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 (11)C-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 (11)C-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.

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 this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-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 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.