Alzheimer's disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n ‫؍‬ 16) and patients with amnestic mild cognitive impairment (aMCI) (n ‫؍‬ 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of restingstate fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs.default mode network ͉ intrinsic brain activity ͉ mild cognitive impairment A lzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by progressive dementia and neuropsychiatric symptoms (1). AD is neuropathologically defined by tau pathology and amyloid aggregations (2). Tau pathology starts in regions of the medial temporal lobe (MTL) and is well correlated with cell loss and atrophy; amyloid deposition primarily affects distributed neocortical regions but is not especially prominent in the MTL (2, 3). Atrophy of the MTL is correlated with the degree of dementia and also the extent of temporoparietal hypometabolism; both results are assumed to reflect changes in cerebral connectivity, especially between the MTL and the neocortex (3-5). In non-human primates, prominent structural connectivity between the MTL and neocortical regions as well as broad neocortical hypometabolism after ablation of parts of the MTL were demonstrated (6, 7). Evidence for disrupted structural and functional connectivity (FC) further suggests that AD includes a disconnection syndrome (5, 8-10).Mild cognitive impairment (MCI) is a syndrome with cognitive decline greater than expected for an individual's age and educational level but not interfering notably with activities of daily living; prevalence of M...

177 Lu-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castrationresistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of 177 Lu-PSMA-617 in a large cohort of patients. Methods: One hundred forty-five patients (median age, 73 y; range, 43-88 y) with mCRPC were treated with 177 Lu-PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1-4 therapy cycles and an activity range of 2-8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician's report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline $ 50% from baseline to at least 2 wk after the start of RLT. Results: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2-30 wk). Nineteen patients died during the observation period. Grade 3-4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. Conclusion: The present retrospective multicenter study of 177 Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC.

This multicenter study examined 18 F-FDG PET measures in the differential diagnosis of Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). Methods: We examined the 18 F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals (''normals'' or NLs), 114 MCI, 199 AD, 98 FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxelbased comparison with generation of disease-specific patterns of cortical and hippocampal 18 F-FDG uptake that were then applied to characterize MCI. Results: Standardized diseasespecific PET patterns were developed that correctly classified 95% AD, 92% DLB, 94% FTD, and 94% NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. 18 F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. Conclusion: Standardized automated analysis of 18 F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia.

The aim of this (15)O-labelled H(2)O bolus positron emission tomography (PET) study was to analyse the hemispheric dominance of the vestibular cortical system. Therefore, the differential effects of caloric vestibular stimulation (right or left ear irrigation with warm water at 44 degrees C) on cortical and subcortical activation were studied in 12 right-handed and 12 left-handed healthy volunteers. Caloric irrigation induces a direction-specific sensation of rotation and nystagmus. Significant regional cerebral blood flow increases were found in a network within both hemispheres, including the superior frontal gyrus/sulcus, the precentral gyrus and the inferior parietal lobule with the supramarginal gyrus. These areas correspond best to the cortical ocular motor centres, namely the prefrontal cortex, the frontal eye field and the parietal eye field, known to be involved in the processing of caloric nystagmus. Furthermore, distinct temporo-parietal activations could be separated in the posterior part of the insula with the adjacent superior temporal gyrus, the inferior parietal lobule and precuneus. These areas fit best to the human homologues of multisensory vestibular cortex areas identified in the monkey and correspond to the parieto-insular vestibular cortex (PIVC), the visual temporal sylvian area (VTS) and areas 7 and 6. Further cortical activations were seen in the anterior insula, the inferior frontal gyrus and anterior cingulum. The subcortical activation pattern in the putamen, thalamus and midbrain is consistent with the organization of efferent ocular motor pathways. Cortical and subcortical activation of the described areas was bilateral during monaural stimulation, but predominant in the hemisphere ipsilateral to the stimulated ear and exhibited a significant right hemispheric dominance for vestibular and ocular motor structures in right-handed volunteers. Similarly, a significant left hemispheric dominance was found in the 12 left-handed volunteers. Thus, this PET study showed for the first time that cortical and subcortical activation by vestibular caloric stimulation depends (i) on the handedness of the subjects and (ii) on the side of the stimulated ear. Maximum activation was therefore found when the non-dominant hemisphere was ipsilateral to the stimulated ear, i.e. in the right hemisphere of right-handed subjects during caloric irrigation of the right ear and in the left hemisphere of left-handed subjects during caloric irrigation of the left ear. The localization of handedness and vestibular dominance in opposite hemispheres might conceivably indicate that the vestibular system and its hemispheric dominance, which matures earlier during ontogenesis, determine right- or left-handedness.