ABSTRACT
OBJECTIVE: Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and ß-amyloid (Aß) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. METHODS: We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aß and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aß interact with amylin in either the pancreas or brain of these subjects. RESULTS: Cytoplasmic tau and Aß protein deposits were detected in pancreatic ß cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aß and tau in both the pancreas and hippocampus. INTERPRETATION: The presence of both tau and Aß inclusions in pancreatic ß cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539-551.
Subject(s)
Alzheimer Disease/metabolism , Diabetes Mellitus, Type 2/metabolism , Islet Amyloid Polypeptide/metabolism , Aged , Aged, 80 and over , Amyloid beta-Peptides/metabolism , Brain/metabolism , Case-Control Studies , Female , Humans , Male , Middle Aged , Pancreas/metabolism , Retrospective Studies , tau Proteins/metabolismABSTRACT
OBJECTIVES: To assess state and trait anger, adjusted by epilepsy type, seizure control, anxiety-depression status and quality of life, in patients treated with brivaracetam (BRV) from an open study. METHODS: We evaluated prospectively consecutive patients with partial onset seizures in an open-label study. Patients had 5 years or longer of epilepsy and were taking between 1 and 3 antiepileptic drugs. They were treated with BRV and compared with a control group selected from outpatients attending our epilepsy unit who met the following criteria: age ≥16 years and diagnosis of epilepsy with focal-onset seizures at least 1 year before inclusion in the study. The following tests were assessed: State-Trait Anger with the Expression Inventory-2, Hospital Anxiety and Depression Scale, and Quality of Life in Epilepsy Inventory. RESULTS: We recruited 39 patients, 17 treated with BRV and 22 with other drugs, including 13 with levetiracetam (LEV). Mean age was 47.3 years, 43.6% were men. Symptomatic cases, 66% and 52% temporal lobe epilepsy. Antiepileptic drug polytherapy was present in 82.1% of the cases (100% BRV vs 68.2% control group). Demographic and clinical characteristics, as well as Quality of Life in Epilepsy Inventory and Hospital Anxiety and Depression Scale scores were similar in both groups. When compared with the subgroup of LEV groups did not differ significantly on their Hospital Anxiety and Depression Scale scores. CONCLUSIONS: This small, open study suggests that BRV increases anger measures less than LEV in epilepsy patients. However, larger, blinded control studies are required to establish whether this apparent difference can be confirmed.
Subject(s)
Anger/drug effects , Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Epilepsy/psychology , Pyrrolidinones/therapeutic use , Adolescent , Adult , Aged , Cross-Sectional Studies , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: Natalizumab is a drug used in multiple sclerosis (MS) and its main side effect is the development of progressive multifocal leukoencephalopathy (PML). Since this is potentially fatal or disabling, treatment must be stopped immediately if it is suspected, taking into account the possible later development of immune reconstitution syndrome or renewed exacerbation of MS. CASE REPORT: We report a case of initially asymptomatic PML within the context of treatment with natalizumab in a female patient with MS. High antibody titers to the John Cunningham virus (JCV) and over two years' treatment were established as risk factors. The polymerase chain reaction for the JCV in cerebrospinal fluid was negative in two determinations. The interval between the radiological diagnosis and the onset of the clinical features was two months. During the course of the disease, the patient developed immune reconstitution inflammatory syndrome and relapses, or renewed exacerbation, of her MS. She responded well after beginning treatment with fingolimod, once the PML had become stabilised. CONCLUSIONS: This case indicates the importance of close clinico-radiological monitoring in patients with MS treated with natalizumab, especially when they present risk factors for the development of PML, as well as its potential incidence on survival and final functional status.
TITLE: Leucoencefalopatia multifocal progresiva asociada al natalizumab: importancia de la resonancia magnetica en el diagnostico precoz.Introduccion. El natalizumab es un farmaco utilizado en la esclerosis multiple (EM), cuyo principal efecto adverso es el desarrollo de una leucoencefalopatia multifocal progresiva (LMP). Como esta es potencialmente mortal o discapacitante, el tratamiento debe suspenderse inmediatamente ante su sospecha, teniendo en cuenta el posible desarrollo posterior de un sindrome de reconstitucion inmune o rebrote de la EM. Caso clinico. Se describe un caso de LMP, inicialmente asintomatico, en el contexto del tratamiento con natalizumab en una paciente con EM. Como factores de riesgo se determinaron titulos altos de anticuerpos contra el virus John Cunningham (VJC) y mas de dos años de tratamiento. La reaccion en cadena de la polimerasa para el VJC en el liquido cefalorraquideo resulto negativa en dos determinaciones. El periodo entre el diagnostico radiologico y el inicio de la clinica fue de dos meses. Durante el curso de la enfermedad, la paciente desarrollo un sindrome inflamatorio de reconstitucion inmune y rebrotes de su EM. Presento una buena respuesta tras el inicio de tratamiento con fingolimod, una vez estabilizada la LMP. Conclusion. Este caso ilustra la importancia de una estrecha vigilancia clinicorradiologica en pacientes con EM tratados con natalizumab, sobre todo cuando presentan factores de riesgo para el desarrollo de LMP, asi como su potencial incidencia en la supervivencia y estado funcional final.
Subject(s)
Immunologic Factors/adverse effects , Leukoencephalopathy, Progressive Multifocal/chemically induced , Leukoencephalopathy, Progressive Multifocal/diagnosis , Magnetic Resonance Imaging , Natalizumab/adverse effects , Early Diagnosis , Female , Humans , Immunologic Factors/therapeutic use , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Natalizumab/therapeutic useABSTRACT
Introducción. El natalizumab es un fármaco utilizado en la esclerosis múltiple (EM), cuyo principal efecto adverso es el desarrollo de una leucoencefalopatía multifocal progresiva (LMP). Como ésta es potencialmente mortal o discapacitante, el tratamiento debe suspenderse inmediatamente ante su sospecha, teniendo en cuenta el posible desarrollo posterior de un síndrome de reconstitución inmune o rebrote de la EM. Caso clínico. Se describe un caso de LMP, inicialmente asintomático, en el contexto del tratamiento con natalizumab en una paciente con EM. Como factores de riesgo se determinaron títulos altos de anticuerpos contra el virus John Cunningham (VJC) y más de dos años de tratamiento. La reacción en cadena de la polimerasa para el VJC en el líquido cefalorraquídeo resultó negativa en dos determinaciones. El período entre el diagnóstico radiológico y el inicio de la clínica fue de dos meses. Durante el curso de la enfermedad, la paciente desarrolló un síndrome inflamatorio de reconstitución inmune y rebrotes de su EM. Presentó una buena respuesta tras el inicio de tratamiento con fingolimod, una vez estabilizada la LMP. Conclusión. Este caso ilustra la importancia de una estrecha vigilancia clinicorradiológica en pacientes con EM tratados con natalizumab, sobre todo cuando presentan factores de riesgo para el desarrollo de LMP, así como su potencial incidencia en la supervivencia y estado funcional final (AU)
Introduction. Natalizumab is a drug used in multiple sclerosis (MS) and its main side effect is the development of progressive multifocal leukoencephalopathy (PML). Since this is potentially fatal or disabling, treatment must be stopped immediately if it is suspected, taking into account the possible later development of immune reconstitution syndrome or renewed exacerbation of MS. Case report. We report a case of initially asymptomatic PML within the context of treatment with natalizumab in a female patient with MS. High antibody titers to the John Cunningham virus (JCV) and over two years treatment were established as risk factors. The polymerase chain reaction for the JCV in cerebrospinal fluid was negative in two determinations. The interval between the radiological diagnosis and the onset of the clinical features was two months. During the course of the disease, the patient developed immune reconstitution inflammatory syndrome and relapses, or renewed exacerbation, of her MS. She responded well after beginning treatment with fingolimod, once the PML had become stabilised. Conclusions. This case indicates the importance of close clinico-radiological monitoring in patients with MS treated with natalizumab, especially when they present risk factors for the development of PML, as well as its potential incidence on survival and final functional status (AU)
