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BACKGROUND: Low back pain (LBP) is a highly prevalent condition that comprise a large portion of outpatient practice, challenging the diagnosis and treatment. However, the diagnostic tools are limited to clinical history, physical examination and imaging. Degenerative disc disease (DDD) is a significant cause of LBP, and emerging literature confirms the elevated levels of biomarkers in the discs. These biomarkers may serve as a tool for diagnosis, but may also be useful in predicting the treatment outcome. Here, we examine the expression of various cytokines on 1-year recovery from patients with LBP. METHODS: Patient-reported outcome (PRO) in terms of pain intensity (VAS), disability (ODI), and quality of life (Eq-5D) is collected from 44 patients at baseline and 12 months after surgery to study the influence of baseline TNF-α, IL-1ß, and IL-6 mRNA expression in both annulus fibrosus (AF) and nucleus pulposus (NP). RESULTS: Between baseline and follow-up, our cohort showed improvement in VAS back pain (p < 0.001), VAS leg pain (p < 0.001), ODI (p = 0.02), and Eq-5D (p = 0.01). Baseline levels of IL-1 ß was positively correlated with VAS back pain scores in AF (p = 0.05) and NP (p = 0.01) at 1-year follow-up. TNF-α expression at baseline was also positively correlated to ODI scores (p = 0.01) at follow-up and inversely correlated to improvements in ODI score between baseline and follow-up, suggesting that high TNF-α expression at baseline is associated with poor outcomes from surgery. CONCLUSION: The results from our study support that TNF-α expression at baseline can serve as a very important predictor of treatment response from lumbar fusion surgery.
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Objective. Most methods for partial volume correction (PVC) of positron emission tomography (PET) data employ anatomical segmentation of images into regions of interest. This approach is not optimal for exploratory functional imaging beyond regional hypotheses. Here, we describe a novel method for unbiased voxel-wise PVC.Approach.B-spline basis functions were combined with geometric transfer matrices to enable a method (bsGTM) that provides PVC or alternatively provides smoothing with minimal regional crosstalk. The efficacy of the proposed method was evaluated using Monte Carlo simulations, human PET data, and murine functional PET data.Main results.In simulations, bsGTM provided recovery of partial volume signal loss comparable to iterative deconvolution, while demonstrating superior resilience to noise. In a real murine PET dataset, bsGTM yielded much higher sensitivity for detecting amphetamine-induced reduction of [11C]raclopride binding potential. In human PET data, bsGTM smoothing enabled increased signal-to-noise ratios with less degradation of binding potentials relative to Gaussian convolution or non-local means.Significance.bsGTM offers improved performance for PVC relative to iterative deconvolution, the current method of choice for voxel-wise PVC, especially in the common PET regime of low signal-to-noise ratio. The new method provides an anatomically unbiased way to compensate partial volume errors in cases where anatomical segmentation is unavailable or of questionable relevance or accuracy.
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Algoritmos , Encéfalo , Humanos , Camundongos , Animais , Tomografia por Emissão de Pósitrons/métodos , Razão Sinal-Ruído , Racloprida , Processamento de Imagem Assistida por Computador/métodosRESUMO
Transient receptor potential (TRP) channels are widely expressed cation channels that play an essential role in mediating Ca2+ homeostasis and are considered potential regulators of inflammatory pain. This study investigates the expression of the TRP channel subtypes TRPV1, TRPV4, TRPC6, TRPM2, TRPM8 in lumbar intervertebral disc (IVD) biopsies from patients with chronic low back pain (LBP). We determined the expression of these TRP channel subtypes in the annulus fibrosus (AF) and the nucleus pulposus (NP) from 46 patients with LBP undergoing 1-2 level lumbar fusion surgery for degenerative disc disease. The mRNA transcripts were analyzed using quantitative real-time polymerase chain reaction (RT-qPCR), and the expression levels were compared against visual analog scale (VAS) and oswestry disability index (ODI) scores (0-100) for pain and disability. A significant positive correlation was demonstrated between VAS score and the mRNA expression of TRPV1, TRPC6, TRPM2, TRPM8 in the AF. We also found a significant positive correlation between ODI scores and expression of TRPV1 and TRPM8. Further, there is a significant positive correlation between TNF-α and TRPV1, TRPM2 and TRPM8 expression in the AF, and IL-6 to TRPV1 in the NP. Interestingly, when investigating treatment response via a 12-month postoperative follow-up ODI, we found a significant correlation between only TRPV1 expression at baseline and the follow-up ODI scores, which indicates this marker could predict the effectiveness of surgery. These results strongly suggest an association between pain, inflammatory mediators, and TRP channel expression in lumbar disc biopsies of patients with chronic LBP.
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Degeneração do Disco Intervertebral , Disco Intervertebral , Canais de Cátion TRPM , Canais de Potencial de Receptor Transitório , Humanos , Degeneração do Disco Intervertebral/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Canal de Cátion TRPC6/metabolismo , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Inflamação/metabolismo , Dor/metabolismo , Biomarcadores/metabolismo , Vértebras Lombares/metabolismo , Resultado do TratamentoRESUMO
Introduction: Increased catabolism of the extracellular matrix is observed under degenerative disc disease (DDD). The cleavage of extracellular matrix proteins in the nucleus pulposus (NP) by either matrix metalloproteinases (MMPs) or a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs) is believed to be involved in the degeneration, but the mechanisms are not known. Research question: Here, we examine the correlation between expression of several MMPs and ADAMTSs subtypes in lumbar discs from 34 patients with low back pain (LBP) undergoing 1-2 level lumbar fusion surgery (L4/L5 and/or L5/S1) for DDD with or without spondylolisthesis. Materials and Methods: The mRNA levels of MMPs (subtypes 1, 2, 3, 10, and 13) and ADAMTSs (subtypes 1, 4, and 5) were analyzed using quantitative real-time polymerase chain reaction (RT-qPCR) and correlated to the Pfirrmann magnetic resonance imaging classification system (grade I-V) of lumbar DDD. Results: We find a highly significant positive correlation between Pfirrmann grades and the gene expression of MMP1 (r=0.67, p=0.0001), MMP3 (r=0.61, p=0.0002), MMP10 (r=0.6701, p=0.0001), MMP13 (r=0.48, p=0.004), ADAMTS1 (r=0.67, p=0.0001), and ADAMTS5 (r=0.53, p=0.0017). The similar regulation of these transcript suggests their involvement in disc degeneration. Interestingly, a post hoc analysis (uncorrected p-values) also demonstrated a positive correlation between expression of TNF-α, IL-6 and both ADAMTSs/MMPs and the Pfirrmann grades. Discussion and Conclusion: These findings show that disc degradation in DDD is strongly associated with the expression of some metalloproteinases.
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Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how the cerebral 5-HT system associates to disturbances in cognition and mood in PD patients with DBS-STN turned on and off. We used psychological tests and questionnaires to evaluate cognitive function and the effects on mood from turning DBS-STN off. We applied a novel PET neuroimaging methodology to evaluate the integrity of the cerebral serotonin system. We measured 5-HT1BR binding in 13 DBS-STN-treated PD patients, at baseline and after turning DBS off. Thirteen age-matched volunteers served as controls. The measures for cognition and mood were correlated to the 5-HT1BR availability in temporal limbic cortex. 5-HT1BR binding was proportional to working memory performance and inverse proportional to affective bias for face recognition. When DBS is turned off, patients feel less vigorous; the higher the limbic and temporal 5-HT1BR binding, the more they are affected by DBS being turned off. Our study suggests that cerebral 5-HTR binding is associated with non-motor symptoms, and that preservation of serotonergic functions may be predictive of DBS-STN effects.
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Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Apart from alleviating the motor symptoms, Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how turning DBS off affects the serotonergic system. We here exploit a novel functional PET neuroimaging methodology to evaluate the preservation of serotonergic neurons and capacity to release serotonin. We measured cerebral 5-HT1BR binding in 13 DBS-STN treated PD patients, at baseline and after turning DBS off. Ten age-matched volunteers served as controls. Clinical measures of motor symptoms were assessed under the two conditions and correlated to the PET measures of the static and dynamic integrity of the serotonergic system. PD patients exhibited a significant loss of frontal and parietal 5-HT1BR, and the loss was significantly correlated to motor symptom severity. We saw a corresponding release of serotonin, but only in brain regions with preserved 5-HT1BR, suggesting the presence of a presynaptic serotonergic deficit. Our study demonstrates that DBS-STN dynamically regulates the serotonin system in PD, and that preservation of serotonergic functions may be predictive of DBS-STN effects.
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Estimulação Encefálica Profunda , Doença de Parkinson/terapia , Tomografia por Emissão de Pósitrons , Núcleo Subtalâmico/fisiopatologia , Idoso , Estudos de Casos e Controles , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Receptor 5-HT1B de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismoRESUMO
Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively capture temporal and spatial information about acute changes in brain neurotransmitter systems. We here evaluate the 5-HT1B receptor partial agonist PET radioligand, [11C]AZ10419369, for its sensitivity to detect changes in endogenous cerebral serotonin levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain serotonin levels, we compared the [11C]AZ10419369 PET signal in the pig brain to simultaneous measurements of extracellular serotonin levels with microdialysis after various acute interventions (saline, escitalopram, fenfluramine). The interventions increased the cerebral extracellular serotonin levels to two to six times baseline, with fenfluramine being the most potent pharmacological enhancer of serotonin release. The interventions induced a varying degree of decline in [11C]AZ10419369 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular serotonin level in the pig brain and the 5-HT1B receptor occupancy indicates that [11C]AZ10419369 binding is sensitive to changes in endogenous serotonin levels to a degree equivalent to that reported of [11C]raclopride to dopamine, a much used approach to detect in vivo change in cerebral dopamine.
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Encéfalo , Modelos Neurológicos , Tomografia por Emissão de Pósitrons , Receptor 5-HT1B de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Serotonina/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , SuínosRESUMO
BACKGROUND: The increasing use of the pig as a research model in neuroimaging requires standardized processing tools. For example, extraction of regional dynamic time series from brain PET images requires parcellation procedures that benefit from being automated. COMPARISON WITH EXISTING METHODS: Manual inter-modality spatial normalization to a MRI atlas is operator-dependent, time-consuming, and can be inaccurate with lack of cortical radiotracer binding or skull uptake. NEW METHOD: A parcellated PET template that allows for automatic spatial normalization to PET images of any radiotracer. RESULTS: MRI and [11C]Cimbi-36 PET scans obtained in sixteen pigs made the basis for the atlas. The high resolution MRI scans allowed for creation of an accurately averaged MRI template. By aligning the within-subject PET scans to their MRI counterparts, an averaged PET template was created in the same space. We developed an automatic procedure for spatial normalization of the averaged PET template to new PET images and hereby facilitated transfer of the atlas regional parcellation. Evaluation of the automatic spatial normalization procedure found the median voxel displacement to be 0.22±0.08mm using the MRI template with individual MRI images and 0.92±0.26mm using the PET template with individual [11C]Cimbi-36 PET images. We tested the automatic procedure by assessing eleven PET radiotracers with different kinetics and spatial distributions by using perfusion-weighted images of early PET time frames. CONCLUSION: We here present an automatic procedure for accurate and reproducible spatial normalization and parcellation of pig PET images of any radiotracer with reasonable blood-brain barrier penetration.
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Mapeamento Encefálico/métodos , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Animais , Atlas como Assunto , Radioisótopos de Carbono , Feminino , Radioisótopos de Flúor , Masculino , Processamento de Sinais Assistido por Computador , SuínosRESUMO
Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT2A receptor agonist PET radioligand, [11C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [11C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [11C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [11C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT2A receptor occupancy indicates that [11C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.
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Benzilaminas/metabolismo , Encéfalo/metabolismo , Fenetilaminas/metabolismo , Tomografia por Emissão de Pósitrons , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Benzilaminas/análise , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Radioisótopos de Carbono/análise , Radioisótopos de Carbono/metabolismo , Feminino , Fenfluramina/farmacologia , Fenetilaminas/análise , Tomografia por Emissão de Pósitrons/métodos , Receptor 5-HT2A de Serotonina/análise , Agonistas do Receptor 5-HT2 de Serotonina/análise , Serotoninérgicos/farmacologia , SuínosRESUMO
[(11)C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT(2A)) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [(11)C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT(2A) receptors with [(11)C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [(11)C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [(11)C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT(2A) receptor antagonist ketanserin before a second PET scan significantly decreased [(11)C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [(11)C]Cimbi-36 binding is selective for 5-HT(2A) receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT(2A) receptors in the human brain. Thus, we here describe [(11)C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT(2A) receptors in the human brain.