F. Turkheimer

[11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy

Microglia, the brain’s intrinsic macrophages, bind (R)-PK11195 when activated by neuronal injury. The authors used [11C](R)-PK11195 PET to localize in vivo microglial activation in patients with multiple system atrophy (MSA). Increased [11C](R)-PK11195 binding was primarily found in the dorsolateral prefrontal cortex, putamen, pallidum, pons, and substantia nigra, reflecting the known distribution of neuropathologic changes in MSA. Providing an indicator of disease activity, [11C](R)-PK11195 PET can thus be used to characterize the in vivo neuropathology of MSA.

Can target-to-pons ratio be used as a reliable method for the analysis of [ 11C]PIB brain scans?

RATIONALEn(11)C]PIB is the most widely used PET imaging marker for amyloid in dementia studies. In the majority of studies the cerebellum has been used as a reference region. However, cerebellar amyloid may be present in genetic Alzheimers (AD), cerebral amyloid angiopathy and prion diseases. Therefore, we investigated whether the pons could be used as an alternative reference region for the analysis of [(11)C]PIB binding in AD. The aims of the study were to: 1) Evaluate the pons as a reference region using arterial plasma input function and Logan graphical analysis of binding. 2) Assess the power of target-to-pons ratios to discriminate controls from AD subjects. 3) Determine the test-retest reliability in AD subjects. 4) Demonstrate the application of target-to-pons ratio in subjects with elevated cerebellar [(11)C]PIB binding.nnnMETHODSn12 sporadic AD subjects aged 65 ± 4.5 yrs with a mean MMSE 21.4 ± 4 and 10 age-matched control subjects had [(11)C]PIB PET with arterial blood sampling. Three additional subjects (two subjects with pre-symptomatic presenilin-1 mutation carriers and one probable familial AD) were also studied. Object maps were created by segmenting individual MRIs and spatially transforming the gray matter images into standard stereotaxic MNI space and then superimposing a probabilistic atlas. Cortical [(11)C]PIB binding was assessed with an ROI (region of interest) analysis. Parametric maps of the volume of distribution (V(T)) were generated with Logan analysis. Additionally, parametric maps of the 60-90 min target-to-cerebellar ratio (RATIO(CER)) and the 60-90 min target-to-pons ratio (RATIO(PONS)) were computed.nnnRESULTSnAll three approaches were able to differentiate AD from controls (p<0.0001, nonparametric Wilcoxon rank sum test) in the target regions with RATIO(CER) and RATIO(PONS) differences higher than V(T) with use of an arterial input function. All methods had a good reproducibility (intraclass correlation coefficient>0.83); RATIO(CER) performed best closely followed by RATIO(PONS). The two subjects with presenilin-1 mutations and the probable familial AD case showed no significant differences in cortical binding using RATIO(CER), but the RATIO(PONS) approach revealed higher [(11)C]PIB binding in cortex and cerebellum.nnnCONCLUSIONnThis study established 60-90 min target-to-pons RATIOs as a reliable method of analysis in [(11)C]PIB PET studies where cerebellum is not an appropriate reference region.

Strategies for the generation of parametric images of [11C]PIB with plasma input functions considering discriminations and reproducibility

Pittsburgh compound B or [11C]PIB is an amyloid imaging agent which shows a clear differentiation between subjects with Alzheimers disease (AD) and controls. However the observed signal difference in other forms of dementia such as dementia with Lewy bodies (DLB) is smaller, and mild cognitively impaired (MCI) subjects and some healthy elderly normals may show intermediate levels of [11C]PIB binding. The cerebellum, a commonly used reference region for non-specific tracer uptake in [11C]PIB studies in AD may not be valid in Prion disorders or monogenic forms of AD. The aim of this work was to: 1-compare methods for generating parametric maps of [11C]PIB retention in tissue using a plasma input function in respect of their ability to discriminate between AD subjects and controls and 2-estimate the test-retest reproducibility in AD subjects. 12 AD subjects (5 of which underwent a repeat scan within 6 weeks) and 10 control subjects had 90 minute [11C]PIB dynamic PET scans, and arterial plasma input functions were measured. Parametric maps were generated with graphical analysis of reversible binding (Logan plot), irreversible binding (Patlak plot), and spectral analysis. Between group differentiation was calculated using Students t-test and comparisons between different methods were made using p values. Reproducibility was assessed by intraclass correlation coefficients (ICC). We found that the 75 min value of the impulse response function showed the best group differentiation and had a higher ICC than volume of distribution maps generated from Logan and spectral analysis. Patlak analysis of [11C]PIB binding was the least reproducible.

In vivo imaging of translocator protein expression in gliomas by Positron Emission Tomography (PET).

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma.INTRODUCTION: Cortical mapping can maximize tumour resection whilst preserving eloquent cortex in glioma surgery. Direct cortical stimulation (DCS) during awake craniotomy remains the current ?gold standard?. Functional MRI (fMRI) presents an alternative but raises theoretical concerns relating to neurovascular de-coupling close to the tumour. Comparative studies are limited by difficulties in accurately recording the locations at which DCS is performed. We present the initial evaluation of a system to facilitate the use of commercial neuro-navigation technology to record DCS outcomes.nnMETHOD: Three patients underwent pre-operative neuropsychological assessment and motor / language fMRI on a Phillips 3T Achieva scanner. fMRI data was available for surgical planning but the surgeon was blinded during DCS to minimise bias. During awake craniotomy, a bipolar cortical stimulator was tracked using a BrainLab VectorVision system networked with a laptop using the VVLink interface. DCS was performed whilst motor and language function was assessed by a neuropsychologist and outcomes recorded by the surgeon using a panel of footswitches to control a custom logging module implemented within the Slicer software package.nnRESULTS: A mean of 103 unique data-points were recorded (range 73-136) with minimal additional operative time. Mean number of areas tested for language function at the highest required stimulation level was 51 (range 26-74). Mean distance to the nearest fMRI activation did not differ between positive and negative DCS (6.8 vs 6.1mm).nnCONCLUSION: Use of fMRI/neuro-navigation to record DCS outcomes is feasible and enables detailed study of the correlation between pre- and intra-operative techniques for cortical mapping.