Marek Kenneth, Jennings Danna, Tamagnan Gilles, Seibyl John
Institute for Neurodegenerative Disorders, New Haven, CT, USA.
Ann Neurol. 2008 Dec;64 Suppl 2:S111-21. doi: 10.1002/ana.21602.
Reliable and well-validated biomarkers for PD to identify individuals "at risk" before motor symptoms, accurately diagnose individuals at the threshold of clinical PD, and monitor PD progression throughout its course would dramatically accelerate research into both PD cause and therapeutics. Biomarkers offer the potential to provide a window onto disease mechanism, potentially generating therapeutic targets for disease. In particular, biomarkers enable investigation of the premotor period of PD before typical symptoms are manifest, but while degeneration has already begun. Given the multiple genetic causes for PD already identified, the marked variability in the loss of dopaminergic markers measured by imaging at motor symptom onset and the clear heterogeneity of clinical symptoms in PD onset and clinical progression, it is likely many biomarkers with a focus ranging from clinical symptoms to PD pathobiology to molecular genetic mechanisms will be necessary to fully map PD risk and progression. Biomarkers are also critical in new drug development for PD, both in early validation studies to assess drug dosing and to determine drug penetrance into the brain, and in later efficacy studies to complement PD clinical outcomes. During the past two decades, much progress has been made in identifying and assessing PD biomarkers, but as yet, no fully validated biomarker for PD is currently available. Nonetheless, there is increasing evidence that molecular genetics, focused -omic (proteomic, metabolomic, and transcriptomic) assessment of blood and cerebrospinal fluid, and advanced in vivo brain imaging will provide critical clues to assist in the diagnosis and medical management of PD patients.
用于帕金森病(PD)的可靠且经过充分验证的生物标志物,能够在运动症状出现之前识别出“有风险”的个体,准确诊断处于临床PD阈值的个体,并在疾病全过程中监测PD的进展,这将极大地加速对PD病因和治疗方法的研究。生物标志物有可能为疾病机制提供一个窗口,从而潜在地生成针对该疾病的治疗靶点。特别是,生物标志物能够在典型症状出现之前,但变性已经开始时,对PD的运动前期进行研究。鉴于已经确定的PD的多种遗传病因、运动症状出现时通过成像测量的多巴胺能标志物丢失的显著变异性以及PD发病和临床进展中临床症状的明显异质性,可能需要许多生物标志物,其关注范围从临床症状到PD病理生物学再到分子遗传机制,才能全面描绘PD的风险和进展情况。生物标志物在PD新药研发中也至关重要,在早期验证研究中用于评估药物剂量和确定药物进入大脑的渗透率,在后期疗效研究中用于补充PD临床结果。在过去二十年中,在识别和评估PD生物标志物方面取得了很大进展,但目前尚无完全经过验证的PD生物标志物。尽管如此,越来越多的证据表明,分子遗传学、对血液和脑脊液进行的聚焦组学(蛋白质组学、代谢组学和转录组学)评估以及先进的体内脑成像将提供关键线索,以协助PD患者的诊断和医疗管理。