RESUMEN
As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple interacting effectors regulated by homeostatic comparators-"homeostats." Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholamines in the neuronal cytoplasm are autotoxic and that catecholamines from storage visicles leak into the cytoplasm continuously during life. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time.
Asunto(s)
Alostasis/fisiología , Catecolaminas/fisiología , Neurotransmisores/fisiología , Enfermedad de Parkinson/fisiopatología , Estrés Fisiológico , Anciano , Homeostasis/fisiología , Humanos , Cuerpos de Lewy/patología , Cuerpos de Lewy/fisiología , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/fisiología , alfa-Sinucleína/fisiologíaRESUMEN
BACKGROUND: Dihydroxyphenylacetaldehyde (DOPAL), a cytotoxic metabolite of dopamine, is the focus of the 'catecholaldehyde hypothesis' about the pathogenesis of Parkinson disease. This study explored whether DOPAL is detectable in human striatum - especially in the putamen (Pu), the main site of dopamine depletion in Parkinson disease - and is related to other neurochemical indices of catecholamine stores and metabolism in Parkinson disease. METHODS: Putamen, caudate (Cd), and frontal cortex (Ctx) catechols were measured in tissue from patients with pathologically proven end-stage Parkinson disease (N=15) and control subjects (N=14) of similar age with similar post-mortem intervals. RESULTS: Putamen DOPAL (3% of dopamine in controls) correlated with dopamine and dihydroxyphenylacetic acid both across all subjects and within the Parkinson disease and control groups. Pu dopamine was decreased by 93% and dihydroxyphenylacetic acid 95% in Parkinson disease vs. controls, with smaller decreases of DOPAL (83%) and norepinephrine (73%) in Pu and of dopamine (74%) and dihydroxyphenylacetic acid (82%) in Cd. In Parkinson disease, Pu DOPAL:dihydroxyphenylacetic acid averaged 3.4 times and DOPAL:dopamine 4.4 times control (P=0.03 each). The main catecholamine in Ctx was norepinephrine, which was decreased by 51% in Parkinson disease patients. CONCLUSIONS: Correlated decreases of DOPAL, dopamine, and dihydroxyphenylacetic acid in Parkinson disease reflect severe loss of Pu dopamine stores, which seems more extensive than loss of Pu norepinephrine or Cd dopamine stores. Increased Pu DOPAL:dihydroxyphenylacetic acid ratios in Parkinson disease suggest decreased detoxification of DOPAL by aldehyde dehydrogenase. Elevated levels of cytosolic DOPAL might contribute to loss of dopaminergic neurons in Parkinson disease.
Asunto(s)
Ácido 3,4-Dihidroxifenilacético/análogos & derivados , Química Encefálica , Dopamina/metabolismo , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Putamen/metabolismo , Ácido 3,4-Dihidroxifenilacético/química , Ácido 3,4-Dihidroxifenilacético/metabolismo , Anciano , Anciano de 80 o más Años , Química Encefálica/fisiología , Femenino , Humanos , Masculino , Putamen/química , Putamen/patologíaRESUMEN
BACKGROUND: Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. METHODS: Here we report results of cardiac sympathetic neuroimaging by 6-[(18)F]fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[(18)F] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common genetic abnormality identified so far in familial PD. RESULTS: The patient had no detectable 6-[(18)F] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[(18)F] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. CONCLUSION: This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process.
Asunto(s)
Arritmias Cardíacas/genética , Enfermedades del Sistema Nervioso Autónomo/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Sustancia Negra/fisiopatología , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Barorreflejo/genética , Análisis Mutacional de ADN , Dihidroxifenilalanina/análogos & derivados , Genotipo , Corazón/diagnóstico por imagen , Corazón/inervación , Corazón/fisiopatología , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Neostriado/diagnóstico por imagen , Neostriado/metabolismo , Neostriado/fisiopatología , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Tomografía de Emisión de Positrones , Reflejo Anormal/genética , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/metabolismo , Maniobra de Valsalva/genéticaRESUMEN
This chapter provides an update about cardiovascular aspects of Parkinson disease (PD), with the following topics: (1) Orthostatic hypotension (OH) as an early finding in PD; (2) neurocirculatory abnormalities in PD + OH independent of levodopa treatment; (3) cardiac and extracardiac noradrenergic denervation in PD + OH; (4) progressive loss of cardiac sympathetic innervation in PD without OH.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Fenómenos Fisiológicos Cardiovasculares , Enfermedad de Parkinson/fisiopatología , Animales , Enfermedades Cardiovasculares/fisiopatología , Circulación Cerebrovascular/fisiología , Humanos , Enfermedad de Parkinson/complicaciones , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
OBJECTIVE: Human pheochromocytoma tumor cells express glucagon receptors, and bolus i.v. glucagon injection rapidly increases plasma epinephrine levels, suggesting that glucagon can directly stimulate adrenomedullary secretion. In this study, we tested whether the catecholamine secretory response to glucagon was present in bovine chromaffin cells or exclusive to the tumor cells. DESIGN AND METHODS: Adrenomedullary cells were cultured in 24-well plates (10(6) cells per well). After 48-72 hours, wells were incubated for 1-20 minutes with (1) incubation medium (control), (2) catecholamine secretagogues (nicotine or potassium ion), or (3) glucagon (10(-8) to 10(-5) M). After incubation, catecholamine contents in medium and cells were assayed by high-pressure liquid chromatography with electrochemical detection. Fractional release rates of epinephrine, norepinephrine, and dopamine were calculated and compared to controls. Reverse-transcriptase PCR was performed to compare expression of mRNA of the glucagon receptor in chromaffin cells and pheochromocytoma cells. RESULTS: Nicotine and potassium evoked time-dependent release of epinephrine, norepinephrine, and dopamine. Glucagon did not affect catecholamine secretion at any concentration. Reverse-transcriptase PCR failed to detect mRNA for glucagon receptor in bovine adrenomedullary cells, but did detect it in human pheochromocytoma cells. CONCLUSIONS: In contrast to pheochromocytoma tumor cells, bovine adrenomedullary chromaffin cells do not express the glucagon receptor, and therefore do not secrete catecholamines in response to glucagon.
Asunto(s)
Catecolaminas/metabolismo , Células Cromafines/metabolismo , Glucagón/farmacología , Animales , Bovinos , Separación Celular , Células Cultivadas , Células Cromafines/efectos de los fármacos , Dopamina/metabolismo , Epinefrina/metabolismo , Norepinefrina/metabolismo , ARN Mensajero/biosíntesis , Receptores de Glucagón/efectos de los fármacos , Receptores de Glucagón/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Pheochromocytomas in von Hippel-Lindau (VHL) syndrome produce exclusively norepinephrine, whereas those in multiple endocrine neoplasia type 2 (MEN 2) produce epinephrine. This study examined the pathways activated in VHL-associated pheochromocytomas by comparing gene expression profiles in VHL and MEN 2 tumors in relationship to profiles in sporadic norepinephrine- and epinephrine-producing tumors. Larger and more distinct differences in gene expression among hereditary than sporadic tumors indicated the importance of the underlying mutation to gene expression profiles. Many of the genes over-expressed in VHL compared with MEN 2 tumors were clearly linked to the hypoxia-driven angiogenic pathways that are activated in VHL-associated tumorigenesis. Such genes included those for the glucose transporter, vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2, tie-1, VEGF receptor 2 and its coreceptor, neuropilin-1. Other up-regulated genes, such as connective tissue growth factor, cysteine-rich 61, matrix metalloproteinase 1, vascular endothelial cadherin, tenascin C, stanniocalcin 1, and cyclooxygenases 1 and 2 are known to be involved in VEGF-regulated angiogenesis. Shared differences in expression of subsets of genes in norepinephrine- versus epinephrine-producing hereditary and sporadic pheochromocytomas indicated other differences in gene expression that may underlie the biochemical phenotype. Over-expression of the hypoxia-inducible transcription factor, HIF-2alpha, in norepinephrine-predominant sporadic and VHL tumors compared with epinephrine-producing tumors indicates that expression of this gene depends on the noradrenergic biochemical phenotype. The findings fit with the known expression of HIF-2alpha in norepinephrine-producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Feocromocitoma/genética , Enfermedad de von Hippel-Lindau/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/complicaciones , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Niño , Epinefrina , Femenino , Perfilación de la Expresión Génica , Humanos , Hipoxia , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/complicaciones , Neoplasia Endocrina Múltiple Tipo 2a/genética , Norepinefrina , Análisis de Secuencia por Matrices de Oligonucleótidos , Feocromocitoma/complicaciones , Enfermedad de von Hippel-Lindau/complicacionesRESUMEN
BACKGROUND: Neurogenic orthostatic hypotension (NOH) usually results from deficient release of the sympathetic neurotransmitter norepinephrine (NE) when the patient stands up. In pure autonomic failure (PAF) and PD with NOH, sympathetic denervation can explain this deficiency, whereas in multiple-system atrophy (MSA), deficient baroreflex regulation of sympathetic traffic to intact terminals probably causes the NOH. From the concept of a unitary sympathoadrenomedullary system, one might predict parallel sympathoneural and adrenomedullary abnormalities in NOH. OBJECTIVE: To test the concept of parallel sympathoneural and adrenomedullary abnormalities in NOH by simultaneous measurements of plasma levels of catechols and metanephrines. METHODS: Antecubital venous blood drawn via an indwelling cannula with the subject supine was assayed for catecholamines (NE, epinephrine [EPI]), dihydroxyphenylglycol (DHPG), and metanephrines (normetanephrine [NMN] and metanephrine [MN]) in patients with PAF, PD + NOH, or MSA + NOH. Control subjects had PD lacking NOH or were normal volunteers at least 35 years old. Cardiac sympathetic innervation was assessed by 6-[18F]fluorodopamine PET scanning. RESULTS: The three NOH groups differed clearly in patterns of plasma catechols and metanephrines. The PAF group had low NE, DHPG, NMN, EPI, and MN levels, the group with MSA + NOH had generally normal levels, and the PD + NOH group low NMN levels and low DHPG levels for given NE levels but normal mean NE, EPI, and MN levels. All patients with PAF or PD + NOH had markedly decreased 6-[18F]fluorodopamine-derived radioactivity throughout the left ventricular myocardium; all patients with MSA + NOH had normal radioactivity. CONCLUSIONS: PAF involves generalized loss of sympathoadrenomedullary cells, MSA + NOH intact sympathoadrenomedullary cells, and PD + NOH intact adrenomedullary cells but organ-selective sympathetic denervation, especially in the heart.
Asunto(s)
Médula Suprarrenal/fisiopatología , Catecoles/sangre , Metanefrina/sangre , Metoxihidroxifenilglicol/análogos & derivados , Normetanefrina/sangre , Síndrome de Shy-Drager/sangre , Sistema Nervioso Simpático/fisiopatología , Anciano , Enfermedades del Sistema Nervioso Autónomo/sangre , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Epinefrina/sangre , Femenino , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Masculino , Metoxihidroxifenilglicol/sangre , Persona de Mediana Edad , Norepinefrina/sangre , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/complicaciones , Síndrome de Shy-Drager/etiología , Posición SupinaRESUMEN
In PD, orthostatic hypotension reflects sympathetic noradrenergic denervation. The authors assessed sympathetic cholinergic innervation by the quantitative sudomotor axon reflex test (QSART) in 12 patients who had sympathetic neurocirculatory failure, markedly decreased cardiac 6-[18F] fluorodopamine-derived radioactivity, and subnormal plasma norepinephrine increments during standing. All 12 had normal QSART results. The sympathetic nervous system lesion in PD involves loss of postganglionic catecholaminergic but not cholinergic nerves.
Asunto(s)
Acetilcolina/fisiología , Dihidroxifenilalanina/análogos & derivados , Norepinefrina/fisiología , Enfermedad de Parkinson/fisiopatología , Simpatectomía , Fibras Autónomas Posganglionares/fisiopatología , Fibras Colinérgicas/fisiología , Radioisótopos de Flúor , Ventrículos Cardíacos/diagnóstico por imagen , Hemodinámica , Humanos , Hipohidrosis/fisiopatología , Hipotensión Ortostática/etiología , Hipotensión Ortostática/fisiopatología , Norepinefrina/sangre , Enfermedad de Parkinson/complicaciones , Radiofármacos , Tomografía Computarizada de Emisión , Maniobra de ValsalvaRESUMEN
Adipose tissue lipolysis is at least in part stimulated by the sympathetic nervous system (SNS). Although there is a generalized decrease in SNS activity with fasting, the rate of lipolysis during fasting increases. The aim of this study was to determine whether there is an association between activation of sympathetic nerves innervating adipose tissue and the increase in lipolysis seen during fasting in humans. We used the isotope dilution technique to measure regional norepinephrine spillover from abdominal sc adipose tissue from seven healthy subjects before and after a 72-h fast. Our results showed a significant increase in adipose tissue spillover of norepinephrine (mean +/- SEM, 0.40 +/- 0.09 vs. 1.08 +/- 0.18 pmol.100 g(-1).min(-1), P < 0.05) and arterial norepinephrine concentrations (0.92 +/- 0.10 vs. 1.23 +/- 0.08 nmol.liter(-1), P < 0.05) after the fast with no significant change in total body norepinephrine spillover, forearm norepinephrine spillover, epinephrine concentrations, or energy expenditure. We show for the first time, in humans, a selective regional increase in adipose tissue norepinephrine spillover in response to a 72-h fast and suggest that the SNS may play a greater role in the regulation of lipid metabolism during fasting than previously thought.
Asunto(s)
Tejido Adiposo/metabolismo , Ayuno/metabolismo , Norepinefrina/metabolismo , Adulto , Arterias , Epinefrina/sangre , Epinefrina/metabolismo , Femenino , Humanos , Masculino , Norepinefrina/sangre , Concentración Osmolar , Periodo Posprandial , Factores de TiempoRESUMEN
BACKGROUND: Patients with PD often have signs or symptoms of autonomic failure, including orthostatic hypotension. Cardiac sympathetic denervation occurs frequently in PD, but this has been thought to occur independently of autonomic failure. METHODS: Forty-one patients with PD (18 with and 23 without orthostatic hypotension) and 16 age-matched healthy volunteers underwent PET scanning to visualize sympathetic innervation after injection of 6-[(18)F]fluorodopamine. Beat-to-beat blood pressure responses to the Valsalva maneuver were used to identify sympathetic neurocirculatory failure and plasma norepinephrine to indicate overall sympathetic innervation. RESULTS: All patients with PD and orthostatic hypotension had abnormal blood pressure responses to the Valsalva maneuver and septal and lateral ventricular myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity >2 SD below the normal mean. In contrast, only 6 of the 23 patients without orthostatic hypotension had abnormal Valsalva responses (p < 0.0001 compared with patients with orthostatic hypotension), and only 11 had diffusely decreased 6-[(18)F]fluorodopamine-derived radioactivity in the left ventricular myocardium (p = 0.0004). Of the 12 remaining patients without orthostatic hypotension, 7 had locally decreased myocardial radioactivity. Supine plasma norepinephrine was lower in patients with than in those without orthostatic hypotension (1.40 +/- 0.15 vs 2.32 +/- 0.26 nmol/L, p = 0.005). 6-[(18)F]fluorodopamine-derived radioactivity was less not only in the myocardium but also in the thyroid and renal cortex of patients with PD than in healthy control subjects. CONCLUSIONS: In PD, orthostatic hypotension reflects sympathetic neurocirculatory failure from generalized sympathetic denervation.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/etiología , Hipotensión Ortostática/etiología , Enfermedad de Parkinson/complicaciones , Sistema Nervioso Simpático/fisiopatología , Inhibidores de Captación Adrenérgica/farmacología , Anciano , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Encéfalo/diagnóstico por imagen , Catecolaminas/sangre , Desipramina/farmacología , Diagnóstico Diferencial , Femenino , Corazón/inervación , Corazón/fisiopatología , Humanos , Hipotensión Ortostática/diagnóstico , Hipotensión Ortostática/fisiopatología , Riñón/diagnóstico por imagen , Riñón/metabolismo , Masculino , Norepinefrina/sangre , Enfermedad de Parkinson/fisiopatología , Posición Supina , Tomografía Computarizada de Emisión , Maniobra de ValsalvaAsunto(s)
Corazón/inervación , Hipotensión Ortostática/etiología , Proteínas del Tejido Nervioso/fisiología , Enfermedad de Parkinson/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Humanos , Mutación , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Sinucleínas , alfa-SinucleínaRESUMEN
Polymorphism of the dopamine receptor type-2 (D(2)) gene is associated with essential hypertension. To assess whether D(2) receptors participate in regulation of blood pressure (BP), we studied mice in which the D(2) receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D(2) homozygous and heterozygous mutant mice than in D(2)+/+ littermates. BP after alpha-adrenergic blockade decreased to a greater extent in D(2)-/- mice than in D(2)+/+ mice. Epinephrine excretion was greater in D(2)-/- mice than in D(2)+/+ mice, and acute adrenalectomy decreased BP to a similar level in D(2)-/- and D(2)+/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D(2)-/- mice but not D(2)+/+ mice. ET(B) receptor expression was greater in D(2)-/- mice than in D(2)+/+ mice. In contrast, blockade of ET(A) and V(1) vasopressin receptors had no effect on BP in either D(2)-/- or D(2)+/+ mice. The hypotensive effect of an AT(1) antagonist was also similar in D(2)-/- and D(2)+/+ mice. Basal Na(+),K(+)-ATPase activities in renal cortex and medulla were higher in D(2)+/+ mice than in D(2)-/- mice. Urine flow and sodium excretion were higher in D(2)-/- mice than in D(2)+/+ mice before and after acute saline loading. Thus, complete loss of the D(2) receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D(2) mutant mice may be caused by increased sympathetic and ET(B) receptor activities.
Asunto(s)
Hipertensión/fisiopatología , Receptores Adrenérgicos/fisiología , Receptores de Dopamina D2/genética , Receptores de Endotelina/fisiología , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas de Receptores de Angiotensina , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Catecoles/orina , Antagonistas de los Receptores de Endotelina , Endotelina-1/farmacología , Femenino , Genotipo , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Losartán/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Oligopéptidos/farmacología , Fentolamina/farmacología , Piperidinas/farmacología , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptor de Endotelina A , Receptor de Endotelina B , Receptores Adrenérgicos/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Receptores de Endotelina/agonistas , Sodio/orina , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Urodinámica , Venenos de Víboras/farmacologíaRESUMEN
Most, but not all, pheochromocytomas can be localized by computed tomography or magnetic resonance imaging. Here we introduce two novel approaches for localization of pheochromocytoma in a patient in whom conventional imaging modalities failed to show the tumor. First, we establish that measurements of plasma free metanephrines coupled with vena caval sampling are useful for localizing occult pheochromocytoma, particularly when elevations in plasma catecholamines are slight or intermittent. Second, we show that positron emission tomographic scanning using the imaging agent 6-[18F]fluorodopamine as a substrate for the norepinephrine transporter offers a highly effective method for tumor localization. These novel approaches may be of value in difficult cases, where biochemical and clinical evidence of pheochromocytoma is compelling, yet conventional imaging modalities fail to locate the tumor.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Dopamina/análogos & derivados , Recurrencia Local de Neoplasia/diagnóstico , Feocromocitoma/diagnóstico , Simportadores , 3-Yodobencilguanidina , Neoplasias de las Glándulas Suprarrenales/sangre , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía , Proteínas Portadoras/análisis , Dopamina/farmacocinética , Epinefrina/sangre , Epinefrina/orina , Radioisótopos de Flúor/farmacocinética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/diagnóstico por imagen , Norepinefrina/sangre , Norepinefrina/orina , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Normetanefrina/sangre , Normetanefrina/orina , Feocromocitoma/sangre , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/cirugía , Radiofármacos , Sensibilidad y Especificidad , Tomografía Computarizada de Emisión , Tomografía Computarizada por Rayos X , Vena Cava InferiorRESUMEN
The diagnosis and treatment of pheochromocytoma depend critically on effective means to localize the tumor. Computed tomography and magnetic resonance imaging have good sensitivity but poor specificity for detecting pheochromocytoma, and nuclear imaging approaches such as (131)I-metaiodobenzylguanidine scintigraphy have limited sensitivity. Here we report initial results using 6-[(18)F]fluorodopamine positron emission tomography (PET) scanning in the diagnostic localization of pheochromocytoma. Twenty-eight patients with known or clinically suspected pheochromocytoma underwent PET scanning after intravenous injection of 6-[(18)F]fluorodopamine. Of the 28 patients, 9 had surgical confirmation of the tumor, 8 had previously diagnosed metastatic pheochromocytoma, and 11 had plasma levels of metanephrines that were within normal limits. All 9 patients with surgically proven pheochromocytoma had abnormal 6-[(18)F]fluorodopamine PET scans that identified the tumors. All 8 patients with metastatic pheochromocytoma had extra-adrenal sites of 6-[(18)F]fluorodopamine-derived activity. Of the 11 patients with normal plasma levels of metanephrines, 9 had negative 6-[(18)F]fluorodopamine PET scans, 1 had extra-adrenal foci of 6-[(18)F]fluorodopamine-derived activity, and 1 had symmetric uptake of 6-[(18)F]fluorodopamine in the region of the adrenal glands. In patients with known disease, 6-[(18)F]fluorodopamine PET scanning can detect and localize pheochromocytomas with high sensitivity. In patients in whom the diagnosis of pheochromocytoma is considered but excluded because of negative plasma metanephrine results, 6-[(18)F]fluorodopamine PET scans are consistently negative. These findings justify a clinical trial of 6-[(18)F]fluorodopamine PET scanning as a diagnostic tool.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Dopamina/análogos & derivados , Feocromocitoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/sangre , Radioisótopos de Flúor , Humanos , Metanefrina/sangre , Feocromocitoma/sangre , Tomografía Computarizada de EmisiónRESUMEN
PURPOSE: Over 31,000 Americans die of androgen-independent metastatic prostate cancer each year. New strategies that do not involve hormonal manipulation but instead recognize the biochemical and molecular characteristics of prostate cancer are needed. Radioimmunotherapy (RIT) uses a tumor-specific monoclonal antibody to deliver systemic, targeted radiation to cancer. The objectives of this Phase I study of (111)In-2IT-BAD-m170 (for imaging) and (90)Y-2IT-BAD-m170 (for therapy) were to determine the toxicity and maximum tolerated dose (MTD), the specificity for targeting metastatic prostate cancer, and the efficacy for palliation of pain. EXPERIMENTAL DESIGN: M170 is a mouse monoclonal antibody that targets adenocarcinomas. Patients with adequate renal and liver function, rising prostate-specific antigen, and androgen-independent metastatic prostate cancer were eligible. After estimation of dosimetry and pharmacokinetics with (111)In-2IT-BAD-m170, a single dose of (90)Y-2IT-BAD-m170 (0.185, 0.370, 0.555, or 0.740 GBq/m(2)) was administered to cohorts of three patients. Pain was assessed objectively by questionnaires before and for 8 weeks after RIT; weekly prostate-specific antigen levels were obtained for 2 months after RIT. RESULTS: The MTD of (90)Y-2IT-BAD-m170 was 0.740 GBq/m(2) for patients that had up to 10% of the axial skeleton involved with prostate cancer. Toxicity was almost exclusively confined to reversible myelosuppression. Metastatic prostate cancer was targeted by (111)In-2IT-BAD-m170 in all 17 patients. The mean radiation dose delivered to 39 bone and 18 nodal metastases by (90)Y-2IT-BAD-m170 was 10.5 Gy/GBq (range 2.8-25.1). Thirteen of 17 patients reported pain before (90)Y-2IT-BAD-m170; 7 of these 13 had a partial or complete resolution of pain that lasted an average of 4.3 weeks. CONCLUSIONS: This study determined the MTD of (111)In/(90)Y-2IT-BAD-m170 in patients with metastatic prostate cancer. The drugs were well tolerated, targeted metastases, and temporarily palliated pain.
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Anticuerpos Monoclonales/uso terapéutico , Terapia Combinada , Radioisótopos de Indio , Neoplasias de la Próstata/terapia , Radioinmunoterapia , Radioisótopos de Itrio/uso terapéutico , Adenocarcinoma/terapia , Anciano , Animales , Anticuerpos Monoclonales/farmacocinética , Estudios de Cohortes , Humanos , Radioisótopos de Indio/farmacocinética , Masculino , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Dolor/tratamiento farmacológico , Antígeno Prostático Específico/biosíntesis , Radiometría , Factores de Tiempo , Resultado del Tratamiento , Radioisótopos de Itrio/farmacocinéticaRESUMEN
This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasia Endocrina Múltiple Tipo 2a/metabolismo , Feocromocitoma/metabolismo , Enfermedad de von Hippel-Lindau/metabolismo , Adolescente , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Catecolaminas/sangre , Niño , Femenino , Humanos , Masculino , Metanefrina/sangre , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/patología , Fenotipo , Feniletanolamina N-Metiltransferasa/genética , Feocromocitoma/patología , ARN Mensajero/análisis , Tirosina 3-Monooxigenasa/genética , Enfermedad de von Hippel-Lindau/patologíaRESUMEN
In healthy men, a decrease in plasma testosterone levels was observed in the context of metabolic stress. While physiological mechanisms underlying this response are unclear, there are several lines of evidence suggesting circulating epinephrine's influence on plasma testosterone levels. The purpose of this study was to directly relate stress-induced changes in plasma testosterone and epinephrine. The stressor used was blockade of glucose metabolism with pharmacological doses (40 mg/kg) of 2 deoxyglucose (2DG). Arterial plasma samples from 10 healthy males were assayed at 20 minutes intervals for 60 minutes for the concentrations of testosterone, epinephrine and related biochemicals. Bolus administration of 2DG resulted in progressive decline in testosterone and increases in epinephrine and norepinephrine plasma levels (mean change from baseline: 29, 2530 and 186%, respectively). Inverse correlation was detected between both absolute (r(s)=-0.72; df=8; p=0.017) and baseline-corrected testosterone concentrations at the 60 minute time point and epinephrine area under the curve values. Our results suggest that adrenomedullary activation may be involved in stress-induced testosterone effects. The implications of these data for the understanding of the role of catecholamines in glucoprivic stress response are discussed.
Asunto(s)
Epinefrina/sangre , Metoxihidroxifenilglicol/análogos & derivados , Estrés Fisiológico/sangre , Testosterona/sangre , Ácido 3,4-Dihidroxifenilacético/sangre , Adulto , Presión Sanguínea/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Desoxiglucosa/farmacología , Dihidroxifenilalanina/sangre , Dopamina/sangre , Frecuencia Cardíaca/efectos de los fármacos , Ácido Homovanílico/sangre , Humanos , Hambre/efectos de los fármacos , Ácido Hidroxiindolacético/sangre , Hipoglucemia/sangre , Hipoglucemia/inducido químicamente , Masculino , Metoxihidroxifenilglicol/sangre , Norepinefrina/sangre , Estrés Fisiológico/fisiopatología , Sed/efectos de los fármacosAsunto(s)
Neoplasias de las Glándulas Suprarrenales/cirugía , Neoplasias Óseas/secundario , Neoplasias Óseas/cirugía , Ablación por Catéter , Feocromocitoma/secundario , Feocromocitoma/cirugía , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Neoplasias Óseas/diagnóstico por imagen , Humanos , Masculino , Feocromocitoma/diagnóstico por imagen , CintigrafíaRESUMEN
OBJECTIVE: In the 1920s, Walter B. Cannon first described the adrenomedullary response to cold, using an ingenious in vivo bioassay based on a denervated heart preparation. Studies in humans about antecubital venous plasma concentrations of norepinephrine, the sympathetic neurotransmitter, and of epinephrine, the main adrenomedullary hormone, have suggested sympathetic nervous system activation without adrenomedullary activation. The present study used arterial levels of these catecholamines, to determine whether adrenomedullary stimulation occurs in response to decreased body temperature. METHODS: Eleven healthy volunteers underwent central intravenous infusion of warm (37 degreeC) physiological saline, followed by infusion of the same volume of cold (4 degreeC) saline. Brachial arterial and antecubital venous plasma concentrations of norepinephrine and epinephrine were measured by liquid chromatography with electrochemical detection. RESULTS: Antecubital venous concentrations of norepinephrine increased markedly during cold saline infusion, with smaller and statistically borderline increases in concentrations of epinephrine. In contrast, concurrently obtained arterial concentrations of both norepinephrine and epinephrine increased significantly. CONCLUSIONS: The results confirm Cannon's original inference that cold evokes adrenomedullary activation. Prior studies about antecubital venous levels of catecholamines did not take into account the local hemodynamic effects of cold, which would increase extraction of circulating catecholamines and underestimate the arterial epinephrine response.