Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease

Abstract

To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers. These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([3H])GBR 12,935 and [3H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [3H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [3H]WIN 35,428 > [3H]DTBZ > [3H]GBR 12, 935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

“…As expected, in the striatum (putamen and caudate) of patients with PD, levels of all four VMAT2 bands I, IIa, III, and IV were markedly and evenly decreased, with the loss significantly more severe in putamen (À92%±1%, À90% ± 2%, À86% ± 2%, and À79% ± 2% for bands I to IV, respectively) than in caudate (À73% ± 8%, À75%±6%, À56%±3%, and À70%±5%, respectively; Figures 3A and 3C). The overall loss of VMAT2 immunoreactivity was À90% ± 2% and À71%±6% for putamen and caudate, respectively, consistent with the literature showing that the putamen has more severe dopamine marker loss in PD than the caudate Wilson et al, 1996). Similarly in the substantia nigra, levels of all five VMAT2-immunoreactive bands were significantly reduced (À47%±4%, À55%±4%, À84% ± 2, À60% ± 3, and À60% ± 8%, respectively) in PD although to a less overall extent (À63% ± 3%) than those in the striatal terminal regions ( Figures 3B and 3C).…”

Is Parkinson's Disease a Vesicular Dopamine Storage Disorder? Evidence from a Study in Isolated Synaptic Vesicles of Human and Nonhuman Primate Striatum

“…In brains from PD patients, reduction of striatal dihydrotetrabenazine (DTBZ)-binding as a measure of VMAT2 levels, was less than the loss of striatal DA (Wilson et al, 1996), indicating a defective DA storage with fewer than normal DA molecules in each parkinsonian vesicle; this being concurrent with an earlier suggestion that "in PD a 'reserpine-like principle' might be active in the brain" (Hornykiewicz, 1964). Recently, a DA storage defect has been deduced from a study of catechol patterns of PD putamen (Goldstein et al, 2013).…”

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

“…Historically, the primary use of the (+)[ 11 C]DTBZ probe in human striatum has been to assess the integrity of nigrostriatal dopamine neurons (eg, in Parkinson's disease), as most VMAT2 is localized in the striatum to dopamine storage vesicles in dopamine neurons (see Frey et al, 1996;Nandhagopal et al, 2011;Wilson et al, 1996c). Animal data indicate that a high dose of MA can both damage dopamine neurons and cause loss of striatal VMAT2 (Frey et al, 2001;Seiden and Ricaurte, 1987), although human findings have been equivocal (Johanson et al, 2006;Kitamura et al, 2007;Tong et al, 2014;Wilson et al, 1996a; for a review, see Kish, 2014).…”