RESUMEN
31 P MR spectroscopic imaging (MRSI) is a versatile technique to study phospholipid precursors and energy metabolism in the healthy and diseased human brain. However, mainly due to its low sensitivity, 31 P MRSI is currently limited to research purposes. To obtain 3D 31 P MRSI spectra with improved signal-to-noise ratio on clinical 3 T MR systems, we used a coil combination consisting of a dual-tuned birdcage transmit coil and a 31 P eight-channel phased-array receive insert. To further increase resolution and sensitivity we applied WALTZ4 1 H decoupling and continuous wave nuclear Overhauser effect (NOE) enhancement and acquired high-quality MRSI spectra with nominal voxel volumes of ~ 17.6 cm3 (effective voxel volume ~ 51 cm3 ) in a clinically relevant measurement time of ~ 13 minutes, without exceeding SAR limits. Steady-state NOE enhancements ranged from 15 ± 9% (γ-ATP) and 33 ± 3% (phosphocreatine) to 48 ± 11% (phosphoethanolamine). Because of these improvements, we resolved and detected all 31 P signals of metabolites that have also been reported for ultrahigh field strengths, including resonances for NAD+ , NADH and extracellular inorganic phosphate. T1 times of extracellular inorganic phosphate were longer than for intracellular inorganic phosphate (3.8 ± 1.4s vs 1.8 ± 0.65 seconds). A comparison of measured T1 relaxation times and NOE enhancements at 3 T with published values between 1.5 and 9.4 T indicates that T1 relaxation of 31 P metabolite spins in the human brain is dominated by dipolar relaxation for this field strength range. Even although intrinsic sensitivity is higher at ultrahigh fields, we demonstrate that at a clinical field strength of 3 T, similar 31 P MRSI information content can be obtained using a sophisticated coil design combined with 1 H decoupling and NOE enhancement.
Asunto(s)
Encéfalo/diagnóstico por imagen , Espectroscopía de Resonancia Magnética , NAD/metabolismo , Adenosina Trifosfato/metabolismo , Adulto , Femenino , Humanos , Masculino , Metaboloma , Fosfatos/análisis , Fosfocreatina/análogos & derivados , Fosfocreatina/metabolismo , Fósforo , Espectroscopía de Protones por Resonancia Magnética , Procesamiento de Señales Asistido por Computador , Factores de TiempoRESUMEN
Three-dimensional phosphorus MR images ((31)P MRI) of teeth are obtained at a nominal resolution of 0.5 mm in less than 15 minutes using acquisition pulse sequences sensitive to ultra-short transversal relaxation times. The images directly reflect the spatially resolved phosphorus content of mineral tissue in dentin and enamel; they show a lack of signal from pulp tissue and reduced signal from de-mineralized carious lesions. We demonstrate for the first time that the signal in (31)P MR images of mineralized tissue is enhanced by a (1)H-(31)P nuclear Overhauser effect (NOE). Using teeth as a model for imaging mineralized human tissue, graded differences in signal enhancement are observed that correlate well with known mineral content. From solid-state NMR experiments we conclude that the NOE is facilitated by spin diffusion and that the NOE difference can be assigned to a higher water content and a different micro-structure of dentin. Thus, a novel method for imaging mineral content without ionizing radiation is proposed. This method has potential use in the assessment of de-mineralization states in humans, such as caries of teeth and osteoporosis of bones.
Asunto(s)
Fósforo/química , Diente/diagnóstico por imagen , Esmalte Dental/química , Esmalte Dental/diagnóstico por imagen , Dentina/química , Dentina/diagnóstico por imagen , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Diente/químicaRESUMEN
AIMS: Hypertension, a risk factor for Alzheimer's disease (AD), is a treatable condition, which offers possibilities for prevention of AD. Elevated angiotensin II (AngII) is an important cause of essential hypertension. AngII has deleterious effects on endothelial function and cerebral blood flow (CBF), which may contribute to AD. AngII blocking agents can thus provide potential candidates to reduce AD risk factors in hypertensive patients. METHODS: We studied the effect of 2 months induced hypertension (AngII-infusion via osmotic micropumps) on systolic blood pressure (SBP) and CBF in 10 months-old wild-type (WT) C57bl/6j and AßPPswe/PS1ΔE9 (AßPP/PS1) mice, and treatment with two different antihypertensives, 1) eprosartan mesylate (EM, 0.35mg/kg) or 2) hydrochlorotiazide (HCT, 7.5mg/kg), after 1 month of induced-hypertension. SBP was monitored twice each month via tail cuff plethysmography. CBF was measured with MR by flow-sensitive alternating inversion recovery. RESULTS: Chronic AngII-infusion induced an increase in SBP in both AßPP/PS1 and WT mice accompanied by a decrease in hippocampal and thalamic CBF only in the AßPP/PS1 mice. An additional difference between the AßPP/PS1 mice and WT mice was that SBP was much higher in AßPP/PS1 mice in both hypertensive and normotensive conditions. Moreover, both antihypertensives were less effective in reducing AngII-induced hypertension to normal levels in AßPP/PS1 mice, while being effective in WT mice. CONCLUSIONS: It can be concluded that AngII-induced elevated SBP results in impaired CBF and a decreased response to blood pressure lowering treatment in a transgenic model of AD. Our findings suggest a relation between midlife hypertension and decreased CBF in an AD mouse model, similar to the relation which has been found in AD patients. This translational mouse model could be used to investigate possible prevention and treatment strategies for AD.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Corteza Cerebral/fisiopatología , Circulación Cerebrovascular/fisiología , Hipocampo/fisiopatología , Hipertensión/fisiopatología , Tálamo/fisiopatología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Angiotensina II , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Corteza Cerebral/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Modelos Animales de Enfermedad , Hipertensión Esencial , Hipocampo/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismo , Tálamo/efectos de los fármacosRESUMEN
Evidence suggests that flavanol consumption can beneficially affect cognition in adults, but little is known about the effect of flavanol intake early in life. The present study aims to assess the effect of dietary flavanol intake during the gestational and postnatal period on brain structure, cerebral blood flow (CBF), cognition, and brain metabolism in C57BL/6J mice. Female wild-type C57BL/6J mice were randomly assigned to either a flavanol supplemented diet or a control diet at gestational day 0. Male offspring remained on the corresponding diets throughout life and performed cognitive and behavioral tests during puberty and adulthood assessing locomotion and exploration (Phenotyper and open field), sensorimotor integration (Rotarod and prepulse inhibition), and spatial learning and memory (Morris water maze, MWM). Magnetic resonance spectroscopy and imaging at 11.7T measured brain metabolism, CBF, and white and gray matter integrity in adult mice. Biochemical and immunohistochemical analyses evaluated inflammation, synaptic plasticity, neurogenesis, and vascular density. Cognitive and behavioral tests demonstrated increased locomotion in Phenotypers during puberty after flavanol supplementation (p = 0.041) but not in adulthood. Rotarod and prepulse inhibition demonstrated no differences in sensorimotor integration. Flavanols altered spatial learning in the MWM in adulthood (p = 0.039), while spatial memory remained unaffected. Additionally, flavanols increased diffusion coherence in the visual cortex (p = 0.014) and possibly the corpus callosum (p = 0.066) in adulthood. Mean diffusion remained unaffected, a finding that corresponds with our immunohistochemical data showing no effect on neurogenesis, synaptic plasticity, and vascular density. However, flavanols decreased CBF in the cortex (p = 0.001) and thalamus (p = 0.009) in adulthood. Brain metabolite levels and neuroinflammation remained unaffected by flavanols. These data suggest that dietary flavanols results in subtle alterations in brain structure, locomotor activity and spatial learning. Comparison of these data to published findings in aging or neurodegeneration suggests that benefits of dietary flavanols may increase with advancing age and in disease.
Asunto(s)
Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Cognición/efectos de los fármacos , Suplementos Dietéticos , Flavonoides/administración & dosificación , Animales , Encéfalo/metabolismo , Circulación Cerebrovascular/fisiología , Cognición/fisiología , Femenino , Flavonoides/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Embarazo , Fenómenos Fisiologicos de la Nutrición Prenatal/efectos de los fármacos , Fenómenos Fisiologicos de la Nutrición Prenatal/fisiologíaRESUMEN
Maternal intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) is critical during perinatal development of the brain. Docosahexaenoic acid (DHA) is the most abundant n-3 PUFA in the brain and influences neuronal membrane function and neuroprotection. The present study aims to assess the effect of dietary n-3 PUFA availability during the gestational and postnatal period on cognition, brain metabolism and neurohistology in C57BL/6J mice. Female wild-type C57BL/6J mice at day 0 of gestation were randomly assigned to either an n-3 PUFA deficient diet (0.05% of total fatty acids) or an n-3 PUFA adequate diet (3.83% of total fatty acids) containing preformed DHA and its precursor α-linolenic acid. Male offspring remained on diet and performed cognitive tests during puberty and adulthood. In adulthood, animals underwent (31)P magnetic resonance spectroscopy to assess brain energy metabolites. Thereafter, biochemical and immunohistochemical analyses were performed assessing inflammation, neurogenesis and synaptic plasticity. Compared to the n-3 PUFA deficient group, pubertal n-3 PUFA adequate fed mice demonstrated increased motor coordination. Adult n-3 PUFA adequate fed mice exhibited increased exploratory behavior, sensorimotor integration and spatial memory, while neurogenesis in the hippocampus was decreased. Selected brain regions of n-3 PUFA adequate fed mice contained significantly lower levels of arachidonic acid and higher levels of DHA and dihomo-γ-linolenic acid. Our data suggest that dietary n-3 PUFA can modify neural maturation and enhance brain functioning in healthy C57BL/6J mice. This indicates that availability of n-3 PUFA in infant diet during early development may have a significant impact on brain development.
Asunto(s)
Cognición/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Hipocampo/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Ácido Araquidónico/farmacología , Homólogo 4 de la Proteína Discs Large , Ácidos Docosahexaenoicos/farmacología , Femenino , Guanilato-Quinasas/genética , Guanilato-Quinasas/metabolismo , Hipocampo/metabolismo , Inmunohistoquímica , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Sinaptofisina/genética , Sinaptofisina/metabolismo , Ácido alfa-Linolénico/farmacologíaRESUMEN
Lipid metabolism and genetic background together strongly influence the development of both cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). A non-pharmacological way to prevent the genotype-induced occurrence of these pathologies is given by dietary behavior. In the present study, we tested the effects of long-term consumption of a specific multi-nutrient diet in two models for atherosclerosis and vascular risk factors in AD: the apolipoprotein ε4 (apoE4) and the apoE knockout (apoE ko) mice. This specific multi-nutrient diet was developed to support neuronal membrane synthesis and was expected to contribute to the maintenance of vascular health. At 12 months of age, both genotypes showed behavioral changes compared to control mice and we found increased neurogenesis in apoE ko mice. The specific multi-nutrient diet decreased anxiety-related behavior in the open field, influenced sterol composition in serum and brain tissue, and increased the concentration of omega-3 fatty acids in the brain. Furthermore, we found that wild-type and apoE ko mice fed with this multi-nutrient diet showed locally increased cerebral blood volume and decreased hippocampal glutamate levels. Taken together, these data suggest that a specific dietary intervention has beneficial effects on early pathological consequences of hypercholesterolemia and vascular risk factors for AD.
Asunto(s)
Enfermedad de Alzheimer/dietoterapia , Apolipoproteína E4/deficiencia , Apolipoproteína E4/genética , Encéfalo/metabolismo , Trastornos del Conocimiento/prevención & control , Dieta , Hemodinámica/genética , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Conducta Exploratoria , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Neurogénesis , Tamaño de los Órganos , Presenilina-1/genéticaRESUMEN
Nutritional intervention may retard the development of Alzheimer's disease (AD). In this study we tested the effects of 2 multi-nutrient diets in an AD mouse model (APPswe/PS1dE9). One diet contained membrane precursors such as omega-3 fatty acids and uridine monophosphate (DEU), whereas another diet contained cofactors for membrane synthesis as well (Fortasyn); the diets were developed to enhance synaptic membranes synthesis, and contain components that may improve vascular health. We measured cerebral blood flow (CBF) and water diffusivity with ultra-high-field magnetic resonance imaging, as alterations in these parameters correlate with clinical symptoms of the disease. APPswe/PS1dE9 mice on control diet showed decreased CBF and changes in brain water diffusion, in accordance with findings of hypoperfusion, axonal disconnection and neuronal loss in patients with AD. Both multinutrient diets were able to increase cortical CBF in APPswe/PS1dE9 mice and Fortasyn reduced water diffusivity, particularly in the dentate gyrus and in cortical regions. We suggest that a specific diet intervention has the potential to slow AD progression, by simultaneously improving cerebrovascular health and enhancing neuroprotective mechanisms.
Asunto(s)
Enfermedad de Alzheimer/dietoterapia , Enfermedad de Alzheimer/fisiopatología , Encéfalo/irrigación sanguínea , Circulación Cerebrovascular , Ácidos Grasos Omega-3/administración & dosificación , Uridina Monofosfato/administración & dosificación , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/prevención & control , Precursor de Proteína beta-Amiloide/genética , Animales , Agua Corporal/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Imagen de Difusión Tensora , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácidos Grasos Omega-3/farmacología , Masculino , Ratones , Ratones Transgénicos , Fármacos Neuroprotectores , Presenilina-1/genética , Uridina Monofosfato/farmacologíaRESUMEN
Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AßPPswe-PS1dE9 mice. Starting from 2 months of age, male AßPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1ß mRNA levels in AßPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AßPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AßPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders.
Asunto(s)
Enfermedad de Alzheimer/dietoterapia , Enfermedad de Alzheimer/prevención & control , Encéfalo/metabolismo , Cognición/fisiología , Alimentos Fortificados/análisis , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Colesterol/sangre , Cognición/efectos de los fármacos , Cartilla de ADN/genética , Ácidos Docosahexaenoicos , Ácido Eicosapentaenoico , Ácidos Grasos/metabolismo , Inmunohistoquímica , Interleucina-1beta/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Mutantes , Reacción en Cadena en Tiempo Real de la Polimerasa , Uridina MonofosfatoRESUMEN
BACKGROUND: Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. METHODS AND RESULTS: Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the L-arginine:glycine amidinotransferase (AGAT) gene (P<2.1 × 10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice and increased in GAMT(-/-) mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT(-/-) mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT(-/-) mice was decreased compared with controls. CONCLUSIONS: Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.
Asunto(s)
Amidinotransferasas/genética , Arginina/genética , Homoarginina/genética , Accidente Cerebrovascular/genética , Adulto , Anciano , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Estudio de Asociación del Genoma Completo , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Accidente Cerebrovascular/diagnóstico , Resultado del TratamientoRESUMEN
PURPOSE: Anticancer dendritic cell (DC) vaccines require the DCs to relocate to lymph nodes (LN) to trigger immune responses. However, these migration rates are typically very poor. Improving the targeting of ex vivo generated DCs to LNs might increase vaccine efficacy and reduce costs. We investigated DC migration in vivo in humans under different conditions. EXPERIMENTAL DESIGN: HLA-A*02:01 patients with melanoma were vaccinated with mature DCs loaded with tyrosinase and gp100 peptides together with keyhole limpet hemocyanin (NCT00243594). For this study, patients received an additional intradermal vaccination with (111)In-labeled mature DCs. The injection site was pretreated with nonloaded, activated DCs, TNFα, or Imiquimod; granulocyte macrophage colony-stimulating factor was coinjected or smaller numbers of DCs were injected. Migration was measured by scintigraphy and compared with an intrapatient control vaccination. In an ex vivo tissue model, we measured CCL21-directed migration of (19)F-labeled DCs over a period of up to 12 hours using (19)F MRI to supplement our patient data. RESULTS: Pretreatment of the injection site induced local inflammatory reactions but did not improve migration rates. Both in vitro and in vivo, reduction of cell numbers to 5 × 10(6) or less cells per injection improved migration. Furthermore, scintigraphy is insufficient to study migration of such small numbers of (111)In-labeled DCs in vivo. CONCLUSION: Reduction of cell density, not pretreatment of the injection site, is crucial for improved migration of DCs to LNs in vivo.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Melanoma/terapia , Adolescente , Adulto , Anciano , Vacunas contra el Cáncer/inmunología , Movimiento Celular , Células Dendríticas/citología , Células Dendríticas/trasplante , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organometálicos/química , Oxiquinolina/análogos & derivados , Oxiquinolina/química , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine synthesis or distribution include mental retardation and muscular weakness. Human mutations in l-arginine:glycine amidinotransferase (AGAT), the first enzyme of Cr synthesis, lead to severely reduced Cr and guanidinoacetate (GuA) levels. Here, we report the generation and metabolic characterization of AGAT-deficient mice that are devoid of Cr and its precursor GuA. AGAT-deficient mice exhibited decreased fat deposition, attenuated gluconeogenesis, reduced cholesterol levels and enhanced glucose tolerance. Furthermore, Cr deficiency completely protected from the development of metabolic syndrome caused by diet-induced obesity. Biochemical analyses revealed the chronic Cr-dependent activation of AMP-activated protein kinase (AMPK), which stimulates catabolic pathways in metabolically relevant tissues such as the brain, skeletal muscle, adipose tissue and liver, suggesting a mechanism underlying the metabolic phenotype. In summary, our results show marked metabolic effects of Cr deficiency via the chronic activation of AMPK in a first animal model of AGAT deficiency. In addition to insights into metabolic changes in Cr deficiency syndromes, our genetic model reveals a novel mechanism as a potential treatment option for obesity and type 2 diabetes mellitus.
Asunto(s)
Amidinotransferasas/genética , Síndrome Metabólico/genética , Adenilato Quinasa/metabolismo , Tejido Adiposo , Animales , Peso Corporal , Encéfalo/metabolismo , Creatina/metabolismo , Activación Enzimática , Hipotálamo/enzimología , Espectroscopía de Resonancia Magnética , Síndrome Metabólico/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MutaciónRESUMEN
This study describes a technique for fast imaging of x-nuclei metabolites. Due to increased sensitivity and larger chemical shift dispersion at high magnetic fields, images of multiple metabolites can be obtained simultaneously by selective excitation of their resonances with a multifrequency selective radiofrequency pulse at any desired flip angle. This aim is achieved by combining a three-dimensional gradient echo imaging sequence with a Shinnar-LeRoux optimized excitation pulse. A proper choice of bandwidth, imaging matrix size, and field of view allows using the chemical shift dispersion of the different resonances to completely separate their images within one large field of view. The method of fast metabolic imaging is illustrated with (13)C measurements of a phantom containing a solution of (13)C labeled glucose, lactate, and sodium octanoate and by dynamic measurements of the (31)P metabolites phosphocreatine and ß-adenosine triphosphate in human femoral muscle in vivo, both at 7T. With dynamic selective (31)P imaging of the larger part of the upper leg, phosphocreatine signal intensity changes of specific muscles can be studied simultaneously by analyzing the sum of phosphocreatine signals within arbitrarily shaped regions of interest following the muscles' contours. This concept of dynamic metabolic imaging can be applied to other organs and further expanded to other MR-detectable nuclei and metabolites.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Algoritmos , Glucosa/metabolismo , Ácido Láctico/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Músculo Esquelético/metabolismo , Fosfocreatina/metabolismo , Humanos , Fósforo , Distribución TisularRESUMEN
PURPOSE: To determine the individual and combined performance of magnetic resonance (MR) spectroscopic imaging and diffusion-weighted (DW) imaging at 3 T in the in vivo assessment of prostate cancer aggressiveness by using histopathologically defined regions of interest on radical prostatectomy specimens to define the prostate cancer regions to be investigated. MATERIALS AND METHODS: The local institutional ethics review board approved this retrospective study and waived the informed consent requirement. Fifty-four patients with biopsy-proved prostate cancer underwent clinical MR spectroscopic imaging followed by prostatectomy. Guided by the histopathologic map, all spectroscopy voxels that contained tumor tissue were selected, and metabolite ratios (choline [Cho] plus creatine [Cr]-to-citrate [Cit] and Cho/Cr ratios) were derived. For each spectroscopic voxel, 25th percentile apparent diffusion coefficient (ADC) of the region corresponding to that voxel was determined, representing the most aberrant tumor part on the ADC map, which was often smaller than spectroscopic imaging voxels. Maximum metabolic ratios and minimum 25th percentile ADC of each tumor were related to tumor aggressiveness and were used to differentiate aggressiveness classes. A logistic regression model (LRM) was used to combine data from both modalities. RESULTS: Significant correlation was found between aggressiveness classes and maximum Cho+Cr/Cit ratio (ρ=0.36), maximum Cho/Cr ratio (ρ=0.35), and minimum 25th percentile ADC (ρ=-0.63) in the peripheral zone (PZ). In the transition zone (TZ), the correlation was significant for only Cho+Cr/Cit and Cho/Cr ratios (ρ=0.58 and ρ=0.60, respectively). For differentiation between aggressiveness classes, LRM use did not result in significantly improved differentiation over any individual variables. CONCLUSION: These findings enabled confirmation that MR spectroscopic imaging and DW imaging offer potential for in vivo noninvasive assessment of prostate cancer aggressiveness, and both modalities have comparable performance. The combination did not result in better performance. Nonetheless, the better performances of metabolite ratios in the TZ and of ADCs in the PZ suggest that they have complementary value.
Asunto(s)
Biomarcadores de Tumor/análisis , Imagen de Difusión por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Imagen Molecular/métodos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Protones , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
(31)P MR spectroscopic imaging of the human prostate provides information about phosphorylated metabolites that could be used for prostate cancer characterization. The sensitivity of a magnetic field strength of 7 T might enable 3D (31)P MR spectroscopic imaging with relevant spatial resolution in a clinically acceptable measurement time. To this end, a (31)P endorectal coil was developed and combined with an eight-channel (1)H body-array coil to relate metabolic information to anatomical location. An extensive safety validation was performed to evaluate the specific absorption rate, the radiofrequency field distribution, and the temperature distribution of both coils. This validation consisted of detailed Finite Integration Technique simulations, confirmed by MR thermometry and B 1+ measurements in a phantom and in vivo temperature measurements. The safety studies demonstrated that the presence of the (31)P endorectal coil had no influence on the specific absorption rate levels and temperature distribution of the external eight-channel (1)H array coil. To stay within a 10 g averaged local specific absorption rate of 10 W/kg, a maximum time-averaged input power of 33 W for the (1)H array coil was allowed. For transmitting with the (31)P endorectal coil, our safety limit of less than 1°C temperature increase in vivo during a 15-min MR spectroscopic imaging experiment was reached at a time-averaged input power of 1.9 W. With this power setting, a second in vivo measurement was performed on a healthy volunteer. Using adiabatic excitation, 3D (31)P MR spectroscopic imaging produced spectra from the entire prostate in 18 min with a spatial resolution of 4 cm(3). The spectral resolution enabled the separate detection of phosphocholine, phosphoethanolamine, inorganic phosphate, and other metabolites that could play an important role in the characterization of prostate cancer.
Asunto(s)
Biomarcadores de Tumor/análisis , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Fósforo/análisis , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Adulto , Estudios de Factibilidad , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Proper delineation of gliomas using contrast-enhanced magnetic resonance imaging (CE-MRI) poses a problem in neuro-oncology. The blood brain barrier (BBB) in areas of diffuse-infiltrative growth may be intact, precluding extravasation and subsequent MR-based detection of the contrast agent gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA). Treatment with antiangiogenic compounds may further complicate tumor detection as such compounds can restore the BBB in angiogenic regions. The increasing number of clinical trials with antiangiogenic compounds for treatment of gliomas calls for the development of alternative imaging modalities. Here we investigated whether CE-MRI using ultrasmall particles of iron oxide (USPIO, Sinerem) as blood pool contrast agent has additional value for detection of glioma in the brain of nude mice. We compared conventional T1-weighted Gd-DTPA-enhanced MRI to T2*-weighted USPIO-enhanced MRI in mice carrying orthotopic U87 glioma, which were either or not treated with the antiangiogenic compound vandetanib (ZD6474, ZACTIMA). In untreated animals, vessel leakage within the tumor and a relatively high tumor blood volume resulted in good MRI visibility with Gd-DTPA- and USPIO-enhanced MRI, respectively. Consistent with previous findings, vandetanib treatment restored the BBB in the tumor vasculature, resulting in loss of tumor detectability in Gd-DTPA MRI. However, due to decreased blood volume, treated tumors could be readily detected in USPIO-enhanced MRI scans. Our findings suggest that Gd-DTPA MRI results in overestimation of the effect of antiangiogenic therapy of glioma and that USPIO-MRI provides an important complementary diagnostic tool to evaluate response to antiangiogenic therapy of these tumors.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/diagnóstico , Medios de Contraste , Glioma/diagnóstico , Hierro , Imagen por Resonancia Magnética , Óxidos , Piperidinas/farmacología , Quinazolinas/farmacología , Administración Oral , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Dextranos , Óxido Ferrosoférrico , Gadolinio DTPA , Glioma/tratamiento farmacológico , Glioma/patología , Inmunohistoquímica , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microcirculación , Piperidinas/administración & dosificación , Valor Predictivo de las Pruebas , Quinazolinas/administración & dosificación , Trasplante HeterólogoRESUMEN
PURPOSE: To differentiate prostate carcinoma from healthy peripheral zone and central gland using quantitative dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging and two-dimensional (1)H MR spectroscopic imaging (MRSI) combined into one clinical protocol. MATERIALS AND METHODS: Twenty-three prostate cancer patients were studied with a combined DCE-MRI and MRSI protocol. Cancer regions were localized by histopathology of whole mount sections after radical prostatectomy. Pharmacokinetic modeling parameters, K(trans) and k(ep), as well as the relative levels of the prostate metabolites citrate, choline, and creatine, were determined in cancer, healthy peripheral zone (PZ), and in central gland (CG). RESULTS: K(trans) and k(ep) were higher (P < 0.05) in cancer and in CG than in normal PZ. The (choline + creatine)/citrate ratio was elevated in cancer compared to the PZ and CG (P < 0.05). While a (choline + creatine)/citrate ratio above 0.68 was found to be a reliable indicator of cancer, elevated K(trans) was only a reliable cancer indicator in the diagnosis of individual patients. K(trans) and (choline + creatine)/citrate ratios in cancer were poorly correlated (Pearson r(2) = 0.07), and thus microvascular and metabolic abnormalities may have complementary value in cancer diagnosis. CONCLUSION: The combination of high-resolution spatio-vascular information from dynamic MRI and metabolic information from MRSI has excellent potential for improved localization and characterization of prostate cancer in a clinical setting. J. Magn. Reson. Imaging 2004;20:279-287.
Asunto(s)
Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Neoplasias de la Próstata/diagnóstico , Anciano , Ácido Cítrico/metabolismo , Protocolos Clínicos , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Próstata/anatomía & histología , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugíaRESUMEN
The effects of creatine (Cr) absence in skeletal muscle caused by a deletion of guanidinoacetate methyltransferase (GAMT) were studied in a knockout mouse model by in vivo (31)P magnetic resonance (MR) spectroscopy. (31)P MR spectra of hindleg muscle of GAMT-deficient (GAMT-/-) mice showed no phosphocreatine (PCr) signal and instead showed the signal for phosphorylated guanidinoacetate (PGua), the immediate precursor of Cr, which is not normally present. Tissue pH did not differ between wild-type (WT) and GAMT-/- mice, while relative inorganic phosphate (P(i)) levels were increased in the latter. During ischaemia, PGua was metabolically active in GAMT-/- mice and decreased at a rate comparable to the decrease of PCr in WT mice. However, the recovery rate of PGua in GAMT-/- mice after ischaemia was reduced compared to PCr in WT mice. Saturation transfer measurements revealed no detectable flux from PGua to gamma-ATP, indicating severely reduced enzyme kinetics. Supplementation of Cr resulted in a rapid increase in PCr signal intensity until only this resonance was visible, along with a reduction in relative P(i) values. However, the PGua recovery rate after ischaemia did not change. Our results show that despite the absence of Cr, GAMT-/- mice can cope with mild ischaemic stress by using PGua for high energy phosphoryl transfer. The reduced affinity of creatine kinase (CK) for (P)Gua only becomes apparent during recovery from ischaemia. It is argued that absence of Cr causes the higher relative P(i) concentration also observed in animals lacking muscle CK, indicating an important role of the CK system in P(i) homeostasis.
Asunto(s)
Glicina/análogos & derivados , Glicina/metabolismo , Metiltransferasas/genética , Músculo Esquelético/metabolismo , Fosfocreatina/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Creatina/farmacología , Guanidinoacetato N-Metiltransferasa , Homeostasis/fisiología , Isquemia/metabolismo , Metiltransferasas/metabolismo , Ratones , Ratones Noqueados , Fenotipo , Fosforilación , Descanso/fisiologíaRESUMEN
Creatine kinases are important in maintaining cellular-energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine-like compounds. Herein we examine whether ablation of the cytosolic brain-type creatine kinase (B-CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B-CK (B-CK-/-) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra- and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr left arrow over right arrow ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B-CK-/- animals showed diminished open-field habituation. In the water maze, adult B-CK-/- mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24-month-old, aged B-CK-/- mice, on top of the age-related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole-induced seizures (creating a high-energy demand) was observed in B-CK-/- mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho-creatine shuttle provides compensation for the loss of B-CK in the brain. Our studies indicate a role for the creatine-phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B-CK can be compensated for by other systems in the versatile and robust metabolic-energy network of the brain.