Rochester Lynn, Galna Brook, Lord Sue, Yarnall Alison J, Morris Rosie, Duncan Gordon, Khoo Tien K, Mollenhauer Brit, Burn David J
From the Institute of Neuroscience (L.R., B.G., S.L., A.J.Y., R.M., G.D., T.K.K., D.J.B.), Clinical Ageing Research Unit, Newcastle University; Department of Geriatric Medicine (G.D.), University of Edinburgh, UK; School of Medicine & Menzies Health Institute (T.K.K.), Griffith University, Australia; and Paracelsus-Elena Klinik, Kassel and University Medical Centre (Institute of Neuropathology and Department of Neurosurgery) (B.M.), Göttingen, Germany.
Neurology. 2017 Apr 18;88(16):1501-1511. doi: 10.1212/WNL.0000000000003840. Epub 2017 Mar 22.
This prospective observational study investigates the role of CSF biomarkers in predicting progression of dopa-resistant gait impairments in Parkinson disease (PD) in the first 36 months from diagnosis.
Quantitative gait analysis was carried out longitudinally using an instrumented walkway (GAITRite) in 108 people with PD and 130 age-matched controls. A subgroup of 44 people with PD underwent lumbar puncture from which a battery of CSF biomarkers was measured: β-amyloid 1-42 and 1-40 (Aβ42 and Aβ40), total and phosphorylated tau protein (t-tau/p-tau), and α-synuclein (αSyn). Linear mixed models examined the association between CSF and dopa-resistant gait characteristics (defined as substantial progression despite optimal medication).
Low baseline CSF Aβ42, and to a lesser extend Aβ40, predicted decline in gait characteristics in the first 3 years following diagnosis, independently explaining up to 12% of progression of step time variability (single task) and step length variability (dual-task). Interestingly, these findings were independent of age and cognition.
These findings implicate underlying amyloid pathology in neural networks involved in locomotor control. Results suggest that disturbed Aβ metabolism may be a biomarker for dopa-resistant gait impairments in early PD. Our findings raise interesting questions regarding therapeutic interventions such as compounds or molecules aimed at reducing amyloid burden to mitigate gait disturbance in early PD and potentially falls risk. Finally, progression of discrete gait characteristics suggests they may have potential as clinical biomarkers of pathology and disease progression.
这项前瞻性观察性研究调查了脑脊液生物标志物在帕金森病（PD）诊断后的前36个月内预测多巴胺抵抗性步态障碍进展中的作用。
对108名帕金森病患者和130名年龄匹配的对照者使用仪器化步道（GAITRite）进行纵向定量步态分析。44名帕金森病患者的亚组接受了腰椎穿刺，测量了一系列脑脊液生物标志物：β-淀粉样蛋白1-42和1-40（Aβ42和Aβ40）、总tau蛋白和磷酸化tau蛋白（t-tau/p-tau）以及α-突触核蛋白（αSyn）。线性混合模型检验了脑脊液与多巴胺抵抗性步态特征（定义为尽管药物治疗最佳但仍有显著进展）之间的关联。
基线脑脊液Aβ42水平低，以及程度较轻的Aβ40水平低，预测了诊断后前3年步态特征的下降，独立解释了步时间变异性（单任务）和步长变异性（双任务）进展的高达12%。有趣的是，这些发现与年龄和认知无关。
这些发现表明参与运动控制的神经网络中存在潜在的淀粉样蛋白病理。结果表明，Aβ代谢紊乱可能是早期帕金森病中多巴胺抵抗性步态障碍的生物标志物。我们的发现提出了关于治疗干预的有趣问题，例如旨在减轻淀粉样蛋白负担以减轻早期帕金森病步态障碍并潜在降低跌倒风险的化合物或分子。最后，离散步态特征的进展表明它们可能有潜力作为病理和疾病进展的临床生物标志物。
