Severe infusion reactions to brentuximab vedotin in two patients with Hodgkin lymphoma previously treated with allogeneic stem cell transplantation.

Brentuximab vendotin is a monoclonal antibody approved in August 2011 for use in patients with Hodgkin disease and a rare systemic lymphoma known as anaplastic large cell lymphoma. Brentuximab is approved in patients with Hodgkin disease who have failed autologous transplantation or after failure of at least two prior multi-agent chemotherapy regimens but has not been studied following allogeneic transplantation. Four patients with relapsed Hodgkin disease have been treated at our institution with at least two doses of brentuximab vendotin. Two patients have experienced significant infusion reactions on multiple occasions, and two patients have tolerated the infusions well. During phase 2 trials, there were no reports of Grade 3 or 4 infusion-related reactions. Both patients with reactions had relapsed following allogeneic stem cell transplants, while neither of the patients who tolerated the infusions had undergone transplantation. We report our experience with brentuximab vendotin-treated patients at our institution, focusing on the two post-allogeneic patients who experienced multiple significant infusion reactions. This report evaluates possible mechanisms behind their reactions, including previous allogeneic stem cell transplantation as a likely precipitating factor.

A Scoping Review of Urban Planning Decision Support Tools and Processes That Account for the Health, Environment, and Economic Benefits of Trees and Greenspace.

Compelling evidence shows that trees and greenspaces positively impact human well-being and the environment and offer economic benefits. Nevertheless, there exists a knowledge gap regarding the extent to which this evidence is efficiently incorporated into existing urban planning decision-making processes. This scoping review identified the extent to which urban planning decision-making frameworks, models, and tools consider the health, environmental, and economic benefits of trees and greenspace. Out of 28 reviewed studies, 11 (39%) reported on frameworks, models, and tools that take into account the health, environmental, and economic dimensions of trees and greenspace. Additionally, seven studies provided comprehensive coverage of at least one of the three key dimensions. However, none of the decision support frameworks, models, or tools comprehensively integrated all three dimensions, with only two tools (7%) scoring above 50% (five or more out of nine) in terms of comprehensiveness. This review highlights the urgent need to incorporate the true economic and monetary values of the health and environmental benefits of trees and greenspace to inform urban development decision making.

Traumatic Brain Injury, Sleep, and Melatonin-Intrinsic Changes with Therapeutic Potential.

Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity in the United States and is associated with numerous chronic sequelae long after the point of injury. One of the most common long-term complaints in patients with TBI is sleep dysfunction. It is reported that alterations in melatonin follow TBI and may be linked with various sleep and circadian disorders directly (via cellular signaling) or indirectly (via free radicals and inflammatory signaling). Work over the past two decades has contributed to our understanding of the role of melatonin as a sleep regulator and neuroprotective anti-inflammatory agent. Although there is increasing interest in the treatment of insomnia following TBI, a lack of standardization and rigor in melatonin research has left behind a trail of non-generalizable data and ambiguous treatment recommendations. This narrative review describes the underlying biochemical properties of melatonin as they are relevant to TBI. We also discuss potential benefits and a path forward regarding the therapeutic management of TBI with melatonin treatment, including its role as a neuroprotectant, a somnogen, and a modulator of the circadian rhythm.

MRI assessment of cerebral perfusion in clinical trials.

Neurodegenerative mechanisms affect the brain through a variety of processes that are reflected as changes in brain structure and physiology. Although some biomarkers for these changes are well established, others are at different stages of development for use in clinical trials. One of the most challenging biomarkers to harmonize for clinical trials is cerebral blood flow (CBF). There are several magnetic resonance imaging (MRI) methods for quantifying CBF without the use of contrast agents, in particular arterial spin labeling (ASL) perfusion MRI, which has been increasingly applied in clinical trials. In this review, we present ASL MRI techniques, including strategies for implementation across multiple imaging centers, levels of confidence in assessing disease progression and treatment effects, and details of image analysis.

Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis.

Atherosclerosis is driven by the expansion of cholesterol-loaded 'foamy' macrophages in the arterial intima. Factors regulating foamy macrophage differentiation and survival in plaque remain poorly understood. Here we show, using trajectory analysis of integrated single-cell RNA sequencing data and a genome-wide CRISPR screen, that triggering receptor expressed on myeloid cells 2 (Trem2) is associated with foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up oxidized low-density lipoprotein (oxLDL). Myeloid-specific deletion of Trem2 showed an attenuation of plaque progression, even when targeted in established atherosclerotic lesions, and was independent of changes in circulating cytokines, monocyte recruitment or cholesterol levels. Mechanistically, we link Trem2-deficient macrophages with a failure to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. Overall, we identify Trem2 as a regulator of foamy macrophage differentiation and atherosclerotic plaque growth and as a putative therapeutic target for atherosclerosis.

Characterizing the specificity and cooperation of aminopeptidases in the cytosol and endoplasmic reticulum during MHC class I antigen presentation.

Many MHC class I-binding peptides are generated as N-extended precursors during protein degradation by the proteasome. These peptides can subsequently be trimmed by aminopeptidases in the cytosol and/or the endoplasmic reticulum (ER) to produce mature epitope. However, the contribution and specificity of each of these subcellular compartments in removing N-terminal amino acids for Ag presentation is not well defined. In this study, we investigated this issue for antigenic precursors that are expressed in the cytosol. By systematically varying the N-terminal flanking sequences of peptides, we show that the amino acids upstream of an epitope precursor are a major determinant of the amount of Ag presentation. In many cases, MHC class I-binding peptides are produced through sequential trimming in the cytosol and ER. Trimming of flanking residues in the cytosol contributes most to sequences that are poorly trimmed in the ER. Because N-terminal trimming has different specificity in the cytosol and ER, the cleavage of peptides in both of these compartments serves to broaden the repertoire of sequences that are presented.

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer's disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.

Novel Fast Marching for Automated Segmentation of the Hippocampus (FMASH): method and validation on clinical data.

With hippocampal atrophy both a clinical biomarker for early Alzheimer's Disease (AD) and implicated in many other neurological and psychiatric diseases, there is much interest in the accurate, reproducible delineation of this region of interest (ROI) in structural MR images. Here we present Fast Marching for Automated Segmentation of the Hippocampus (FMASH): a novel approach using the Sethian Fast Marching (FM) technique to grow a hippocampal ROI from an automatically-defined seed point. Segmentation performance is assessed on two separate clinical datasets, utilising expert manual labels as gold standard to quantify Dice coefficients, false positive rates (FPR) and false negative rates (FNR). The first clinical dataset (denoted CMA) contains normal controls (NC) and atrophied AD patients, whilst the second is a collection of NC and bipolar (BP) patients (denoted BPSA). An optimal and robust stopping criterion is established for the propagating FM front and the final FMASH segmentation estimates compared to two commonly-used methods: FIRST/FSL and Freesurfer (FS). Results show that FMASH outperforms both FIRST and FS on the BPSA data, with significantly higher Dice coefficients (0.80±0.01) and lower FPR. Despite some intrinsic bias for FIRST and FS on the CMA data, due to their training, FMASH performs comparably well on the CMA data, with an average bilateral Dice coefficient of 0.82±0.01. Furthermore, FMASH most accurately captures the hippocampal volume difference between NC and AD, and provides a more accurate estimation of the problematic hippocampus-amygdala border on both clinical datasets. The consistency in performance across the two datasets suggests that FMASH is applicable to a range of clinical data with differing image quality and demographics.

Automated analysis of two- and three-color fluorescent Elispot (Fluorospot) assays for cytokine secretion.

The Elispot effectively measures the frequencies of cells secreting particular molecules, especially low-frequency cells such as antigen-specific T cells. The Fluorospot assay adapted this analysis to two products per cell, and this has now been extended to three-color measurement of both mouse and human cytokine-secreting cells. Due to the increased data complexity, and particularly the need to define single-, double- and triple-producing cells, it is critical to objectively quantify spot number, size, intensity, and coincidence with other spots. An automated counting program, Exploraspot, was therefore developed to detect and quantify Fluorospots in automated fluorescence microscope images. Morphological parameters, including size, intensity, location, circularity and others are calculated for each spot, exported in FCS format, and further analyzed by gating and graphical display in popular flow cytometry analysis programs. The utility of Exploraspot is demonstrated by identification of single-, double- and triple-secreting T cells; tolerance of variable background fluorescence; and estimation of the numbers of genuine versus random multiple events.

Semi-Automated Analysis of Diaphragmatic Motion with Dynamic Magnetic Resonance Imaging in Healthy Controls and Non-Ambulant Subjects with Duchenne Muscular Dystrophy.

Subjects with Duchenne Muscular Dystrophy (DMD) suffer from progressive muscle damage leading to diaphragmatic weakness that ultimately requires ventilation. Emerging treatments have generated interest in better characterizing the natural history of respiratory impairment in DMD and responses to therapy. Dynamic (cine) Magnetic Resonance Imaging (MRI) may provide a more sensitive measure of diaphragm function in DMD than the commonly used spirometry. This study presents an analysis pipeline for measuring parameters of diaphragmatic motion from dynamic MRI and its application to investigate MRI measures of respiratory function in both healthy controls and non-ambulant DMD boys. We scanned 13 non-ambulant DMD boys and 10 age-matched healthy male volunteers at baseline, with a subset (n = 10, 10, 8) of the DMD subjects also assessed 3, 6, and 12 months later. Spirometry-derived metrics including forced vital capacity were recorded. The MRI-derived measures included the lung cross-sectional area (CSA), the anterior, central, and posterior lung lengths in the sagittal imaging plane, and the diaphragm length over the time-course of the dynamic MRI. Regression analyses demonstrated strong linear correlations between lung CSA and the length measures over the respiratory cycle, with a reduction of these correlations in DMD, and diaphragmatic motions that contribute less efficiently to changing lung capacity in DMD. MRI measures of pulmonary function were reduced in DMD, controlling for height differences between the groups: at maximal inhalation, the maximum CSA and the total distance of motion of the diaphragm were 45% and 37% smaller. MRI measures of pulmonary function were correlated with spirometry data and showed relationships with disease progression surrogates of age and months non-ambulatory, suggesting that they provide clinically meaningful information. Changes in the MRI measures over 12 months were consistent with weakening of diaphragmatic and inter-costal muscles and progressive diaphragm dysfunction. In contrast, longitudinal changes were not seen in conventional spirometry measures during the same period. Dynamic MRI measures of thoracic muscle and pulmonary function are, therefore, believed to detect meaningful differences between healthy controls and DMD and may be sensitive to changes in function over relatively short periods of follow-up in non-ambulant boys with DMD.

T2 relaxation mapping MRI of healthy and inflamed gingival tissue.

OBJECTIVES: To investigate the use and reproducibility of MRI transverse relaxation time (T2) mapping in healthy and inflamed gingivae. METHODS: 21 subjects were recruited into 2 groups: those without evidence of gingivitis ("healthy"; n = 11, age 24.0 ± 3.66 years) by visual assessment and those with moderate to severe gingivitis ("gingivitis"; n = 10, age 28.9 ± 6.03 years) exhibited across the second mandibular premolar and first mandibular molar buccal gingivae. Subjects were imaged by MRI twice in a single day. Three T2 weighted turbo spin-echo volumes with 0.25 × 0.25 × 0.8-mm3 resolution were acquired at echo times of 16, 32 and 48 ms for T2 decay fitting. Image analysis was fully blinded; the two imaging sessions were not identifiable as coming from the same subject. Each imaging session had independent regions of interest drawn on the first echo image and applied to the calculated T2 decay maps. RESULTS: The coefficient of variation was low and similar in healthy and gingivitis populations: 6.10 and 5.25% populations, respectively, with 5.65% populations across both groups. Bland-Altman analysis revealed no bias (mean -2.93%; 95% confidence intervals -22.20 to 16.34%) between sessions. The intersession agreement was good (r = 0.744, ρ = 0.568, intraclass correlation coefficient = 0.68). T2 mapping did not differentiate healthy from gingivitis groups. The mean T2 value in the healthy group (63.7 ms) was similar to that of the gingivitis group (65.23 ms) (p = 0.30). CONCLUSIONS: Mapping of the T2 decay in the gingivae was a repeatable process; however, T2 value alone did not differentiate those with clinical examination-determined gingivitis from those without signs of gingivitis.

A Comparison of Magnetization Transfer Methods to Assess Brain and Cervical Cord Microstructure in Multiple Sclerosis.

BACKGROUND: Demyelination is a core pathological feature of multiple sclerosis (MS) and spontaneous remyelination appears to be an important mechanism for repair in the disease. Magnetization transfer ratio imaging (MTR) has been used extensively to evaluate demyelination, although limitations to its specificity are recognized. MT saturation imaging (MTsat) removes some of the T1 dependence of MTR. We have performed a comparative evaluation of MTR and MTsat imaging in a mixed group of subjects with active MS, to explore their relative sensitivity to pathology relevant to explaining clinical outcomes. METHODS: A total of 134 subjects underwent MRI of their brain and cervical spinal cord. Isotropic 3-dimensional pre- and postcontrast T1-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) volumes were segmented into brain normal appearing white matter (NAWM), brain WM lesions (WML), normal appearing spinal cord (NASC), and spinal cord lesions. Volumes and metrics for MTR and MTsat histograms were calculated for each region. RESULTS: Significant Spearman correlations were found with the Expanded Disability Status Scale and timed 25-foot walk for the whole brain and WML MTR, but not in that from the NAWM or any cervical spinal cord region. By contrast, the MTsat was correlated with both disability metrics in all these regions in both the brain and spine. CONCLUSIONS: This study extends prior work relating atrophy and lesion load with disability, by characterization of MTsat parameters. MTsat is practical in routine clinical applications and may be more sensitive to tissue damage than MTR for both brain and cervical spinal cord.

Respiratory magnetic resonance imaging biomarkers in Duchenne muscular dystrophy.

OBJECTIVE: To examine the diaphragm and chest wall dynamics with cine breathing magnetic resonance imaging (MRI) in ambulatory boys with Duchenne muscular dystrophy (DMD) without respiratory symptoms and controls. METHODS: In 11 DMD boys and 15 controls, cine MRI of maximal breathing was recorded for 10 sec. The lung segmentations were done by an automated pipeline based on a Holistically-Nested Network model (HNN method). Lung areas, diaphragm, and chest wall motion were measured throughout the breathing cycle. RESULTS: The HNN method reliably identified the contours of the lung and the diaphragm in every frame of each dataset (~180 frames) within seconds. The lung areas at maximal inspiration and expiration were reduced in DMD patients relative to controls (P = 0.02 and <0.01, respectively). The change in the lung area between inspiration and expiration correlated with percent predicted forced vital capacity (FVC) in patients (rs  = 0.75, P = 0.03) and was not significantly different between groups. The diaphragm position, length, contractility, and motion were not significantly different between groups. Chest wall motion was reduced in patients compared to controls (P < 0.01). INTERPRETATION: Cine breathing MRI allows independent and reliable assessment of the diaphragm and chest wall dynamics during the breathing cycle in DMD patients and controls. The MRI data indicate that ambulatory DMD patients breathe at lower lung volumes than controls when their FVC is in the normal range. The diaphragm moves normally, whereas chest wall motion is reduced in these boys with DMD.

Analysis of ageing-associated grey matter volume in patients with multiple sclerosis shows excess atrophy in subcortical regions.

Age of onset in multiple sclerosis (MS) exerts an influence on the course of disease. This study examined whether global and regional brain volumes differed between "younger" and "older" onset MS subjects who were matched for short disease duration, mean 1.9 years and burden as measured by the MS Severity Score and relapses. 21 younger-onset MS subjects (age 30.4 ± 3.2 years) were compared with 17 older-onset (age 48.7 ± 3.3 years) as well as age-matched controls (n = 31, 31.9 ± 3.5 years and n = 21, 47.3 ± 4.0 years). All subjects underwent 3D volumetric T1 and T2-FLAIR imaging. White matter (WM) and grey matter (GM) lesions were outlined manually. Lesions were filled prior to tissue and structural segmentation to reduce classification errors. Volume loss versus control was predominantly in the subcortical GM, at > 13% loss. Younger and older-onset MS subjects had similar, strong excess loss in the putamen, thalamus, and nucleus accumbens. No excess loss was detected in the amygdala or pallidum. The hippocampus and caudate showed significant excess loss in the younger group (p < 0.001) and a strong trend in the older-onset group. These results provide a potential imaging correlate of published neuropsychological studies that reported the association of younger age at disease onset with impaired cognitive performance, including decreased working memory.

Quantifying disease activity in fatty-infiltrated skeletal muscle by IDEAL-CPMG in Duchenne muscular dystrophy.

The purpose of this study was to explore the use of iterative decomposition of water and fat with echo asymmetry and least-squares estimation Carr-Purcell-Meiboom-Gill (IDEAL-CPMG) to simultaneously measure skeletal muscle apparent fat fraction and water T2 (T2,w) in patients with Duchenne muscular dystrophy (DMD). In twenty healthy volunteer boys and thirteen subjects with DMD, thigh muscle apparent fat fraction was measured by Dixon and IDEAL-CPMG, with the IDEAL-CPMG also providing T2,w as a measure of muscle inflammatory activity. A subset of subjects with DMD was followed up during a 48-week clinical study. The study was in compliance with the Patient Privacy Act and approved by the Institutional Review Board. Apparent fat fraction in the thigh muscles of subjects with DMD was significantly increased compared to healthy volunteer boys (p <0.001). There was a strong correlation between Dixon and IDEAL-CPMG apparent fat fraction. Muscle T2,w measured by IDEAL-CPMG was independent of changes in apparent fat fraction. Muscle T2,w was higher in the biceps femoris and vastus lateralis muscles of subjects with DMD (p <0.05). There was a strong correlation (p <0.004) between apparent fat fraction in all thigh muscles and six-minute walk distance (6MWD) in subjects with DMD. IDEAL-CPMG allowed independent and simultaneous quantification of skeletal muscle fatty degeneration and disease activity in DMD. IDEAL-CPMG apparent fat fraction and T2,w may be useful as biomarkers in clinical trials of DMD as the technique disentangles two competing biological processes.

Magnetic resonance imaging reveals the complementary effects of decongestant and Breathe Right Nasal Strips on internal nasal anatomy.

OBJECTIVES/HYPOTHESIS: This magnetic resonance imaging (MRI) study of 26 subjects with nasal congestion was performed to assess in the complete nasal passage both the anatomical effect of the marketed Breathe Right Nasal Strip (BRNS) relative to placebo and the potential adjunctive effect of using a decongestant in combination with the BRNS. STUDY DESIGN: Randomized, crossover study. METHODS: The study consisted of two parts, the first involving application of either the BRNS or the placebo strip in a randomized, crossover design with evaluator blinding, and repeated MRI scanning; and the second a sequential process of decongestant administration, MRI scanning, application of the BRNS, and repeated MRI. The same anatomical MRI protocol was used throughout. Nasal patency was assessed in the whole nasal passage and eight subregions (by inferior-superior, anterior-posterior division). Numerical response scores representing subjective nasal congestion were also obtained. RESULTS: Results demonstrate significant anatomical enlargement with the BRNS relative to placebo (P < .001), as well as an additive effect of using a decongestant in combination with the BRNS; both supported by a strong and significant negative correlation with the subjective nasal response measures of nasal congestion (r = -0.98, P = .002). Furthermore, analysis of the nasal subregions indicates that this adjunctive effect arises from a partially localized action of the complementary products: the BRNS acting primarily anteriorly in the nose and the decongestant mainly posteriorly. CONCLUSIONS: The BRNS alone significantly increases nasal patency and alleviates perceived nasal congestion, and additional relief of symptoms can be obtained with simultaneous use of a decongestant. LEVEL OF EVIDENCE: 1b. Laryngoscope, 126:2205-2211, 2016.

Evidence of Brain Inflammation in Patients with Human T-Lymphotropic Virus Type 1-Associated Myelopathy (HAM): A Pilot, Multimodal Imaging Study Using 11C-PBR28 PET, MR T1-Weighted, and Diffusion-Weighted Imaging.

HTLV-1-associated myelopathy (HAM; HTLV-1 is human T-lymphotropic virus type 1) is a chronic debilitating neuroinflammatory disease with a predilection for the thoracic cord. Tissue damage is attributed to the cellular immune response to HTLV-1-infected lymphocytes. The brains of HTLV-1-infected patients, with and without HAM but no clinical evidence of brain involvement, were examined using a specific 18-kDa translocator protein ligand, 11C-PBR28, and T1-weighted and diffusion-weighted MRI. METHODS: Five subjects with HAM and 2 HTLV-1 asymptomatic carriers were studied. All underwent clinical neurologic assessment including cognitive function and objective measures of gait, quantification of HTLV-1 proviral load in peripheral blood mononuclear cells, and human leukocyte antigen-antigen D related expression on circulating CD8+ lymphocytes. 11C-PBR28 PET and MRI were performed on the same day. 11C-PBR28 PET total volume of distribution and distribution volume ratio (DVR) were estimated using 2-tissue-compartment modeling. MRI data were processed using tools from the FMRIB Software Library to estimate mean diffusivity (MD) and gray matter (GM) fraction changes. The results were compared with data from age-matched healthy volunteers. RESULTS: Across the whole brain, the total volume of distribution for the subjects with HAM (5.44 ± 0.84) was significantly greater than that of asymptomatic carriers (3.44 ± 0.80). The DVR of the thalamus in patients with severe and moderate HAM was higher than that in the healthy volunteers, suggesting increased translocator protein binding (z > 4.72). Subjects with more severe myelopathy and with high DR expression on CD8+ lymphocytes had increased DVR and MD (near-significant correlation found for the right thalamus MD: P = 0.06). On the T1-weighted MRI scans, the GM fraction of the brain stem was reduced in all HTLV-1-infected patients compared with controls (P < 0.001), whereas the thalamus GM fraction was decreased in patients with HAM and correlated with the disease severity. There was no correlation between neurocognitive function and these markers of central nervous system inflammation. CONCLUSION: This pilot study suggests that some patients with HAM have asymptomatic inflammation in the brain, which can be detected and monitored by 11C-PBR28 PET together with structural and diffusion-weighted MRI.

Neuroinflammation in treated HIV-positive individuals: A TSPO PET study.

OBJECTIVE: To explore the effects of microglial activation on brain function and structure, and its relationship with peripheral inflammatory markers, in treated, HIV-positive individuals, using in vivo [(11)C]PBR28 PET (to measure the 18 kDa translocator protein [TSPO]). METHODS: Cognitively healthy HIV-positive individuals on suppressive antiretroviral therapy and HIV-negative individuals (controls) underwent brain [(11)C]PBR28 PET and MRI. HIV-positive patients completed neuropsychological testing and CSF testing for chemokines. The concentration of bacterial ribosomal 16sDNA in plasma was measured as a marker of microbial translocation. RESULTS: HIV-positive individuals showed global increases in TSPO expression compared to controls (corrected p < 0.01), with significant regional increases in the parietal (p = 0.001) and occipital (p = 0.046) lobes and in the globus pallidus (p = 0.035). TSPO binding in the hippocampus, amygdala, and thalamus were associated with poorer global cognitive performance in tasks assessing verbal and visual memory (p < 0.05). Increased TSPO binding was associated with increased brain white matter diffusion MRI mean diffusivity in HIV-positive individuals, a lower CD4/CD8 ratio, and both high pretreatment HIV RNA and plasma concentration ribosomal 16s DNA (p < 0.05). CONCLUSIONS: Cognitively healthy HIV-positive individuals show evidence for a chronically activated brain innate immune response and elevated blood markers of microbial translocation despite effective control of plasma viremia. Increased brain inflammation is associated with poorer cognitive performance and white matter microstructural pathology, suggesting a possible role in cognitive impairments found in some HIV-positive patients despite effective treatment.

Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis.

BACKGROUND: Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging. METHODS: The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS. RESULTS: Patients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio. CONCLUSIONS: Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.