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1.
Ann Neurol ; 95(3): 471-486, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38061895

RESUMEN

OBJECTIVE: Older people with multiple sclerosis (MS) have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group? METHODS: We used data from the UK MS Register to characterize demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≥50 years), compared with adult-onset MS (AOMS; onset 18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n = 18, mean age of onset 54 years) versus AOMS (n = 23, mean age of onset 29 years). RESULTS: In the Register cohort, there were 1,608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of women, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 vs. 28.3, p < 0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease-modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whereas actively demyelinating lesions and compartmentalized inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalized inflammation, correlated with disability outcomes in older-onset MS patients. INTERPRETATION: The more progressive nature of older-onset MS is associated with significant neurodegeneration, but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. ANN NEUROL 2024;95:471-486.


Asunto(s)
Esclerosis Múltiple , Patología Clínica , Adulto , Humanos , Femenino , Anciano , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/diagnóstico , Estudios de Cohortes , Edad de Inicio , Progresión de la Enfermedad , Inflamación , Demografía
2.
Acta Neuropathol ; 143(1): 75-91, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34767070

RESUMEN

To better define roles that astrocytes and microglia play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.


Asunto(s)
Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Encéfalo/patología , Microglía/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Transcriptoma
3.
Br J Clin Pharmacol ; 88(9): 4230-4236, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35524344

RESUMEN

XBD173 and etifoxine are translocator protein (TSPO) ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the Ki for etifoxine in human brain derived here (7.8 µM, 95% CI 4.5-14.6 µM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily.


Asunto(s)
Purinas , Receptores de GABA , Proteínas Portadoras/metabolismo , Humanos , Oxazinas/farmacocinética , Purinas/farmacología , Receptores de GABA/metabolismo
4.
Glia ; 69(10): 2447-2458, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34145928

RESUMEN

To monitor innate immune responses in the CNS, the 18 kDa Translocator protein (TSPO) is a frequently used target for PET imaging. The frequent assumption that increased TSPO expression in the human CNS reflects pro-inflammatory activation of microglia has been extrapolated from rodent studies. However, TSPO expression does not increase in activated human microglia in vitro. Studies of multiple sclerosis (MS) lesions reveal that TSPO is not restricted to pro-inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia. Here, we investigated quantitative relationships between TSPO expression and microglia/macrophage phenotypes in white matter and lesions of brains with MS pathology. In white matter from brains with no disease pathology, normal appearing white matter (NAWM), active MS lesions and chronic active lesion rims, over 95% of TSPO+ cells are microglia/macrophages. Homeostatic microglial markers in NAWM and control tissue are lost/reduced in active lesions and chronic active lesion rims, reflecting cell activation. Nevertheless, pixel analysis of TSPO+ cells (n = 12,225) revealed that TSPO expression per cell is no higher in active lesions and chronic active lesion rims (where myeloid cells are activated) relative to NAWM and control. This data suggests that whilst almost all the TSPO signal in active lesions, chronic active lesion rims, NAWM and control is associated with microglia/macrophages, their TSPO expression predominantly reflects cell density and not activation phenotype. This finding has implications for the interpretation of TSPO PET signal in MS and other CNS diseases, and further demonstrates the limitation of extrapolating TSPO biology from rodents to humans.


Asunto(s)
Esclerosis Múltiple , Sustancia Blanca , Encéfalo/metabolismo , Humanos , Macrófagos/metabolismo , Microglía/metabolismo , Esclerosis Múltiple/metabolismo , Tomografía de Emisión de Positrones , Receptores de GABA/genética , Receptores de GABA/metabolismo , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismo
5.
Acta Neuropathol ; 142(3): 449-474, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34309761

RESUMEN

Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular "window" of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Enfermedad por Cuerpos de Lewy/genética , Enfermedad por Cuerpos de Lewy/patología , Patología Molecular/métodos , Anciano , Empalme Alternativo , Enfermedad de Alzheimer , Bancos de Muestras Biológicas , Núcleo Celular/genética , Núcleo Celular/ultraestructura , Giro del Cíngulo/patología , Humanos , Cuerpos de Lewy/patología , Microglía/patología , Microglía/ultraestructura , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/ultraestructura , Enfermedad de Parkinson , ARN/genética , Transcriptoma
6.
Eur J Nucl Med Mol Imaging ; 48(11): 3530-3539, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33825022

RESUMEN

OBJECTIVE: The mitochondrial 18-kDa translocator protein (TSPO) is expressed by activated microglia and positron emission tomography enables the measurement of TSPO levels in the brain. Findings in schizophrenia have shown to vary depending on the outcome measure used and this discrepancy in TSPO results could be explained by lower non-displaceable binding (VND) in schizophrenia, which could obscure increases in specific binding. In this study, we have used the TSPO ligand XBD173 to block the TSPO radioligand [11C]-PBR28 and used an occupancy plot to quantify VND in patients with schizophrenia. METHODS: A total of 7 patients with a diagnosis of schizophrenia were recruited for this study. Each patient received two separate PET scans with [11C]PBR28, one at baseline and one after the administration of the TSPO ligand XBD173. All patients were high-affinity binders (HABs) for the TSPO gene. We used an occupancy plot to quantify the non-displaceable component (VND) using 2TCM kinetic estimates with and without vascular correction. Finally we computed the VND at a single subject level using the SIME method. RESULTS: All patients showed a global and generalized reduction in [11C]PBR28 uptake after the administration of XBD173. Constraining the VND to be equal for all patients, the population VND was estimated to be 1.99 mL/cm3 (95% CI 1.90 to 2.08). When we used vascular correction, the fractional TSPO occupancy remained similar. CONCLUSIONS: In schizophrenia patients, a substantial component of the [11C]PBR28 signal represents specific binding to TSPO. Furthermore, the VND in patients with schizophrenia is similar to that previously reported in healthy controls. These results suggest that changes in non-specific binding between schizophrenia patients and healthy controls do not account for discrepant PET findings in this disorder.


Asunto(s)
Esquizofrenia , Encéfalo/metabolismo , Radioisótopos de Carbono , Humanos , Tomografía de Emisión de Positrones , Unión Proteica , Receptores de GABA/metabolismo , Esquizofrenia/diagnóstico por imagen , Tomografía Computarizada por Rayos X
7.
Eur J Nucl Med Mol Imaging ; 49(1): 146-163, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-33433698

RESUMEN

The 18 kDa translocator protein (TSPO) is a highly conserved protein located in the outer mitochondrial membrane. TSPO binding, as measured with positron emission tomography (PET), is considered an in vivo marker of neuroinflammation. Indeed, TSPO expression is altered in neurodegenerative, neuroinflammatory, and neuropsychiatric diseases. In PET studies, the TSPO signal is often viewed as a marker of microglial cell activity. However, there is little evidence in support of a microglia-specific TSPO expression. This review describes the cellular sources and functions of TSPO in animal models of disease and human studies, in health, and in central nervous system diseases. A discussion of methods of analysis and of quantification of TSPO is also presented. Overall, it appears that the alterations of TSPO binding, their cellular underpinnings, and the functional significance of such alterations depend on many factors, notably the pathology or the animal model under study, the disease stage, and the involved brain regions. Thus, further studies are needed to fully determine how changes in TSPO binding occur at the cellular level with the ultimate goal of revealing potential therapeutic pathways.


Asunto(s)
Receptores de GABA , Tomografía Computarizada por Rayos X , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Humanos , Microglía/metabolismo , Tomografía de Emisión de Positrones , Receptores de GABA/genética , Receptores de GABA/metabolismo
8.
Eur J Nucl Med Mol Imaging ; 49(1): 125-136, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34405276

RESUMEN

PURPOSE: Positron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[11C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [18F]GE387, which we have previously shown to have low sensitivity to this polymorphism. METHODS: Dynamic PET scans were conducted in male Wistar rats and female rhesus macaques to investigate the in vivo behaviour of (S)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]GE387 was further evaluated in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Sensitivity to polymorphism of (S)-GE387 was evaluated in genotyped human brain tissue. RESULTS: (S)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]GE387 was found in the inflamed striatum of LPS-treated rodents. In genotyped human brain tissue, (S)-GE387 was shown to bind similarly in low affinity binders (LABs) and high affinity binders (HABs) with a LAB to HAB ratio of 1.8. CONCLUSION: We established that (S)-[18F]GE387 has favourable kinetics in healthy rats and non-human primates and that it can distinguish inflamed from normal brain regions in the LPS model of neuroinflammation. Crucially, we have reconfirmed its low sensitivity to the TSPO polymorphism on genotyped human brain tissue. Based on these factors, we conclude that (S)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation.


Asunto(s)
Radiofármacos , Receptores de GABA , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Proteínas Portadoras , Femenino , Humanos , Macaca mulatta/genética , Masculino , Polimorfismo Genético , Tomografía de Emisión de Positrones , Ratas , Ratas Wistar , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores de GABA-A
9.
Brain ; 142(11): 3440-3455, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31578541

RESUMEN

The 18 kDa translocator protein (TSPO) is increasingly used to study brain and spinal cord inflammation in degenerative diseases of the CNS such as multiple sclerosis. The enhanced TSPO PET signal that arises during disease is widely considered to reflect activated pathogenic microglia, although quantitative neuropathological data to support this interpretation have not been available. With the increasing interest in the role of chronic microglial activation in multiple sclerosis, characterising the cellular neuropathology associated with TSPO expression is of clear importance for understanding the cellular and pathological processes on which TSPO PET imaging is reporting. Here we have studied the cellular expression of TSPO and specific binding of two TSPO targeting radioligands (3H-PK11195 and 3H-PBR28) in tissue sections from 42 multiple sclerosis cases and 12 age-matched controls. Markers of homeostatic and reactive microglia, astrocytes, and lymphocytes were used to investigate the phenotypes of cells expressing TSPO. There was an approximate 20-fold increase in cells double positive for TSPO and HLA-DR in active lesions and in the rim of chronic active lesion, relative to normal appearing white matter. TSPO was uniformly expressed across myeloid cells irrespective of their phenotype, rather than being preferentially associated with pro-inflammatory microglia or macrophages. TSPO+ astrocytes were increased up to 7-fold compared to normal-appearing white matter across all lesion subtypes and accounted for 25% of the TSPO+ cells in these lesions. To relate TSPO protein expression to ligand binding, specific binding of the TSPO ligands 3H-PK11195 and 3H-PBR28 was determined in the same lesions. TSPO radioligand binding was increased up to seven times for 3H-PBR28 and up to two times for 3H-PK11195 in active lesions and the centre of chronic active lesions and a strong correlation was found between the radioligand binding signal for both tracers and the number of TSPO+ cells across all of the tissues examined. In summary, in multiple sclerosis, TSPO expression arises from microglia of different phenotypes, rather than being restricted to microglia which express classical pro-inflammatory markers. While the majority of cells expressing TSPO in active lesions or chronic active rims are microglia/macrophages, our findings also emphasize the significant contribution of activated astrocytes, as well as smaller contributions from endothelial cells. These observations establish a quantitative framework for interpretation of TSPO in multiple sclerosis and highlight the need for neuropathological characterization of TSPO expression for the interpretation of TSPO PET in other neurodegenerative disorders.


Asunto(s)
Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/genética , Receptores de GABA/genética , Acetamidas , Anciano , Anciano de 80 o más Años , Astrocitos/patología , Autopsia , Femenino , Genotipo , Homeostasis , Humanos , Isoquinolinas , Linfocitos/patología , Masculino , Microglía/patología , Persona de Mediana Edad , Esclerosis Múltiple/patología , Tomografía de Emisión de Positrones , Piridinas , Radiofármacos
11.
Brain ; 141(2): 459-471, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29272357

RESUMEN

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = -23.30%, 95% confidence interval -40.9 to -5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.


Asunto(s)
Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Microglía/efectos de los fármacos , Minociclina/uso terapéutico , Enfermedades Neurodegenerativas/etiología , Adulto , Anciano , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Estudios Transversales , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Microglía/patología , Persona de Mediana Edad , Enfermedades Neurodegenerativas/inducido químicamente , Proteínas de Neurofilamentos/metabolismo , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Pirimidinas/farmacocinética , Estadísticas no Paramétricas , Adulto Joven
12.
Biochem J ; 474(23): 3985-3999, 2017 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-29074640

RESUMEN

The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.


Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Proteínas Portadoras/genética , Hidrocortisona/sangre , Polimorfismo de Nucleótido Simple , Receptores de GABA-A/genética , Receptores de GABA/genética , Adolescente , Adulto , Animales , Secuencia de Bases , Proteínas Portadoras/metabolismo , Ésteres del Colesterol/biosíntesis , Ésteres del Colesterol/sangre , Gonadotropina Coriónica/farmacología , Clonación Molecular , Corticosterona/biosíntesis , Corticosterona/sangre , Embrión de Mamíferos , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Humanos , Hidrocortisona/biosíntesis , Masculino , Plásmidos/química , Plásmidos/metabolismo , Pregnanolona/biosíntesis , Pregnanolona/sangre , Ratas , Ratas Transgénicas , Receptores de GABA/metabolismo , Receptores de GABA-A/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Testosterona/biosíntesis , Testosterona/sangre , Dedos de Zinc , Cigoto/efectos de los fármacos , Cigoto/crecimiento & desarrollo , Cigoto/metabolismo
13.
Rheumatology (Oxford) ; 56(11): 1837-1846, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28181650

RESUMEN

Imaging techniques, such as US, are well recognized as important tools to aid early diagnosis and assess response to treatment in RA. PET offers a means of imaging the inflammatory processes of RA at a cellular level and thus may be a highly sensitive method of assessing synovitis. In this review we discuss the advantages of PET as an imaging modality for RA and summarize the existing clinical studies of PET in RA. We also highlight potentially important preclinical studies of PET in arthritis and discuss current limitations of PET as well as ongoing developments in PET technology likely to be of benefit for arthritis imaging.


Asunto(s)
Artritis Reumatoide/diagnóstico por imagen , Sinovitis/diagnóstico por imagen , Radioisótopos de Carbono , Colina , Fluorodesoxiglucosa F18 , Radioisótopos de Galio , Humanos , Radioisótopos de Yodo , Isoquinolinas , Tomografía de Emisión de Positrones , Radiofármacos , Receptores de GABA , Rituximab , Fluoruro de Sodio
14.
J Immunol ; 194(2): 761-72, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25505283

RESUMEN

In multiple sclerosis, successful remyelination within the injured CNS is largely dependent on the survival and differentiation of oligodendrocyte progenitor cells. During inflammatory injury, oligodendrocytes and oligodendrocyte progenitor cells within lesion sites are exposed to secreted products derived from both infiltrating immune cell subsets and CNS-resident cells. Such products may be considered either proinflammatory or anti-inflammatory and have the potential to contribute to both injury and repair processes. Within the CNS, astrocytes also contribute significantly to oligodendrocyte biology during development and following inflammatory injury. The overall objective of the current study was to determine how functionally distinct proinflammatory and anti-inflammatory human immune cell subsets, implicated in multiple sclerosis, can directly and/or indirectly (via astrocytes) impact human oligodendrocyte progenitor cell survival and differentiation. Proinflammatory T cell (Th1/Th17) and M1-polarized myeloid cell supernatants had a direct cytotoxic effect on human A2B5(+) neural progenitors, resulting in decreased O4(+) and GalC(+) oligodendrocyte lineage cells. Astrocyte-conditioned media collected from astrocytes pre-exposed to the same proinflammatory supernatants also resulted in decreased oligodendrocyte progenitor cell differentiation without an apparent increase in cell death and was mediated through astrocyte-derived CXCL10, yet this decrease in differentiation was not observed in the more differentiated oligodendrocytes. Th2 and M2 macrophage or microglia supernatants had neither a direct nor an indirect impact on oligodendrocyte progenitor cell differentiation. We conclude that proinflammatory immune cell responses can directly and indirectly (through astrocytes) impact the fate of immature oligodendrocyte-lineage cells, with oligodendrocyte progenitor cells more vulnerable to injury compared with mature oligodendrocytes.


Asunto(s)
Diferenciación Celular/inmunología , Sistema Nervioso Central/inmunología , Células-Madre Neurales/inmunología , Oligodendroglía/inmunología , Astrocitos/citología , Astrocitos/inmunología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Sistema Nervioso Central/citología , Quimiocina CXCL10/inmunología , Medios de Cultivo Condicionados/farmacología , Femenino , Humanos , Macrófagos/citología , Macrófagos/inmunología , Masculino , Células-Madre Neurales/citología , Oligodendroglía/citología , Células TH1/citología , Células TH1/inmunología , Células Th17/citología , Células Th17/inmunología , Células Th2/citología , Células Th2/inmunología
15.
Brain ; 138(Pt 5): 1138-59, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25823474

RESUMEN

The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease.


Asunto(s)
Lesiones Encefálicas/terapia , Encéfalo/crecimiento & desarrollo , Homeostasis/fisiología , Microglía/citología , Neurogénesis/fisiología , Animales , Encéfalo/patología , Lesiones Encefálicas/patología , Humanos , MicroARNs/metabolismo
16.
Nat Commun ; 15(1): 2243, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38472200

RESUMEN

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased ß-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Angiogénesis , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Perfilación de la Expresión Génica
17.
Eur Heart J ; 33(15): 1902-10, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21933781

RESUMEN

AIMS: We sought to determine whether intraplaque inflammation could be measured with positron emission tomography/computed tomography angiography (PET/CTA) using (11)C-PK11195, a selective ligand of the translocator protein (18 kDa) (TSPO) which is highly expressed by activated macrophages. METHODS AND RESULTS: Patients (n = 32; mean age 70 ± 9 years) with carotid stenoses (n = 36; 9 symptomatic and 27 asymptomatic) underwent (11)C-PK11195 PET/CTA imaging. (11)C-PK11195 uptake into carotid plaques was measured using target-to-background ratios (TBR). On CTA images, plaque composition was assessed by measuring CT attenuation of the carotid plaque. Eight patients underwent carotid endarterectomy and ultrathin contiguous sections were processed for TSPO and CD68 (using immunohistochemical staining, (3)H-PK11195 autoradiography, and confocal fluorescence microscopy). Carotid plaques associated with ipsilateral symptoms (stroke or transient ischaemic attack) had higher TBR (1.06 ± 0.20 vs. 0.86 ± 0.11, P = 0.001) and lower CT attenuation [(median, inter-quartile range) 37, 24-40 vs. 71, 56-125 HU, P = 0.01] than those without. On immunohistochemistry and confocal fluorescence microscopy, CD68 and PBR co-localized with (3)H-PK11195 uptake at autoradiography. There was a significant correlation between (11)C-PK11195 TBR and autoradiographic percentage-specific binding (r = 0.77, P = 0.025). Both TBR and CT plaque attenuation had high negative predictive values (91 and 92%, respectively) for detecting symptomatic patients. However, the best positive predictive value (100%) was achieved when TBR and CT attenuation were combined. CONCLUSION: Imaging intraplaque inflammation in vivo with (11)C-PK11195 PET/CTA is feasible and can distinguish between recently symptomatic and asymptomatic plaques. Patients with a recent ischaemic event had ipsilateral plaques with lower CT attenuation and increased (11)C-PK11195 uptake.


Asunto(s)
Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Estenosis Carotídea/diagnóstico por imagen , Isoquinolinas , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones , Radiofármacos , Tomografía Computarizada por Rayos X , Anciano , Autorradiografía , Radioisótopos de Carbono , Femenino , Humanos , Inmunohistoquímica , Masculino , Microscopía Fluorescente , Persona de Mediana Edad
18.
Percept Mot Skills ; 130(1): 434-460, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36176046

RESUMEN

A large portion of the U.S. population desires to lose weight, but only a small portion maintains a desirable body weight. We examined weight loss success and the psychological benefits of exercise among men and women who were obese and initially sedentary (N = 33). These participants completed anthropometric assessments and psychological inventories before and after graded exercise tests (GXTs) at the beginning and end of their enrollment in a 6-month behavioral weight loss program (BWLP). Participants significantly decreased their body weight, body mass index (BMI), and % body fat; they also increased their aerobic capacity and exercise time. They reported long-term increases in their stage of change, self-efficacy, exercise enjoyment and processes of change. They also reported immediate changes toward more positive affect, as measured with pre-to post-GXTs on both the Profile of Mood States (POMS) and State Anxiety Subscale (A-State) at the beginning and again at end of the BWLP. Mood benefits were reported on the POMS subscales of Tension, Depression, Anger, Vigor, and Confusion. At the end of the BWLP, Fatigue and Confusion continued to improve after a 20-min post-GXT recovery period. Finally, reductions in Depression and Fatigue after the first GXT were correlated with program success, as indicated by decreases in BMI, percent body fat, and body weight. Initial scores on trait enjoyment were associated with decreased BMI and body weight. Psychological benefits of exercise may help individuals who are obese and sedentary change their behavior and exercise perceptions from something they "should do" to something they "want to do." Feeling good during weight loss efforts is an important pathway to change and should be an explicit component goal of BWLPs.


Asunto(s)
Emociones , Ejercicio Físico , Masculino , Humanos , Femenino , Afecto , Obesidad/terapia , Obesidad/psicología , Fatiga , Pérdida de Peso
19.
Front Neuroimaging ; 2: 1142463, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37554649

RESUMEN

Objective: Translocator protein (TSPO) targeting positron emission tomography (PET) imaging radioligands have potential utility in epilepsy to assess the efficacy of novel therapeutics for targeting neuroinflammation. However, previous studies in healthy volunteers have indicated limited test-retest reliability of TSPO ligands. Here, we examine test-retest measures using TSPO PET imaging in subjects with epilepsy and healthy controls, to explore whether this biomarker can be used as an endpoint in clinical trials for epilepsy. Methods: Five subjects with epilepsy and confirmed mesial temporal lobe sclerosis (mean age 36 years, 3 men) were scanned twice-on average 8 weeks apart-using a second generation TSPO targeting radioligand, [11C]PBR28. We evaluated the test-retest reliability of the volume of distribution and derived hemispheric asymmetry index of [11C]PBR28 binding in these subjects and compared the results with 8 (mean age 45, 6 men) previously studied healthy volunteers. Results: The mean (± SD) of the volume of distribution (VT), of all subjects, in patients living with epilepsy for both test and retest scans on all regions of interest (ROI) is 4.49 ± 1.54 vs. 5.89 ± 1.23 in healthy volunteers. The bias between test and retest in an asymmetry index as a percentage was small (-1.5%), and reliability is demonstrated here with Bland-Altman Plots (test mean 1.062, retest mean 2.56). In subjects with epilepsy, VT of [11C]PBR28 is higher in the (ipsilateral) hippocampal region where sclerosis is present than in the contralateral region. Conclusion: When using TSPO PET in patients with epilepsy with hippocampal sclerosis (HS), an inter-hemispheric asymmetry index in the hippocampus is a measure with good test-retest reliability. We provide estimates of test-retest variability that may be useful for estimating power where group change in VT represents the clinical outcome.

20.
Brain Commun ; 5(2): fcad084, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37020532

RESUMEN

Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington's disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller-Gartner algorithm) were applied. Differences were sought in Unified Huntington's Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.

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