Point of viewDeficient vesicular storage: A common theme in catecholaminergic neurodegeneration
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Section snippets
Methods to assess vesicular storage in catecholaminergic neurons
Several in vivo and post-mortem approaches have been used for assessing vesicular storage in putamen dopaminergic and sympathetic noradrenergic neurons. The following summarizes the ones we used; detailed descriptions are found in an Appendix.
Catecholaminergic denervation is associated with decreased vesicular storage across compared groups
We reviewed in vivo or post-mortem data across a total of 20 different diagnostic groups characterized in terms of intact or decreased catecholaminergic innervation in the brain or periphery. This section and Table 1 provide overviews; detailed descriptions of each group are in an Appendix.
Putamen in vivo 18F-DOPA data were reviewed from a total of 142 subjects and post-mortem DA:DOPA data from a total of 53 subjects. Myocardial in vivo 18F-DA data were reviewed from a total of 271 subjects,
Regional denervation and decreased vesicular storage
Certain patient groups had putamen dopaminergic denervation without cardiac noradrenergic denervation (MSA-P), putamen dopaminergic denervation with generalized sympathetic denervation (PD + OH), generalized sympathetic denervation without putamen dopaminergic denervation (PAF), dopaminergic denervation with sympathetic denervation predominantly in the heart (PD No OH), decreased cardiac noradrenergic innervation without a neurodegenerative disease (SNS-x), or decreased post-ganglionic
Decreased vesicular storage across etiologies and pathogenetic mechanisms
Data from patient groups with inherited neurodegeneration confirmed an association between catecholaminergic denervation and a vesicular storage defect across disease etiologies—PARK1 from mutation of the gene encoding alpha-synuclein, PARK4 from triplication of the alpha-synuclein gene, PARK8 from mutation of the LRRK2 gene, FD from mutation of the IKBKAP gene, and Gaucher/PD from mutation of the gene encoding glucocerebrosidase. Evidence for such an association was also obtained in diseases
Perspective
Several studies have noted decreased binding of tetrabenazine or hydrotetrabenazine in PD putamen [22], [30], [31], [32], demonstrating decreased availability of the type 2 VMAT; however, this approach cannot easily separate denervation from decreased VMAT2 expression or decreased vesicle populations in residual neurons as determinants of decreased VMAT2 availability. The same limitation applies to decreased cardiac 123I-metaiodobenzylguanidine-derived radioactivity in a variety of
Implications for the pathogenesis of PD and related disorders
Since DA is synthesized in the neuronal cytoplasm, a vesicular storage defect in putamen terminals could promote accumulation of cytoplasmic DA and consequently increase formation of cytotoxic products of DA metabolism [35], [41], [42], [43]. There are two general mechanisms by which buildup of cytoplasmic catecholamine may contribute to the death of catecholamine neurons. First, catecholamines such as DA oxidize spontaneously to quinones, chromes, and indoles, each of which may be toxic.
Study limitations
Neither in vivo neuroimaging nor in vivo neurochemical data, considered in isolation, specifically identifies a vesicular storage defect. For instance, accelerated loss of 18F-DOPA-derived radioactivity in the putamen might reflect increased DA release with decreased reuptake [27], [57]. The combination of in vivo neuroimaging and neurochemical data in the same patient groups makes a stronger case, especially when confirmed by post-mortem neurochemistry.
There were insufficient data in some of
Conflicts of interest
The authors have no conflicts of interest to report.
Funding source
Division of Intramural Research, NINDS, NIH.
Acknowledgment
The research reported here was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke.
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2019, Parkinsonism and Related DisordersCitation Excerpt :Whether this functional abnormality is an early finding, however, has been unknown. One can assess vesicular storage in myocardial sympathetic nerves indirectly using data from 18F-dopamine (18F-DA) positron emission tomographic (PET) scanning, as described previously [14]. Briefly, decreasing vesicular uptake diverts the fate of cytoplasmic 18F-DA toward metabolism by monoamine oxidase to form 18F-dihydroxyphenylacetic acid (18F-DOPAC), which rapidly exits the nerves (see the concept diagram in the Supplementary Figure), so that tissue 18F-DA-derived radioactivity declines at an increased rate [11].
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