Cass Wayne A, Grondin Richard, Andersen Anders H, Zhang Zhiming, Hardy Peter A, Hussey-Andersen Lindsay K, Rayens William S, Gerhardt Greg A, Gash Don M
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536-0298, USA.
Neurobiol Aging. 2007 Feb;28(2):258-71. doi: 10.1016/j.neurobiolaging.2005.12.010. Epub 2006 Jan 26.
Changes in the nigrostriatal system may be involved with the motor abnormalities seen in aging. These perturbations include alterations in dopamine (DA) release, regulation and transport in the striatum and substantia nigra, striatal atrophy and elevated iron levels in the basal ganglia. However, the relative contribution of these changes to the motor deficits seen in aging is unclear. Thus, using the rhesus monkey as a model, the present study was designed to examine several of these key alterations in the basal ganglia in order to help elucidate the mechanisms contributing to age-related motor decline. First, 32 female rhesus monkeys ranging from 4 to 32 years old were evaluated for their motor capabilities using an automated hand-retrieval task. Second, non-invasive MRI methods were used to estimate brain composition and to indirectly measure relative iron content in the striatum and substantia nigra. Third, in vivo microdialysis was used to evaluate basal and stimulus-evoked levels of DA and its metabolites in the striatum and substantia nigra of the same monkeys. Our results demonstrated significant decreases in motor performance, decreases in striatal DA release, and increases in striatal iron levels in rhesus monkeys as they age from young adulthood. A comprehensive statistical analysis relating age, motor performance, DA release, and iron content indicated that the best predictor of decreases in motor ability, above and beyond levels of performance that could be explained by age alone, was iron accumulation in the striatum. This suggests that striatal iron levels may be a biomarker of motor dysfunction in aging; and as such, can be monitored non-invasively by longitudinal brain MRI scans. The results also suggest that treatments aimed at reducing accumulation of excess iron in the striatum during normal aging may have beneficial effects on age-related deterioration of motor performance.
黑质纹状体系统的变化可能与衰老过程中出现的运动异常有关。这些扰动包括纹状体和黑质中多巴胺（DA）释放、调节和转运的改变、纹状体萎缩以及基底神经节中铁水平升高。然而，这些变化对衰老过程中出现的运动缺陷的相对贡献尚不清楚。因此，本研究以恒河猴为模型，旨在研究基底神经节中的一些关键改变，以帮助阐明导致与年龄相关的运动能力下降的机制。首先，使用自动手部抓取任务对32只年龄在4至32岁之间的雌性恒河猴的运动能力进行评估。其次，采用非侵入性MRI方法估计脑成分，并间接测量纹状体和黑质中的相对铁含量。第三，使用体内微透析评估同一批猴子纹状体和黑质中DA及其代谢产物的基础水平和刺激诱发水平。我们的结果表明，随着恒河猴从青年期开始衰老，其运动表现显著下降，纹状体DA释放减少，纹状体铁水平升高。一项综合的统计分析将年龄、运动表现、DA释放和铁含量联系起来，结果表明，在仅由年龄解释的表现水平之上，运动能力下降的最佳预测指标是纹状体中的铁积累。这表明纹状体铁水平可能是衰老过程中运动功能障碍的一个生物标志物；因此，可以通过纵向脑部MRI扫描进行非侵入性监测。结果还表明，旨在减少正常衰老过程中纹状体中过量铁积累的治疗方法可能对与年龄相关的运动表现恶化具有有益影响。
