By applying a unique and novel neuroimaging-neurochemical approach we obtained evidence for decreased vesicular uptake of neuronal catecholamines in Lewy body diseases (Goldstein DS, Holmes C, Kopin IJ, Sharabi Y. Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases. J Clin Invest 2011;121:3320-3330). Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies, cytoplasmic inclusions containing alpha-synuclein protein aggregatesin the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH;also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons. We used 6-18F-dopamine (18F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal 18F-DA was followed by assessment of arterial plasma levels of the 18F-DA metabolite 18F-dihydroxyphenylacetic acid (18F-DOPAC). The ratio of myocardial 18F-DA to arterial 18F-DOPAC provided an index of vesicular uptake. Tracer concentrations were measured in patients with PD with or without orthostatic hypotension (PD+OH, PD-No-OH);in patients with pure autonomic failure (PAF, a Lewy body disease without Parkinsonism);in patients with multiple system atrophy (MSA, a nonLewy body synucleinopathy);and in normal controls. Patients with PD+OH or PAF had decreased vesicular 18F-DA uptake and accelerated 18F-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial 18F-DA uptake. From these findings we were able to infer that sympathetic denervation in Lewy body diseases is associated with decreased vesicular uptake of neuronal catecholamines, suggesting that vesicular monoamine transport is impaired. Vesicular uptake may constitute a novel target for diagnosis, treatment, and prevention. According to the catecholaldehyde hypothesis, cytoplasmic dopamine is converted by mitochondrial monoamine oxidase to the toxic catecholaldehyde, dihydroxyphenylacetaldehyde (DOPAL). DOPAL is detoxified by aldehyde dehydrogenase (ALDH), to form dihydroxyphenylacetic acid (DOPAC). Using a sensitive assay method for measuring DOPAL, DOPAC, and dopamine simultaneously, we found that putamen tissue from patients with end-stage PD contains an increased concentration of DOPAL after adjustment for decreased dopaminergic innervation and that ALDH activity measured by the DOPAC:DOPAL ratio is decreased (Goldstein DS, Sullivan P, Holmes C, Kopin IJ, Basile MJ, Mash DC. Catechols in post-mortem brain of patients with Parkinson disease. Eur J Neurol 2011;18:703-710). These findings are consistent with DOPAL buildup and decreased putamen ALDH activity in PD. In collaboration with Gary Miller (Emory) and Randy Strong (Univ. of Texas) we are studying brain and cardiac tissue concentrations of catechols in mice with very low activity of the type 2 vesicular monoamine transporter (VMAT) or with double knockout of the genes encoding ALDH1A and ALDH2. Both animal models are expected to increase cytosolic catecholamines and catecholaldehydes and produce motor and non-motor manifestations resembling those in PD. Preliminarily, mice with very low VMAT2 activity have striatal and cardiac catecholamine depletion, and mice with double knockout of ALDH1A and ALDH2 have neurochemical evidence for low striatal ALDH activity and catecholaldehyde buildup. With appropriate support we plan to producing Lo VMAT-double ALDH knockout mice, which may provide a valuable model of catecholaminergic lesions found in PD. In vitro studies have shown that DOPAL, the catecholaldehyde produced from enzymatic oxidation of cytosolic dopamine, potently oligomerizes alpha-synuclein. We have found that metal ions (especially ionized copper) augment DOPAL-induced oligomerization of alpha-synuclein, suggesting that deleterious interactions of catecholaldehydes, metal ions, and alpha-synuclein might explain relatively selective loss of catecholaminergic neurons in Lewy body diseases. Studies are under way about whether DOPAL oligomerizes alpha-synuclein in cells conditionally over-expressing the protein. The Braak staging concept of Lewy body disease pathogenesis is based on post-mortem evidence for a spatiotemporal sequence of alpha-synuclein deposition, with autonomic nervous system involvement before synucleinopathy in substantia nigra neurons. A patient with primary chronic autonomic failure underwent biennial brain 6-18FDOPA and myocardial 6-18Fdopamine scanning over four years. Low myocardial radioactivity indicated cardiac noradrenergic denervation that persisted. Striatal 6-18FDOPA-derived radioactivity initially was normal, two years later was decreased subtly, and by four years was clearly decreased and accompanied by dementia and parkinsonism. In this case, neuroimaging evidence of cardiac noradrenergic denervation and subsequent progressive striatal dopaminergic denervation provided in vivo support for Braak staging (Goldstein DS, Holmes C, Sewell L, Park M-Y, Sharabi Y. Sympathetic noradrenergic before striatal dopaminergic denervation: Relevance to Braak staging of synucleinopathy. Clin Auton Res 2011 Jul 28. Epub ahead of print).

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Landrock, Kerstin K; Sullivan, Patti; Martini-Stoica, Heidi et al. (2018) Pleiotropic neuropathological and biochemical alterations associated with Myo5a mutation in a rat Model. Brain Res 1679:155-170
Isonaka, Risa; Sullivan, Patti; Jinsmaa, Yunden et al. (2018) Spectrum of abnormalities of sympathetic tyrosine hydroxylase and alpha-synuclein in chronic autonomic failure. Clin Auton Res 28:223-230
Goldstein, David S; Kopin, Irwin J (2018) Linking Stress, Catecholamine Autotoxicity, and Allostatic Load with Neurodegenerative Diseases: A Focused Review in Memory of Richard Kvetnansky. Cell Mol Neurobiol 38:13-24
Goldstein, David S; Holmes, Courtney; Sullivan, Patti et al. (2017) Autoimmunity-associated autonomic failure with sympathetic denervation. Clin Auton Res 27:57-62
Goldstein, David S; Sharabi, Yehonatan (2017) The heart of PD: Lewy body diseases as neurocardiologic disorders. Brain Res :
Isonaka, Risa; Holmes, Courtney; Cook, Glen A et al. (2017) Pure autonomic failure without synucleinopathy. Clin Auton Res 27:97-101
Goldstein, David S; Sullivan, Patti; Holmes, Courtney et al. (2017) Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy. Parkinsonism Relat Disord 35:88-91
Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto et al. (2017) Natural history of pure autonomic failure: A United States prospective cohort. Ann Neurol 81:287-297
Pasqua, Teresa; Mahata, Sumana; Bandyopadhyay, Gautam K et al. (2016) Erratum to: Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo. Cell Tissue Res 363:823
Goldstein, David S; Sims-O'Neil, Cathy (2016) Systemic hemodynamics during orthostasis in multiple system atrophy. Parkinsonism Relat Disord 25:106-7

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