CSF Biomarkers of Parkinson Disease (PD) and Related Disorders: The diagnosis of PD and other alpha-synucleinopathies is clinical and often uncertain in early, mild cases. We hypothesized that cerebrospinal fluid (CSF) levels of neuronal metabolites of catecholamines would detect central catecholamine deficiency and thereby help diagnose these disorders. We measured CSF levels of catechols including dopamine, norepinephrine, and their main respective neuronal metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG) in PD and two other synucleinopathies, multiple system atrophy (MSA) and pure autonomic failure (PAF). The PD, MSA, and PAF groups all had lower CSF DOPAC and DHPG levels than did the controls. DOPAC was lower in PD than in PAF and DHPG lower in PAF than in PD. CSF DOPAC was 100% sensitive at 89% specificity in separating patients with recent onset of Parkinsonism from controls. From these findings we conclude that synucleinopathies feature CSF neurochemical evidence for central dopamine and norepinephrine deficiency, that PD and PAF involve differential dopaminergic vs. noradrenergic lesions, and that CSF DOPAC provides a sensitive clinical laboratory means to identify PD, even early in the disease (Goldstein et al., Brain 2012;135:1900-1913). In collaboration with J. Zhang, of the Univ. of Washington, we are exploring CSF proteomic biomarkers of PD, MSA, and PAF. Phosphorylated alpha-synuclein (PS-129), a protein critically involved in the pathogenesis of PD, was measured along with total alpha-synuclein in patients with PD and controls. CSF PS-129 levels correlated with PD severity and when combined with total synuclein provided high sensitivity and specificity for differential diagnosis among clinically overlapping Parkinsonian disorders (Wang et al., Science Transl Med 2012;4:121ra20). Additional CSF samples from our patients have been sent to Dr. Zhang, to test for increased CSF PS-129/total alpha-synuclein and correlate CSF PS-129/total alpha-synuclein with CSF catechols in the same patients with PD, MSA, or PAF. Comparison of LCMS vs LCED for Levels of Catechols: CSF levels of DOPAC and especially of dopamine are extremely low. We compared liquid chromatography and triple quadrupole mass spectroscopy (LCMS) vs. liquid chromatography and electrochemical detection (LCED) for high-sensitivity measurements of catecholamines in human biological fluids such as plasma. So far LCED has proven more sensitive and more reliable than LCMS for detection of low levels of catecholamines such as dopamine. In an important extension of this work we are developing means to track catecholamine metabolism using LCMS by measuring levels of 13C-labeled compounds after administration of 13C-dopamine. 13C is a stable, non-radioactive isotope of carbon. Biomarkers of Risk of PD: We are testing whether people with multiple risk factors for PD have biomarkers of loss of catecholamine neurons in the brain or periphery and if so whether they develop clinical PD during follow-up. Via a unique Protocol-specific website (https://pdrisk.ninds.nih.gov) visited by more than 50,000 people to date, more than 250 people with multiple statistical risk factors for PD have been identified. We are screening eligible people to confirm their risk factors and then admitting them for inpatient biomarkers testing including brain 18F-DOPA PET, cardiac 18F-dopamine PET, and CSF catechols. Preliminarily, CSF DOPAC is decreased in people with multiple risk factors. Biomarkers Validation by Post-mortem Neurochemistry: Validation of neurochemical or neuroimaging biomarkers of PD and related disorders depends on post-mortem confirmation. We are testing whether patients with neuroimaging evidence of cardiac sympathetic denervation have low myocardial norepinephrine concentrations. Preliminarily, myocardial norepinephrine content is decreased by more than 90% in patients with Lewy body diseases compared to controls without Lewy body diseases. 11C-Methylreboxetine PET to Visualize Noradrenergic Innervation: Until recently, no radioligand for neuroimaging successfully and specifically visualized central neural sites of noradrenergic innervation. 11C-Methylreboxetine (11C-MRB) has these capabilities. In humans, after 11C-MRB administration positron emission tomographic (PET) scanning with a High Resolution Research Tomograph (HRRT) can visualize the locus ceruleus, the pontine cluster of neurons that is the main source of norepinephrine in the brain. Under an approved Amendment to NIH Clinical Protocol 03-N-0004 we are introducing 11C-MRB PET scanning at the NIH Clinical Center, to detect and measure the extent of noradrenergic lesions in PD and related disorders.

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Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio; Palma, Jose-Alberto et al. (2018) Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol 83:522-531
Cheshire Jr, William P; Goldstein, David S (2018) The physical examination as a window into autonomic disorders. Clin Auton Res 28:23-33
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; Cheshire Jr, William P (2018) Roles of cardiac sympathetic neuroimaging in autonomic medicine. Clin Auton Res 28:397-410
Goldstein, David S; Holmes, Courtney; Lopez, Grisel J et al. (2018) Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease. Parkinsonism Relat Disord 50:108-112
Goldstein, David S; Holmes, Courtney; Lopez, Grisel J et al. (2018) Cardiac sympathetic denervation predicts PD in at-risk individuals. Parkinsonism Relat Disord 52:90-93
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 Jr, Glen A et al. (2017) Is pure autonomic failure a distinct nosologic entity? Clin Auton Res 27:121-122
Isonaka, Risa; Holmes, Courtney; Cook, Glen A et al. (2017) Pure autonomic failure without synucleinopathy. Clin Auton Res 27:97-101

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