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1.
Alzheimers Dement (Amst) ; 14(1): e12346, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187197

RESUMO

Introduction: Few studies have investigated how neuroinflammation early in the disease course may affect Alzheimer's disease (AD) progression over time despite evidence that neuroinflammation is associated with AD. Methods: Research participants with cerebrospinal fluid (CSF) biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in this study. Cox models were used to investigate whether baseline CSF neuroinflammation was associated with incident mild cognitive impairment (MCI) or AD. Moderating effects of sex and apolipoprotein E (APOE) ε4 were also examined. Results: Elevated levels of tumor necrosis factor α (TNF-α), interleukin (IL)-9, and IL-12p40 at baseline were associated with higher rates of conversion to MCI/AD. Interactions with sex and APOE ε4 were observed, such that women with elevated TNF-α and all APOE ε4 carriers with elevated IL-9 levels had shorter times to conversion. In addition, TNF-α mediated the relationship between elevated IL-12p40 and IL-9. Discussion: Elevated neuroinflammation markers are associated with incident MCI/AD, and the factors of sex and APOE ε4 status modify the time to conversion.

2.
Neuroimage Clin ; 36: 103199, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36137496

RESUMO

Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disorder affecting motor neurons in the spinal cord and brain. Studies have reported on atrophy within segments of the cervical cord, but we are not aware of previous investigations of the whole spinal cord. Herein we present our findings from a 3T MRI study involving 32 subjects (15 ALS participants and 17 healthy controls) characterizing cross-sectional area along the entire cord. We report atrophy of the cervical enlargement in ALS participants, but no evidence of atrophy of the thoracolumbar enlargement. These results suggest that MR-based analyses of the cervical cord may be sufficient for in vivo investigations of spinal cord atrophy in ALS, and that atrophy of the cervical enlargement (C4-C7) is a potential imaging marker for quantifying lower motor neuron degradation.


Assuntos
Esclerose Lateral Amiotrófica , Medula Cervical , Humanos , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/diagnóstico por imagem , Atrofia/patologia , Neurônios Motores/patologia , Medula Cervical/diagnóstico por imagem , Medula Cervical/patologia
3.
Brain Behav Immun ; 102: 89-97, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35181440

RESUMO

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.


Assuntos
COVID-19 , Pandemias , Biomarcadores/metabolismo , Encéfalo/metabolismo , Controle de Doenças Transmissíveis , Humanos , Doenças Neuroinflamatórias , Receptores de GABA/metabolismo , SARS-CoV-2
4.
Brain Behav Immun ; 94: 299-307, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33486003

RESUMO

CNS inflammation is a key factor in Alzheimer's Disease (AD), but its relation to pathological Aß, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aß and tau in cognitively normal older adults. Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [18F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [18F]florbetapir (FBP; n = 58), which binds to Aß. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions. Unexpectedly, we detected significant negative associations between regional Aß and tau PET uptake and CSF inflammatory markers. For Aß PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aß (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aß and tau PET levels were observed in spatially distinct regions from those showing CSF-Aß/tau relationships. Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Estudos Transversais , Humanos , Tomografia por Emissão de Pósitrons , Proteínas tau
5.
Pain ; 162(4): 1241-1249, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065737

RESUMO

ABSTRACT: Using positron emission tomography, we recently demonstrated elevated brain levels of the 18 kDa translocator protein (TSPO), a glial activation marker, in chronic low back pain (cLBP) patients, compared to healthy controls (HCs). Here, we first sought to replicate the original findings in an independent cohort (15 cLBP, 37.8 ± 12.5 y/o; 18 HC, 48.2 ± 12.8 y/o). We then trained random forest machine learning algorithms based on TSPO imaging features combining discovery and replication cohorts (totaling 25 cLBP, 42.4 ± 13.2 y/o; 27 HC, 48.9 ± 12.6 y/o), to explore whether image features other than the mean contain meaningful information that might contribute to the discrimination of cLBP patients and HC. Feature importance was ranked using SHapley Additive exPlanations values, and the classification performance (in terms of area under the curve values) of classifiers containing only the mean, other features, or all features was compared using the DeLong test. Both region-of-interest and voxelwise analyses replicated the original observation of thalamic TSPO signal elevations in cLBP patients compared to HC (P < 0.05). The random forest-based analyses revealed that although the mean is a discriminating feature, other features demonstrate similar level of importance, including the maximum, kurtosis, and entropy. Our observations suggest that thalamic neuroinflammatory signal is a reproducible and discriminating feature for cLBP, further supporting a role for glial activation in human cLBP, and the exploration of neuroinflammation as a therapeutic target for chronic pain. This work further shows that TSPO signal contains a richness of information that the simple mean might fail to capture completely.


Assuntos
Dor Crônica , Dor Lombar , Encéfalo/metabolismo , Dor Crônica/diagnóstico por imagem , Estudos de Coortes , Humanos , Dor Lombar/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Receptores de GABA/metabolismo
6.
Ann Biomed Eng ; 49(1): 345-353, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32632531

RESUMO

Issues with model fitting (i.e. suboptimal standard deviation, linewidth/full-width-at-half-maximum, and/or signal-to-noise ratio) in multi-voxel MRI spectroscopy, or chemical shift imaging (CSI) can result in the significant loss of usable voxels. A potential solution to minimize this problem is to estimate the value of unusable voxels by utilizing information from reliable voxels in the same image. We assessed an image restoration method called inpainting as a tool to restore unusable voxels, and compared it with traditional interpolation methods (nearest neighbor, trilinear interpolation and tricubic interpolation). In order to evaluate the performance across varying image contrasts and spatial resolutions, we applied the same techniques to a T1-weighted MRI brain dataset, and N-acetylaspartate (NAA) spectroscopy maps from a CSI dataset. For all image types, inpainting exhibited superior performance (lower normalized root-mean-square errors, NRMSE) compared to all other methods considered (p's < 0.001). Inpainting maintained an average NRMSE of less than 5% even with 50% missing voxels, whereas the other techniques demonstrated up to three times that value, depending on the nature of the image. For CSI maps, inpainting maintained its superiority whether the previously unusable voxels were randomly distributed, or located in regions most commonly affected by voxel loss in real-world data. Inpainting is a promising approach for recovering unusable or missing voxels in voxel-wise analyses, particularly in imaging modalities characterized by low SNR such as CSI. We hypothesize that this technique may also be applicable for datasets from other imaging modalities, such as positron emission tomography, or dynamic susceptibility contrast MRI.


Assuntos
Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Espectral , Adulto Jovem
7.
Ann Neurol ; 87(6): 939-949, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32239542

RESUMO

OBJECTIVE: Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. METHODS: We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). RESULTS: MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT. INTERPRETATION: A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders. ANN NEUROL 2020;87:939-949.


Assuntos
Inflamação/diagnóstico por imagem , Meninges/diagnóstico por imagem , Enxaqueca com Aura/diagnóstico por imagem , Adolescente , Adulto , Idoso , Depressão Alastrante da Atividade Elétrica Cortical , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Inflamação/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Meninges/fisiopatologia , Pessoa de Meia-Idade , Enxaqueca com Aura/fisiopatologia , Imagem Multimodal , Lobo Occipital/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Crânio/diagnóstico por imagem , Adulto Jovem
8.
Neuroimage ; 211: 116656, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068162

RESUMO

BACKGROUND: Chronic pain and mood disorders share common neuroanatomical substrates involving disruption of the reward system. Although increase in negative affect (NA) and decrease in positive affect (PA) are well-known factors complicating the clinical presentation of chronic pain patients, our understanding of the mechanisms underlying the interaction between pain and PA/NA remains limited. Here, we used a validated task probing behavioral and neural responses to monetary rewards and losses in conjunction with functional magnetic resonance imaging (fMRI) to test the hypothesis that dysfunction of the striatum, a key mesolimbic structure involved in the encoding of motivational salience, relates to mood alterations comorbid with chronic pain. METHODS: Twenty-eight chronic musculoskeletal pain patients (chronic low back pain, n=15; fibromyalgia, n=13) and 18 healthy controls underwent fMRI while performing the Monetary Incentive Delay (MID) task. Behavioral and neural responses were compared across groups and correlated against measures of depression (Beck Depression Inventory) and hedonic capacity (Snaith-Hamilton Pleasure Scale). RESULTS: Compared to controls, patients demonstrated higher anhedonia and depression scores, and a dampening of striatal activation and incentive-related behavioral facilitation (reduction in reaction times) during reward and loss trials of the MID task (ps â€‹< â€‹0.05). In all participants, lower activation of the right striatum during reward trials was correlated with lower incentive-related behavioral facilitation and higher anhedonia scores (ps â€‹< â€‹0.05). Finally, among patients, lower bilateral striatal activation during loss trials was correlated with higher depression scores (ps â€‹< â€‹0.05). CONCLUSIONS: In chronic pain, PA reduction and NA increase are accompanied by striatal hypofunction as measured by the MID task.


Assuntos
Anedonia/fisiologia , Mapeamento Encefálico , Dor Crônica/fisiopatologia , Corpo Estriado/fisiologia , Desvalorização pelo Atraso/fisiologia , Depressão/fisiopatologia , Fibromialgia/fisiopatologia , Dor Lombar/fisiopatologia , Adulto , Dor Crônica/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Depressão/diagnóstico por imagem , Feminino , Fibromialgia/diagnóstico por imagem , Humanos , Dor Lombar/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Punição , Recompensa
9.
Brain Behav Immun ; 87: 498-507, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32027960

RESUMO

Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HCVET, n = 8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1ß). SUVR were validated against volume of distribution ratio (n = 13). Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines. Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.


Assuntos
Síndrome do Golfo Pérsico , Veteranos , Astrócitos , Guerra do Golfo , Humanos , Síndrome do Golfo Pérsico/diagnóstico por imagem , Brometo de Piridostigmina , Receptores de GABA
10.
Neurology ; 92(17): e2038-e2050, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30918090

RESUMO

OBJECTIVE: To determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions. METHODS: Thirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [11C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses. RESULTS: Compared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks. CONCLUSIONS: These findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.


Assuntos
Encéfalo/diagnóstico por imagem , Encefalite/diagnóstico por imagem , Enxaqueca com Aura/diagnóstico por imagem , Adolescente , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Adulto Jovem
11.
Brain Behav Immun ; 75: 72-83, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30223011

RESUMO

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.


Assuntos
Fibromialgia/diagnóstico por imagem , Fibromialgia/metabolismo , Neuroglia/metabolismo , Acetamidas/metabolismo , Adulto , Astrócitos/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono/metabolismo , Feminino , Fibromialgia/fisiopatologia , Humanos , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Neuroglia/fisiologia , Neuroimunomodulação/fisiologia , Dor/metabolismo , Dor/fisiopatologia , Tomografia por Emissão de Pósitrons/métodos , Piridinas/metabolismo , Receptores de GABA/metabolismo
12.
J Clin Invest ; 129(1): 364-372, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30530989

RESUMO

BACKGROUND: Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET). METHODS: In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS: Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls. CONCLUSIONS: These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans. FUNDING: National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.


Assuntos
Regulação Enzimológica da Expressão Gênica , Histona Desacetilases/biossíntese , Neuroimagem , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal , Esquizofrenia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/enzimologia , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/enzimologia , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/enzimologia
14.
Pain ; 159(5): 968-977, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29419657

RESUMO

Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far, the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared with both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared with more superior segments). Furthermore, the neuroforaminal translocator protein signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.


Assuntos
Dor Crônica/diagnóstico por imagem , Inflamação/diagnóstico por imagem , Radiculopatia/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Raízes Nervosas Espinhais/diagnóstico por imagem , Adulto , Idoso , Dor Crônica/metabolismo , Dor Crônica/fisiopatologia , Estudos Transversais , Feminino , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Radiculopatia/metabolismo , Radiculopatia/fisiopatologia , Receptores de GABA/metabolismo , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Raízes Nervosas Espinhais/metabolismo , Raízes Nervosas Espinhais/fisiopatologia , Adulto Jovem
15.
J Nucl Med ; 59(1): 107-114, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28818984

RESUMO

The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. Although TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudoreference approaches can minimize within-group variability and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing 2 different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received 11C-PBR28 PET scans. The occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudoreference regions by testing for the absence of group differences in SUV and distribution volume (VT) estimated with an arterial input function. The SUV from target regions (cLBP study, thalamus; ALS study, precentral gyrus) was normalized with the SUV from candidate pseudoreference regions (i.e., occipital cortex, cerebellum, and whole brain) to obtain SUVRoccip, SUVRcereb, and SUVRWB The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without arterial input function (refDVR), and VT Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudoreference VT or SUV, excepting whole-brain VT, which was higher in cLBP patients than controls. Target VT elevations in patients (P = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVRoccip and SUVRWB, and by refDVR and blDVR (less reliably by SUVRcereb). In voxelwise analyses, SUVRoccip, but not SUVRcereb, identified regional group differences initially observed with SUVRWB, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with VT. Although important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology-related group differences in 11C-PBR28 signal as classic kinetic modeling techniques. The occipital cortex may be a suitable pseudoreference region, at least for the populations evaluated, pending further validation in larger cohorts.


Assuntos
Neuroglia/citologia , Tomografia por Emissão de Pósitrons/normas , Estudos de Coortes , Humanos , Cinética , Pirimidinas , Padrões de Referência
16.
Mol Imaging Biol ; 20(2): 188-193, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28983743

RESUMO

PURPOSE: Brown adipose tissue (BAT) in adult humans has been recently rediscovered and intensively investigated as a new potential therapeutic target for obesity and type 2 diabetes (T2D). However, reliable assessment of BAT mass in vivo represents a considerable challenge. The purpose of this investigation is to demonstrate for the first time that human BAT depots can be imaged with a translocator protein (TSPO)-specific positron emission tomography (PET) tracer [11C]PBR28 under thermoneutral conditions. PROCEDURES: In this retrospective analysis, we analyzed the images of three healthy volunteers who underwent PET/magnetic resonance (MR) imaging after injection of 14 m Ci of [11C]PBR28 at room temperature. Thirty-minute static PET images were reconstructed from the data obtained 60-90 min after the injection of the tracer. RESULTS: [11C]PBR28 uptake in the neck/supraclavicular regions was identified, which was parallel to the known distribution pattern of human BAT depots. These areas co-localized with the areas of hyperintensity and corresponded to fat on T1-weighted MR images. Standardized uptake value (SUV) was used to quantify [11C]PBR28 signal in BAT depots. The average (± SD) SUV(mean) and SUVmax for BAT depots was 2.13 (± 0.33) and 3.19 (± 0.34), respectively, while the average SUV(mean) for muscle and subcutaneous adipose tissue was 0.79 (± 0.1) and 0.18 (± 0.04), respectively. CONCLUSIONS: In this brief article, we provide the first evidence suggesting that [11C]PBR28, a widely available TSPO-specific PET tracer, can be used for imaging human BAT mass under thermoneutral conditions.


Assuntos
Tecido Adiposo Marrom/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Pirimidinas/química , Receptores de GABA/metabolismo , Adulto , Feminino , Voluntários Saudáveis , Humanos , Imageamento por Ressonância Magnética , Masculino , Pirimidinas/administração & dosagem
17.
ACS Chem Neurosci ; 7(4): 470-83, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-26985861

RESUMO

Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of "neuroinflammation" and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [(11)C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [(99m)Tc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future.


Assuntos
Mapeamento Encefálico , Sistema Nervoso Central/diagnóstico por imagem , Inflamação/patologia , Neuroimagem , Humanos , Inflamação/diagnóstico por imagem
18.
Drug Alcohol Depend ; 160: 163-9, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26832934

RESUMO

BACKGROUND: Striatal dopamine (DA) has been implicated in alcohol use disorders, but it is still unclear whether or not alcohol can induce dopamine release in social drinkers. Furthermore, no data exist on dopamine responses to alcohol in dependent drinkers. We sought to characterize the DA responses to alcohol intoxication in moderately large samples of social drinkers (SD) and nontreatment-seeking alcoholics (NTS). METHODS: Twenty-four SD and twenty-one NTS received two [(11)C]raclopride (RAC) PET scans; one at rest, and one during an intravenous alcohol infusion, with a prescribed ascent to a target breath alcohol concentration (BrAC), at which it was then "clamped." The alcohol clamp was started 5min after scan start, with a linear increase in BrAC over 15min to the target of 80mg%, the legal threshold for intoxication. Target BrAC was maintained for 30min. Voxel-wise binding potential (BPND) was estimated with MRTM2. RESULTS: IV EtOH induced significant increases in DA in the right ventral striatum in NTS, but not SD. No decreases in DA were observed in either group. CONCLUSIONS: Alcohol intoxication results in distinct anatomic profiles of DA responses in SD and NTS, suggesting that in NTS, the striatal DA system may process effects of alcohol intoxication differently than in SD.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/metabolismo , Depressores do Sistema Nervoso Central/metabolismo , Dopamina/metabolismo , Etanol/metabolismo , Estriado Ventral/metabolismo , Administração Intravenosa , Adulto , Intoxicação Alcoólica/metabolismo , Testes Respiratórios , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Racloprida , Receptores de Dopamina D2/metabolismo
19.
Brain Imaging Behav ; 10(3): 829-39, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26497890

RESUMO

Approximately 30 % of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [(18)F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and 11 female controls completed study procedures. Subjects received one FAL PET scan while performing a "2-back" task, and one while performing a "0-back" (attentional control, "baseline") task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain.


Assuntos
Dopamina/metabolismo , Fibromialgia/metabolismo , Adulto , Atenção/fisiologia , Benzamidas , Mapeamento Encefálico , Dor Crônica/diagnóstico por imagem , Dor Crônica/metabolismo , Dor Crônica/psicologia , Feminino , Fibromialgia/diagnóstico por imagem , Fibromialgia/psicologia , Humanos , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Medição da Dor , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Autorrelato
20.
Psychopharmacology (Berl) ; 232(12): 2207-16, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25563235

RESUMO

RATIONALE: Dopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood. OBJECTIVES: To determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD). METHODS: NTS subjects (n = 10) and SD (n = 13) received PET scans at baseline with the D2/D3 radioligand [(11)C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND. RESULTS: Across all subjects, greater impulsive choice for $20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p = 0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST. CONCLUSIONS: Preference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Alcoólicos/psicologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Receptores Dopaminérgicos/metabolismo , Adulto , Corpo Estriado/diagnóstico por imagem , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Escolaridade , Feminino , Humanos , Comportamento Impulsivo , Masculino , Pessoa de Meia-Idade , Racloprida/farmacologia , Cintilografia , Compostos Radiofarmacêuticos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Reforço Psicológico , Recompensa , Adulto Jovem
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