RESUMO
Biomarker research across the health-to-disease continuum is being increasingly applied. We applied blood-based metabolomics in order to identify patient clusters with a first demyelinating episode, and explored the prognostic potential of the method by thoroughly characterizing each cluster in terms of clinical, laboratory and MRI markers of established prognostic potential for Multiple Sclerosis (MS). Recruitment consisted of 11 patients with Clinically Isolated Syndrome (CIS), 37 patients with a first demyelinating episode in the context of Relapsing-Remitting MS (RRMS) and 11 control participants. Blood-based metabolomics and hierarchical clustering analysis (HCL) were applied. Constructed OPLS-DA models illustrated a discrimination between patients with CIS and the controls (p = 0.0014), as well as between patients with RRMS and the controls (p = 1 × 10−5). Hierarchical clustering analysis (HCL) for patients with RRMS identified three clusters. RRMS-patients-cluster-3 exhibited higher mean cell numbers in the Cerebro-spinal Fluid (CSF) compared to patients with CIS (18.17 ± 6.3 vs. 1.09 ± 0.41, p = 0.004). Mean glucose CSF/serum ratio and infratentorial lesion burden significantly differed across CIS- and HCL-derived RRMS-patient clusters (F = 14.95, p < 0.001 and F = 6.087, p = 0.002, respectively), mainly due to increased mean values for patients with RRMS-cluster-3. HCL discriminated a cluster of patients with a first demyelinating episode in the context of RRMS with increased disability, laboratory findings linked with increased pathology burden and MRI markers of poor prognosis.
Assuntos
Doenças Desmielinizantes , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Progressão da Doença , Doenças Desmielinizantes/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/patologiaRESUMO
While the vast majority of Alzheimer's disease (AD) is non-familial, the animal models of AD that are commonly used for studying disease pathogenesis and development of therapy are mostly of a familial form. We aimed to generate a model reminiscent of the etiologies related to the common late-onset Alzheimer's disease (LOAD) sporadic disease that will recapitulate AD/dementia features. Naïve female mice underwent ovariectomy (OVX) to accelerate aging/menopause and were fed a high fat-sugar-salt diet to expose them to factors associated with increased risk of development of dementia/AD. The OVX mice fed a high fat-sugar-salt diet responded by dysregulation of glucose/insulin, lipid, and liver function homeostasis and increased body weight with slightly increased blood pressure. These mice developed AD-brain pathology (amyloid and tangle pathologies), gliosis (increased burden of astrocytes and activated microglia), impaied blood vessel density and neoangiogenesis, with cognitive impairment. Thus, OVX mice fed on a high fat-sugar-salt diet imitate a non-familial sporadic/environmental form of AD/dementia with vascular damage. This model is reminiscent of the etiologies related to the LOAD sporadic disease that represents a high portion of AD patients, with an added value of presenting concomitantly AD and vascular pathology, which is a common condition in dementia. Our model can, thereby, provide a valuable tool for studying disease pathogenesis and for the development of therapeutic approaches.
Assuntos
Doença de Alzheimer , Demência Vascular , Dieta Hiperlipídica , Modelos Animais de Doenças , Ovariectomia , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Feminino , Camundongos , Demência Vascular/etiologia , Demência Vascular/patologia , Ovariectomia/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Cloreto de Sódio na Dieta/efeitos adversos , Gliose/patologia , Encéfalo/patologia , Encéfalo/metabolismoRESUMO
Both Helicobacter pylori (H. pylori) infection and metabolic syndrome (MetS) are highly prevalent worldwide. The emergence of relevant research suggesting a pathogenic linkage between H. pylori infection and MetS-related cardio-cerebrovascular diseases and neurodegenerative disorders, particularly through mechanisms involving brain pericyte deficiency, hyperhomocysteinemia, hyperfibrinogenemia, elevated lipoprotein-a, galectin-3 overexpression, atrial fibrillation, and gut dysbiosis, has raised stimulating questions regarding their pathophysiology and its translational implications for clinicians. An additional stimulating aspect refers to H. pylori and MetS-related activation of innate immune cells, mast cells (MC), which is an important, often early, event in systemic inflammatory pathologies and related brain disorders. Synoptically, MC degranulation may play a role in the pathogenesis of H. pylori and MetS-related obesity, adipokine effects, dyslipidemia, diabetes mellitus, insulin resistance, arterial hypertension, vascular dysfunction and arterial stiffness, an early indicator of atherosclerosis associated with cardio-cerebrovascular and neurodegenerative disorders. Meningeal MC can be activated by triggers including stress and toxins resulting in vascular changes and neurodegeneration. Likewise, H.pylori and MetS-related MC activation is linked with: (a) vasculitis and thromboembolic events that increase the risk of cardio-cerebrovascular and neurodegenerative disorders, and (b) gut dysbiosis-associated neurodegeneration, whereas modulation of gut microbiota and MC activation may promote neuroprotection. This narrative review investigates the intricate relationship between H. pylori infection, MetS, MC activation, and their collective impact on pathophysiological processes linked to neurodegeneration. Through a comprehensive search of current literature, we elucidate the mechanisms through which H. pylori and MetS contribute to MC activation, subsequently triggering cascades of inflammatory responses. This highlights the role of MC as key mediators in the pathogenesis of cardio-cerebrovascular and neurodegenerative disorders, emphasizing their involvement in neuroinflammation, vascular dysfunction and, ultimately, neuronal damage. Although further research is warranted, we provide a novel perspective on the pathophysiology and management of brain disorders by exploring potential therapeutic strategies targeting H. pylori eradication, MetS management, and modulation of MC to mitigate neurodegeneration risk while promoting neuroprotection.
Assuntos
Encefalopatias , Infecções por Helicobacter , Helicobacter pylori , Síndrome Metabólica , Doenças Neurodegenerativas , Humanos , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Mastócitos/metabolismo , Disbiose/complicações , Infecções por Helicobacter/tratamento farmacológico , Doenças Neurodegenerativas/metabolismoRESUMO
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency of the survival motor neuron (SMN) protein. Although SMA is a genetic disease, environmental factors contribute to disease progression. Common pathogen components such as lipopolysaccharides (LPS) are considered significant contributors to inflammation and have been associated with muscle atrophy, which is considered a hallmark of SMA. In this study, we used the SMNΔ7 experimental mouse model of SMA to scrutinize the effect of systemic LPS administration, a strong pro-inflammatory stimulus, on disease outcome. Systemic LPS administration promoted a reduction in SMN expression levels in CNS, peripheral lymphoid organs, and skeletal muscles. Moreover, peripheral tissues were more vulnerable to LPS-induced damage compared to CNS tissues. Furthermore, systemic LPS administration resulted in a profound increase in microglia and astrocytes with reactive phenotypes in the CNS of SMNΔ7 mice. In conclusion, we hereby show for the first time that systemic LPS administration, although it may not precipitate alterations in terms of deficits of motor functions in a mouse model of SMA, it may, however, lead to a reduction in the SMN protein expression levels in the skeletal muscles and the CNS, thus promoting synapse damage and glial cells' reactive phenotype.
Assuntos
Modelos Animais de Doenças , Lipopolissacarídeos , Atrofia Muscular Espinal , Animais , Lipopolissacarídeos/farmacologia , Atrofia Muscular Espinal/patologia , Atrofia Muscular Espinal/metabolismo , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Camundongos Endogâmicos C57BL , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Inflamação/patologiaRESUMO
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with a profound neurodegenerative component early in the disease pathogenesis. Age is a factor with a well-described effect on the primary disease phenotype, namely, the relapsing-remitting vs. the primary progressive disease. Moreover, aging is a prominent factor contributing to the transition from relapsing-remitting MS (RRMS) to secondary progressive disease. However, sex also seems to, at least in part, dictate disease phenotype and evolution, as evidenced in humans and in animal models of the disease. Sex-specific gene expression profiles have recently elucidated an association with differential immunological signatures in the context of experimental disease. This review aims to summarize current knowledge stemming from experimental autoimmune encephalomyelitis (EAE) models regarding the effects of sex, either independently or as a factor combined with aging, on disease phenotype, with relevance to the immune system and the CNS.
RESUMO
Ocrelizumab is a B-cell-depleting monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) and active primary progressive MS (aPPMS). This prospective, uncontrolled, open-label, observational study aimed to assess the efficacy of ocrelizumab in patients with aPPMS and to dissect the clinical, radiological and laboratory attributes of treatment response. In total, 22 patients with aPPMS followed for 24 months were included. The primary efficacy outcome was the proportion of patients with optimal response at 24 months, defined as patients free of relapses, free of confirmed disability accumulation (CDA) and free of T1 Gd-enhancing lesions and new/enlarging T2 lesions on the brain and cervical MRI. In total, 14 (63.6%) patients and 13 patients (59.1%) were classified as responders at 12 and 24 months, respectively. Time exhibited a significant effect on mean absolute and normalized gray matter cerebellar volume (F = 4.342, p = 0.23 and F = 4.279, p = 0.024, respectively). Responders at 24 months exhibited reduced peripheral blood ((%) of CD19+ cells) plasmablasts compared to non-responders at the 6-month point estimate (7.69 ± 4.4 vs. 22.66 ± 7.19, respectively, p = 0.043). Response to ocrelizumab was linked to lower total and gray matter cerebellar volume loss over time. Reduced plasmablast depletion was linked for the first time to sub-optimal response to ocrelizumab in aPPMS.
Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Anticorpos Monoclonais Humanizados , Biomarcadores , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Estudos ProspectivosRESUMO
The localization of bacterial components and/or metabolites in the central nervous system may elicit neuroinflammation and/or neurodegeneration. Helicobacter pylori (a non-commensal symbiotic gastrointestinal pathogen) infection and its related metabolic syndrome have been implicated in the pathogenesis of gastrointestinal tract and central nervous system disorders, thus medications affecting the nervous system - gastrointestinal tract may shape the potential of Helicobacter pylori infection to trigger these pathologies. Helicobacter pylori associated metabolic syndrome, by impairing gut motility and promoting bacterial overgrowth and translocation, might lead to brain pathologies. Trimebutine maleate is a prokinetic drug that hastens gastric emptying, by inducing the release of gastrointestinal agents such as motilin and gastrin. Likewise, it appears to protect against inflammatory signal pathways, involved in inflammatory disorders including brain pathologies. Trimebutine maleate also acts as an antimicrobial agent and exerts opioid agonist effect. This study aimed to investigate a hypothesis regarding the recent advances in exploring the potential role of gastrointestinal tract microbiota dysbiosis-related metabolic syndrome and Helicobacter pylori in the pathogenesis of gastrointestinal tract and brain diseases. We hereby proposed a possible neuroprotective role for trimebutine maleate by altering the dynamics of the gut-brain axis interaction, thus suggesting an additional effect of trimebutine maleate on Helicobacter pylori eradication regimens against these pathologies.
Assuntos
Encefalopatias/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Trimebutina/uso terapêutico , Encefalopatias/epidemiologia , Encefalopatias/fisiopatologia , Disbiose/tratamento farmacológico , Disbiose/epidemiologia , Disbiose/fisiopatologia , Fármacos Gastrointestinais/farmacologia , Gastroenteropatias/epidemiologia , Gastroenteropatias/fisiopatologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/fisiologia , Humanos , Resultado do Tratamento , Trimebutina/farmacologiaRESUMO
An increase of multiple sclerosis (MS) incidence has been reported during the last decade, and this may be connected to environmental factors. This review article aims to encapsulate the current advances targeting the study of the gut-brain axis, which mediates the communication between the central nervous system and the gut microbiome. Clinical data arising from many research studies, which have assessed the effects of administered disease-modifying treatments in MS patients to the gut microbiome, are also recapitulated.