Kim Jinho, Amante Daniel J, Moody Jennifer P, Edgerly Christina K, Bordiuk Olivia L, Smith Karen, Matson Samantha A, Matson Wayne R, Scherzer Clemens R, Rosas H Diana, Hersch Steven M, Ferrante Robert J
Geriatric Research Education Clinical Center, New England Veterans Administration VISN 1, Bedford, MA 01730, USA.
Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):673-81. doi: 10.1016/j.bbadis.2010.05.001. Epub 2010 May 9.
A major goal of current clinical research in Huntington's disease (HD) has been to identify preclinical and manifest disease biomarkers, as these may improve both diagnosis and the power for therapeutic trials. Although the underlying biochemical alterations and the mechanisms of neuronal degeneration remain unknown, energy metabolism defects in HD have been chronicled for many years. We report that the brain isoenzyme of creatine kinase (CK-BB), an enzyme important in buffering energy stores, was significantly reduced in presymptomatic and manifest disease in brain and blood buffy coat specimens in HD mice and HD patients. Brain CK-BB levels were significantly reduced in R6/2 mice by approximately 18% to approximately 68% from 21 to 91 days of age, while blood CK-BB levels were decreased by approximately 14% to approximately 44% during the same disease duration. Similar findings in CK-BB levels were observed in the 140 CAG mice from 4 to 12 months of age, but not at the earliest time point, 2 months of age. Consistent with the HD mice, there was a grade-dependent loss of brain CK-BB that worsened with disease severity in HD patients from approximately 28% to approximately 63%, as compared to non-diseased control patients. In addition, CK-BB blood buffy coat levels were significantly reduced in both premanifest and symptomatic HD patients by approximately 23% and approximately 39%, respectively. The correlation of CK-BB as a disease biomarker in both CNS and peripheral tissues from HD mice and HD patients may provide a powerful means to assess disease progression and to predict the potential magnitude of therapeutic benefit in this disorder.
亨廷顿舞蹈症（HD）当前临床研究的一个主要目标是识别临床前和明显疾病的生物标志物，因为这些标志物可能会改善诊断以及治疗试验的效能。尽管潜在的生化改变和神经元变性机制仍然未知，但HD中的能量代谢缺陷已有多年记载。我们报告称，肌酸激酶脑同工酶（CK-BB）是一种在缓冲能量储备中起重要作用的酶，在HD小鼠和HD患者的脑及血液血沉棕黄层标本的症状前和明显疾病阶段均显著降低。R6/2小鼠在21至91日龄时，脑CK-BB水平显著降低了约18%至约68%，而在相同病程中，血液CK-BB水平降低了约14%至约44%。在4至12月龄的140 CAG小鼠中观察到了类似的CK-BB水平变化，但在最早的2月龄时间点未观察到。与HD小鼠一致，HD患者脑CK-BB水平也呈分级下降，且随疾病严重程度加重，与非患病对照患者相比，下降幅度约为28%至约63%。此外，在症状前和有症状的HD患者中，血沉棕黄层血液中的CK-BB水平分别显著降低了约23%和约39%。HD小鼠和HD患者的中枢神经系统和外周组织中CK-BB作为疾病生物标志物的相关性，可能为评估疾病进展以及预测该疾病治疗益处的潜在程度提供有力手段。
