Association between clinical measures and florbetapir F18 PET neuroimaging in mild or moderate Alzheimer's disease dementia.

Clinical diagnosis of Alzheimer's disease (AD) is challenging, with 20% or more of patients misdiagnosed, even by expert clinicians. The authors conducted a retrospective, cross-sectional analysis comparing baseline neuropsychiatric and other clinical characteristics in 199 expert-diagnosed mild and moderate AD dementia patients participating in industry-sponsored clinical trials of an investigational therapy, where 18% lacked florbetapir positron emission tomography (PET) evidence of AD neuropathology. Significant differences were found only for cognition and ApoE ε4 status, but the large degree of score overlap would preclude using these measures to predict AD misdiagnosis. This study highlights the value of amyloid PET when evaluating patients with seemingly typical AD.

Evaluation of [¹²³I]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation.

PURPOSE: The purpose of this study was to assess the feasibility and sensitivity of the high-affinity translocator protein (TSPO) ligand [(123)I]-CLINDE in imaging TSPO changes in vivo and characterise and compare astroglial and TSPO changes in the cuprizone model of demyelination and remyelination in C57BL/6 mice. METHODS: C57BL/6 mice were fed with cuprizone for 4 weeks to induce demyelination followed by 2-4 weeks of standard diet (remyelination). Groups of mice were followed by in vivo single photon emission computed tomography (SPECT)/CT imaging using [(123)I]-CLINDE and uptake correlated with biodistribution, autoradiography, immunohistochemistry, immunofluorescence and real-time polymerase chain reaction (RT-PCR). RESULTS: The uptake of [(123)I]-CLINDE in the brain as measured by SPECT imaging over the course of treatment reflects the extent of the physiological response, with significant increases observed during demyelination followed by a decrease in uptake during remyelination. This was confirmed by autoradiography and biodistribution studies. A positive correlation between TSPO expression and astrogliosis was found and both activated astrocytes and microglial cells expressed TSPO. [(123)I]-CLINDE uptake reflects astrogliosis in brain structures such as corpus callosum, caudate putamen, medium septum and olfactory tubercle as confirmed by both in vitro and in vivo results. CONCLUSION: The dynamics in the cuprizone-induced astroglial and TSPO changes, observed by SPECT imaging, were confirmed by immunofluorescence, RT-PCR and autoradiography. The highly specific TSPO radioiodinated ligand CLINDE can be used as an in vivo marker for early detection and monitoring of a variety of neuropathological conditions using noninvasive brain imaging techniques.

Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning.

Degeneration of cholinergic neurons is a well known characteristic of Alzheimer's disease (AD). Two radioligands were studied in a rat model of cholinergic degeneration to evaluate their potential efficacy for molecular imaging of AD. Following specific cholinergic-cell immunolesioning with 192 IgG-saporin (SAP), ex vivo autoradiography was performed with (123)IBVM, a radioligand which targets the vesicular acetylcholine transporter (VAChT). Following the decay of (123)I, the same animals had in vitro autoradiography performed with (125)I-A-85380, a marker for nicotinic acetylcholine receptors (nAChRs). As expected significant, widespread decreases in (123)IBVM uptake were observed in SAP treated animals. Moderate but significant reductions in (125)I-A-85380 binding in the hippocampus (Hip) and cerebellum (Cbm) were also observed following SAP immunolesioning. The results with (123)IBVM confirm and extend previous work investigating the uptake of radioiodinated IBVM in this animal model. The results with (125)I-A-85380 are unique and are in contrast with work performed in this animal model with other nAChR radioligands, indicating the favourable properties of this radioligand for molecular imaging.

Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter.

The tricyclic tropane analogues (1S,3S,6R,10S)-(Z)-10-(benzoyloxymethyl)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0(3,7)]decane, 1, and (1S,3S,6R,10S)-(Z)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0(3,7)]decane-10-carboxylic acid methyl ester, 2, have been shown to be potent and selective serotonin transporter (SERT) ligands. They possess nanomolar affinity for the SERT (Ki = 0.06 nM and 1.8 nM respectively) and are suitable for radiolabelling using iodine-123. In the present study we prepared [(123)I]1 and [(123)I]2 from the appropriate tributylstannane precursors using acidic media with chloramine-T as the oxidising agent. The radiochemical yield obtained for [(123)I]1 varied between 50-60% while for [(123)I]2 the range was 65-80%. Both radioligands were obtained with radiochemical purity > 97% and specific activity estimated to be > 185 GBq/micromol. The biodistribution of [(123)I]1 demonstrated low degree of brain penetration at 5 min (0.14%ID/g) with a homogeneous distribution. The radioactivity cleared quickly from all brain regions with no preferential localization. In comparison, [(123)I]2 demonstrated on average a higher brain uptake at 5 min (0.5%ID/g). However the distribution of radioactivity was homogeneous and cleared to levels similar to [(123)I]1 at 1 hr post-injection. Pre-administration of citalopram failed to show any significant inhibition of [(123)I]2 uptake in the rat brain. The high lipophilicity of 1 and 2 (HPLC-derived log P(7.4) values of 6.41 and 4.25 respectively) and in vivo metabolism, seen by high thyroid uptake would explain the absence of any specific binding observed in the rat brain. In view of these results [(123)I]1 and [(123)I]2 do not appear to be suitable radioligands for in vivo studies of the SERT.

Consistent efficacy and safety of gemcitabine-paclitaxel in patients with metastatic breast cancer: a retrospective comparison of East Asian and global studies.

AIMS: The incidence of breast cancer in China is increasing at a rate greater than the global average. For treatment of metastatic breast cancer, a phase 3 trial of 529 patients (study JHQG) found that the combination of gemcitabine, a cytotoxic nucleoside analog, and paclitaxel, a taxane, significantly improved both overall and progression-free survival compared with paclitaxel monotherapy. As ethnic differences in the safety and efficacy of some anticancer therapies have been reported, this review provides oncologists treating East Asian patients with an evidence base to extrapolate results of the predominately Caucasian phase 3 JHQG study to their patients. METHODS: Three phase 2 studies in Chinese or Japanese patients with metastatic breast cancer are reviewed with reference to the global study JHQG. The results of pharmacokinetic, efficacy and safety analyses are descriptively compared between the global and Asian studies. RESULTS: Peak and total drug exposure values differed by less than 10% across the studies. Response rate, overall and progression-free survival values were similar, although values from the Asian studies for each of these parameters were slightly higher. Asian patients had higher rates of hematologic toxicities but lower rates of other adverse events. CONCLUSION: Examination of the data from three studies of the gemcitabine-paclitaxel combination reveals no clinically significant ethnic differences in efficacy and safety between East Asian patients and their global counterparts. Given its demonstrated efficacy and safety profile, the gemcitabine-paclitaxel regimen should be one of the standard treatments for East Asian patients with metastatic breast cancer.

PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy.

BACKGROUND: Recently, 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. METHODS: Status 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. RESULTS: Animals 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). CONCLUSION: Both 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.