Multimarker Parkinson's Diagnotic test kit for monitoring disease progression based on electroanalytical detection of protein changes in blood.

仅在英国，痴呆症就影响了60多万帕金森病患者，这是一个重要且不断增长的组成部分。随着平均人口年龄的增长，这些数字正在增加，对福利制度、NHS和家庭构成了非常沉重的负担。帕金森氏病是一种异质性疾病，其特征是进行性神经元丧失，导致运动和其他功能下降。高达80%的帕金森病长期幸存者会发展为痴呆症，而相当大比例的患者会出现早期运动障碍，如姿势不稳和跌倒。目前还没有改善疾病的治疗方法，这部分是由于缺乏客观的标记物来对这些患者亚组进行分层，并客观地衡量他们的疾病进展。迫切需要这样的生物标志物来促进旨在减缓神经退行性变的临床试验的发展，重要的是还可以告知预后和更好地计划护理。基于我们对血清样本的初步研究，我们预测这样一种生物标志物可以通过对外周循环中低丰度的几种疾病特异性反应蛋白变化进行多路采样和定量的技术来开发。这种方法需要鉴定创新的生物标志物候选物和超灵敏、无标记的蛋白质检测方法的可用性。目前筛选蛋白质的方法涉及昂贵和高度专业化的设备，或容易产生低水平的灵敏度和/或复杂的分析程序，并伴有显著（高达200%）的分析误差。电检测方法具有便携、高灵敏度、廉价、高通量（测量时间为几分钟——在筛选许多样品时尤其重要）和可复用性（同时检测多种蛋白质，在相关情况下可提供健康的“指纹”）。人造电子器件与生物受体分子的界面可以实现对疾病标志物的特异性和校准检测。围绕这些原则建造的设备已经对临床诊断和那些不幸患有慢性疾病（如糖尿病）的人的生活质量产生了深远的影响。生物体液（尿液、唾液、血清、脊髓液）中蛋白质水平的评估是当前健康状况的重要反映，也可能反映疾病的进展。我们已经证明，身体对帕金森病患者大脑中积累的小蛋白（α -突触核蛋白）的反应之一是产生抗α -突触核蛋白抗体，我们已经测量了这种抗体，并使用电化学将其与疾病阶段联系起来。我们还表明，患者血清中的循环微泡具有独特的生物活性和蛋白质组成。我们建议通过集成的微流控多路复用装置来测量这些微囊泡相关蛋白，并结合我们早期的自身抗体数据开发一个多参数试剂盒来监测疾病进展。我们有独特的优势来开发这项技术，并在两个广泛表征的纵向患者队列中提供概念证明。具体来说，我们将通过将一系列血清水平与详细的临床评估相关联，来询问在精心挑选的患者样本中，蛋白质标记物的组合是否反映了痴呆症或严重运动障碍的进展速度。总之，我们正在寻求通过开发一种独特的多参数受体化学装置来解决神经退行性疾病领域的一个深刻的临床挑战，我们相信这种装置将具有前所未有的应用和效力。

In England alone, dementia affects more than 600,000 people with Parkinson's pathology constituting a significant and growing part of this. These numbers are increasing as the mean population age grows and represent a very substantial burden on the welfare system, the NHS and families. Parkinson's disease is a heterogeneous disease characterised by progressive neuronal loss, causing a decline in movement and other functions. Up to 80% of long-term survivors with Parkinson's develop dementia whereas a significant percentage reach early motor disability such as postural instability and falls. Currently there is no disease-modifying therapy, which in part is hindered by the lack of an objective marker that stratifies these patient subgroups and objectively measures their disease progression. Such a biomarker is urgently needed to facilitate the development of clinical trials that aim to slow down neurodegeneration and importantly to also inform prognosis and better plan care. Based on our preliminary work in serum samples, our prediction is that such a biomarker can be developed with technology that enables multiplexed sampling and quantitation of several disease-specific reactive protein changes that are present in low abundance in the peripheral circulation. This approach requires the identification of innovative biomarker-candidates and the availability of ultrasensitive, label-free protein detection methods. The current methods of screening proteins involve expensive and highly specialized pieces of equipment or are prone to low levels of sensitivity and/or complicated analytical procedures associated with significant (up to 200%) analytical error. Electrical detection methodologies are portable, highly sensitive, cheap, high throughput (measurement time of minutes - particularly important if many samples are being screened) and multiplexable (multiple proteins detected simultaneously giving, in relevant cases, a "fingerprint" of health). The interfacing of man-made electronics with biological receptor molecules can enable the specific and calibrated detection of markers of disease. Devices built around these principles have already had a profound impact on clinical diagnostics and the quality of life of those unfortunate enough to live with chronic diseases such as diabetes. An assessment of protein levels in biological fluid (urine, saliva, blood serum, spinal fluid) constitutes a critical reflection of current health and may be reflective of the disease progression. We have already shown that one of the body's responses to the small protein (alpha-synuclein) that accumulates in the brains of patient with Parkinson's disease is to generate anti-alpha-synuclein antibodies, which we have measured and correlated with the disease stage using electrochemistry. We have also shown that circulating microvesicles in the serum of patients have distinct bioactivity and protein composition. We propose to measure these microvesicle-associated proteins by integrated microfluidic multiplexed devises and in combination with our earlier data on auto-antibodies develop a multi-parameter kit to monitor disease progression. We are uniquely positioned to develop this technology and provide proof of concept in two extensively characterized longitudinal patient cohorts. Specifically, we will ask whether a combination of protein markers reflect the rate of progression to dementia or severe movement disability in carefully selected patient samples by correlating serial serum levels with detailed clinical assessments. In summary, we are seeking to solve a profound clinical challenge in the area of neurodegeneration by developing a unique multi-parameter receptor chemistry device that we believe will have unprecedented application and potency.