帕金森病和路易体痴呆与进行性核上性麻痹、正常压力脑积水和其他神经疾病（p<0·0001；AUC=0·711）。该队列中测试的其他预测变量包括 CSF tau（p=0·0798）、血清α-突触核蛋白（p=0·0502）和年龄（p=0·0335）。脑脊液α-突触核蛋白浓度为 1·6 pg/μL 或更低时，对帕金森病的诊断具有 70·72%的敏感性（95%CI 65·3-76·1%）和 52·83%的特异性（39·4-66·3%）。在该截点时，任何突触核蛋白病的阳性预测值为 90·7%（95%CI 87·3-94·2%），阴性预测值为 20·4%（13·7-27·2%）。
通过 ELISA 测量的脑脊液α-突触核蛋白浓度在帕金森病、路易体痴呆和多系统萎缩中明显低于其他神经疾病。尽管特异性较低，但在以突触核蛋白病为特征的帕金森病患者中，脑脊液α-突触核蛋白浓度的高阳性预测值可能有助于未来临床试验中患者的分层。
美国帕金森病协会、施蒂弗特协会、迈克尔·J·福克斯基金会帕金森病研究、美国国立卫生研究院、渥太华帕金森病研究联盟和加拿大政府。
