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OBJECTIVE: To investigate the coexistence of anterograde and retrograde trans-synaptic axonal degeneration, and to explore the relationship between selective visual pathway damage and global brain involvement in longstanding multiple sclerosis (MS). METHODS: In this single-centre, cross-sectional study, patients with longstanding MS (N=222) and healthy controls (HC, N=62) were included. We analysed thickness of retinal layers (optical coherence tomography), damage within optic radiations (OR) (lesion volume and fractional anisotropy and mean diffusivity by diffusion tensor imaging) and atrophy of the visual cortex and that of grey and white matter of the whole-brain (structural MRI). Linear regression analyses were used to assess associations between the different components and for comparing patients with and without optic neuritis and HC. RESULTS: In patients with MS, an episode of optic neuritis (MSON) was significantly associated with decreased integrity of the ORs and thinning of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (GCC). Lesion volume in the OR was negatively associated with pRNFL and GCC thickness in patients without optic neuritis (MSNON). The pRNFL and GCC showed associations with integrity of the OR, thickness of the primary visual cortex (only in patients with MSON), and also with global white and grey matter atrophy. In HCs, no such relationships were demonstrated. INTERPRETATION: This study provides evidence for presence of bidirectional (both anterograde and retrograde) trans-synaptic axonal degeneration in the visual pathway of patients with MS. Additionally, thinning of the retinal pRNFL and GCC are related to global white and grey matter atrophy in addition to pathology of the visual pathway.
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Axones/patología , Esclerosis Múltiple/patología , Degeneración Nerviosa/patología , Sinapsis/patología , Vías Visuales/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Atrofia , Encéfalo/patología , Estudios de Cohortes , Imagen de Difusión Tensora , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
OBJECTIVE: Trans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent trans-synaptic axonal degeneration takes place within the visual pathway in multiple sclerosis (MS). METHODS: A single-centre study, including patients with long-standing MS and healthy controls. Structural imaging of the brain (MRI) and retina (spectral-domain optical coherence tomography) were used to quantify the extent of atrophy of individual retinal layers and the primary and secondary visual cortex. Generalised estimation equations and multivariable regression analyses were used for comparisons. RESULTS: Following rigorous quality control (OSCAR-IB), data from 549 eyes of 293 subjects (230 MS, 63 healthy controls) were included. Compared with control data, there was a significant amount of atrophy of the inner retinal layers in MS following optic neuritis (ON) and also in absence of ON. For both scenarios, atrophy stopped at the level of the inner nuclear layer. In contrast, there was significant localised atrophy of the primary visual cortex and secondary visual cortex in MS following ON, but not in MS in absence of ON. INTERPRETATION: These data suggest that retrograde (trans-synaptic) axonal degeneration stops at the inner nuclear layer, a neuronal network capable of plasticity. In contrast, there seems to be no neuroplasticity of the primary visual cortex, rendering the structure vulnerable to anterograde (trans-synaptic) degeneration.
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Esclerosis Múltiple/patología , Degeneración Nerviosa/patología , Vías Visuales/patología , Adulto , Anciano , Anciano de 80 o más Años , Atrofia , Encéfalo/patología , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Retina/patología , Tomografía de Coherencia ÓpticaRESUMEN
INTRODUCTION: Atrophy of the spinal cord is known to occur in multiple sclerosis (MS). The mean upper cervical cord area (MUCCA) can be used to measure this atrophy. Currently, several (semi-)automated methods for MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking. METHODS: Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region. First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3â¯T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A). Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3â¯T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations. RESULTS: In dataset A, MUCCA differed between MR machines (pâ¯<â¯0.001) and methods (pâ¯<â¯0.001) used, but not between scan sessions. With respect to MUCCA values, Xinapse JIM showed the highest within-scanner reproducibility (ICC absolute agreementâ¯=â¯0.995) while Xinapse JIM and SCT-PropSeg showed the highest between-scanner robustness (ICC consistencyâ¯=â¯0.981 and 0.976, respectively). Reproducibility of segmentations between scan sessions was highest in Xinapse JIM and SCT-PropSeg segmentations (median SIâ¯≥â¯0.921), with a significant main effect of method (pâ¯<â¯0.001), but not of MR machine or subject group. In dataset B, SI with manual outlines did not differ between patients with or without cervical lesions for any of the segmentation methods (pâ¯>â¯0.176). However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both pâ¯<â¯0.001). Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreementâ¯=â¯0.940 and median SIâ¯=â¯0.962). CONCLUSION: Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods. Cervical cord lesions do not affect MUCCA measurement performance.
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Médula Cervical/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Esclerosis Múltiple/diagnóstico por imagen , Neuroimagen/métodos , Adulto , Atrofia/diagnóstico por imagen , Atrofia/patología , Médula Cervical/patología , Imagen de Difusión Tensora/instrumentación , Imagen de Difusión Tensora/métodos , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Neuroimagen/instrumentación , Reproducibilidad de los Resultados , Programas InformáticosRESUMEN
BACKGROUND AND PURPOSE: Spinal cord atrophy is a common and clinically relevant characteristic in multiple sclerosis. We aimed to perform a multicenter validation study of mean upper cervical cord area measurements in patients with multiple sclerosis and healthy controls from head MR images and to explore the effect of gadolinium administration on mean upper cervical cord area measurements. MATERIALS AND METHODS: We recruited 97 subjects from 3 centers, including 60 patients with multiple sclerosis of different disease types and 37 healthy controls. Both cervical cord and head 3D T1-weighted images were acquired. In 11 additional patients from 1 center, head images before and after gadolinium administration and cervical cord images after gadolinium administration were acquired. The mean upper cervical cord area was compared between cervical cord and head images by using intraclass correlation coefficients (ICC) for both consistency (ICCconsist) and absolute (ICCabs) agreement. RESULTS: There was excellent agreement of mean upper cervical cord area measurements from head and cervical cord images in the entire group (ICCabs = 0.987) and across centers and disease subtypes. The mean absolute difference between the mean upper cervical cord area measured from head and cervical cord images was 2 mm(2) (2.3%). Additionally, excellent agreement was found between the mean upper cervical cord area measured from head images with and without gadolinium administration (ICCabs = 0.991) and between the cervical cord and head images with gadolinium administration (ICCabs = 0.992). CONCLUSIONS: Excellent agreement between mean upper cervical cord area measurements on head and cervical cord images was observed in this multicenter study, implying that upper cervical cord atrophy can be reliably measured from head images. Postgadolinium head or cervical cord images may also be suitable for measuring mean upper cervical cord area.
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Médula Cervical/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagen , Adulto , Anciano , Atrofia , Médula Cervical/patología , Medios de Contraste , Evaluación de la Discapacidad , Femenino , Gadolinio , Cabeza , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND AND PURPOSE: Immune therapy against amyloid-ß appears to be a promising target in Alzheimer disease. However, a dose-related risk for ARIA on FLAIR images thought to represent parenchymal vasogenic edema or sulcal effusion (termed "ARIA-E"), has been observed in clinical trials. To assess the intensity of ARIA-E presentation, an MR imaging scale that is both reproducible and easily implemented would assist in monitoring and evaluating this adverse event. MATERIALS AND METHODS: On the basis of a review of existing cases from a phase II bapineuzumab study, a scale was constructed with a 6-point score for the 6 regions on each side of the brain (range, 0-60). Scores would be obtained for both parenchymal and sulcal hyperintensities and frequently co-occurring gyral swelling. Inter-rater reliability between 2 neuroradiologists was evaluated in 20 patients, 10 with known ARIA-E and 10 without, by using the intraclass correlation coefficient. RESULTS: The 2 raters had excellent agreement in the identification of ARIA-E cases. A high inter-rater agreement was observed for scores of parenchymal hyperintensity (ICC = 0.83; 95% CI, 48-96) and sulcal hyperintensity (ICC = 0.89; 95% CI, 63-97) and for the combined scores of the 2 ARIA-E findings (ICC = 0.89; 95% CI, 62-97). Gyral swelling scores were observed to have lower inter-rater agreement (ICC = 0.54; 95% CI, -0.06-0.86). CONCLUSIONS: The proposed rating scale provides a reliable and easily implemented instrument to grade ARIA-E imaging findings. We currently do not recommend including swelling.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Edema Encefálico/inducido químicamente , Edema Encefálico/patología , Angiopatía Amiloide Cerebral/patología , Imagen por Resonancia Magnética/métodos , Efusión Subdural/inducido químicamente , Efusión Subdural/patología , Anciano , Algoritmos , Angiopatía Amiloide Cerebral/complicaciones , Angiopatía Amiloide Cerebral/tratamiento farmacológico , Femenino , Humanos , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
We show that the previously described alloantisera Ond and Mart, which recognize the alloantigens Ond(a) and Mart(a), react with polymorphic variants of alpha L and alpha M subunits of the beta 2 integrin family (CD11a and CD11b molecules). This was shown by testing the alloantisera in a monoclonal antibody-specific immobilization of leukocyte antigens, immunoprecipitation, and immunofluorescence assay against cells from normal donors and from patients with leukocyte adhesion deficiency (beta 2 intergrin deficient). To elucidate the molecular basis of the Ond(a) and Mart(a) alloantigens, RNA was isolated from mononuclear leukocytes derived from individuals of known serologic phenotype. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the entire coding region of the alpha L and alpha M mRNAs. The Ond(a) antigen was found to be due to a G2466C substitution in the DNA coding for the alpha L subunit, which predicts an Arg766Thr amino-acid polymorphism. The Mart(a) antigen was also found to be due to a single nucleotide substitution (G302A) in the DNA coding for the alpha M subunit, which predicts an Arg61His amino acid polymorphism. Using allele-specific restriction enzyme analysis, the association between point mutations and phenotypes was confirmed. The localization of these alloantigens on integrin molecules further illustrates the polymorphic nature of this class of proteins. Whether the polymorphisms influence the adhesive capacity of the leukocyte integrins remains to be investigated.