Predicting neurodegeneration in living patients by IR imaging of skin fibroblasts

摘要 尽管神经退行性疾病通常可以通过迟发的行为特征或 通过尸检病理，我们往往缺乏可靠的方法来预测生命早期的疾病状态。它仍然存在 在许多情况下很难明确神经退行性疾病亚型之间的区别 在症状出现之前，或确定疾病何时会发生。需要新的生物标志物。 我们开发了一种傅里叶变换红外(FTIR)光谱显微镜方法来预测疾病状态 基于化学终点的细胞图像。细胞暴露于红外光和细胞的光谱表型 图像产生吸光度信号，作为疾病状态的快速生理指示器。我们将测试 该方法是否能在没有行为或组织异常的情况下准确地对疾病状态进行分类 对具有已知疾病特征的小鼠的预测进行基准测试。在人类细胞中，我们将测试FTIR 使用人类患者成纤维细胞和生物标志物可以准确预测神经退行性疾病的类别 淋巴母细胞作为替代细胞。将测试FTIR光谱，以区分神经退行性变 经常相互混淆的亚型，例如阿尔茨海默病(AD)和非AD痴呆。 这些原则性证明实验旨在确定FTIR方法是否可以产生 可靠的早期疾病生物标志物以及签名是否有能力区分不同的 疾病亚型。 1

ABSTRACT Although neurodegenerative diseases most often can be identified by late onset behavioral characteristics or by post-mortem pathology, we often lack reliable methods to predict disease status early in life. It remains extraordinarily difficult in many cases to make clear distinctions among neurodegenerative disease subtypes before the onset of symptoms, or to determine when disease onset will occur. New biomarkers are needed. We have developed a Fourier transform infrared (FTIR) spectromicroscopy approach to predict disease status from cell images based on chemical endpoints. Cells are exposed to IR light and spectral phenotyping ofthe cell images produces an absorbance signature as a rapid physiological indicator of disease state. We will test whether the method can accurately classify disease status in the absence of behavioral or tissue abnormalities and benchmark the predictions in mice with known disease features. In human cells, we will test whether the FTIR biomarker can accurately predict neurodegenerative disease class using human patient fibroblasts and lymphoblasts as surrogate cells. The FTIR spectrum will be tested to distinguish among neurodegenerative subtypes that are often confused with each other, e.g., Alzheimer’s disease (AD) and non-AD dementias. These proof of principle experiments are designed to establish whether the FTIR method can generate a reliable early disease biomarker and whether the signature has the power to discriminate among distinct disease subtypes. 1