RESUMEN
Background T1-weighted MRI and quantitative longitudinal relaxation rate (R1) mapping have been used to evaluate gadolinium retention in the brain after gadolinium-based contrast agent (GBCA) administration. Whether MRI measures accurately reflect gadolinium regional distribution and concentration in the brain remains unclear. Purpose To compare gadolinium retention in rat forebrain measured with in vivo quantitative MRI R1 and ex vivo laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) mapping after gadobenate, gadopentetate, gadodiamide, or gadobutrol administration. Materials and Methods Adult female Sprague-Dawley rats were randomly assigned to one of five groups (eight per group) and administered gadobenate, gadopentetate, gadodiamide, gadobutrol (2.4 mmol/kg per week for 5 weeks), or saline (4.8 mL/kg per week for 5 weeks). MRI R1 mapping was performed at baseline and 1 week after the final injection to determine R1 and ΔR1. Postmortem brains from the same rats were analyzed with LA-ICP-MS elemental mapping to determine regional gadolinium concentrations. Student t tests were performed to compare results between GBCA and saline groups. Results Rats that were administered gadobenate showed gadolinium-related MRI ΔR1 in 39.5% of brain volume (ΔR1 = 0.087 second-1 ± 0.051); gadopentetate, 20.6% (ΔR1 = 0.069 second-1 ± 0.018); gadodiamide, 5.4% (ΔR1 = 0.055 second-1 ± 0.019); and gadobutrol, 2.2% (ΔR1 = 0.052 second-1 ± 0.041). Agent-specific gadolinium-related ΔR1 was detected in multiple forebrain regions (neocortex, hippocampus, dentate gyrus, thalamus, and caudate-putamen) in rats treated with gadobenate or gadopentetate, whereas rats treated with gadodiamide showed gadolinium-related ΔR1 in caudate-putamen. By contrast, LA-ICP-MS elemental mapping showed a similar regional distribution pattern of heterogeneous retained gadolinium in the forebrain of rats treated with gadobenate, gadopentetate, or gadodiamide, with the average gadolinium concentration of 0.45 µg · g-1 ± 0.07, 0.50 µg · g-1 ± 0.10, and 0.60 µg · g-1 ± 0.11, respectively. Low levels (0.01 µg · g-1 ± 0.00) of retained gadolinium were detected in the forebrain of gadobutrol-treated rats. Conclusion Differences in in vivo MRI longitudinal relaxation rate versus ex vivo elemental mass spectrometry measures of retained gadolinium in rat forebrains suggest that some forms of retained gadolinium may escape detection with MRI. © RSNA, 2022 Online supplemental material is available for this article.
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Gadolinio , Compuestos Organometálicos , Ratas , Femenino , Animales , Ratas Sprague-Dawley , Gadolinio DTPA , Medios de Contraste , Meglumina , Imagen por Resonancia Magnética/métodos , Encéfalo , Espectrometría de MasasRESUMEN
Background Gadolinium retention after repeated gadolinium-based contrast agent (GBCA) exposure has been reported in subcortical gray matter. However, gadolinium retention in the cerebral cortex has not been systematically investigated. Purpose To determine whether and where gadolinium is retained in rat and human cerebral cortex. Materials and Methods The cerebral cortex in Sprague-Dawley rats treated with gadopentetate dimeglumine (three doses over 4 weeks; cumulative gadolinium dose, 7.2 mmol per kilogram of body weight; n = 6) or saline (n = 6) was examined with antemortem MRI. Two human donors with repeated GBCA exposure (three and 15 doses; 1 and 5 months after exposure), including gadopentetate dimeglumine, and two GBCA-naive donors were also evaluated. Elemental brain maps (gadolinium, phosphorus, zinc, copper, iron) for rat and human brains were constructed by using laser ablation inductively coupled plasma mass spectrometry. Results Gadopentetate dimeglumine-treated rats showed region-, subregion-, and layer-specific gadolinium retention in the neocortex (anterior cingulate cortex: mean gadolinium concentration, 0.28 µg â g-1 ± 0.04 [standard error of the mean]) that was comparable (P > .05) to retention in the allocortex (mean gadolinium concentration, 0.33 µg â g-1 ± 0.04 in piriform cortex, 0.24 µg â g-1 ± 0.04 in dentate gyrus, 0.17 µg â g-1 ± 0.04 in hippocampus) and subcortical structures (0.47 µg â g-1 ± 0.10 in facial nucleus, 0.39 µg â g-1 ± 0.10 in choroid plexus, 0.29 µg â g-1 ± 0.05 in caudate-putamen, 0.26 µg â g-1 ± 0.05 in reticular nucleus of the thalamus, 0.24 µg â g-1 ± 0.04 in vestibular nucleus) and significantly greater than that in the cerebellum (0.17 µg â g-1 ± 0.03, P = .01) and white matter tracts (anterior commissure: 0.05 µg â g-1 ± 0.01, P = .002; corpus callosum: 0.05 µg â g-1 ± 0.02, P = .001; cranial nerve: 0.02 µg â g-1 ± 0.01, P = .004). Retained gadolinium colocalized with parenchymal iron. T1-weighted MRI signal intensification was not observed. Gadolinium retention was detected in the cerebral cortex, pia mater, and pia-ensheathed leptomeningeal vessels in two GBCA-exposed human brains but not in two GBCA-naive human brains. Conclusion Repeated gadopentetate dimeglumine exposure is associated with gadolinium retention in specific regions, subregions, and layers of cerebral cortex that are critical for higher cognition, affect, and behavior regulation, sensorimotor coordination, and executive function. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kanal in this issue.
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Corteza Cerebral/metabolismo , Medios de Contraste/farmacocinética , Gadolinio DTPA/farmacocinética , Administración Intravenosa , Adulto , Animales , Medios de Contraste/administración & dosificación , Femenino , Gadolinio DTPA/administración & dosificación , Humanos , Masculino , Espectrometría de Masas/métodos , Persona de Mediana Edad , Modelos Animales , Ratas , Ratas Sprague-DawleyRESUMEN
The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.
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Traumatismos en Atletas/complicaciones , Conmoción Encefálica/etiología , Traumatismos Craneocerebrales/complicaciones , Traumatismos Craneocerebrales/etiología , Tauopatías/etiología , Lesiones del Sistema Vascular/etiología , Potenciales de Acción/fisiología , Adolescente , Animales , Atletas , Encéfalo/patología , Proteínas de Unión al Calcio , Estudios de Cohortes , Simulación por Computador , Traumatismos Craneocerebrales/diagnóstico por imagen , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/fisiología , Hipocampo/fisiopatología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos , Modelos Neurológicos , Corteza Prefrontal/fisiopatología , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8A/metabolismo , Adulto JovenRESUMEN
Although concussion has been a subject of interest for centuries, this condition remains poorly understood. The mechanistic underpinnings and accepted definition of concussion remain elusive. To make sense of these issues, this article presents a brief history of concussion studies, detailing the evolution of motivations and experimental conclusions over time. Interest in concussion as a subject of scientific inquiry has increased with growing concern about the long-term consequences of mild traumatic brain injury (TBI). Although concussion is often associated with mild TBI, these conditions-the former a neurological syndrome, the latter a neurological event-are distinct, both mechanistically and pathobiologically. Modern research primarily focuses on the study of the biomechanics, pathophysiology, potential biomarkers and neuroimaging to distinguish concussion from mild TBI. In addition, mild TBI and concussion outcomes are influenced by age, sex, and genetic differences in people. With converging experimental objectives and methodologies, future concussion research has the potential to improve clinical assessment, treatment, and preventative measures.