RESUMEN
OBJECTIVE: Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface-in" process of injury suggesting progressive biology may begin. METHODS: We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation-based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. RESULTS: Twenty-seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow-up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface-in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44-4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12-0.54, p = 0.0021). INTERPRETATION: Our results suggest that a multiple sclerosis disease-specific surface-in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340-351.
Asunto(s)
Esclerosis Múltiple/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Enfermedades Autoinmunes Desmielinizantes SNC/diagnóstico por imagen , Enfermedades Autoinmunes Desmielinizantes SNC/patología , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/patología , Tamaño de los Órganos , Tálamo/patologíaRESUMEN
Brain volume change measured from magnetic resonance imaging (MRI) provides a widely used and useful in vivo measure of irreversible tissue loss. These measurements, however, can be influenced by reversible factors such as shifts in brain water content. Given the strong effect of water on T2 relaxation, we investigated whether an estimate of T2 relaxation time would correlate with brain volume changes induced by physiologically manipulating hydration status. We used a clinically feasible estimate of T2 ("pseudo-T2") computed from a dual turbo spin-echo MRI sequence and correlated pseudo-T2 changes to percent brain volume changes in 12 healthy subjects after dehydration overnight (16-hour thirsting) and rehydration (drinking 1.5 L of water). We found that the brain volume significantly increased between the dehydrated and rehydrated states (mean brain volume change = 0.36%, p = 0.0001) but did not change significantly during the dehydration interval (mean brain volume change = 0.04%, p = 0.57). The changes in brain volume and pseudo-T2 significantly correlated with each other, with marginal and conditional correlations (R (2)) of 0.44 and 0.65, respectively. Our results show that pseudo-T2 may be used in conjunction with the measures of brain volume to distinguish reversible water fluctuations and irreversible brain tissue loss (atrophy) and to investigate disease mechanisms related to neuro-inflammation, e.g., in multiple sclerosis, where edema-related water fluctuations may occur with disease activity and anti-inflammatory treatment.
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Encéfalo/patología , Deshidratación/patología , Fluidoterapia , Imagen por Resonancia Magnética/métodos , Relajación , Adulto , Atrofia/metabolismo , Atrofia/patología , Encéfalo/metabolismo , Deshidratación/metabolismo , Femenino , Fluidoterapia/métodos , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/fisiología , Relajación/fisiología , Factores de TiempoRESUMEN
Clinical investigation of autologous hematopoietic stem cell transplantation (HSCT) as therapy for multiple sclerosis (MS) has been ongoing for over a decade. While several phase II studies have been finalized or are in progress, no definitive prospective randomized studies comparing HSCT versus alternative therapies for MS have been completed. In this conference report of North American and European experts who are involved in the care of MS patients, including neurologists and HSCT physicians, and representatives of the Center for International Blood and Marrow Transplant Research (CIBMTR) and European Group for Blood and Marrow Transplantation (EBMT), we (1) critically review progress to date in HSCT for MS; (2) describe current registry based projects including long-term follow-up studies in HSCT for MS and harmonization of the MS disease-specific research forms that will be used in future by both databases; (3) discuss challenges in study design for a prospective randomized clinical trial of HSCT versus alternative therapy for MS such as feasibility, and the importance of multidisciplinary clinical teams, need for a large sample size and duration of observation required for outcomes assessment; and (4) address future directions in HSCT therapy for MS. To undertake a definitive multicenter clinical trial in autologous HSCT for MS, it will be important to begin well in advance to assemble the team, evaluate proposals for study design, and consider options for the infrastructure and logistical support that will be needed. International collaboration, including partnership with the CIBMTR and EBMT, may be desirable and may in fact be critical for successful completion of a definitive comparative study.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Esclerosis Múltiple/terapia , Ensayos Clínicos Fase II como Asunto , Supervivencia sin Enfermedad , Estudios de Factibilidad , Estudios de Seguimiento , Humanos , Sistema de Registros , Trasplante Autólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: Early prediction of imminent failure during chemotherapy for malignant glioma has the potential to guide proactive alterations in treatment before frank tumor progression. We prospectively followed patients with recurrent malignant glioma receiving tamoxifen chemotherapy using proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to identify intratumoral metabolic changes preceding clinical and radiological failure. METHODS: We performed serial (1)H-MRSI examinations to assess intratumoral metabolite intensities in 16 patients receiving high-dose oral tamoxifen monotherapy for recurrent malignant glioma (WHO grade III or IV) as part of a phase II clinical trial. Patients were followed until treatment failure, death, or trial termination. RESULTS: Patients were officially classified as responders (7 patients) or non-responders (9 patients) 8 weeks into treatment. At 8 weeks, responders and non-responders had different intratumoral intensities across all measured metabolites except choline. Beyond 8 weeks, metabolite intensities remained stable in all responders, but changed again with approaching disease progression. Choline, lipid, choline/NAA, and lactate/NAA were significantly elevated (P < 0.02), while creatine (P < 0.04) was significantly reduced, compared to stabilized levels on average 4 weeks prior to failure. Lactate was significantly elevated (P = 0.036) fully 8 weeks prior to failure. In one patient who was still responding to tamoxifen at the conclusion of the trial, metabolite intensities never deviated from 8-week levels for the duration of follow-up. CONCLUSIONS: Characteristic global intratumoral metabolic changes, detectable on serial (1)H-MRSI studies, occur in response to chemotherapy for malignant glioma and may predict imminent treatment failure before actual clinical and radiological disease progression.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Espectroscopía de Resonancia Magnética , Tamoxifeno/uso terapéutico , Adulto , Anciano , Ácido Aspártico/análogos & derivados , Ácido Aspártico/efectos de los fármacos , Ácido Aspártico/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Colina/metabolismo , Creatina/efectos de los fármacos , Creatina/metabolismo , Progresión de la Enfermedad , Femenino , Glioma/metabolismo , Glioma/patología , Humanos , Ácido Láctico/metabolismo , Masculino , Persona de Mediana Edad , ProtonesRESUMEN
During the multicenter, phase III trial of intrathecal BDNF in ALS, we evaluated the neuronal marker N-acetylaspartate (NAA) as a surrogate marker of therapeutic efficacy using proton magnetic resonance spectroscopic imaging (MRSI) in a prospective and blinded manner. Selected subjects tolerated the study well without pump malfunction. The NAA to creatine (Cr) intensity ratio (NAA/Cr) was measured in the precentral and postcentral gyri, the superior parietal lobule, the supplementary motor area, and the premotor cortex. After 4.5+/-0.6 weeks treatment, NAA/Cr did not change significantly in any of the regions in the BDNF-treated group (n=5) compared to the placebo group (n=6). The lack of change in NAA correlated with the lack of clinical efficacy and supports the validity of NAA/Cr as a surrogate in this setting. MRSI is a feasible and safe method to evaluate intrathecal therapies in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Factor Neurotrófico Derivado del Encéfalo/administración & dosificación , Corteza Motora/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Adulto , Esclerosis Amiotrófica Lateral/metabolismo , Ácido Aspártico/análisis , Ácido Aspártico/química , Biomarcadores/análisis , Biomarcadores/química , Química Encefálica , Estudios de Factibilidad , Femenino , Humanos , Bombas de Infusión Implantables , Inyecciones Espinales , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Corteza Motora/química , Corteza Motora/metabolismo , Neuronas Motoras/química , Neuronas Motoras/metabolismo , Placebos , Estudios Prospectivos , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Proton MR spectroscopy has revealed impaired neuronal integrity in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). We hypothesized that the N-acetylaspartate (NAA)-creatine (Cr) ratios in the motor cortex and adjacent brain could reflect the therapeutic effectiveness of gabapentin (GBP) treatment in ALS. METHODS: Eight patients with ALS underwent MR spectroscopy before and 26.5 days +/- 8.8 after starting GBP. In 10 patients with ALS who were not treated with GBP, paired spectra were obtained 21.4 days +/- 7.2 apart. Fourteen healthy subjects underwent a single MR spectroscopic examination. The NAA/Cr ratio was measured in the precentral gyrus, the postcentral gyrus, the superior parietal lobule, the supplementary motor area, and the premotor cortex. RESULTS: The NAA/Cr ratio was decreased in the precentral and postcentral gyri of patients with ALS compared with healthy controls. In those with ALS, the change in the NAA/Cr ratio was not different between treated patients and untreated patients in any of the regions studied. CONCLUSION: No improvement in neuronal integrity was detected in motor and nonmotor cerebral regions after GBP treatment. This result agrees with that of prior investigations showing the equivocal clinical effectiveness of GBP for ALS and supports the validity of the NAA/Cr ratio as a surrogate of therapeutic effectiveness.