Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to parkinsonism.

Aging is the most prominent risk factor for Parkinson's disease. Yet, consensus of how advancing age may predispose the dopamine (DA) system to parkinsonism is lacking. Three age ranges of female rhesus monkeys, 8-9, 15-17, and 21-31 years, received unilateral DA depletion with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Morphological and biochemical analyses of DA-depleted and intact hemispheres revealed three primary findings: (1) The intact striatum exhibited age-related declines in dopamine (DA) and homovanillic acid (HVA) that were present by middle age; (2) In the MPTP-treated striatum, the compensatory increase in DA activity was absent in old monkeys; and (3) Age-associated morphological changes included declines in the density of tyrosine hydroxylase (TH) positive fibers in striatum, decreased nigral soma size, and optical density of TH, but no significant loss of neurons. These findings suggest that aging produces changes in the nigrostriatal DA system that approach the threshold for expression of parkinsonian features, and that progressive impairment of plasticity may be central to the role of aging in development of parkinsonism.