Validity and value of metabolic connectivity in mouse models of ß-amyloid and tauopathy.

Among functional imaging methods, metabolic connectivity (MC) is increasingly used for investigation of regional network changes to examine the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) or movement disorders. Hitherto, MC was mostly used in clinical studies, but only a few studies demonstrated the usefulness of MC in the rodent brain. The goal of the current work was to analyze and validate metabolic regional network alterations in three different mouse models of neurodegenerative diseases (ß-amyloid and tau) by use of 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) imaging. We compared the results of FDG-µPET MC with conventional VOI-based analysis and behavioral assessment in the Morris water maze (MWM). The impact of awake versus anesthesia conditions on MC read-outs was studied and the robustness of MC data deriving from different scanners was tested. MC proved to be an accurate and robust indicator of functional connectivity loss when sample sizes ≥12 were considered. MC readouts were robust across scanners and in awake/ anesthesia conditions. MC loss was observed throughout all brain regions in tauopathy mice, whereas ß-amyloid indicated MC loss mainly in spatial learning areas and subcortical networks. This study established a methodological basis for the utilization of MC in different ß-amyloid and tau mouse models. MC has the potential to serve as a read-out of pathological changes within neuronal networks in these models.

Long-term outcome of patients with WHO Grade III and IV gliomas treated by fractionated intracavitary radioimmunotherapy.

OBJECT: The aim in this study was to present long-term results regarding overall survival (OS), adverse effects, and toxicity following fractionated intracavitary radioimmunotherapy (RIT) with iodine-131- or yttrium-90-labeled anti-tenascin monoclonal antibody ((131)I-mAB or (90)Y-mAB) for the treatment of patients with malignant glioma. METHODS: In 55 patients (15 patients with WHO Grade III anaplastic astrocytoma [AA] and 40 patients with WHO Grade IV glioblastoma multiforme [GBM]) following tumor resection and conventional radiotherapy, radioimmunoconjugate was introduced into the postoperative resection cavity. Patients received 5 cycles of (90)Y-mAB (Group A, average dose 18 mCi/cycle), 5 cycles of (131)I-mAB (Group B, average dose 30 mCi/cycle), or 3 cycles of (131)I-mAB (Group C, 50, 40, and 30 mCi). RESULTS: Median OS of patients with AA was 77.2 months (95% CI 30.8 to > 120). Five AA patients (33%) are currently alive, with a median observation time of 162.2 months. Median OS of all 40 patients with GBM was 18.9 months (95% CI 15.8-25.3), and median OS was 25.3 months (95% CI18-30) forthose patients treated with the (131)I-mAB. Three GBM patients are currently alive. One-, 2-, and 3-year survival probabilities were 100%, 93.3%, and 66.7%, respectively, for AA patients and 82.5%, 42.5%, and 15.9%, respectively, for GBM patients. Restratification of GBM patients by recursive partitioning analysis (RPA) Classes III, IV, and V produced median OSs of 31.1, 18.9, and 14.5 months, respectively (p = 0.004), which was higher than expected. Multivariate analysis confirmed the role of RPA class, age, and treatment in predicting survival. No Grade 3 or 4 hematological, nephrologic, or hepatic toxic effects were observed; 4 patients developed Grade 3 neurological deficits. Radiological signs of radionecrosis were observed in 6 patients, who were all responding well to steroids. CONCLUSIONS: Median OS of GBM and AA patients treated with (131)I-mABs reached 25.3 and 77.2 months, respectively, thus markedly exceeding that of historical controls. Adverse events remained well controllable with the fractionated dosage regimen.