RESUMEN
In a very brief period, the COVID-19 pandemic has swept across the planet leaving governments, societies, and healthcare systems unprepared and under-resourced. New York City now represents the global viral epicenter with roughly one-third of all mortalities in the United States. To date, our hospital has treated thousands of COVID-19 positive patients and sits at the forefront of the United States response to this pandemic. The goal of this paper is to share the lessons learned by our spine division during a crisis when hospital resources and personnel are stretched thin. Such experiences include management of elective and emergent cases, outpatient clinics, physician redeployment, and general health and wellness. As peak infections spread across the United States, we hope this article will serve as a resource for other spine departments on how to manage patient care and healthcare worker deployment during the COVID-19 crisis.
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Atención a la Salud , Procedimientos Quirúrgicos Electivos , Procedimientos Ortopédicos , Ortopedia , Betacoronavirus , COVID-19 , Infecciones por Coronavirus , Personal de Salud , Hospitales , Humanos , Ciudad de Nueva York , Pandemias , Neumonía Viral , SARS-CoV-2RESUMEN
We report a significant reduction in plasma methionine concentrations in relapse remitting multiple sclerosis (MS) patients compared to controls. In vivo studies demonstrate that changes in peripheral methionine levels in mice can regulate histone H3 methylation and expression of DNA methyltransferase 3A (DNMT3A) centrally, in the cerebral cortex. Therefore, we propose that decreases in circulating methionine represent one of the earliest manifestations of dysregulated methionine metabolism in MS with potential impacts on both histone H3 and DNA methylation in the central nervous system.
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Corteza Cerebral/metabolismo , Metionina/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Adulto , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , ADN Metiltransferasa 3A , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Metionina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patologíaRESUMEN
Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.
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Esquizofrenia/tratamiento farmacológico , Tetrahidrofolatos/farmacología , Adulto , Antipsicóticos/uso terapéutico , Cognición/efectos de los fármacos , Método Doble Ciego , Femenino , Ácido Fólico/metabolismo , Ácido Fólico/farmacología , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Tetrahidrofolatos/uso terapéutico , Resultado del TratamientoRESUMEN
Genetic variants in one-carbon folate metabolism have been identified as risk factors for disease because they may impair the production or use of one-carbon folates required for nucleotide synthesis and methylation. p.R653Q (1958G>A) is a single-nucleotide polymorphism (SNP) in the 10-formyltetrahydrofolate (formylTHF) synthetase domain of the trifunctional enzyme MTHFD1; this domain produces the formylTHF which is required for the de novo synthesis of purines. Approximately 20% of Caucasians are homozygous for the Q allele. MTHFD1 p.R653Q has been proposed as a risk factor for neural tube defects (NTDs), congenital heart defects (CHDs) and pregnancy losses. We have generated a novel mouse model in which the MTHFD1 synthetase activity is inactivated without affecting protein expression or the other activities of this enzyme. Complete loss of synthetase activity (Mthfd1S(-/-)) is incompatible with life; embryos die shortly after 10.5 days gestation, and are developmentally delayed or abnormal. The proportion of 10-formylTHF in the plasma and liver of Mthfd1S(+/-) mice is reduced (P < 0.05), and de novo purine synthesis is impaired in Mthfd1S(+/-) mouse embryonic fibroblasts (MEFs, P < 0.005). Female Mthfd1S(+/-) mice had decreased neutrophil counts (P < 0.05) during pregnancy and increased incidence of developmental defects in embryos (P = 0.052). These findings suggest that synthetase deficiency may lead to pregnancy complications through decreased purine synthesis and reduced cellular proliferation. Additional investigation of the impact of synthetase polymorphisms on human pregnancy is warranted.
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Aminohidrolasas/genética , Aminohidrolasas/metabolismo , Desarrollo Embrionario/genética , Formiato-Tetrahidrofolato Ligasa/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/metabolismo , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , Complicaciones del Embarazo/genética , Purinas/biosíntesis , Aminohidrolasas/deficiencia , Animales , Proliferación Celular , Células Cultivadas , Colina/metabolismo , Anomalías Congénitas/genética , Pérdida del Embrión , Femenino , Ácido Fólico/metabolismo , Formiato-Tetrahidrofolato Ligasa/deficiencia , Formiato-Tetrahidrofolato Ligasa/metabolismo , Técnicas de Sustitución del Gen , Variación Genética , Humanos , Leucovorina/análogos & derivados , Leucovorina/química , Recuento de Leucocitos , Masculino , Metionina/metabolismo , Metilenotetrahidrofolato Deshidrogenasa (NADP)/deficiencia , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Complejos Multienzimáticos/deficiencia , Enzimas Multifuncionales/genética , Enzimas Multifuncionales/metabolismo , Mutagénesis Sitio-Dirigida , Polimorfismo de Nucleótido Simple , Embarazo , Complicaciones del Embarazo/metabolismoRESUMEN
We overview the pathophysiological bases, clinical approaches and potential therapeutic options for succinate semialdehyde dehydrogenase (SSADH; EC1.2.1.24) deficiency (gamma-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of gamma-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH-/- (e.g. Aldh5a1-/-) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1-/- mice accumulate GHB and gamma-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1-/- mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Oxibato de Sodio/orina , Succionato-Semialdehído Deshidrogenasa/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Noqueados , Fenotipo , Succionato-Semialdehído Deshidrogenasa/genética , Ácido gamma-Aminobutírico/metabolismoRESUMEN
OBJECTIVE: To evaluate the independent and joint effects of dietary folate, vitamin B(12) consumption and methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677C>T and 1298A>C) on the circulating folate and homocysteine (Hcy) levels among Mexican women of reproductive age. DESIGN: A cross-sectional, population-based study. SUBJECTS: The first 130 healthy non-pregnant women (aged 16-34 years) who agreed to participate in a reproductive cohort in Morelos, Mexico. MAIN OUTCOME MEASUREMENTS: Dietary intakes of vitamin B(12) and folate were estimated using a semiquantitative food frequency questionnaire. MTHFR 677C>T and 1298A>C polymorphisms were ascertained using the PCR-based method. Serum levels of Hcy and folate were determined using high-performance liquid chromatography and radioimmunoassay, respectively. RESULTS: Genotype frequencies for the MTHFR 677C>T polymorphism were 21.5% (CC), 52.3% (CT) and 26.2% (TT) among Mexican women. Of the population, 22% had the MTHFR 1298AC genotype, while no individual carried the 1298CC genotype. We observed an increased level of Hcy among carriers of the 677TT genotype, compared to carriers of the 677CC genotype. The highest level of Hcy was observed among MTHFR 677TT carriers with low B(12) intake (<2.0 microg/day), which resulted with a significant interaction (P=0.01). CONCLUSION: Vitamin B(12) is an important determinant of Hcy levels in Mexico. Supplementation of folic acid with vitamin B(12) may be preferable when the MTHFR 677T variant allele is prevalent.
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Ácido Fólico/administración & dosificación , Homocisteína/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético , Vitamina B 12/administración & dosificación , Adolescente , Adulto , Alelos , Cromatografía Líquida de Alta Presión , Estudios de Cohortes , Estudios Transversales , Femenino , Frecuencia de los Genes , Genotipo , Humanos , México , Reacción en Cadena de la Polimerasa , Radioinmunoensayo , Encuestas y CuestionariosRESUMEN
BACKGROUND: Microvascular brain injury, typically measured by extent of white matter hyperintensity (WMH) on MRI, is an important contributor to cognitive impairment in the elderly. Recent studies suggest a role for circulating beta-amyloid peptide in microvascular dysfunction and white matter disease. METHODS: The authors performed a cross-sectional study of clinical, biochemical, and genetic factors associated with WMH in 54 subjects with Alzheimer disease (AD) or mild cognitive impairment (AD/MCI) and an independent group of 42 subjects with cerebral amyloid angiopathy (CAA). Extent of WMH was determined by computer-assisted volumetric measurement normalized to intracranial size (nWMH). Biochemical measurements included plasma concentrations of the 40- and 42-amino acid species of beta-amyloid (Abeta40 and Abeta42) detected by specific enzyme-linked immunosorbent assays. RESULTS: Plasma Abeta40 concentrations were associated with nWMH in both groups (correlation coefficient = 0.48 in AD/MCI, 0.42 in CAA, p < or = 0.005). Plasma Abeta40 remained independently associated with nWMH after adjustment for potential confounders among age, hypertension, diabetes, homocysteine, creatinine, folate, vitamin B12, and APOE genotype. The presence of lacunar infarctions was also associated with increased Abeta40 in both groups. nWMH was greater in CAA (19.8 cm3) than AD (11.1 cm3) or MCI (10.0 cm3; p < 0.05 for both comparisons). CONCLUSIONS: Plasma beta-amyloid 40 concentration is independently associated with extent of white matter hyperintensity in subjects with Alzheimer disease, mild cognitive impairment, or cerebral amyloid angiopathy. If confirmed in longitudinal studies, these data would suggest circulating beta-amyloid peptide as a novel biomarker or risk factor for microvascular damage in these common diseases of the elderly.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Encéfalo/patología , Angiopatía Amiloide Cerebral/diagnóstico , Trastornos del Conocimiento/diagnóstico , Fibras Nerviosas Mielínicas/patología , Fragmentos de Péptidos/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/fisiopatología , Biomarcadores/sangre , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Infarto Encefálico/sangre , Infarto Encefálico/diagnóstico , Infarto Encefálico/fisiopatología , Angiopatía Amiloide Cerebral/sangre , Angiopatía Amiloide Cerebral/fisiopatología , Arterias Cerebrales/metabolismo , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Trastornos Cerebrovasculares/sangre , Trastornos Cerebrovasculares/diagnóstico , Trastornos Cerebrovasculares/fisiopatología , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/fisiopatología , Estudios Transversales , Femenino , Humanos , Masculino , Microcirculación/metabolismo , Microcirculación/patología , Microcirculación/fisiopatología , Persona de Mediana Edad , Fibras Nerviosas Mielínicas/metabolismo , Valor Predictivo de las Pruebas , PronósticoRESUMEN
BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease and is reported to be an independent risk factor for Alzheimer disease (AD) and cognitive decline. tHcy may potentiate neurotoxic and vasculopathic processes, including amyloid beta protein (Abeta) metabolism, implicated in neurodegenerative diseases. OBJECTIVE: To examine the relationship of plasma total tHcy levels with clinical, demographic, biochemical, and genetic factors in aging, mild cognitive impairment (MCI), AD, cerebral amyloid angiopathy (CAA), and Parkinson disease (PD). METHODS: Plasma tHcy, folate, vitamin B(12), creatinine, and Abeta levels were assessed in individuals evaluated in the Memory, Stroke, and Movement Disorders Units of Massachusetts General Hospital with diagnoses of AD (n = 145), MCI (n = 47), PD (n = 93), CAA (67), hypertensive intracerebral hemorrhage (hICH) (n = 25), and no dementia (n = 88). RESULTS: The tHcy levels did not differ across AD, MCI, CAA, hICH, and nondemented control subjects but were increased in the PD group (p < 0.01). The elevated levels within the PD group were due to high tHcy in individuals taking levodopa (p < 0.0001). Increasing tHcy was associated with worse cognition in the PD cases, but not the other diagnostic groups. tHcy levels positively correlated with plasma Abeta levels even after adjustments for age and creatinine (p < 0.0001). CONCLUSIONS: Mean tHcy levels increased with age but did not discriminate diagnostic groups aside from significant elevation in patients with PD taking levodopa. The positive association between tHcy and plasma Abeta levels raises the possibility that these circulating factors could interact to affect AD risk and cognition in PD.
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Envejecimiento/metabolismo , Péptidos beta-Amiloides/sangre , Encéfalo/metabolismo , Trastornos del Conocimiento/sangre , Homocisteína/sangre , Enfermedades Neurodegenerativas/sangre , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Causalidad , Angiopatía Amiloide Cerebral/sangre , Angiopatía Amiloide Cerebral/fisiopatología , Trastornos del Conocimiento/fisiopatología , Creatinina/sangre , Femenino , Ácido Fólico/sangre , Humanos , Levodopa/farmacología , Masculino , Trastornos de la Memoria/sangre , Trastornos de la Memoria/fisiopatología , Persona de Mediana Edad , Enfermedades Neurodegenerativas/fisiopatología , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/fisiopatología , Valor Predictivo de las Pruebas , Vitamina B 12/sangreRESUMEN
BACKGROUND: Homocysteine may be involved in the pathogenesis of late onset Alzheimer's disease. It is implicated in the metabolism of several important pathways in the brain. Methylmalonic acid (MMA) is related to the metabolism of branched chained amino acids and fatty acids. OBJECTIVES: To compare cerebrospinal fluid (CSF) total homocysteine and MMA in elderly subjects, patients with Alzheimer's disease, and younger healthy controls. SUBJECTS: CSF samples were obtained from 33 patients under 20 years of age; 28 patients aged 21 to 60 years; 22 normal elderly subjects aged over 60; and 38 Alzheimer patients aged over 60. RESULTS: CSF total homocysteine increased with age (mean (SD): 57 (35) nmol/l in the youngest group v 123 (89) nmol/l in the elderly group (p<0.001)). There was no difference between the elderly group and Alzheimer patients (115 (62) nmol/l). CSF MMA did not differ in the elderly group and the Alzheimer group (38 (13) v 35 (14) ng/ml). In the youngest group, it was significantly higher (60 (15) ng/ml). CONCLUSIONS: CSF total homocysteine is not increased in Alzheimer's disease compared with age matched controls. CSF total homocysteine was correlated with age. The decrease in CSF MMA levels with age eliminates a lack of vitamin B-12 at neuronal level.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/fisiopatología , Homocisteína/líquido cefalorraquídeo , Ácido Metilmalónico/líquido cefalorraquídeo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Encéfalo/metabolismo , Líquido Cefalorraquídeo/metabolismo , Ácido Fólico/sangre , Síndrome de Rett/líquido cefalorraquídeo , Tetrahidrofolatos/líquido cefalorraquídeo , Adolescente , Adulto , Biomarcadores/líquido cefalorraquídeo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiopatología , Encéfalo/fisiopatología , Niño , Preescolar , Femenino , Deficiencia de Ácido Fólico/complicaciones , Deficiencia de Ácido Fólico/tratamiento farmacológico , Deficiencia de Ácido Fólico/metabolismo , Humanos , Leucovorina/uso terapéutico , Valor Predictivo de las Pruebas , Valores de Referencia , Síndrome de Rett/sangre , Síndrome de Rett/fisiopatología , Resultado del TratamientoRESUMEN
The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.
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Trastorno Autístico/tratamiento farmacológico , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/crecimiento & desarrollo , Discapacidades del Desarrollo/tratamiento farmacológico , Deficiencia de Ácido Fólico/tratamiento farmacológico , Leucovorina/administración & dosificación , Convulsiones/tratamiento farmacológico , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/fisiología , Trastorno Autístico/líquido cefalorraquídeo , Trastorno Autístico/etiología , Corteza Cerebral/metabolismo , Niño , Discapacidades del Desarrollo/líquido cefalorraquídeo , Discapacidades del Desarrollo/etiología , Progresión de la Enfermedad , Femenino , Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/fisiopatología , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/etiología , Discapacidad Intelectual/metabolismo , Mutación/genética , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Proteína Portadora de Folato Reducido/genética , Convulsiones/líquido cefalorraquídeo , Convulsiones/etiología , Tetrahidrofolatos/líquido cefalorraquídeo , Factores de Transcripción/genética , Resultado del TratamientoRESUMEN
BACKGROUND: The histopathology of AIDS-associated myelopathy (AM) closely resembles that of myelopathies due to cobalamin or folate deficiency, with white matter vacuolization in the spinal cord. The pathogenesis of AM appears unrelated to direct HIV infection of the spinal cord. There is abnormal trans-methylation metabolism in AM, with decreased availability of the methyl group donor S-adenosyl-methionine (SAM). The authors hypothesized that treatment with l-methionine, the direct metabolic precursor of SAM, might improve AM. OBJECTIVE: To determine the safety and efficacy of l-methionine treatment in AM. METHODS: Fifty-six patients with clinical diagnosis of AM were randomized to a Phase II, double-blind, placebo-controlled study comparing the effect of l-methionine 6 g/day in two divided doses with that of placebo. Study duration was 12 weeks. All patients had somatosensory evoked potentials with prolonged central conduction time (CCT) at entry. Change in CCT was the primary endpoint of the study. Frequency of adverse events (AEs) was used to assess safety. Secondary endpoints were strength, spasticity, and urinary function. Biochemical measurements included serum methionine and homocysteine and CSF SAM. RESULTS: There were no significant differences in AEs between the two groups. Serum homocysteine increased in l-methionine-treated patients from 7.2 (+/-5.2 SD) to 12.6 (+/-6.15 SD) micromol/L. The mean CCT at baseline was 25.9 milliseconds (+/-7.3 SD) for the treatment group and 24.1 milliseconds (+/-7.0 SD) for the placebo group. At completion, it was 3.0 milliseconds (+/-6.1 SD) for the treatment group and 23.6 milliseconds (+/-5.5 SD) for the placebo group (p = 0.17). In a subset of 15 patients with CSF studies, SAM levels increased in the l-methionine but not in the placebo group (p = 0.07). There was no significant effect of treatment on strength, spasticity, or urinary function. CONCLUSIONS: l-methionine was safe and well tolerated although in some patients induced an increase of serum homocysteine. There was a nonsignificant improvement in CCT in treated patients but no benefit in any of the clinical measures.
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Síndrome de Inmunodeficiencia Adquirida/complicaciones , Metionina/uso terapéutico , Enfermedades de la Médula Espinal/tratamiento farmacológico , Adulto , Terapia Antirretroviral Altamente Activa , Método Doble Ciego , Femenino , Homocisteína/sangre , Humanos , Masculino , Metionina/efectos adversos , Metionina/sangre , Persona de Mediana Edad , Músculos/efectos de los fármacos , Músculos/fisiopatología , Conducción Nerviosa/efectos de los fármacos , S-Adenosilmetionina/líquido cefalorraquídeo , Enfermedades de la Médula Espinal/fisiopatología , Enfermedades de la Médula Espinal/virología , Micción/efectos de los fármacosRESUMEN
Hyperhomocysteinemia is common in Alzheimer's disease and is negatively correlated with cognitive function. Hyperhomocysteinemia can increase S-adenosylhomocysteine (SAH), a potent methyltransferase inhibitor. This study investigates the role of brain SAH in the cognitive and neurological disruption in Alzheimer's disease. SAH was significantly (26%) higher in prefrontal cortex of Alzheimer patients than normals. Brain homogenates from Alzheimer patients inhibited an exogenous methyltransferase 15% more than normal homogenates (P <.001). Brain SAH levels correlated (r=.508) with methyltransferase inhibition by brain homogenates. Methyltransferase inhibition by Alzheimer brain homogenates correlated inversely with cognitive function as determined by MMSE (r=-0.36). Phenylethanolamine N-methyltransferase (PNMT) and catechol O-methyltransferase (COMT) activities were more than 30% lower (P<0.001) in Alzheimer than normal brains. Brain PNMT activity correlated significantly with cognitive function (r=0.243), age of Alzheimer's onset (r=0.272), and choline acetyltransferase activity (r=0.333), but negatively with neurofibrillary tangles (r=-0.332). COMT activity also correlated significantly with cognitive function (r=0.324), age of disease onset (r=0.209), choline acetyltransferase activity (r=0.326), levels of synaptophysin (r=0.506), and negatively with tangles (r=-0.216 P=0.039). Elevated SAH in Alzheimer brain inhibits methyltransferases and is related to markers of disease progression and cognitive impairment.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Cognición , Metiltransferasas/metabolismo , S-Adenosilhomocisteína/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Femenino , Humanos , Hiperhomocisteinemia/metabolismo , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Factores de TiempoRESUMEN
The role of hyperhomocysteinemia as independent risk factor for stroke needs to be confirmed. The aims of our study were to assess (i) the association between risk of stroke and increasing values of plasma homocysteine and (ii) the interaction between mild hyperhomocysteinemia and conventional vascular risk factors. We studied 161 consecutive patients with first-ever ischemic stroke classified using TOAST criteria and 152 neurologically healthy controls. Homocysteine was measured using high performance liquid chromatography (HPLC). Homocysteinemia was elevated in all stroke subtypes: 13.0+/-2.5 micromol/l in patients with cardioembolic disease, 13.9+/-5.4 micromol/l in those with small vessel diseases, 15.5+/-6.8 micromol/l in cases of undetermined stroke, and 17.8+/-13.5 micromol/l in patients with large vessel disease. Mean homocysteinemia was 8.10 micromol/l (SD=2.5) in controls. The logistic regression analysis showed that important independent risk factors for ischemic stroke were hypertension (p<0.0001; OR= 3.205; 95% CI, 1.788-5.742), hyperhomocysteinemia (p<0.0001; OR=1.425; 95% CI, 1.300-1562) and hyperlipidemia (p=0.018; OR=2.243; 95% CI, 1.147-4.385). Hyperhomocyst(e)inemia is an independent risk factor for all stroke subtypes and should be routinely measured and treated in stroke patients.
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Homocisteína/sangre , Hiperhomocisteinemia/complicaciones , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Anciano , Cromatografía Líquida de Alta Presión , Complicaciones de la Diabetes , Femenino , Humanos , Hiperlipidemias/complicaciones , Hipertensión/complicaciones , Masculino , Factores de Riesgo , Fumar/efectos adversosRESUMEN
Metabolite profiling in succinate semialdehyde dehydrogenase (SSADH; Aldh5a1-/-) deficient mice previously revealed elevated gamma-hydroxybutyrate (GHB) and total GABA in urine and total brain and liver extracts. In this study, we extend our metabolic characterization of these mutant mice by documenting elevated GHB and total GABA in homogenates of mutant kidney, pancreas and heart. We quantified beta-alanine (a GABA homolog and putative neurotransmitter) to address its potential role in pathophysiology. We found normal levels of beta-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in mutant kidney and liver extracts. Amino acid analysis in mutant total brain homogenates revealed no abnormalities except for significantly decreased glutamine, which was normal in mutant liver and kidney extracts. Regional amino acid analysis (frontal cortex, parietal cortex, hippocampus and cerebellum) in mutant mice confirmed glutamine results. Glutamine synthetase protein and mRNA levels in homogenates of mutant mouse brain were normal. We profiled organic acid patterns in mutant brain homogenates to assess brain oxidative metabolism and found normal concentrations of Kreb's cycle intermediates but increased 4,5-dihydroxyhexanoic acid (a postulated derivative of succinic semialdehyde) levels. We conclude that SSADH-deficient mice represent a valid metabolic model of human SSADH deficiency, manifesting focal neurometabolic abnormalities which could provide key insights into pathophysiologic mechanisms.
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Aldehído Oxidorreductasas/deficiencia , Encéfalo/metabolismo , Animales , Western Blotting , Ácidos Carboxílicos/metabolismo , Modelos Animales de Enfermedad , Femenino , Glutamato-Amoníaco Ligasa/metabolismo , Glutamina/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Miocardio/metabolismo , Especificidad de Órganos , Oxidación-Reducción , Páncreas/metabolismo , ARN Mensajero/metabolismo , Oxibato de Sodio/metabolismo , Succionato-Semialdehído Deshidrogenasa , beta-Alanina/metabolismo , beta-Alanina/orina , Ácido gamma-Aminobutírico/metabolismoRESUMEN
BACKGROUND: White matter vacuolization of the spinal cord is common in patients with AIDS and may lead to clinical manifestations of myelopathy. The pathogenesis of AIDS-associated myelopathy (AM) is unknown and may be related to metabolic abnormalities rather than to direct HIV infection. The striking pathologic similarity between AM and the vacuolar myelopathy associated with vitamin B(12) deficiency suggests that abnormal metabolism of the B(12)-dependent transmethylation pathway may be important in the pathogenesis of AM. METHODS: The authors compared S-adenosyl-methionine (SAM), methionine, homocysteine, and glutathione in serum and CSF of 15 patients with AM vs. 13 HIV-infected controls without myelopathy (HWM). They also compared the results with a non-HIV--infected reference population (NC). All patients had normal B(12), folate, and methylmalonic acid levels. RESULTS: There was a decrease in CSF SAM in the AM group compared with the HWM group (p < 0.0001) and the NC group (p < 0.0001). CSF SAM in the HWM group was also lower than that in the NC group (p = 0.015). Serum methionine was also reduced in serum of the myelopathic group compared with the NC group (p = 0.006). CONCLUSIONS: AM is associated with an abnormality of the vitamin B(12)-dependent transmethylation pathway.
Asunto(s)
Infecciones por VIH/metabolismo , Enfermedades de la Médula Espinal/metabolismo , Vitamina B 12/metabolismo , Adulto , Femenino , Glutatión/sangre , Glutatión/líquido cefalorraquídeo , Infecciones por VIH/complicaciones , Homocisteína/sangre , Homocisteína/líquido cefalorraquídeo , Humanos , Masculino , Metionina/sangre , Metionina/líquido cefalorraquídeo , Metilación , Persona de Mediana Edad , S-Adenosilmetionina/líquido cefalorraquídeo , Enfermedades de la Médula Espinal/etiologíaRESUMEN
Hyperhomocysteinemia is a known risk factor for vascular disease and commonly occurs in the elderly. Several studies have shown an association between elevated plasma homocysteine levels and cognitive impairment, indicating that it may play a role in the pathophysiology of dementia. We studied plasma homocysteine, folate, vitamin B12 levels and the MTHFR C677T genotype in an Italian population of patients with dementia. We confirmed that elevated plasma tHcy (>14 micromol/l) is common in elderly subjects with dementia. Although we found a high prevalence of the MTHFR TT genotype (21.2%) the allele frequency is not over-represented relative to the control population. We also observed a high incidence of folate deficiency (38%) in subjects with dementia. Elevated homocysteine was associated with low plasma folate (<5.7 nmol/l) and the MTHFR TT genotype. Moderate to severe hyperhomocysteinemia (>26.1 nmol/l) was associated with a significantly lower MMSE score. Hyperhomocysteinemia may be neurotoxic by several different mechanisms affecting cognitive function. Further studies are needed to fully explore the potential of B vitamin supplementation to lower plasma homocysteine and improve cognitive function.
Asunto(s)
Demencia/enzimología , Homocisteína/sangre , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Mutación Puntual , Anciano , Alanina/genética , Alanina/metabolismo , Demencia/sangre , Demencia/genética , Demencia/metabolismo , Femenino , Ácido Fólico/sangre , Humanos , Italia , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Valina/genética , Valina/metabolismo , Vitamina B 12/sangreRESUMEN
Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-/- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-/- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1-/- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.
Asunto(s)
Aldehído Oxidorreductasas/genética , Anticonvulsivantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Animales , Secuencia de Bases , Encéfalo/metabolismo , Cartilla de ADN , Genotipo , Proteína Ácida Fibrilar de la Glía/metabolismo , Hidroxibutiratos/metabolismo , Inmunohistoquímica , Ratones , Ratones Noqueados , Fenobarbital/uso terapéutico , Fenitoína/uso terapéutico , Receptores de GABA-B/metabolismo , Convulsiones/enzimología , Succionato-Semialdehído DeshidrogenasaRESUMEN
Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine (SAM) and its metabolite S-adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine beta-synthase-deficient (CBS(+/-)) and wild-type (CBS(+/+)) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS(+/-) mice compared with CBS(+/+) mice after 7 weeks (27.1+/-5.2 versus 8.8+/-1.1 micromol/L; P<0.001) and 15 weeks (23.9+/-3.0 versus 13.0+/-2.3 micromol/L; P<0.01). After 15 weeks, but not 7 weeks, relaxation of aortic rings to acetylcholine was selectively impaired by 35% (P<0.05) and thrombomodulin anticoagulant activity was decreased by 20% (P<0.05) in CBS(+/-) mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated approximately 2-fold in liver and brain of CBS(+/-) mice, and correlations were observed between plasma total homocysteine and SAH in liver (r=0.54; P<0.001) and brain (r=0.67; P<0.001). These results indicate that endothelial dysfunction occurs in hyperhomocysteinemic mice even in the absence of folate deficiency. Endothelial dysfunction in CBS(+/-) mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.
Asunto(s)
Cistationina betasintasa/deficiencia , Endotelio Vascular/fisiopatología , Hiperhomocisteinemia/fisiopatología , S-Adenosilhomocisteína/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/fisiopatología , Encéfalo/metabolismo , Enfermedad Crónica , Cistationina betasintasa/genética , Modelos Animales de Enfermedad , Ácido Fólico/sangre , Alimentos Fortificados , Heterocigoto , Homocisteína/sangre , Hiperhomocisteinemia/sangre , Técnicas In Vitro , Hígado/metabolismo , Metionina/sangre , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , S-Adenosilmetionina/metabolismo , Trombomodulina/metabolismo , Vasoconstrictores/farmacología , Vasodilatadores/farmacología , Sistema Vasomotor/efectos de los fármacos , Sistema Vasomotor/fisiopatologíaRESUMEN
BACKGROUND AND PURPOSE: The pathogenesis of cervical artery dissection (CAD) remains unknown in most cases. Hyperhomocyst(e)inemia [hyperH(e)], an independent risk factor for cerebrovascular disease, induces damage in endothelial cells in animal cell culture. Consecutive patients with CAD and age-matched control subjects have been studied by serum levels of homocyst(e)ine and the genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR). METHODS: Twenty-six patients with CAD, admitted to our Stroke Unit (15 men and 11 women; 16 vertebral arteries, 10 internal carotid arteries), were compared with age-matched control subjects. All patients underwent duplex ultrasound, MR angiography, and/or conventional angiography. RESULTS: Mean plasma homocyst(e)ine level was 17.88 micromol/L (range 5.95 to 40.0 micromol/L) for patients with CAD and 6.0+/-0.99 micromol/L for controls (P:<0.001). The genetic analysis for the thermolabile form of MTHFR in CAD patients showed heterozygosity in 54% and homozygosity in 27%; comparable figures for controls were 40% (P:=0.4) and 10% (P:=0.1), respectively. CONCLUSIONS: Mild hyperH(e) might represent a risk factor for cervical artery dissection. The MTHFR mutation is not significantly associated with CAD. An interaction between different genetic and environmental factors probably takes place in the cascade of pathogenetic events leading to arterial wall damage.