Peripheral blood C-reactive protein (CRP) is a biomarker used clinically to measure systemic inflammation and is reproducibly increased in a subset of patients with major depressive disorder (MDD). Furthermore, increased peripheral blood CRP in MDD has been associated with altered reward circuitry and increased brain glutamate in relation with symptoms of anhedonia. Nevertheless, the relationship between peripheral CRP and other peripheral and central markers of inflammation in depressed patients has not been established. Plasma (n=89) and CSF (n=73) was collected from medically-stable, currently-unmedicated adult outpatients with MDD. Associations among plasma and CSF CRP and plasma and CSF inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF] and IL-1beta) and their soluble receptors/antagonists were examined. Relationships between plasma and CSF inflammatory markers and depressive symptoms including anhedonia and reduced motivation (RM) were also explored. Plasma CRP was correlated with multiple plasma inflammatory markers (all p<0.05), and a strong correlation was found between plasma and CSF CRP (r=0.855, p<0.001). CSF CRP in turn correlated with CSF cytokine receptors/antagonists (all p<0.05). Principal component analyses revealed clusters of CSF inflammatory markers that were associated with high plasma CRP (>3mg/L) and correlated with depressive symptom severity. These findings were driven by CSF TNF, which correlated with RM (r=0.236, p=0.045), and CSF IL-6 soluble receptor, which correlated with anhedonia (r=0.301, p=0.010) in the sample as a whole and particularly females. CRP appears to be a peripheral biomarker that reflects peripheral and central inflammation and seems well-suited for guiding immunotherapies targeting TNF and IL-6 in patients with MDD.

Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-α to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.

Kynurenine pathway (KP) metabolites are believed to be a link between inflammation and depression through effects on brain glutamate receptors. However, neither the relationship between plasma and cerebrospinal fluid (CSF) KP metabolites nor their association with inflammatory mediators is well-established in depression. Moreover, the clinical profile associated with combined activation of plasma inflammatory and kynurenine pathways is unknown. Accordingly, plasma and CSF-KP metabolites and inflammatory markers along with depressive symptoms and antidepressant treatment response were measured in 72 unmedicated depressed patients. Following bivariate analyses, component factors representing immune and kynurenine variables in the plasma and CSF were extracted and were used to examine directionality of associations in a path model. In addition, patients were clustered using individual markers that most accounted for the association between plasma immune and KP systems. Path analysis revealed a directional association extending from plasma inflammatory markers to plasma kynurenines, to CSF kynurenines. Among immune markers, plasma tumor necrosis factor (TNF) was robustly associated with plasma kynurenine (KYN) and KYN/tryptophan (TRP), which was in turn significantly associated with CSF KYN, kynurenic acid, and quinolinic acid. Clustering of patients based on plasma TNF and KYN/TRP yielded subgroups of high (N = 17) and low (N = 55) TNF-KYN/TRP groups. High TNF-KYN/TRP subjects exhibited greater depression severity, anhedonia, and treatment nonresponse. In conclusion, plasma-KP metabolites may mediate an inflammation-associated depressive symptom profile via CNS KP metabolites that can serve as a target for intervention at the level of inflammation, peripheral KYN metabolism, KYN transport to the brain, or effects of KP metabolites on glutamate receptors.

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Vertebral compression fractures are common in malignant disease and frequently cause severe back pain. However, management of that pain with conventional medical, radiotherapy, or surgical modalities is often inadequate. Vertebral augmentation techniques, such as vertebroplasty and kyphoplasty, are minimally invasive techniques in which methylmethacrylate bone cement is percutaneously injected into compressed vertebral bodies. Vertebral augmentation often improves mechanical stability of compressed vertebrae, provides pain relief, and may prevent progression of vertebral collapse. Kyphoplasty may provide increased chance for vertebral body height restoration, but the clinical importance of slight change in vertebral body height is unclear. Vertebral augmentation can be used in conjunction with other treatment modalities, and associated pain relief may improve patient tolerance of needed antitumor therapies, such as radiation therapy. Vertebral augmentation is generally very well tolerated, and complications associated with bone cement extravasation beyond the vertebral body have rarely been reported. Because it often provides good to excellent relief of otherwise intractable pain and is generally well tolerated, vertebral augmentation is becoming a first-line agent for management of painful vertebral compression fractures, especially in the setting of malignant disease.

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Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.

Background Radiofrequency ablation (RFA) is a denervation therapy commonly performed for pain of facet etiology. Degenerative spondylolisthesis, a malalignment of the spinal vertebrae, may be a co-existing condition contributing to pain; yet the effect of RFA on advancing listhesis is unknown. To the extent that denervating RFA may weaken paraspinal muscles that provide stability to the spine, the therapy can potentially contribute to progressive spinal instability. Methods Single-center, prospective, observational pilot study in an interventional pain practice to test the hypothesis that RFA of painful facets in the setting of spondylolisthesis may contribute to advancement of further degenerative spondylolisthesis. Fifteen participants with pre-existing degenerative Grade I or Grade II spondylolisthesis and coexisting axial lumbar pain underwent lumbar RFA encompassing spondylolisthesis level and followed with post-RFA imaging at 12 months and beyond to measure percent change in spondylolisthesis. Results The primary outcome was the percent advancement of spondylolisthesis per year measured on post-RFA lateral lumbar spine imaging compared with non-intervention inferred baseline advancement of 2% per very limited observational studies. Among the 15 participants enrolled, 14 completed the study (median age 66; 64.3% women; median BMI 33.5; mean follow-up time 23.9 months). The mean advancement of spondylolisthesis per year after RFA was 1.30% (95% CI −0.14 to 2.78%), with 9/14 below 1.25%. Conclusion Among patients with lumbar pain originating from facets in the setting of degenerative spondylolisthesis who underwent lumbar RFA, the observed advancement of spondylolisthesis is clinically similar to the estimated maximum baseline of 2% per year change. The study findings did not find a destabilizing effect of lumbar RFA in advancing spondylolisthesis in this patient population.