Among patients with Parkinson disease (PD), PD with neurogenic orthostatic hypotension, or pure autonomic failure (PAF), the extent of cardiac noradrenergic denervation, indicated by septal myocardial 6-(18F)fluorodopamine-derived radioactivity, was independent of the extent of nigrostriatal dopaminergic denervation, indicated by the putamen:occipital cortex ratio of 6-(18F)fluorodopa-derived radioactivity. This independence suggests different mechanisms of loss of noradrenergic and dopaminergic neurons in these diseases.? ? Other studies revealed clinical laboratory overlaps between PD and PAF but also distinctions providing further support for different mechanisms of loss of dopaminergic, noradrenergic, and adrenergic cells in Lewy body diseases. About 40% of PD patients have neurogenic orthostatic hypotension (NOH), which can dominate the clinical picture, as in PAF. Virtually all PD+NOH patients have neuroimaging evidence for cardiac sympathetic denervation; however, whether PD+NOH, like PAF, entails extra-cardiac NE denervation has been less clear. Both groups were found to have low renal cortical concentrations of 6-(18F)fluorodopamine-derived radioactivity, consistent with renal sympathetic denervation. Skeletal muscle microdialysate concentrations of the neuronal NE metabolite, dihydroxyphenylglycol (DHPG), were similarly low in PD+NOH and PAF, and the groups had similarly small plasma DHPG responses to tyramine and NE responses to yohimbine and isoproterenol. Since PD+NOH patients had normal bradycardia responses to edrophonium and normal epinephrine responses to glucagon, the parasympathetic cholinergic and adrenomedullary hormonal components of the autonomic nervous system seem intact in PD+NOH. PD+NOH therefore entails generalized and neurotransmitter-selective noradrenergic denervation, as in PAF. Mechanisms resulting in intact adrenomedullary function in PD+NOH, in contrast with adrenomedullary failure in PAF, remain unknown.? ? Although PAF and PD both are Lewy body diseases, and both involve sympathetic noradrenergic denervation, PAF manifests as neurogenic orthostatic hypotension (NOH) without parkinsonism, and PD manifests as a characteristic movement disorder, and only a minority of patients have NOH. We tested the hypothesis that preservation of nigrostriatal dopaminergic innervation explains the absence of motor dysfunction in PAF. Patients with PAF or PD underwent brain 6-(18F)fluorodopa positron emission tomographic scanning and lumbar puncture under fluoroscopic guidance for assays of cerebrospinal fluid (CSF) catechols. A patient with PAF and another with PD had rapid postmortem striatal, nigral, and sympathetic ganglion sampling, with assays of tissue catechols and tyrosine hydroxylase (TH) activity. The groups had similarly low mean substantia nigra (SN):occipital (OCC) ratios of 6-(18F)fluorodopa-derived radioactivity and low CSF dihydroxyphenylacetic acid (DOPAC) and DOPA levels. Only the PD group had low putamen (PUT):OCC ratios. The PAF and PD cases had similarly low SN concentrations of dopamine (DA) and TH activity, but the PD patient had tenfold lower PUT DA and the PAF patient 15-fold lower myocardial norepinephrine concentrations. Parkinsonism therefore appears to reflect striatal DA deficiency rather than loss of nigral DA neurons per se. More severe loss of striatal DA terminals in PD than in PAF and more severe loss of sympathetic terminals in PAF than in PD explain the distinctive clinical manifestations of the two Lewy body diseases. PAF patients may have a specific, previously undescribed mechanism that promotes catecholaminergic neuronal sprouting as cell bodies die off.? ? PD and PAF patients had low CSF DOPA and DOPAC but normal DA levels. CSF DOPAC correlated positively with PUT:OCC ratios of 6-(18F)fluorodopa-derived radioactivity, but CSF DA did not. Net release of DA into the extracellular fluid therefore can be normal in Lewy body diseases, despite decreased central DA synthesis and turnover. This pattern is consistent with compensatorily increased pathway traffic to remaining terminals and consequently increased transmitter release. ? ? Studies of rare diseases of development of catecholamine systems have also suggested compensatory increases in catecholamine biosynthesis and net transmitter release in response to decreased catecholaminergic terminal innervation. Familial dysautonomia (FD) is a rare pediatric neurodevelopmental disorder. FD patients had decreased uptake and accelerated loss of myocardial 6-(18F)fluorodopamine-derived radioactivity compared to untreated controls, indicating attenuated development of cardiac noradrenergic innervation and compensatorily increased net neurotransmitter release from extant nerves. We tested whether FD involves progressive loss of noradrenergic nerves in adulthood. There were no changes in plasma levels of individual catechols over a mean of 13 years. An increasing DOPA:DHPG ratio suggested slight but consistent, progressive loss of noradrenergic neurons and compensatorily increased TH activity in sympathetic nerves. Both FD and PD therefore involve cardiac noradrenergic hypo-innervation, but in FD this is mainly due to arrested development of the sympathetic noradrenergic system, whereas in PD this is mainly due to progressive neurodegeneration.? ? Menkes disease is another pediatric neurodevelopmental disorder, caused by diverse mutations in a gene encoding a copper transporter ATPase. Exploiting the deficiency of a copper enzyme, DA-beta-hydroxylase (DBH), which catalyzes the conversion of DA to NE, we prospectively evaluated the diagnostic usefulness of plasma catechols and the clinical significance of early detection. There were no false-negative or false-positive results in 81 infants at risk. All affected newborns had elevated ratios of DA:NE and DOPAC:DHPG, coupled with high plasma DOPA levels. Among 12 newborns with positive screening tests who were treated early with copper, survival was markedly improved, compared to a control group with late diagnosis and late treatment. Therefore, neonatal diagnosis of Menkes disease by plasma neurochemical measurements enables early, successful treatment of this otherwise invariably lethal disease. Similar patterns of plasma catechol abnormalities in FD and in Menkes disease probably reflect compensatorily increased TH activity in response to NE deficiency in both diseases.? ? Catecholamines in the neuronal cytoplasm are converted to catecholaldehydes via monoamine oxidase (MAO). We obtained preliminary evidence that the catecholaldehyde produced by the action of MAO on DA, dihydroxyphenylacetaldehyde (DOPAL), oligomerizes alpha-synuclein, possibly converting the normally soluble protein into a potentially pathogenic form. We developed an assay method to quantify DOPAL levels. Using this assay we have found preliminarily that reaction of DA with MAO produces DOPAL and augments DA-induced oligomerization of alpha-synuclein. To pursue these positive in silico findings, we have begun a collaboration to assay catechols including DOPAL in brain tissue from mice with genetic manipulations mimicking those in familial PD or with knockout of the aldehyde dehydrogenase 1A1 gene. We also have begun to explore the possibility of developing cellular and zebrafish models of PD, based on over-expressing wild type or mutant alpha-synuclein and on manipulations that should augment catecholadehyde-induced neurotoxicity. Finally, now that we know that both PAF and PD+NOH entail generalized noradrenergic denervation, under a Material Transfer Agreement and Amendment to one of our clinical research Protocols, we plan to study skin biopsy specimens from patients with PAF or PD+NOH, to evaluate possible links between local alpha-synuclein deposition and catecholaminergic denervation in living patients.

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Imrich, Richard; Eldadah, Basil A; Bentho, Oladi et al. (2009) Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension. Parkinsonism Relat Disord 15:122-7
Goldstein, David S; Holmes, Courtney; Bentho, Oladi et al. (2008) Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 14:600-7
Kaler, Stephen G; Holmes, Courtney S; Goldstein, David S et al. (2008) Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 358:605-14
Sharabi, Yehonatan; Imrich, Richard; Holmes, Courtney et al. (2008) Generalized and neurotransmitter-selective noradrenergic denervation in Parkinson's disease with orthostatic hypotension. Mov Disord 23:1725-32
Goldstein, David S (2008) Genotype and vascular phenotype linked by catecholamine systems. Circulation 117:458-61
Goldstein, David S; Holmes, Courtney (2008) Neuronal source of plasma dopamine. Clin Chem 54:1864-71
Donsante, Anthony; Tang, Jingrong; Godwin, Sarah C et al. (2007) Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet 44:492-7
Moak, Jeffrey P; Goldstein, David S; Eldadah, Basil A et al. (2007) Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation. Heart Rhythm 4:1523-9
Goldstein, D S; Imrich, R; Peckham, E et al. (2007) Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation. Neurology 69:1580-4
Goldstein, David S (2007) Cardiac denervation in patients with Parkinson disease. Cleve Clin J Med 74 Suppl 1:S91-4

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