Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand ¹¹C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for ¹¹C-PBR28, nine patient–control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29–63 for patients and 28–65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.

The study of patients with semantic dementia, a variant of frontotemporal lobar degeneration, has emerged over the last two decades as an important lesion model for studying human semantic memory. Although it is well-known that semantic dementia is associated with temporal lobe degeneration, controversy remains over whether the semantic deficit is due to diffuse temporal lobe damage, damage to only a sub-region of the temporal lobe or even less severe damage elsewhere in the brain. The manner in which the right and left temporal lobes contribute to semantic knowledge is also not fully elucidated. In this study we used unbiased imaging analyses to correlate resting cerebral glucose metabolism and behavioural scores in tests of verbal and non-verbal semantic memory. In addition, a region of interest analysis was performed to evaluate the role of severely hypometabolic areas. The best, indeed the only, strong predictor of semantic scores across a set of 21 patients with frontotemporal lobar degeneration with semantic impairment was degree of hypometabolism in the anterior fusiform region subjacent to the head and body of the hippocampus. As hypometabolism in the patients’ rostral fusiform was even more extreme than the abnormality in other regions with putative semantic relevance, such as the temporal poles, the significant fusiform correlations cannot be attributed to floor-level function in these other regions. More detailed analysis demonstrated more selective correlations: left anterior fusiform function predicted performance on two expressive verbal tasks, whereas right anterior fusiform metabolism predicted performance on a non-verbal test of associative semantic knowledge. This pattern was further supported by an additional behavioural study performed on a wider cohort of patients with semantic dementia, in which the patients with more extensive right-temporal atrophy (when matched on degree of naming deficit to a set of cases with more extensive left temporal atrophy) were significantly more impaired on the test of non-verbal semantics. Our preferred interpretation of this laterality effect involves differential strength of connectivity between different regions of a widespread semantic network in the human brain.

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

The Ingenuity TF PET-MRI is a newly released whole-body hybrid PET-MR imaging system with a Philips time-of-flight GEMINI TF PET and Achieva 3T X-series MRI system. Compared to PET-CT, modifications to the positron emission tomography (PET) gantry were made to avoid mutual system interference and deliver uncompromising performance which is equivalent to the standalone systems. The PET gantry was redesigned to introduce magnetic shielding for the photomultiplier tubes (PMTs). Stringent electromagnetic noise requirements of the MR system necessitated the removal of PET gantry electronics to be housed in the PET-MR equipment room. We report the standard NEMA measurements for the PET scanner. PET imaging and performance measurements were done at Geneva University Hospital as described in the NEMA Standards NU 2-2007 manual. The scatter fraction (SF) and noise equivalent count rate (NECR) measurements with the NEMA cylinder (20 cm diameter) were repeated for two larger cylinders (27 cm and 35 cm diameter), which better represent average and heavy patients. A NEMA/IEC torso phantom was used for overall assessment of image quality. The transverse and axial resolution near the center was 4.7 mm. Timing and energy resolution of the PET-MR system were measured to be 525 ps and 12%, respectively. The results were comparable to PET-CT systems demonstrating that the effect of design modifications required on the PET system to remove the harmful effect of the magnetic field on the PMTs was negligible. The absolute sensitivity of this scanner was 7.0 cps kBq(-1), whereas SF was 26%. NECR measurements performed with cylinders having three different diameters, and image quality measurements performed with IEC phantom yielded excellent results. The Ingenuity TF PET-MRI represents the first commercial whole-body hybrid PET-MRI system. The performance of the PET subsystem was comparable to the GEMINI TF PET-CT system using phantom and patient studies. It is conceived that advantages of hybrid PET-MRI will become more evident in the near future.

A cross-sectional group study of the effects of aging on brain metabolism as measured with (18)F-FDG-PET was performed using several different partial volume correction (PVC) methods: no correction (NoPVC), Meltzer (MZ), Müller-Gärtner (MG), and the symmetric geometric transfer matrix (SGTM) using 99 subjects aged 65-87years from the Harvard Aging Brain study. Sensitivity to parameter selection was tested for MZ and MG. The various methods and parameter settings resulted in an extremely wide range of conclusions as to the effects of age on metabolism, from almost no changes to virtually all of cortical regions showing a decrease with age. Simulations showed that NoPVC had significant bias that made the age effect on metabolism appear to be much larger and more significant than it is. MZ was found to be the same as NoPVC for liberal brain masks; for conservative brain masks, MZ showed few areas correlated with age. MG and SGTM were found to be similar; however, MG was sensitive to a thresholding parameter that can result in data loss. CSF uptake was surprisingly high at about 15% of that in gray matter. The exclusion of CSF from SGTM and MG models, which is almost universally done, caused a substantial loss in the power to detect age-related changes. This diversity of results reflects the literature on the metabolism of aging and suggests that extreme care should be taken when applying PVC or interpreting results that have been corrected for partial volume effects. Using the SGTM, significant age-related changes of about 7% per decade were found in frontal and cingulate cortices as well as primary visual and insular cortices.

Accurate γ-photon attenuation correction (AC) is essential for quantitative PET/MRI as there is no simple relation between MR image intensity and attenuation coefficients. Attenuation maps (μ-maps) can be derived by segmenting MR images and assigning attenuation coefficients to the compartments. Ultrashort-echo-time (UTE) sequences have been used to separate cortical bone and air, and the Dixon technique has enabled differentiation between soft and adipose tissues. Unfortunately, sequential application of these sequences is time-consuming and complicates image registration. Methods: A UTE triple-echo (UTILE) MRI sequence is proposed, combining UTE sampling for bone detection and gradient echoes for Dixon water–fat separation in a radial 3-dimensional acquisition (repetition time, 4.1 ms; echo times, 0.09/1.09/2.09 ms; field strength, 3 T). Air masks are derived mainly from the phase information of the first echo; cortical bone is segmented using a dual-echo technique. Soft-tissue and adipose-tissue decomposition is achieved using a 3-point Dixon-like decomposition. Predefined linear attenuation coefficients are assigned to classified voxels to generate MRI-based μ-maps. The results of 6 patients are obtained by comparing μ-maps, reciprocal sensitivity maps, reconstructed PET images, and brain region PET activities based on either CT AC, two 3-class MRI AC techniques, or the proposed 4-class UTILE AC. Results: Using the UTILE MRI sequence, an acquisition time of 214 s was achieved for the head-and-neck region with 1.75-mm isotropic resolution, compared with 164 s for a single-echo UTE scan. MRI-based reciprocal sensitivity maps show a high correlation with those derived from CT scans (R² = 0.9920). The same is true for PET activities (R² = 0.9958). An overall voxel classification accuracy (compared with CT) of 81.1% was reached. Bone segmentation is inaccurate in complex regions such as the paranasal sinuses, but brain region activities in 48 regions across 6 patients show a high correlation after MRI-based and CT-based correction (R² = 0.9956), with a regression line slope of 0.960. All overall correlations are higher and brain region PET activities more accurate in terms of mean and maximum deviations for the 4-class technique than for 3-class techniques. Conclusion: The UTILE MRI sequence enables the generation of MRI-based 4-class μ-maps without anatomic priors, yielding results more similar to CT-based results than can be obtained with 3-class segmentation only.