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OBJECTIVES: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. METHODS: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. RESULTS: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. CONCLUSIONS: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.
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Envejecimiento , Enfermedad de Alzheimer , Encéfalo , Disfunción Cognitiva , Envejecimiento Saludable , Imagen por Resonancia Magnética , Humanos , Masculino , Femenino , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Imagen por Resonancia Magnética/métodos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Envejecimiento/patología , Envejecimiento/fisiología , Persona de Mediana Edad , Biomarcadores , Anciano de 80 o más Años , Estudios RetrospectivosRESUMEN
Post-mortem T2 weighted images of canine heads were acquired at 1.5T, 3T, and 7T. This study aimed to (1) identify anatomical structures of the canine brain using an ultra-high-field magnetic resonance imaging (MRI) (7T) to help to facilitate their localization on high field MRI images (3T and 1.5T), where these structures may appear less well defined and delineated and (2) evaluate the visibility of canine brain anatomical structures on 1.5T, 3T, and 7T MRI images for optimizing clinical utility. Our hypothesis was that the provided subjective image quality comparison at different field strengths may offer a general baseline for canine brain anatomy and may help clinicians evaluate MRI options better. Six canine heads were examined with 1.5T, 3T, and 7T MRI scanners. T2-weighted images were acquired in three orthogonal planes at each field strength using a turbo spin-echo sequence. Fifty neuroanatomic structures were identified and evaluated on the 7T MR images; subsequently, those were found on the 3T and 45 out of the 50 structures were detected on the 1.5T imaging. The structures that were not able to be identified on the 1.5T imaging included the septum pellucidum, oculomotor nucleus, substantia nigra, claustrum, and thalamic nucleus griseus. Images acquired at 7T were subjective of higher spatial and contrast resolution. However, the ultra-high-field images were prone to artifacts at the interface between tissues of different magnetic properties. In conclusion, 3T MR imaging appears to be the best comprise for evaluating canine brain anatomy on MRI with fewer imaging artifacts.
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Encéfalo , Imagen por Resonancia Magnética , Animales , Autopsia , Encéfalo/diagnóstico por imagen , Perros , Neuroanatomía , Sustancia NegraRESUMEN
We report a case of anti-protein death 1-induced sarcoid-like reaction in a 63-year-old Caucasian male who was diagnosed with stage IV-M1a melanoma. He was initially treated with pembrolizumab monotherapy (Q3W) and had a complete response after 14 cycles. However, relapse was suspected 3 months later with appearance of hilar, mediastinal and hepatic hilar lymph nodes as well as a skin lesion. Biopsy of both the hilar lymph nodes and the skin lesion demonstrated sarcomatoid granulomatosis. Pembrolizumab was discontinued temporarily. While on F-FDG-PET/CT, all sarcoid-like lesions regressed in size and activity, a new hypermetabolic solitary skeletal lesion was detected in a lumbar vertebra, suspicious for metastasis. However, since the patient was asymptomatic, a watchful-waiting attitude was taken. During this period, a spontaneous and complete resolution of the metabolic activity was observed of the skeletal lesion. Until today, the patient remains in complete remission. Current case presents an atypical presentation and evolution of anti-PD-1-induced sarcoid-like reaction, illustrating the difficulty of differentiating it from disease progression. Before considering (re-)initiation of anti-melanoma therapy, a tissue biopsy of one of the suspected lesions may be performed to confirm diagnosis. Physicians treating patients with ICI should be aware of this difficulty and critically assess the nature of lesions suspect of progression in patients responding to ICI and presenting with a sarcoid-like reaction.
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Melanoma/complicaciones , Neoplasias Cutáneas/complicaciones , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS. METHODS: The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume. DISCUSSION: We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest. TRIAL REGISTRATION: Clinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.
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Bosentán/uso terapéutico , Circulación Cerebrovascular/efectos de los fármacos , Antagonistas de los Receptores de Endotelina/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Bélgica , Bosentán/efectos adversos , Método Doble Ciego , Antagonistas de los Receptores de Endotelina/efectos adversos , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/psicología , Prueba de Estudio Conceptual , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Resultado del Tratamiento , Ultrasonografía Doppler TranscranealAsunto(s)
Encéfalo/diagnóstico por imagen , Disección de la Arteria Carótida Interna/complicaciones , Trastornos Migrañosos/etiología , Enfermedades de la Lengua/etiología , Adulto , Atrofia/diagnóstico por imagen , Atrofia/etiología , Disección de la Arteria Carótida Interna/diagnóstico por imagen , Femenino , Humanos , Trastornos Migrañosos/diagnóstico por imagen , Enfermedades de la Lengua/diagnóstico por imagenRESUMEN
INTRODUCTION: Up to 60% of patients with metastatic melanoma develop melanoma brain metastasis (MBM) during the course of their disease. Surgery, radiosurgery (SRS), stereotactic radiotherapy (SRT), and whole-brain radiation therapy (WBRT) or combinations of these are commonly used local treatment modalities. Inhibitory monoclonal antibodies against the CTLA-4 and PD-1 immune checkpoint receptors significantly improved the survival of metastatic melanoma patients, including patients with MBM. This prolonged survival, and potentially also the immunostimulatory mechanisms, may expose patients to a higher risk for long-term complications such as focal postradiation necrosis of the brain (RNB). METHODS: We analyzed the incidence of pseudotumoral RNB in a single institution cohort of 142 melanoma patients that were prospectively followed after starting treatment with pembrolizumab in an expanded access program. RESULTS: Of the 142 patients, 43 (30.7%) patients had MBM at initiation pembrolizumab. Of these, 31 (72.1%) were treated with SRS, 8 (18.6%) with WBRT while 4 (9.3%) had no prior local therapy. Of patients treated with RT, 28 (71.1%) received RT before the initiation of pembrolizumab. 5 (12.8%) patients developed a new symptomatic pseudotumoral lesion at a median time of 11.15 months (range 8-46) after the RT. In all patients, the diagnosis of RNB was radiologically confirmed. The RNB was treated with corticosteroids in two patients, bevacizumab in two patients, and surgery in three symptomatic patients. The diagnosis was histologically confirmed in the patients treated with surgery. CONCLUSION: Melanoma patients with MBM treated with radiosurgery and showing a beneficial response to pembrolizumab are at risk for late RNB. In case of suspected isolated progression at the site of a previously irradiated MBM, the diagnosis of RNB should be considered.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Neoplasias Encefálicas/terapia , Encéfalo/patología , Irradiación Craneana/efectos adversos , Melanoma/terapia , Traumatismos por Radiación/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Traumatismos por Radiación/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system (CNS). Myelin basic protein (MBP), which is one of the main compounds of CNS myelin, appears to be hypercitrullinated in the brain of patients with MS. We hypothesized that MS is associated with an increased release of citrulline from the brain. METHODS: Twenty-five patients with MS, 25 controls without neurological disease (CwND) and 25 subjects with non-MS cerebral white matter lesions were included in this study. Groups were matched for age and gender. Clinical MS disability measures were recorded by means of Expanded Disability Status Scale (EDSS) scores and Multiple Sclerosis Severity Scores (MSSS). Citrulline was assessed in plasma obtained from an antecubital peripheral vein (PV) in all participants. Additional internal jugular vein (IJV) samples were examined in 10 patients with MS and 10 CwND. Twelve patients with MS underwent brain magnetic resonance imaging to determine total brain and T2 fluid-attenuated inversion recovery lesion volume. RESULTS: Median [IQR] PV citrulline levels were increased in patients with MS (50.47 [86.61] µM), as compared to CwND (33.58 [43.65] µM, Pâ¯=â¯0.042) and subjects with non-MS cerebral white matter lesions (32.41 [28.86] µM, Pâ¯=â¯0.006). Citrulline IJV levels and IJV/PV ratios were comparable between patients with MS and CwND. No significant correlations were found between PV citrulline levels and any of the clinical, nor radiological, disease measures. CONCLUSION: PV plasma levels of citrulline are elevated in patients with MS but this does not seem to result from an augmented release from the brain. Increased plasma citrulline may be a promising new biomarker in MS but the origin and significance need to be further elucidated.
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Citrulina/sangre , Esclerosis Múltiple/sangre , Adulto , Anciano , Arginina/sangre , Evaluación de la Discapacidad , Femenino , Glutamina/sangre , Humanos , Factores Inmunológicos/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/fisiopatología , Proteína Básica de Mielina/metabolismo , Óxido Nítrico/sangre , Estadísticas no ParamétricasRESUMEN
INTRODUCTION: As neurodegeneration is recognized as a major contributor to disability in multiple sclerosis (MS), brain atrophy quantification could have a high added value in clinical practice to assess treatment efficacy and disease progression, provided that it has a sufficiently low measurement error to draw meaningful conclusions for an individual patient. METHOD: In this paper, we present an automated longitudinal method based on Jacobian integration for measuring whole-brain and gray matter atrophy based on anatomical magnetic resonance images (MRI), named MSmetrix. MSmetrix is specifically designed to measure atrophy in patients with MS, by including iterative lesion segmentation and lesion filling based on FLAIR and T1-weighted MRI scans. RESULTS: MS metrix is compared with SIENA with respect to test-retest error and consistency, resulting in an average test-retest error on an MS data set of 0.13% (MS metrix) and 0.17% (SIENA) and a consistency error of 0.07% (MS metrix) and 0.05% (SIENA). On a healthy subject data set including physiological variability the test-retest is 0.19% (MS metrix) and 0.31% (SIENA). CONCLUSION: Therefore, we can conclude that MSmetrix could be of added value in clinical practice for the follow-up of treatment and disease progression in MS patients.
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Tyrosine kinase signaling through the vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor- α (PDGFR-α) and KIT cell surface receptors mediates neo-angiogenesis and contributes to cancer cell survival in recurrent anaplastic and low-grade glioma. Thirteen patients with temozolomide-refractory recurrent anaplastic or low-grade glioma were treated with sunitinib malate, a small-molecule tyrosine kinase inhibitor of the VEGFR, PDGFR, and KIT receptors, in combination with lomustine. The most frequent grade 3 and 4 adverse events were fatigue, thrombocytopenia, neutropenia and lymphopenia. The best objective tumor response by Response Assessment in Neuro-Oncology (RANO) criteria was one complete response, one unconfirmed partial response and three cases of stable disease. The median progression-free survival was 1.8 months (95% confidence interval=1.0-2.7 months) with 6-month progression-free survival of 15% (95% confidence interval=0-35%). The median overall survival was 6.7 months (95% confidence interval=0.7-12 months). The investigated combination regimen of sunitinib and lomustine is well-tolerated but insufficiently active to warrant further investigation in an unselected population of patients with temozolomide-refractory recurrent anaplastic and low-grade glioma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Dacarbazina/farmacología , Femenino , Estudios de Seguimiento , Glioma/mortalidad , Glioma/patología , Humanos , Indoles/administración & dosificación , Lomustina/administración & dosificación , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Pirroles/administración & dosificación , Sunitinib , Tasa de Supervivencia , TemozolomidaRESUMEN
OBJECTIVE: To investigate early changes in leukocyte subsets and autonomic function as predictors of the development of poststroke infections. METHODS: We assessed the time course of leukocyte subsets in the blood of 59 patients with acute ischemic stroke. We divided the patients into 2 groups: those who developed infections during the first 7 days after stroke onset and those who did not. We measured urinary norepinephrine and epinephrine concentrations and pulse rate variability indices within 24 hours of admission. RESULTS: We found that the number of circulating natural killer (NK) cells within the first hours after stroke was higher in stroke patients who developed infections (mean 435 cells/mL; 95% confidence interval [CI] 321-588) than in stroke patients who did not develop infections (mean 236 cells/mL; 95% CI 186-300; p = 0.001). This was followed by a decrease in all lymphocyte subsets from admission to day 1, varying between 22% and 40%, which was not seen in patients without poststroke infection (mean increase varied between 2% and 23%; all p < 0.005). In the group that developed infections, pulse rate variability revealed a decreased high frequency component. These findings all remained significant after adjustment for age and stroke volume. CONCLUSIONS: High circulating NK cell count within the first hours after ischemic stroke onset followed by a drop in all lymphocyte subsets identified patients who developed infections and may be caused by a sympathovagal imbalance with sympathetic overweight. These findings need to be validated in larger studies.
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Metastasis to the brain is a frequent event in patients with advanced melanoma. Despite treatment with neurosurgery, pancranial irradiation and high-precision conformal radiotherapy, the prognosis of patients suffering from melanoma brain metastasis has remained very poor. Ipilimumab is a new effective immunotherapy for the treatment of advanced melanoma and has demonstrated activity against brain metastases. We report three patients successfully treated with ipilimumab who subsequently developed focal necrosis of the brain following prior radiotherapy of their melanoma brain metastases. As new active systemic treatment options become available that improve the survival of patients with melanoma brain metastases, adequate diagnosis and management of the late sequela from radiation to the brain is likely to gain importance in the management of these patients.