Aging Produces a Specific Pattern of Striatal Dopamine Loss: Implications for the Etiology of Idiopathic Parkinson's Disease

Abstract

To examine the possible causal contribution of normal or accelerated aging to the neurodegenerative process of Parkinson's disease, we measured the influence of aging on subregional striatal dopamine and homovanillic acid levels in postmortem brain of 23 neurologically and psychiatrically normal human subjects 14-92 years old. We observed a significant decline in striatal dopamine levels and increase in the homovanillic acid/dopamine molar ratios with increasing age. The dopamine loss, on average, was of the same magnitude in the caudate nucleus and the putamen (-60% in the 84-year-old group as compared with the 22-year-old group), with the caudal component of both nuclei being more affected than the rostral subdivisions. The level of subregional dopamine metabolism, as measured by the homovanillic acid/dopamine ratio, in our young individuals (mean age, 22 years) was found to be inversely correlated to the degree of subregional dopamine loss suffered by the individuals in the older age groups. We conclude the following: (a) Striatal subdivisions with physiologically higher dopamine metabolism are not at a greater risk of suffering dopamine neuronal damage with advancing age, as would seem to be implied by the oxidative stress hypothesis; thus, formation of dopamine-derived oxy radicals in the human striatum appears unlikely to be a primary factor responsible for the age-related striatal dopamine loss. (b) The regional and subregional pattern of striatal dopamine loss in normal aging differs substantially from the pattern typically observed in idiopathic Parkinson's disease; therefore, the cause of idiopathic Parkinson's disease cannot be primarily an age-dependent neurodegenerative process.

Striatal dopamine transporters correlate with simple reaction time in elderly subjects

“…They thus provide further contrary evidence for the older doctrine-derived from both autopsy studies of PD [4] and early animal lesion studies [33]-that a depletion of striatal dopamine in excess of 80% was necessary for functional impairment to occur. Kish et al [24] have extrapolated that, in normal aging, this threshold would only be reached at about the age of 110 years. Our results demonstrate, on the contrary, that among healthy subjects of retirement age with no clinical evidence of PD, diminished nigrostriatal dopaminergic function is associated with slowing of reaction speed.…”

“…Our failure to detect a significant correlation between striatal DAT availability and CVLT learning strategy in our healthy elderly subjects may be a consequence of inadequate statistical power. Alternatively, it may reflect the qualitative difference between the disease process of PD and the normal aging of the nigrostriatal dopaminergic system that has been suggested by previous postmortem [24] and neuroimaging [44] studies.…”

In Vivo Measurement of Density and Affinity of the Monoamine Vesicular Transporter in a Unilateral 6-Hydroxydopamine Rat Model of PD

“…The intact striatum was used as an internal control condition for each animal. Although tracers binding to VMAT2 such as DTBZ are not specific for the dopaminergic terminals alone, 90% of monoaminergic innervation in the striatum is of dopaminergic origin (Kish et al, 1992), thus making DTBZ an ideal tracer to assess lesion severity (LS) in a unilateral model of PD. Indeed, a previous study has shown a significant correlation between PET binding measures and post-mortem autoradiographic measurements using the racemic form of this tracer ([ 11 C](7) dihydrotetrabenazine) (Strome et al, 2006).…”

Ethanol withdrawal posttranslationally decreases the activity of cytochrome c oxidase in an estrogen reversible manner

“…Therefore, damage to this enzyme can cause serious clinical consequences. Indeed, the decreased activity of COX has been found in a variety of neurodegenerative illnesses such as Parkinson′s disease and Alzheimer′s disease [1][2][3].…”

“…Therefore, damage to this enzyme can cause serious clinical consequences. Indeed, the decreased activity of COX has been found in a variety of neurodegenerative illnesses such as Parkinson′s disease and Alzheimer′s disease [1][2][3].Accumulated evidence indicates that mitochondria are vulnerable to ethanol/EW toxicity. Reactive oxygen species produced during ethanol metabolism altered mitochondrial function in rodents [4,5].…”