Neurobiology of Aging 28 (2007) 258–271 Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys Wayne A. Cass a,∗,1 , Richard Grondin a,b,1 , Anders H. Andersen a,b , Zhiming Zhang a,b , Peter A. Hardy a,c , Lindsay K. Hussey-Andersen a , William S. Rayens d , Greg A. Gerhardt a,b , Don M. Gash a,b a Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY, USA b Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky, Lexington, KY, USA c Center for Biomedical Engineering, University of Kentucky, Lexington, KY, USA d Department of Statistics, University of Kentucky, Lexington, KY, USA Received 11 August 2005; received in revised form 7 December 2005; accepted 16 December 2005 Available online 26 January 2006 Abstract 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 mon- key 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 evalu- ated 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. © 2005 Elsevier Inc. All rights reserved. Keywords: Aging; Iron levels; Motor function; MRI; Dopamine; Microdialysis 1. Introduction Aging in humans is often characterized by the progres- sive impairment of motor abilities. In some individuals these ∗ Corresponding author at: Department of Anatomy and Neurobiology, MN-225 Chandler Medical Center, University of Kentucky, Lexington, KY 40536-0298, USA. Tel.: +1 859 323 1142; fax: +1 859 323 5946. E-mail address: wacass1@uky.edu (W.A. Cass). 1 These authors contributed equally to this work. changes include bradykinesia, stooped posture and shuffling gait, all of which resemble the clinical features of Parkinson’s disease (PD) [8,59]. It is possible that the similarities in move- ment dysfunction in aging and PD arise in part from alter- ations of the same neuronal circuitry, namely the nigrostriatal dopamine (DA) pathway. PD is characterized by an extensive, >60% loss of midbrain dopaminergic neurons in the sub- stantia nigra pars compacta. However, major changes in the number of DA-containing nigral neurons (i.e. >50% loss) do not occur during normal aging in either humans or in animal 0197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2005.12.010