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Neuropsychiatric diseases have traditionally been studied from brain, and mind-centric perspectives. However, mounting epidemiological and clinical evidence shows a strong correlation of neuropsychiatric manifestations with immune system activation, suggesting a likely mechanistic interaction between the immune and nervous systems in mediating neuropsychiatric disease. Indeed, immune mediators such as cytokines, antibodies, and complement proteins have been shown to affect various cellular members of the central nervous system in multitudinous ways, such as by modulating neuronal firing rates, inducing cellular apoptosis, or triggering synaptic pruning. These observations have in turn led to the exciting development of clinical therapies aiming to harness this neuro-immune interaction for the treatment of neuropsychiatric disease and symptoms. Besides the clinic, important theoretical fundamentals can be drawn from the immune system and applied to our understanding of the brain and neuropsychiatric disease. These new frameworks could lead to novel insights in the field and further potentiate the development of future therapies to treat neuropsychiatric disease.
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Trastornos Neurocognitivos/inmunología , Neuroinmunomodulación , Animales , Encéfalo , Citocinas , Humanos , NeuronasRESUMEN
Aseptic surgical trauma provokes the release of HMGB1, which engages the innate immune response after binding to pattern-recognition receptors on circulating bone marrow-derived monocytes (BM-DM). The initial systemic inflammation, together with HMGB1, disrupts the blood-brain barrier allowing penetration of CCR2-expressing BM-DMs into the hippocampus, attracted by the chemokine MCP-1 that is upregulated by HMGB1. Within the brain parenchyma quiescent microglia are activated and, together with the translocated BM-DMs, release proinflammatory cytokines that disrupt synaptic plasticity and hence memory formation and retention, resulting in postoperative cognitive decline (PCD). Neutralizing antibodies to HMGB1 prevents the inflammatory response to trauma and PCD.
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Proteína HMGB1/metabolismo , Trastornos Neurocognitivos/metabolismo , Animales , Modelos Animales de Enfermedad , Proteína HMGB1/genética , Proteína HMGB1/inmunología , Humanos , Trastornos Neurocognitivos/genética , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/patología , Periodo Perioperatorio , Procesamiento Proteico-PostraduccionalRESUMEN
Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) derived lipids play key roles in initiating and resolving inflammation. Neuro-inflammation is thought to play a causal role in perioperative neurocognitive disorders, yet the role of these lipids in the human central nervous system in such disorders is unclear. Here we used liquid chromatography-mass spectrometry to quantify AA, DHA, and EPA derived lipid levels in non-centrifuged cerebrospinal fluid (CSF), centrifuged CSF pellets, and centrifuged CSF supernatants of older adults obtained before, 24 h and 6 weeks after surgery. GAGE analysis was used to determine AA, DHA and EPA metabolite pathway changes over time. Lipid mediators derived from AA, DHA and EPA were detected in all sample types. Postoperative lipid mediator changes were not significant in non-centrifuged CSF (p > 0.05 for all three pathways). The AA metabolite pathway showed significant changes in centrifuged CSF pellets and supernatants from before to 24 h after surgery (p = 0.0000247, p = 0.0155 respectively), from before to 6 weeks after surgery (p = 0.0000497, p = 0.0155, respectively), and from 24 h to 6 weeks after surgery (p = 0.0000499, p = 0.00363, respectively). These findings indicate that AA, DHA, and EPA derived lipids are detectable in human CSF, and the AA metabolite pathway shows postoperative changes in centrifuged CSF pellets and supernatants.
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Factores Inmunológicos/líquido cefalorraquídeo , Metabolismo de los Lípidos/inmunología , Lípidos/inmunología , Trastornos Neurocognitivos/genética , Anciano , Anciano de 80 o más Años , Ácido Araquidónico/líquido cefalorraquídeo , Ácido Araquidónico/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Cromatografía Liquida , Ácidos Docosahexaenoicos/líquido cefalorraquídeo , Ácidos Docosahexaenoicos/inmunología , Ácido Eicosapentaenoico/líquido cefalorraquídeo , Ácido Eicosapentaenoico/inmunología , Femenino , Humanos , Factores Inmunológicos/inmunología , Inflamación/líquido cefalorraquídeo , Inflamación/inmunología , Lípidos/líquido cefalorraquídeo , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Trastornos Neurocognitivos/líquido cefalorraquídeo , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/patología , Medicina PerioperatoriaRESUMEN
BACKGROUND: Schizophrenia (SCZ) and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased high mobility group protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-related protein (DKK1), a Wnt/ß-catenin signaling antagonist, affect the blood-brain barrier and induce neurotoxic effects and neurocognitive deficits. AIM: The present study aims to examine HMGB1 and DDK1 in nonresponders to treatments (NRTT) with antipsychotics (n = 60), partial RTT (PRTT, n = 55), and healthy controls (n = 43) in relation to established markers of SCZ, including interleukin (IL)-6, IL-10, and CCL11 (eotaxin), and to delineate whether these proteins are associated with the SCZ symptom subdomains and neurocognitive impairments. RESULTS: HMGB1, DKK1, IL-6, and CCL11 were significantly higher in SCZ patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls, while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that SCZ was best predicted by increased DDK1 and HMGB1, while NRTT (vs PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism, and negative (PHEMN) symptoms and formal thought disorders was explained by HMGB1, IL-6, and CCL11, while most neurocognitive functions were predicted by HMGB1, DDK1, and CCL11. CONCLUSIONS: The neurotoxic effects of HMGB1, DKK1, IL-6, and CCL11 including the effects on the blood-brain barrier and the Wnt/ß-catenin signaling pathway may cause impairments in executive functions and working, episodic, and semantic memory and explain, in part, PHEMN symptoms and a nonresponse to treatment with antipsychotic drugs.
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Antipsicóticos/farmacología , Quimiocina CCL11/sangre , Función Ejecutiva , Proteína HMGB1/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Interleucina-6/sangre , Trastornos de la Memoria , Trastornos Neurocognitivos , Esquizofrenia , Adolescente , Adulto , Función Ejecutiva/fisiología , Femenino , Humanos , Masculino , Trastornos de la Memoria/sangre , Trastornos de la Memoria/inmunología , Trastornos de la Memoria/fisiopatología , Persona de Mediana Edad , Trastornos Neurocognitivos/sangre , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/fisiopatología , Esquizofrenia/sangre , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inmunología , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the involvement of nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in schizophrenia-like behaviour in young animals exposed to maternal immune activation (MIA). METHODS: To this aim, on the 15th gestational day, the females received an injection of lipopolysaccharides. When the animals completed 7, 14 and 45 postnatal days, they were killed and the whole brain was dissected for biochemical analysis. Animals with 45 postnatal days were submitted to behavioural tests of locomotor activity, social interaction and stereotyped movements. RESULTS: It was observed that the animals presented schizophrenia-like behaviour at 45 postnatal days associated with the increase of NLRP3 inflammasome expression and IL-1ß levels on 7, 14 and 45 postnatal days. CONCLUSION: This study shows that MIA may be associated with a schizophrenia-like behaviour. This behaviour can be induced to a neuroinflammatory profile in the brain. These evidences may base future studies on the relationship between neuroinflammation and psychiatric disorders.
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Animales Recién Nacidos/psicología , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Esquizofrenia/diagnóstico , Animales , Animales Recién Nacidos/metabolismo , Escala de Evaluación de la Conducta/normas , Encéfalo/metabolismo , Femenino , Edad Gestacional , Conducta de Enfermedad/fisiología , Inmunidad Activa/efectos de los fármacos , Inflamasomas/inmunología , Inyecciones Intraperitoneales , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Madres , Trastornos Neurocognitivos/inmunología , Esquizofrenia/sangreRESUMEN
HIV associated neurocognitive disorders (HAND) are the spectrum of cognitive impairments present in patients infected with human immunodeficiency virus type 1 (HIV-1). The number of patients affected with HAND ranges from 30 to 50% of HIV infected individuals and although the development of combinational antiretroviral therapy (cART) has improved longevity, HAND continues to pose a significant clinical problem as the current standard of care does not alleviate or prevent HAND symptoms. At present, the pathological mechanisms contributing to HAND remain unclear, but evidence suggests that it stems from neuronal injury due to chronic release of neurotoxins, chemokines, viral proteins, and proinflammatory cytokines secreted by HIV-1 activated microglia, macrophages and astrocytes in the central nervous system (CNS). Furthermore, the blood-brain barrier (BBB) not only serves as a route for HIV-1 entry into the brain but also prevents cART therapy from reaching HIV-1 brain reservoirs, and therefore could play an important role in HAND. The goal of this review is to discuss the current data on the epidemiology, pathology and research models of HAND as well as address the potential pharmacological treatment approaches that are being investigated.
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Antiinfecciosos/farmacología , Antiinflamatorios/farmacología , Antirretrovirales/farmacología , Cannabinoides/farmacología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Infecciones por VIH/complicaciones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipoglucemiantes/farmacología , Factores Inmunológicos/farmacología , Trastornos Neurocognitivos/tratamiento farmacológico , Trastornos Neurocognitivos/etiología , Animales , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Trastornos Neurocognitivos/diagnóstico , Trastornos Neurocognitivos/inmunologíaRESUMEN
Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/ß-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit ß-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to ß-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of ß-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of ß-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect ß-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.
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Analgésicos Opioides/efectos adversos , Infecciones por VIH/complicaciones , VIH-1/efectos de los fármacos , Morfina/efectos adversos , Trastornos Neurocognitivos/etiología , Trastornos Relacionados con Sustancias/complicaciones , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/inmunología , Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Astrocitos/virología , Línea Celular , Células Cultivadas , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/virología , Trastornos Relacionados con Sustancias/inmunología , beta Catenina/inmunologíaRESUMEN
Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in a cross-sectional study that enrolled schizophrenia patients with (n = 40) and without (n = 40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial least squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), which lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA, and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.
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Arildialquilfosfatasa/fisiología , Inmunoglobulina M/inmunología , Malondialdehído/sangre , Trastornos Neurocognitivos/etiología , Neuroinmunomodulación/fisiología , Esquizofrenia/sangre , Psicología del Esquizofrénico , Factor de Necrosis Tumoral alfa/sangre , Adolescente , Adulto , Anciano , Especificidad de Anticuerpos , Antipsicóticos/uso terapéutico , Arildialquilfosfatasa/inmunología , Índice de Masa Corporal , Femenino , Humanos , Inmunidad Innata , Interleucina-4/sangre , Interleucina-6/sangre , Análisis de los Mínimos Cuadrados , Modelos Logísticos , Masculino , Malondialdehído/inmunología , Persona de Mediana Edad , Trastornos Neurocognitivos/sangre , Trastornos Neurocognitivos/inmunología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inmunología , Índice de Severidad de la Enfermedad , Factores Socioeconómicos , Factor de Necrosis Tumoral alfa/fisiología , Adulto JovenRESUMEN
The human immunodeficiency virus-1 (HIV-1) envelope protein gp120 is the major contributor to the pathogenesis of HIV-associated neurocognitive disorder (HAND). Neuroinflammation plays a pivotal role in gp120-induced neuropathology, but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown. Here, we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy. Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1ß production in microglia. Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury. Importantly, we showed that chronic administration of MCC950, a novel selective NLRP3 inhibitor, to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function. In conclusion, our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.
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Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Trastornos Neurocognitivos/inmunología , Neuronas/inmunología , Piroptosis/inmunología , Animales , Línea Celular , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/genética , Ratones , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Trastornos Neurocognitivos/genética , Trastornos Neurocognitivos/patología , Neuronas/patología , Piroptosis/genéticaRESUMEN
INTRODUCTION: The demographics of aging of the surgical population has increased the risk for perioperative neurocognitive disorders in which trauma-induced neuroinflammation plays a pivotal role. SOURCES OF DATA: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. AREAS OF AGREEMENT: Neuroinflammation is a sine qua non for development of perioperative neurocognitive disorders. AREAS OF CONTROVERSY: What is the best method for ameliorating trauma-induced neuroinflammation while preserving inflammation-based wound healing. GROWING POINTS: This review considers how to prepare for and manage the vulnerable elderly surgical patient through the entire spectrum, from preoperative assessment to postoperative period. AREAS TIMELY FOR DEVELOPING RESEARCH: What are the most effective and safest interventions for preventing and/or reversing Perioperative Neurocognitive Disorders.
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Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Trastornos Neurocognitivos/tratamiento farmacológico , Trastornos Neurocognitivos/prevención & control , Atención Perioperativa , Envejecimiento/inmunología , Humanos , Inflamación/inmunología , Inflamación/prevención & control , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/fisiopatología , Factores de Riesgo , Cicatrización de Heridas/inmunologíaRESUMEN
Today, HIV-infected (HIV+) patients can be treated efficiently with combined antiretroviral therapy (cART), leading to long-term suppression of viral load, in turn increasing life expectancy. While cART reduced the occurrence of HIV-associated dementia, the prevalence of subtle forms of HIV-associated neurocognitive disorders (HAND) is unchanged. This is related to persistent immune activation within the CNS, which is not addressed by cART. Pathologic processes leading to HAND consist of the release of proinflammatory cytokines, chemokines, reactive oxygen metabolites and glutamate, and the release of HIV proteins. Some of those processes can be targeted using medications with immunomodulatory and neuroprotective properties such as dimethyl fumarate, teriflunomide, or minocycline. In this review, we will summarize the knowledge about key pathogenic processes involved in HAND and potential therapeutic avenues to target HAND.
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Infecciones por VIH , Factores Inmunológicos/uso terapéutico , Trastornos Neurocognitivos , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Humanos , Trastornos Neurocognitivos/tratamiento farmacológico , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/inmunologíaRESUMEN
HIV associated neurocognitive disorders (HAND) is a unique form of neurological impairment that stems from HIV. This disease and its characteristics can be accredited to incorporation of DNA and mRNA of HIV-1 into the CNS. A proper understanding of the intricacies of HAND and the underlying mechanisms associated with corresponding immune reactions are vital for the potential development of a reliable treatment for HAND. A common phenomenon observed in CNS cells, specifically microglia, that are infected with HAND is inflammation, which is a consequence of the activation of innate immune response due to a variety of stimuli, in this case, being the HIV infection. The CNS based inflammation is mediated by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers, which occurs at CNS glia, endothelial cells and peripherally derived immune cells. Inflammasomes play a significant role with regard to neuroinflammation due to their ability to dictate the activation of various inflammatory responses. Certain stimuli can result in the activation of caspase-1; hence, leading to the processing of interleukin-1ß and interleukin-18 pro-inflammatory cytokines. The processed IL-1ß and IL-18 activate signaling pathways that begin the process of neuroinflammation. Due to the fact that the NLRP3 inflammasome is the most abundant in the CNS, it is the most extensively investigated inflammasome with regard to the nervous system. Due to the importance of neuroinflammation in the evolution of HAND and proliferation of neuroinflammation due to HAND, it can be concluded that there exists a relationship between HAND and inflammasomes. The aim of our review is to consolidate current knowledge of important mechanisms in HAND, specifically related to its relationship with neuroinflammation and inflammasomes to shed light on a possible improved treatment for HAND.
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Complejo SIDA Demencia/fisiopatología , Inflamasomas/fisiología , Trastornos Neurocognitivos/fisiopatología , Neuroinmunomodulación/fisiología , Complejo SIDA Demencia/inmunología , Sistema Nervioso Central/fisiopatología , Citocinas/metabolismo , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , VIH-1/inmunología , VIH-1/patogenicidad , Humanos , Inmunidad Innata , Inflamasomas/inmunología , Inflamación/metabolismo , Microglía/inmunología , Trastornos Neurocognitivos/inmunología , Neuroinmunomodulación/inmunología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Viral infection in the brain can be acute or chronic, with the responses often producing foci of increasingly cytotoxic inflammation. This can lead to effects beyond the central nervous system (CNS). To stimulate discussion, this commentary addresses four questions: What drives the development of human immunodeficiency virus (HIV)-associated neurocognitive disorders, does the phenotype of macrophages in the CNS spur development of HIV encephalitis (HIVE), does continual activation of astrocytes drive the development of HIV-associated neurocognitive disorders/subclinical disease, and neuroinflammation: friend or foe? A unifying theory that connects each question is the issue of continued activation of glial cells, even in the apparent absence of simian immunodeficiency virus/HIV in the CNS. As the CNS innate immune system is distinct from the rest of the body, it is likely there could be a number of activation profiles not observed elsewhere.
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Enfermedades Virales del Sistema Nervioso Central/inmunología , Infecciones por VIH/inmunología , Inflamación/virología , Trastornos Neurocognitivos/inmunología , Animales , Astrocitos/inmunología , Astrocitos/virología , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/virología , Enfermedades Virales del Sistema Nervioso Central/patología , Enfermedad Crónica , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Humanos , Inflamación/patología , Macrófagos/inmunología , Macrófagos/virología , Trastornos Neurocognitivos/virología , Neuroglía/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidadRESUMEN
RATIONALE: Deficit schizophrenia, as defined by the Schedule for Deficit Syndrome, may represent a distinct diagnostic class defined by neurocognitive impairments coupled with changes in IgA/IgM responses to tryptophan catabolites (TRYCATs). Adequate classifications should be based on supervised and unsupervised learning rather than on consensus criteria. METHODS: This study used machine learning as means to provide a more accurate classification of patients with stable phase schizophrenia. RESULTS: We found that using negative symptoms as discriminatory variables, schizophrenia patients may be divided into two distinct classes modelled by (A) impairments in IgA/IgM responses to noxious and generally more protective tryptophan catabolites, (B) impairments in episodic and semantic memory, paired associative learning and false memory creation, and (C) psychotic, excitation, hostility, mannerism, negative, and affective symptoms. The first cluster shows increased negative, psychotic, excitation, hostility, mannerism, depression and anxiety symptoms, and more neuroimmune and cognitive disorders and is therefore called "major neurocognitive psychosis" (MNP). The second cluster, called "simple neurocognitive psychosis" (SNP) is discriminated from normal controls by the same features although the impairments are less well developed than in MNP. The latter is additionally externally validated by lowered quality of life, body mass (reflecting a leptosome body type), and education (reflecting lower cognitive reserve). CONCLUSIONS: Previous distinctions including "type 1" (positive)/"type 2" (negative) and DSM-IV-TR (eg, paranoid) schizophrenia could not be validated using machine learning techniques. Previous names of the illness, including schizophrenia, are not very adequate because they do not describe the features of the illness, namely, interrelated neuroimmune, cognitive, and clinical features. Stable-phase schizophrenia consists of 2 relevant qualitatively distinct categories or nosological entities with SNP being a less well-developed phenotype, while MNP is the full blown phenotype or core illness. Major neurocognitive psychosis and SNP should be added to the DSM-5 and incorporated into the Research Domain Criteria project.
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Reserva Cognitiva/fisiología , Trastornos Psicóticos , Calidad de Vida , Esquizofrenia , Triptófano/metabolismo , Aprendizaje Automático no Supervisado , Adulto , Síntomas Conductuales/diagnóstico , Citocinas/inmunología , Femenino , Humanos , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/psicología , Neuroinmunomodulación , Gravedad del Paciente , Escalas de Valoración Psiquiátrica , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/inmunología , Trastornos Psicóticos/psicología , Esquizofrenia/diagnóstico , Esquizofrenia/inmunología , Esquizofrenia/fisiopatología , Psicología del EsquizofrénicoRESUMEN
Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects roughly half the HIV-positive population. The symptoms of cognitive slowing, poor concentration, and memory problems can impact on everyday life. Its diagnosis is validated where possible by identifying deficits in two cognitive domains on neuropsychologic testing in patients either with or without symptoms. Corroborating evidence may be found on imaging, blood tests, and cerebrospinal fluid analysis, though sensitive and specific biomarkers are currently lacking. The introduction of combined antiretroviral therapy in the 1990s has generated a therapeutic paradox whereby the number of severe cases of HAND has fallen, yet milder forms continue to rise in prevalence. New emphasis has been placed on identifying the cause of apparent ongoing HIV infection and inflammation of the central nervous system (CNS) in the face of durable systemic viral suppression, and how this equates to the neuronal dysfunction underlying HAND. The interaction with aging and comorbidities is becoming increasingly common as the HIV-positive population enters older adulthood, with neurodegenerative, metabolic, and vascular causes of cognitive impairment combining and probably accelerating in the context of chronic HIV infection. Therapies targeted to the CNS, but without neurotoxic side-effects, are being investigated to attempt to reduce the likelihood of developing, and improving, HAND.
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Complejo SIDA Demencia/sangre , Complejo SIDA Demencia/diagnóstico , Infecciones por VIH/sangre , Infecciones por VIH/diagnóstico , Mediadores de Inflamación/sangre , Complejo SIDA Demencia/inmunología , Animales , Terapia Antirretroviral Altamente Activa/métodos , Biomarcadores/sangre , Infecciones por VIH/inmunología , Humanos , Mediadores de Inflamación/inmunología , Trastornos Neurocognitivos/sangre , Trastornos Neurocognitivos/diagnóstico , Trastornos Neurocognitivos/inmunologíaRESUMEN
HIV reservoirs persist despite antiretroviral therapy (ART) and are established within a few days after infection. Infected myeloid cells in the central nervous system (CNS) may contribute to the establishment of a CNS viral reservoir. The mature CD14+ CD16+ monocyte subset enters the CNS in response to chemokines, including CCL2. Entry of infected CD14+ CD16+ monocytes may lead to infection of other CNS cells, including macrophages or microglia and astrocytes, and to release of neurotoxic early viral proteins and additional cytokines. This contributes to neuroinflammation and neuronal damage leading to HIV-associated neurocognitive disorders (HAND) in ~50% of HIV-infected individuals despite ART. We examined the mechanisms of monocyte entry in the context of HIV infection and report for the first time that HIV+ CD14+ CD16+ monocytes preferentially transmigrate across the blood-brain barrier (BBB). The junctional proteins JAM-A and ALCAM and the chemokine receptor CCR2 are essential to their preferential transmigration across the BBB to CCL2. We show here that JAM-A and ALCAM are increased on HIV+ CD14+ CD16+ monocytes compared to their expression on HIVexp CD14+ CD16+ monocytes-cells that are uninfected but exposed to HIV, viral proteins, and inflammatory mediators. Antibodies against JAM-A and ALCAM and the novel CCR2/CCR5 dual inhibitor cenicriviroc prevented or significantly reduced preferential transmigration of HIV+ CD14+ CD16+ monocytes. This indicates that JAM-A, ALCAM, and CCR2 may be potential therapeutic targets to block entry of these infected cells into the brain and prevent or reduce the establishment and replenishment of viral reservoirs within the CNS.IMPORTANCE HIV infects different tissue compartments of the body, including the central nervous system (CNS). This leads to establishment of viral reservoirs within the CNS that mediate neuroinflammation and neuronal damage, contributing to cognitive impairment. Our goal was to examine the mechanisms of transmigration of cells that contribute to HIV infection of the CNS and to continued replenishment of CNS viral reservoirs, to establish potential therapeutic targets. We found that an HIV-infected subset of monocytes, mature HIV+ CD14+ CD16+ monocytes, preferentially transmigrates across the blood-brain barrier. This was mediated, in part, by increased junctional proteins JAM-A and ALCAM and chemokine receptor CCR2. We show that the CCR2/CCR5 dual inhibitor cenicriviroc and blocking antibodies against the junctional proteins significantly reduce, and often completely block, the transmigration of HIV+ CD14+ CD16+ monocytes. This suggests new opportunities to eliminate infection and seeding or reseeding of viral reservoirs within the CNS, thus reducing neuroinflammation, neuronal damage, and cognitive impairment.
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Sistema Nervioso Central/virología , Infecciones por VIH/virología , Monocitos/inmunología , Monocitos/virología , Trastornos Neurocognitivos/virología , Antígenos CD/genética , Barrera Hematoencefálica/inmunología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular Neuronal/genética , Sistema Nervioso Central/inmunología , Proteínas Fetales/genética , Proteínas Ligadas a GPI/inmunología , Infecciones por VIH/complicaciones , Humanos , Receptores de Lipopolisacáridos/inmunología , Monocitos/fisiología , Trastornos Neurocognitivos/inmunología , Trastornos Neurocognitivos/fisiopatología , Receptores CCR2/genética , Receptores CCR2/inmunología , Receptores de Superficie Celular/genética , Receptores de IgG/inmunologíaRESUMEN
Traumatic brain injury (TBI) results in rapid recruitment of leukocytes into the injured brain. Monocytes constitute a significant proportion of the initial infiltrate and have the potential to propagate secondary brain injury or generate an environment of repair and regeneration. Monocytes are a diverse population of cells (classical, intermediate, and nonclassical) with distinct functions, however, the recruitment order of these subpopulations to the injured brain largely remains unknown. Thus, we examined which monocyte subpopulations are required for the generation of early inflammatory infiltrate within the injured brain, and whether their depletion attenuates secondary injury or neurocognitive outcome. Global monocyte depletion correlated with significant improvements in brain edema, motor coordination, and working memory, and abrogated neutrophil infiltration into the injured brain. However, targeted depletion of classical monocytes alone had no effect on neutrophil recruitment to the site of injury, implicating the nonclassical monocyte in this process. In contrast, mice that have markedly reduced numbers of nonclassical monocytes (CX3CR1-/-) exhibited a significant reduction in neutrophil infiltration into the brain after TBI as compared with control mice. Our data suggest a critical role for nonclassical monocytes in the pathology of TBI in mice, including important clinical outcomes associated with mortality in this injury process.
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Lesiones Traumáticas del Encéfalo/inmunología , Macrófagos/inmunología , Trastornos Neurocognitivos/inmunología , Infiltración Neutrófila , Neutrófilos/inmunología , Animales , Lesiones Traumáticas del Encéfalo/fisiopatología , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Microambiente Celular , Edema , Humanos , Memoria a Corto Plazo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trastornos Neurocognitivos/fisiopatología , Desempeño PsicomotorRESUMEN
Vaccines against human papilloma virus (HPV) have been demonstrated to be very effective to prevent infection-related neoplasms. However, several reports describing heterogeneous post-vaccination phenomena have been published in last few years. The spectrum of these disorders includes both immune-mediated neurological diseases and neuropsychiatric functional disorders. Some researchers speculated about a genetic predisposition, but others hypothesized a role of adjuvants, including some metals and, particularly, aluminum. Here, we tested sixteen young girls developing somatoform and neurocognitive syndromes after the HPV immunization, through MELISA® test, detecting cell-mediated hypersensitivity to several metals. We found no association between these neurocognitive disorders and the results provided by this test; importantly, no patients showed hypersensitivity to aluminum, which is the inorganic adjuvant included in HPV vaccines. Thus, if aluminum played a role in the pathophysiology of musculoskeletal and neurocognitive disturbances occurring in some young girls after HPV immunization, that should recognize other mechanisms than the activation of aluminum-specific lymphocytes.
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Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Hipersensibilidad/etiología , Vacunas contra Papillomavirus/efectos adversos , Fosfatos/administración & dosificación , Adolescente , Adulto , Niño , Femenino , Humanos , Hipersensibilidad/sangre , Hipersensibilidad/inmunología , Linfocitos/inmunología , Metales/administración & dosificación , Metales/efectos adversos , Trastornos Neurocognitivos/sangre , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/inmunología , Vacunas contra Papillomavirus/administración & dosificación , Trastornos Somatomorfos/sangre , Trastornos Somatomorfos/etiología , Trastornos Somatomorfos/inmunología , Adulto JovenRESUMEN
Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing neuropsychiatric disorders, cognitive impairment, and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including cytokine/chemokine release, production of reactive oxygen species (ROS), circulating and local formation of trophic factors and of renin-angiotensin system (RAS) molecules, could also be involved, especially in the absence of obvious cerebrovascular disease. In this review, we discuss experimental and clinical evidence for the role of these mechanisms in kidney-brain cross-talk. In addition, we hypothesize potential pathways for the interactions between kidney and brain and their pathophysiological role in neuropsychiatric and cognitive changes found in patients with CKD. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment and to develop new strategies for innovative pharmacological treatment.
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Mediadores de Inflamación/metabolismo , Trastornos Neurocognitivos/etiología , Insuficiencia Renal Crónica/psicología , Encéfalo/inmunología , Citocinas/metabolismo , Humanos , Riñón/inmunología , Trastornos Neurocognitivos/inmunología , Estrés Oxidativo/fisiología , Insuficiencia Renal Crónica/inmunología , Sistema Renina-Angiotensina/fisiologíaRESUMEN
BACKGROUND: Human immunodeficiency virus (HIV)-associated neurocognitive disorders persist despite suppressive antiretroviral therapy (ART). Because latent Toxoplasma infection (LTI) may adversely impact brain function, we investigated its impact on neurocognitive impairment (NCI) in people living with HIV disease. METHODS: Two hundred sixty-three HIV-infected adults underwent comprehensive neurocognitive assessments and had anti-Toxoplasma gondii immunoglobulin G (anti-Toxo IgG) measured by qualitative and quantitative enzyme-linked immunosorbent assays. RESULTS: Participants were mostly middle-aged white men who were taking ART (70%). LTI was detected in 30 (11.4%) participants and was associated with a significantly greater prevalence of global NCI (LTI positive [LTI+] = 57% and LTI negative [LTI-] = 34%) (odds ratio, 1.67; 95% confidence interval, 1.17-2.40; P = .017). Deficits were more prevalent in the LTI+ vs the LTI- group in 6 of 7 cognitive domains with statistical significance reached for delayed recall (P < .01). The probability of NCI increased with higher CD4+ T-cell counts among LTI+ individuals but with lower CD4+ T-cell counts in LTI- persons. A strong correlation (r = .93) between anti-Toxo IgG levels and global deficit score was found in a subgroup of 9 patients. Biomarkers indicative of central nervous system inflammation did not differ between LTI+ and LTI- participants. CONCLUSIONS: In this cross-sectional analysis, LTI was associated with NCI, especially in those with higher CD4+ T-cell counts. Longitudinal studies to investigate the role of neuroinflammation and neuronal injury in LTI patients with NCI and trials of anti-Toxoplasma therapy should be pursued.