Neuroimaging is increasingly used to supplement the clinical diagnosis of dementia with Lewy bodies (DLB) by showing reduced occipital metabolism and perfusion and reduced striatal dopaminergic innervation. We aimed to optimize the interpretation of 18 F-FDG PET images for differentiating DLB from Alzheimer disease (AD) and to compare the results with dopamine transporter imaging using 123 I-b-carbomethoxy-3ß-(4-iodophenyl)-tropane ( 123 I-b-CIT) SPECT. Methods: Fourteen subjects with a clinical diagnosis of DLB and 10 with AD underwent both 18 F-FDG PET and 123 I-b-CIT SPECT. Four DLB and 1 AD diagnoses were subsequently confirmed at autopsy. Diagnostic accuracy was calculated for visual interpretation by 3 readers of standard 3-plane and stereotactic surface projection 18 F-FDG PET images, receiver-operating-characteristic analysis of regional 18 F-FDG uptake, and a cutoff value for the striatal-to-occipital binding ratio of b-CIT defined by receiver-operating-characteristic analysis. Results: Visual interpretation of 3-plane 18 F-FDG PET images had a sensitivity of 83% and specificity of 93% for DLB, slightly higher than the results with the stereotactic surface projection images. Regionally, hypometabolism in the lateral occipital cortex had the highest sensitivity (88%), but relative preservation of the mid or posterior cingulate gyrus (cingulate island sign) had the highest specificity (100%). Region-of-interest analysis revealed that occipital hypometabolism and relative preservation of the posterior cingulate both had a sensitivity of 77% and specificity of 80%. b-CIT achieved 100% accuracy and greater effect size than did 18 F-FDG PET (Cohen d 5 4.1 vs. 1.9). Conclusion: Both 18 F-FDG PET and 123 I-b-CIT SPECT appear useful for the diagnosis of DLB, although the latter provides more robust results. The cingulate island sign may enhance the specificity of 18 F-FDG PET.

TSPO expression was dynamically upregulated during epileptogenesis, persisted in the chronic phase and correlated with microglia activation rather than reactive astrocytes. TSPO expression was correlating with spontaneous seizures and its high expression during the latent phase might possibly suggest being an important switching point in disease ontogenesis which could be further investigated by PET imaging.

The extracellular deposition of misfolded proteins is a characteristic of many debilitating age-related disorders. However, little is known about the specific mechanisms that act to suppress this process in vivo. Clusterin (CLU) is an extracellular chaperone that forms stable and soluble complexes with misfolded client proteins. Here we explore the fate of complexes formed between CLU and misfolded proteins both in vitro and in a living organism. We show that proteins injected into rats are cleared more rapidly from circulation when complexed with CLU as a result of their more efficient localization to the liver and that this clearance is delayed by pre-injection with the scavenger receptor inhibitor fucoidan. The CLU-client complexes were found to bind preferentially, in a fucoidan-inhibitable manner, to human peripheral blood monocytes and isolated rat hepatocytes and in the latter cell type were internalized and targeted to lysosomes for degradation. The data suggest, therefore, that CLU plays a key role in an extracellular proteostasis system that recognizes, keeps soluble, and then rapidly mediates the disposal of misfolded proteins.

BackgroundRecently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET.MethodsStatus epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (Vt) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio.ResultsAnimals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in Vt and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01).ConclusionBoth post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments.

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