Catecholamine Metabolites Research Articles

Magnetic resonance imaging of bladder pheochromocytomas: a review.

Bladder pheochromocytomas (PCCs) are rare tumors that account for 0.06% of all bladder tumors and makeup 1% of all PCCs. Most PCCs are functional, and they secrete catecholamines that lead to clinical symptoms such as paroxysmal hypertension, headaches, palpitations, and sweating. However, some are nonfunctional and asymptomatic and are hence difficult to diagnose. Cystoscopy and biopsy should not be performed when bladder PCCs are suspected. They may provoke a hypertensive crisis if preventative antiadrenergic blockers are not administered prior to the procedure. The diagnostic workup begins with obtaining blood or urine catecholamine and catecholamine metabolite values to make a presumptive diagnosis of bladder PCC. Computed tomography (C.T.) and magnetic resonance imaging (MRI) are then used to localize and stage the tumor for surgical resection. MRI, due to its superior soft tissue resolution and the ability to use multiparametric MRI (mpMRI) to differentiate between layers of the bladder wall and from other bladder masses, is the optimal imaging modality to detect extra-adrenal bladder PCCs and determine locoregional staging. Once antiadrenergic medications are given, the tumor is resected, and the diagnosis is confirmed histologically. However, the differential diagnosis of bladder PCC often gets overlooked, leading to surgical resection in the absence of antiadrenergic medications, increasing the chances of a fatal hypertensive crisis. This makes MRI an essential diagnostic tool for staging bladder PCCs before surgery. This review discusses the indications for MRI in bladder PCCs and describes findings from these tumors on various MRI sequences and when to use them. We also discuss how MRI can differentiate bladder PCCs from other bladder neoplasms.

UPLC-MS/MS assay for the simultaneous determination of catecholamines and their metabolites at low pg/mg in rat/mouse striatum

Catecholamines and their metabolites act as neurotransmitters in the brain and are important for nervous system function. In the current work, a highly selective and sensitive UPLC-MS/MS assay was developed for quantitation of six catecholamines and their metabolites, including dopamine, norepinephrine, serotonin, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindolacetic acid from rat and mouse striatum as pharmacodynamic biomarkers to support neuroscience and pharmaceutical research. A fit-for-purpose strategy for method development, assay qualification and study support were adopted for this assay. A surrogate matrix (brain homogenizing solution absent of targeted analytes) was used for preparation of calibration samples and certain levels of quality control samples to avoid interference from endogenous baselines. Homogenized rodent striatum was derivatized by dansyl chloride to enhance the sensitivity, followed by liquid-liquid extraction with ethyl acetate in 96-well plate format. The lower limit of quantitation (LLOQ) was 0.2 ng/mL in tissue homogenate, equivalent to 3.2 pg/mg in brain tissue, which could be further reduced to ten times lower by changing the re-dissolving and injecting volume in the last sample purification step. Acceptable accuracy, precision, linearity, specificity, recovery, and matrix effect was obtained. Bench-top stability (2 h), freeze-thaw stability (3 cycles at −20 °C), and − 80 °C storage stability (up to 51 days) in both tissue homogenate and surrogate matrix along with autosampler stability (60 h at 4°C) all met acceptance criteria. This assay was successfully applied to measure the six analytes in striatum from mice treated with the neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an animal model of Parkinsonism for which dosing protocols can vary widely, and further confirmed the metabolic pathway of neurotoxicity by the quantification of catecholamine metabolites. Our study is the first detailed the step-by-step recovery and pointed out the key factors for the assay to simultaneously quantify these six neurotransmitters in rodent striatum with superior sensitivity.

The Role of Metanephrines in the Diagnosis of Pheochromocytoma

Introduction: Pheochromocytomas are rare neuroendocrine catecholamine-producing tumors that arise from either the adrenal medulla (PHEO) or extra-adrenal paraganglionic tissues (paraganglioma/PGLs). PHEO is responsible for 0.01-0.1% of the cases of hypertension. Assessment of the plasma/urinary levels of metanephrines (catecholamines metabolites) is considered the gold standard for the diagnosis of PHEOs.

A Simple, Fast, and Reliable LC-MS/MS Method for the Measurement of Homovanillic Acid and Vanillylmandelic Acid in Urine Specimens.

Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are catecholamine metabolites used in the diagnostic workup of neuroendocrine tumors. Here we describe a simple dilute-and-shoot method for simultaneously quantitating HVA and VMA in human urine specimens. The method employs analyte separation on a reverse-phase liquid chromatography column followed by detection using electrospray ionization triple quadrupole mass spectrometry (ESI-MS/MS), wherein qualifier and quantifier ion transitions are monitored. This is a simple and fast analytical method with an injection-to-injection time of 4min.

Adrenal Hemorrhage Versus Neuroblastoma in Newborn with Right Suprarenal Mass and Hypertension: A Case Report

Adrenal hemorrhage is a potentially life-threatening condition that rarely presents in the neonatal period. The large size and increased vascularity of the average infant adrenal gland increase the tendency of bleeding. Predisposing factors may include macrosomia, birth asphyxia, perinatal injuries, septicemia, and coagulopathy. It can also occur without obvious risk factors. The most common presenting findings are poor feeding, vomiting, persistent jaundice, anemia, and abdominal mass. However, the event may be asymptomatic and be detected incidentally. Ultrasound imaging is the cornerstone of diagnosis and follow-up monitoring. Herein, we report an unusual case of a male newborn with an adrenal hemorrhage associated with hypertension. The lesion was detected by ultrasound as an echogenic cystic mass at the right suprarenal area. The mass was initially mimicking neuroblastoma. Nevertheless, the normal levels of urine catecholamine metabolites and the regression of the mass size verified the diagnosis. The infant was successfully managed conservatively, and the mass completely resolved without calcification or adrenal insufficiency.

Quantitation of Neuroblastoma Markers Homovanillic Acid (HVA) and Vanillylmandelic Acid (VMA) in Urine by Gas Chromatography-Mass Spectrometry (GC/MS).

Neuroblastoma and other neural crest tumors can be characterized by the increased production and excretion of catecholamines and their metabolites. Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are important catecholamine metabolites that can be measured to provide relatively rapid laboratory diagnosis and clinical follow-up of neuroblastoma. We present a procedure to quantify HVA and VMA in urine samples which have been diluted to a creatinine concentration of 2mg/dL. Diluted samples are spiked with deuterated internal standards, acidified, and extracted with an organic solvent. A bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) and pyridine mixture is added to the dried extract to create trimethylsilyl derivatives of HVA and VMA. The derivatized compounds are measured using gas chromatography-mass spectrometry (GC/MS).

Detection of catecholamine metabolites in urine based on ultra-high-performance liquid chromatography-tandem mass spectrometry.

The excretion of neurotransmitter metabolites in normal individuals is of great significance for health monitoring. A rapid quantitative method was developed with ultra-performance liquid chromatography-tandem mass spectrometry. The method was further applied to determine catecholamine metabolites vanilymandelic acid (VMA), methoxy hydroxyphenyl glycol (MHPG), dihydroxy-phenyl acetic acid (DOPAC), and homovanillic acid (HVA) in the urine. The urine was collected from six healthy volunteers (20-22 years old) for 10 consecutive days. It was precolumn derivatized with dansyl chloride. Subsequently, the sample was analyzed using triple quadrupole mass spectrometry with an electrospray ion in positive and multireaction monitoring modes. The method was sensitive and repeatable with the recoveries 92.7-104.30%, limits of detection (LODs) 0.01-0.05 μg/mL, and coefficients no less than 0.9938. The excretion content of four target compounds in random urine samples was 0.20 ± 0.086 μg/mL (MHPG), 1.27 ± 1.24 μg/mL (VMA), 3.29 ± 1.36 μg/mL (HVA), and 1.13 ± 1.07 μg/mL (DOPAC). In the urine, the content of VMA, the metabolite of norepinephrine and adrenaline, was more than MHPG, and the content of HVA, the metabolite of dopamine, was more than DOPAC. This paper detected the levels of catecholamine metabolites and summarized the characteristics of excretion using random urine samples, which could provide valuable information for clinical practice.

Abstract 14194: Dynamic Metabolite Profiles of Heart Failure and Central Hemodynamics

Aim: Large-scale plasma metabolite profiling is garnering considerable interest for the discovery of therapeutic targets and facilitation of precision medicine across a range of conditions. Heart failure (HF) represents a particularly promising application of metabolite profiling for precision medicine. Here, we performed untargeted metabolite profiling of heart failure cases and healthy controls, and studied transplant dynamics and central hemodynamic correlates of identified metabolites. Methods and Results: Metabolite profiling was conducted with liquid chromatography-tandem mass spectrometry methods in two independent case-control samples: one sample with advanced HF patients undergoing right-heart catheterization (RHC, n=248) and healthy controls of matching age and sex (n=30), and one sample with HF outpatients (n=83) and controls from a population-based cohort (n=583). Metabolites associated with HF were identified based on multivariable-adjusted logistic regression models. In total, 93 of 1370 studied metabolites were significantly associated with HF in both cohorts with concordant directionality, after Bonferroni correction. A subset of the advanced HF patients underwent heart transplantation (n=28), after which a second sample was obtained at the routine 6 month follow up exam. In linear mixed-effects regression models, 17 metabolites (18%) returned significantly towards healthy control levels. Of these, 13 (76%) were associated with at least one of 14 central hemodynamic parameters. Most associations were with right atrial pressure (RAP, 10 metabolites), mixed venous oxygen saturation (12 metabolites) and left-ventricular stroke work index (9 metabolites). For example, vanillylmandelate, a catecholamine metabolite, was associated with stroke volume and cardiac index, while kynurenine, an immunomodulatory tryptophan metabolite mainly produced in the liver and previously associated with kidney function, was associated with higher left-sided (pulmonary arterial wedge pressure) and right sided (RAP) filling pressures. Conclusions: Here, we comprehensively identified metabolites associated with HF and describe the hemodynamic correlates and metabolite dynamics upon HF reversal by transplantation.

Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders.

Trace amines, including β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP), and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, links between trace amines and the monoaminergic system have long been suspected. Trace amine-associated receptor 1 (TAAR1), the most well characterized receptor in the TAAR family, has been shown to be potently activated by trace amines such as TYR and PEA. Further, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating the receptor in mediating the monoaminergic system and in substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic, and glutamatergic transmission, and genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl) benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display significant potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, including substance use disorders.

Diagnostic algorithm of the subclinical forms of adrenal neoplasms

The possibility of modifying the existing diagnostic algorithm of latent forms of hormone-active and potentially malignant formations in the adrenal glands using modern methods of laboratory diagnostics and radiation imaging is substantiated. In the clinic of a faculty of surgery and on its clinical base, experience in the examination and treatment of 1457 patients with various formations of the adrenal glands has been accumulated. Among them, 270 (14.9%) patients were selected, in whom precursor hormones of steroidogenesis and metabolites of catecholamines in the blood plasma were specially studied by high-performance liquid chromatography, tumor marker measurement, and three-phase computed tomography with intravenous contrast enhancement. Determination of steroidogenesis precursor hormones and catecholamine metabolites in the blood plasma by high-performance liquid chromatography in combination with traditional methods of laboratory diagnostics, use of computed tomography with intravenous contrast enhancement, construction of multiplanar reconstructions, and postprocessor image processing are the basis of a modified algorithm for verification of latent forms of hormone-active and potentially malignant tumors of the adrenal glands. The implementation of the diagnostic algorithm developed in the clinic made early diagnosis of the subclinical forms of NP neoplasms possible, as well as ensure the implementation of minimally invasive surgical interventions before the development of endocrine and metabolic disorders and consequently prevent the development of intraoperative and postoperative complications, which thereby reduce the duration of rehabilitation and disability of patients with good long-term treatment results and high quality of life.

The evaluation of urinary vanillylmandelic acid level in patients with generalized anxiety disorder

Background and objectives: The prevalence of anxiety disorders is increasing in the world. Studies revealed that generalized anxiety disorder may lead to change in circulating catecholamine levels. Thus, the changes of catecholamine metabolite like urinary vanillylmandelic acid may increase the future risk of thrombotic diseases in patients with generalized anxiety disorder (GAD). The aim of this present study is to evaluate urinary vanillylmandelic acid (VMA) levels in patients with generalized anxiety disorder. Materials and methods: A cross-sectional study was performed in the Department of Physiology, Dhaka Medical College, Dhaka from July 2019 to June 2020.After obtaining ethical clearance, a total 144 individuals were selected based on inclusion and exclusion criteria with age ranging from 18-50 years. Group A was study group selected from Out Patient Department of Psychiatry of Dhaka Medical College Hospital, Dhaka diagnosed by the experienced psychiatrist. Group B was control group who were apparently healthy adults selected from different area of Dhaka city. The subjects were interviewed and detailed history regarding personal, family, medical and drug history were taken. Prior to sample collection, informed written consent was taken from the participants. Urinary vanillylmandelic acid levels were measured in the Department of Endocrinology, BIRDEM General Hospital, Dhaka. Statistical analysis: For statistical analysis, Unpaired Student’s ‘t’ test was considered using SPSS 25.0 version. Results: Urinary vanillylmandelic acid of generalized anxiety disorder patients was significantly higher (p< 0.001) than control group. Conclusion: It can be concluded that generalized anxiety disorder patients may have more chance of thrombotic diseases due to significantly higher urinary vanillylmandelic acid (VMA) levels than healthy adults.

Associations between plasma metabolite profiles and blood pressure: the HELIUS study

Abstract Background Blood pressure (BP) is regulated by plasma metabolites from different neurohumoral and cardiometabolic systems. Since there are established differences in hypertension pathogenesis and treatment response between ethnicities, we hypothesized that plasma metabolites may be differently associated with BP across ethnic groups. Purpose To investigate associations between plasma metabolite profiles and BP in a multi-ethnic population-based cohort. Methods From the Healthy Living In an Urban Setting (HELIUS) study, 369 subjects (mean age 52±11 years, 51%F) of African and non-African descent were included. Office systolic (136±21 mmHg) and diastolic (83±12 mmHg) BP levels were recorded. Plasma metabolites were measured semi-quantitively with LC-MS (Metabolon) from fasting plasma samples. Associations between metabolite profiles and BP were assessed with machine learning prediction models using the XGBoost algorithm with nested cross-validation. Associations between the resulting best predictors and BP were assessed with linear regression models while adjusting for age, sex, estimated glomerular filtration rate and diabetes. Results Plasma metabolite profiles explained 14.1% of systolic BP variance and 10.6% of diastolic BP variance. These were attenuated to 3.1% and 1.4% respectively, when using residuals of BP after adjusting for age and sex. Top predictors for both systolic and diastolic BP included N-formylmethionine, several acylcarnitines and polyunsaturated fatty acids such as hexadecadienoate. These metabolites were significantly associated with higher systolic BP with estimates ranging from 3.0 to 4.5 mmHg per 1 SD increase in the adjusted models. Associations with hexadecadienoate, dihomolinoleate and catecholamine metabolites, including vanillactate had significant interactions (p<0.05) with ethnicity, and were only significant in subjects of non-African descent. Conclusions Plasma metabolome composition explained a large proportion of BP variance, but this association was attenuated when adjusting for confounders. Polyunsaturated fatty acids and catecholamine metabolites were only associated with BP in the non-African descent subjects. N-formylmethionine was the most consistent predictor for systolic BP across all subgroups. Future studies could focus on translating these findings in vitro in order to decipher the role of N-formylmethionine in BP regulation. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Dutch Heart Foundation, the Netherlands Organization for Health Research and Development, the European Integration Fund and the European Union (Seventh Framework Programme) Explained variances of machine learningLinear regression models

Voltammetric Behavior of Acidic Catecholamine Metabolites in Presence of Cationic Surfactants

The voltammetric behavior of two acidic catecholamine metabolites, vanillylmandelic acid (VMA) and homovanillic acid (HVA) in the presence of cationic, anionic, or nonionic surfactants was monitored at the disposable screen-printed electrodes. In basic medium above their pKa values, the cationic surfactant cetylpyridinium chloride (CPC) enhanced the oxidation peak current based on electrostatic and hydrophobic interactions with the ionized carboxylic group and stabilization of some of the electrochemical reaction intermediates. Under the optimum measuring conditions at pH 9.5, calibration graphs were linear within HVA concentration range from 0.25 to 2.5 × 10−6 mol l−1 and LOD 0.021 × 10−6 mol l−1. Simultaneous assay of HVA in the presence of VMA within the submicromolar concentration range can be performed with acceptable average recovery of 106.0 ± 3.4%. This preliminary study represents the base for simultaneous quantification of both compounds in of urine samples for Neuroblastoma diagnosis.

Plasma catecholamine levels in the acute and subacute stages of takotsubo syndrome: Results from the Stockholm myocardial infarction with normal coronaries 2 study.

AimsIt is well‐accepted that takotsubo syndrome (TS) is characterized by a massive surge of plasma catecholamines despite lack of solid evidence. The objective of this study was to examine the hypothesis of a massive catecholamine elevation in TS by studying plasma‐free catecholamine metabolites in patients participating in the Stockholm myocardial infarction (MI) with normal coronaries 2 (SMINC‐2) study where TS constituted more than one third of the patients.Methods and resultsThe patients included in the SMINC‐2 study were classified, according to cardiac magnetic resonance (CMR) imaging findings (148 patients), which was performed at a median of 3 days after hospital admission. Plasma‐free catecholamine metabolites; metanephrine, normetanephrine, and methoxy‐tyramine were measured on day 2–4 after admission. Catecholamine metabolite levels were available in 125 patients. One hundred and ten (88%) of the 125 patients included in SMINC‐2 study, and 38 (86.4%) of the 44 patients with TS had completely normal plasma metanephrine and normetanephrine levels. All patients had normal plasma methoxy‐tyramine levels. Fourteen (11.2%) of the 125 patients included in SMINC‐2 study, and 5 (11.6%) of the 43 patients with TS had mild elevations (approximately 1.2 times the upper normal limits) of either plasma metanephrine or normetanephrine. One patient with pheochromocytoma‐triggered TS had marked elevation of plasma metanephrine and mild elevation of plasma normetanephrine. There were no significant differences between the number or degree of catecholamine metabolite elevations between the different groups of patients with CMR imaging diagnosis included in SMINC‐2 study.ConclusionThere was no evidence of massive catecholamine elevations in the acute and subacute stages of TS apart from one patient with pheochromocytoma‐induced TS. Most of the TS patients had normal catecholamine metabolites indicating that blood‐borne catecholamines do not play a direct role in the pathogenesis of TS.

Tyrosine Supplementation A Nutraceutical Approach to Counter Heat Stress Induced Cognitive Decline

Supplementation of tyrosine, non-essential amino acid, and precursor of catecholamine was found to ameliorate the heat-induced alterations in latencies of event-related potential P300 and contingent negative variation. Here we present the effect of tyrosine supplementation on heat stress (exposure to ambient temperature 45 oC and relative humidity 30 %) induced alterations in behavior (attention, mood) and levels of plasma monoamines. Ten healthy male participants received a placebo food bar or tyrosine-containing food bar (6.5 g in 50 g) 90 min before heat stress exposure of 90 min. Plasma and urine samples were assayed for catecholamine levels, their precursor, and metabolites using high-performance liquid chromatography. A computer-based automated test battery was used to assess attention and mood by profile of mood states questionnaire. A significantly higher plasma tyrosine (p<0.001) leading to an increased norepinephrine (p<0.05) levels in the tyrosine supplemented group was observed. Selective (p<0.001) and sustained attention (p<0.02) in the tyrosine group were significantly better compared to the placebo group. Reaction time and anger scores decreased (p<0.001) with tyrosine supplementation. It may be concluded that tyrosine supplementation improves heat stress-induced decrement in attention by maintaining the synthesis and turnover of norepinephrine.

The case of a patient with MIRAGE syndrome with familial dysautonomia-like symptoms

We describe a case of posthumously diagnosed MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital problems, and Enteropathy) in a girl with a new pathogenic SAMD9 variant (p.F437S), who was initially considered to have familial dysautonomia (FD)-like disease due to increased levels of catecholamine metabolites. Functional analyses of F437S-SAMD9 were performed, showing characteristics of disease-causing variants. This new SAMD9 variant (p.F437S) also causes MIRAGE syndrome.

Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo.

In Parkinson's disease, dopamine‐containing nigrostriatal neurons undergo profound degeneration. Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in dopamine biosynthesis. TH increases in vitro formation of reactive oxygen species, and previous animal studies have reported links between cytosolic dopamine build‐up and oxidative stress. To examine effects of increased TH activity in catecholaminergic neurons in vivo, we generated TH‐over‐expressing mice (TH‐HI) using a BAC‐transgenic approach that results in over‐expression of TH with endogenous patterns of expression. The transgenic mice were characterized by western blot, qPCR, and immunohistochemistry. Tissue contents of dopamine, its metabolites, and markers of oxidative stress were evaluated. TH‐HI mice had a 3‐fold increase in total and phosphorylated TH levels and an increased rate of dopamine synthesis. Coincident with elevated dopamine turnover, TH‐HI mice showed increased striatal production of H2O2 and reduced glutathione levels. In addition, TH‐HI mice had elevated striatal levels of the neurotoxic dopamine metabolites 3,4‐dihydroxyphenylacetaldehyde and 5‐S‐cysteinyl‐dopamine and were more susceptible than wild‐type mice to the effects of amphetamine and methamphetamine. These results demonstrate that increased TH alone is sufficient to produce oxidative stress in vivo, build up autotoxic dopamine metabolites, and augment toxicity.

Application of an LC-MS/MS Method for the Simultaneous Quantification of Homovanillic Acid and Vanillylmandelic Acid for the Diagnosis and Follow-Up of Neuroblastoma in 357 Patients.

Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are end-stage metabolites of catecholamine and are clinical biomarkers for the diagnosis of neuroblastoma. For the first time in Korea, we implemented and validated a liquid chromatography tandem mass spectrometry (LC–MS/MS) assay to measure urinary concentrations of HVA and VMA according to Clinical and Laboratory Standards Institute guidelines. Our LC–MS/MS assay with minimal sample preparation was validated for linearity, lower limit of detection (LOD), lower limit of quantification (LLOQ), precision, accuracy, extraction recovery, carryover, matrix effect, and method comparison. A total of 1209 measurements was performed to measure HVA and VMA in spot urine between October 2019 and September 2020. The relationship between the two urinary markers, HVA and VMA, was analyzed and exhibited high agreement (89.1% agreement, kappa’s k = 0.6) and a strong correlation (Pearson’s r = 0.73). To our knowledge, this is the first study to utilize LC–MS/MS for simultaneous quantitation of spot urinary HVA and VMA and analyze the clinical application of both markers on a large scale for neuroblastoma patients.

Re-evaluating the prevalence and factors characteristic of catecholamine secreting head and neck paragangliomas.

IntroductionWe sought to characterize the prevalence and factors characteristic of head and neck paragangliomas (HNPGLs) that secrete catecholamines to inform best practices for diagnosis and management.MethodsThis was a retrospective cohort study from 2000 to 2020 at a single‐institution tertiary centre. One‐hundred fifty‐two patients (182 tumours) with HNPGLs with at least one measurement of urine or plasma catecholamines and/or catecholamine metabolite levels prior to treatment were included. We differentiated and characterized those patients with increased level(s) of any nature and those with ‘clinically significant’ versus ‘clinically insignificant’ catecholamine production.ResultsThirty‐one (20.4%) patients had increased catecholamine and/or catecholamine metabolite levels. In most patients, these levels were ≤5‐fold above the upper limit of the reference range. Four of these 31 patients with increased levels were ultimately found to have an additional catecholamine secreting mediastinal paraganglioma or pheochromocytoma. Fourteen of 31 patients with HNPGL were deemed clinically significant secretors of catecholamines based on hyper‐adrenergic symptoms and/or profound levels of normetanephrines. This cohort was enriched for patients with paragangliomas of the carotid body or cervical sympathetic chain and those with SDHB genetic mutations. Ultimately, the prevalence of clinically significant catecholamine secreting Hangs was determined to be 9.2% and 7.7% based on a per‐patient and per‐tumour basis, respectively.ConclusionsThe rate of catecholamine excess in the current cohort of patients with HNPGLs was higher than previously reported. Neuroendocrine tumours of any anatomic subsite may secrete catecholamines, although not all increased laboratory level(s) are indicative of clinically significant catecholamine secretion causing symptoms or warranting adrenergic blockade.

Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies.

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p<.0001 each by Dunnett's post hoc test), DHPG (p=.004; p<.0001; p<.0001) and norepinephrine (p=.017; p=.0003; p=.044). CSF HVA and DOPAC were decreased in PD (p<.0001 each) and MSA (p<.0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen 18 F-DOPA and cardiac 18 F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.