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1.
Braz J Psychiatry ; 46: e20233267, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38712923

RESUMEN

OBJECTIVES: Evidence from diffusion tensor imaging (DTI) and postmortem studies has demonstrated white-matter (WM) deficits in bipolar disorder (BD). Changes in peripheral blood biomarkers have also been observed; however, studies evaluating the potential relationship between brain alterations and the periphery are scarce. The objective of this systematic review is to investigate the relationship between blood-based biomarkers and WM in BD. METHODS: PubMed, Embase, and PsycINFO were used to conduct literature searches. Cross-sectional or longitudinal studies reporting original data which investigated both a blood-based biomarker and WM (by neuroimaging) in BD were included. RESULTS: Of 3,750 studies retrieved, 23 were included. Several classes of biomarkers were found to have a significant relationship with WM in BD. These included cytokines and growth factors (interleukin-8 [IL-8], tumor necrosis factor alpha [TNF-a], and insulin-like growth factor binding protein 3 [IGFBP-3]), innate immune system (natural killer cells [NK]), metabolic markers (lipid hydroperoxidase, cholesterol, triglycerides), the kynurenine (Kyn) pathway (5-hydroxyindoleacetic acid, kynurenic acid [Kyna]), and various gene polymorphisms (serotonin-transporter-linked promoter region). CONCLUSION: This systematic review revealed that blood-based biomarkers are associated with markers of WM deficits observed in BD. Longitudinal studies investigating the potential clinical utility of these specific biomarkers are encouraged.


Asunto(s)
Biomarcadores , Trastorno Bipolar , Vaina de Mielina , Sustancia Blanca , Trastorno Bipolar/sangre , Humanos , Biomarcadores/sangre , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Vaina de Mielina/patología , Citocinas/sangre
2.
J Neuroinflammation ; 21(1): 127, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38741181

RESUMEN

HIV-associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression through antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV protein Nef has been implicated in HAND pathogenesis, but its effect on white matter damage has not been well characterized. Here, utilizing in vivo, ex vivo, and in vitro methods, we demonstrate that Nef-containing extracellular vesicles (Nef EVs) disrupt myelin sheaths and inflict damage upon oligodendrocytes within the murine central nervous system. Intracranial injection of Nef EVs leads to reduced myelin basic protein (MBP) staining and a decreased number of CC1 + oligodendrocytes in the corpus callosum. Moreover, cerebellar slice cultures treated with Nef EVs exhibit diminished MBP expression and increased presence of unmyelinated axons. Primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures exposed to Nef EVs display a decreased number of O4 + cells, indicative of oligodendrocyte impairment. These findings underscore the potential contribution of Nef EV-mediated damage to oligodendrocytes and myelin maintenance in the pathogenesis of HAND.


Asunto(s)
Vesículas Extracelulares , VIH-1 , Ratones Endogámicos C57BL , Oligodendroglía , Productos del Gen nef del Virus de la Inmunodeficiencia Humana , Animales , Oligodendroglía/metabolismo , Oligodendroglía/patología , Oligodendroglía/virología , Ratones , Vesículas Extracelulares/metabolismo , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/metabolismo , VIH-1/metabolismo , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Células Cultivadas , Humanos , Masculino
3.
J Affect Disord ; 356: 363-370, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38615848

RESUMEN

BACKGROUND: Previous neuroimaging and pathological studies have found myelin-related abnormalities in bipolar disorder (BD), which prompted the use of magnetic resonance (MR) imaging technology sensitive to neuropathological changes to explore its neuropathological basis. We holistically investigated alterations in myelin within BD patients by inhomogeneous magnetization transfer (ihMT), which is sensitive and specific to myelin content. METHODS: Thirty-one BD and 42 healthy controls (HC) were involved. Four MR metrics, i.e., ihMT ratio (ihMTR), pseudo-quantitative ihMT (qihMT), magnetization transfer ratio and pseudo-quantitative magnetization transfer (qMT), were compared between groups using analysis methods based on whole-brain voxel-level and white matter regions of interest (ROI), respectively. RESULTS: The voxel-wise analysis showed significantly inter-group differences of ihMTR and qihMT in the corpus callosum. The ROI-wise analysis showed that ihMTR, qihMT, and qMT values in BD group were significantly lower than that in HC group in the genu and body of corpus callosum, left anterior limb of the internal capsule, left anterior corona radiate, and bilateral cingulum (p < 0.001). And the qihMT in genu of corpus callosum and right cingulum were negatively correlated with depressive symptoms in BD group. LIMITATIONS: This study is based on cross-sectional data and the sample size is limited. CONCLUSION: These findings suggest the reduced myelin content of anterior midline structure in the bipolar patients, which might be a critical pathophysiological feature of BD.


Asunto(s)
Trastorno Bipolar , Imagen por Resonancia Magnética , Vaina de Mielina , Humanos , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/patología , Femenino , Masculino , Adulto , Vaina de Mielina/patología , Persona de Mediana Edad , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Estudios de Casos y Controles , Encéfalo/diagnóstico por imagen , Encéfalo/patología
4.
Acta Neuropathol ; 147(1): 75, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38656399

RESUMEN

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa , Encefalomielitis Autoinmune Experimental , Microglía , Vaina de Mielina , Piperidinas , Pirimidinas , Animales , Femenino , Ratones , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Compuestos de Bifenilo/farmacología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Ratones Endogámicos C57BL , Microglía/patología , Microglía/efectos de los fármacos , Microglía/metabolismo , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Remielinización/fisiología , Remielinización/efectos de los fármacos
5.
Trends Mol Med ; 30(5): 459-470, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38582621

RESUMEN

Pelizaeus-Merzbacher disease (PMD) is caused by mutations in the proteolipid protein 1 (PLP1) gene encoding proteolipid protein (PLP). As a major component of myelin, mutated PLP causes progressive neurodegeneration and eventually death due to severe white matter deficits. Medical care has long been limited to symptomatic treatments, but first-in-class PMD therapies with novel mechanisms now stand poised to enter clinical trials. Here, we review PMD disease mechanisms and outline rationale for therapeutic interventions, including PLP1 suppression, cell transplantation, iron chelation, and intracellular stress modulation. We discuss available preclinical data and their implications on clinical development. With several novel treatments on the horizon, PMD is on the precipice of a new era in the diagnosis and treatment of patients suffering from this debilitating disease.


Asunto(s)
Proteína Proteolipídica de la Mielina , Vaina de Mielina , Enfermedad de Pelizaeus-Merzbacher , Enfermedad de Pelizaeus-Merzbacher/genética , Enfermedad de Pelizaeus-Merzbacher/terapia , Enfermedad de Pelizaeus-Merzbacher/diagnóstico , Enfermedad de Pelizaeus-Merzbacher/patología , Humanos , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Animales , Proteína Proteolipídica de la Mielina/genética , Proteína Proteolipídica de la Mielina/metabolismo , Mutación
6.
Neurology ; 102(7): e209174, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38513194

RESUMEN

BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Mutación de Línea Germinal , Femenino , Humanos , Masculino , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Vaina de Mielina/patología , Nervios Periféricos/diagnóstico por imagen , Fenotipo , Estudios Transversales , Estudios Retrospectivos , Linaje , Adulto Joven , Persona de Mediana Edad , Anciano
7.
Int J Mol Sci ; 25(6)2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38542441

RESUMEN

One of the major challenges in multiple sclerosis (MS) is to accurately monitor and quantify disability over time. Thus, there is a pressing need to identify new biomarkers for disease progression. Peripheral blood DNA methylation has been demonstrated to be an easily accessible and quantifiable marker in many neurodegenerative diseases. In this study, we aimed to investigate whether methylation patterns that were previously determined in chronic inactive white matter lesions of patients with progressive MS are also reflected in the blood, and whether the latter can serve as a biomarker for disease progression in MS. While our initial analysis revealed differences in the blood methylation state of important myelin-related genes between patients with progressive MS and controls, these findings could not be validated in other independent patient cohorts. Subsequent investigation suggests that sample storage can selectively influence DNA methylation patterns, potentially hindering accurate epigenetic analysis. Therefore, sample storage time should be taken into consideration during the initial sample selection stage in biomarker studies.


Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Vaina de Mielina/patología , Esclerosis Múltiple Crónica Progresiva/patología , Metilación de ADN , Biomarcadores , Progresión de la Enfermedad
8.
Ann Clin Transl Neurol ; 11(4): 973-988, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38425098

RESUMEN

OBJECTIVE: Multiple sclerosis (MS) is a chronic central nervous system disease whose white matter lesion origin remains debated. Recently, we reported subtle changes in the MS normal appearing white matter (NAWM), presenting with an increase in myelin blisters and myelin protein citrullination, which may recapitulate some of the prodromal degenerative processes involved in MS pathogenesis. Here, to clarify the relevance of these changes for subsequent MS myelin degeneration we explored their prevalence in WM regions characterized by subtly reduced myelination (dubbed as micro-diffusely abnormal white matter, mDAWM). METHODS: We used an in-depth (immuno)histochemistry approach in 27 MS donors with histological presence of mDAWM and 5 controls. An antibody panel against degenerative markers was combined and the presence of myelin/axonal aberrations was analyzed and compared with the NAWM from the same cases/slices/regions. RESULTS: mDAWM-defined areas exhibit ill-defined borders, no signs of Wallerian degeneration, and they associate with visible veins. Remarkably, such areas present with augmented myelin blister frequency, enhanced prevalence of polar myelin phospholipids, citrullination, and degradation of myelin basic protein (MBP) when compared with the NAWM. Furthermore, enhanced reactivity of microglia/macrophages against citrullinated MBP was also observed in this tissue. INTERPRETATION: We report a new histologically defined early phase in MS lesion formation, namely mDAWM, which lacks signs of Wallerian pathology. These results support the prelesional nature of the mDAWM. We conceptualize that evolution to pathologically evident lesions comprises the previously documented imbalance of axo-myelinic units (myelin blistering) leading to their degeneration and immune system activation by released myelin components.


Asunto(s)
Esclerosis Múltiple , Sustancia Blanca , Humanos , Vaina de Mielina/patología , Esclerosis Múltiple/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Vesícula/patología , Imagen por Resonancia Magnética/métodos , Enfermedad Crónica
9.
BMC Vet Res ; 20(1): 90, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38459498

RESUMEN

BACKGROUND: Multiple sclerosis (MS) is a chronic condition that primarily manifests as demyelination of neuronal axons in the central nervous system, due to the loss or attack of oligodendroglia cells that form myelin. Stem cell therapy has shown promising results for the treatment of MS due to its capability to halt the immune attack, stop apoptosis and axonal degeneration, and differentiate into oligodendrocytes. Stem cell-derived Exosomes (Exosomes) have shown great capabilities for neuronal diseases as they have growth factors, complex sets of miRNA, enzymes, proteins, major peptides, lipids, and macromolecules with anti-inflammatory, angiogenesis, and neurogenesis activities. METHODS: This study aimed to compare the healing properties of stem cells, against Exosomes for the treatment of an experimentally induced MS dog model. Dog models of MS received either a single treatment of stem cells or a single treatment of Exosomes intrathecally and the treatment process was evaluated clinically, radiologically, histopathologically, and electron microscopy and cerebrospinal fluid analysis. RESULTS: showed marked amelioration of the clinical signs in both treated groups compared to the control one, magnetic resonance scans showed the resolution of the hyperintense lesions at the end of the study period, the histopathology and electron microscopy showed marked healing properties and remyelination in treated groups with superiority of the stem cells compared to Exosomes. CONCLUSIONS: Although stem cell results were superior to Exosomes therapy; Exosomes have proven to be effective and safe important actors in myelin regeneration, and their use in diseases like MS helps to stimulate remyelination.


Asunto(s)
Enfermedades de los Perros , Exosomas , Esclerosis Múltiple , Perros , Animales , Esclerosis Múltiple/veterinaria , Esclerosis Múltiple/tratamiento farmacológico , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Células Madre , Tratamiento Basado en Trasplante de Células y Tejidos/veterinaria , Enfermedades de los Perros/patología
11.
Exp Neurol ; 375: 114730, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38401853

RESUMEN

Demyelination is a proper syndrome in plenty of central nervous system (CNS) diseases, which is the main obstacle to recovery and still lacks an effective treatment. To overcome the limitations of the brain-blood barrier on drug permeability, we modified an exosome secreted by neural stem cells (NSCs), which had transfected with lentivirus armed with platelet-derived growth factors A (PDGFA)-ligand. Through the in vivo and in vitro exosomes targeting test, the migration ability to the lesion areas and OPCs significantly improved after ligand modification. Furthermore, the targeted exosomes loaded with 3,5, 30-L-triiodothyronine (T3) have a critical myelination ability in CNS development, administrated to the cuprizone animal model treatment. The data shows that the novel drug vector loaded with T3 significantly promotes remyelination compared with T3 alone. At the same time, it improved the CNS microenvironment by reducing astrogliosis, inhibiting pro-inflammatory microglia, and alleviating axon damage. This investigation provides a straightforward strategy to produce a targeting exosome and indicates a possible therapeutic manner for demyelinating disease.


Asunto(s)
Enfermedades Desmielinizantes , Exosomas , Animales , Ratones , Enfermedades Desmielinizantes/terapia , Enfermedades Desmielinizantes/tratamiento farmacológico , Oligodendroglía , Ligandos , Exosomas/metabolismo , Triyodotironina/metabolismo , Triyodotironina/farmacología , Triyodotironina/uso terapéutico , Cuprizona/toxicidad , Ratones Endogámicos C57BL , Vaina de Mielina/patología , Modelos Animales de Enfermedad
12.
EBioMedicine ; 100: 104982, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38306899

RESUMEN

BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).


Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple , Sustancia Blanca , Porcinos , Humanos , Animales , Ratones , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/patología , Cuprizona , Porcinos Enanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Vaina de Mielina/patología , Sustancia Blanca/patología , Microscopía Electrónica , Modelos Animales de Enfermedad
13.
CNS Neurosci Ther ; 30(1): e14552, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38287523

RESUMEN

AIMS: Multiple sclerosis (MS) is a chronic neurological disease that currently lacks effective curative treatments. There is a need to find effective therapies, especially to reverse the progressive demyelination and neuronal damage. Oligodendrocytes form the myelin sheath around axons in the central nervous system (CNS) and oligodendrocyte precursor cells (OPCs) undergo mechanisms that enable spontaneously the partial repair of damaged lesions. The aim of this study was to discover small molecules with potential effects in demyelinating diseases, including (re)myelinating properties. METHODS: Recently, it has been shown how LRRK2 inhibition promotes oligodendrogliogenesis and therefore an efficient repair or myelin damaged lesions. Here we explored small molecules inhibiting LRRK2 as potential enhancers of primary OPCs proliferation and differentiation, and their potential impact on the clinical score of experimental autoimmune encephalomyelitys (EAE) mice, a validated model of the most frequent clinical form of MS, relapsing-remitting MS. RESULTS: One of the LRRK2 inhibitors presented in this study promoted the proliferation and differentiation of OPC primary cultures. When tested in the EAE murine model of MS, it exerted a statistically significant reduction of the clinical burden of the animals, and histological evidence revealed how the treated animals presented a reduced lesion area in the spinal cord. CONCLUSIONS: For the first time, a small molecule with LRRK2 inhibition properties presented (re)myelinating properties in primary OPCs cultures and potentially in the in vivo murine model. This study provides an in vivo proof of concept for a LRRK2 inhibitor, confirming its potential for the treatment of MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Células Precursoras de Oligodendrocitos , Ratones , Animales , Encefalomielitis Autoinmune Experimental/patología , Células Precursoras de Oligodendrocitos/patología , Modelos Animales de Enfermedad , Vaina de Mielina/patología , Oligodendroglía/patología , Diferenciación Celular , Benzotiazoles/farmacología , Benzotiazoles/uso terapéutico , Ratones Endogámicos C57BL
14.
Brain ; 147(4): 1331-1343, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38267729

RESUMEN

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.


Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Vaina de Mielina/patología , Esclerosis Múltiple/patología , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/patología , Progresión de la Enfermedad , Atrofia/patología
15.
Brain ; 147(4): 1294-1311, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38289861

RESUMEN

Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8 weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Ratones , Animales , Humanos , Anciano , Vaina de Mielina/patología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patología , Oligodendroglía/patología , Neuronas , Diferenciación Celular/fisiología
16.
Neurobiol Dis ; 192: 106414, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38253209

RESUMEN

Alteration in protein citrullination (PC), a common posttranslational modification (PTM), contributes to pathogenesis in various inflammatory disorders. We previously reported that PC and protein arginine deiminase 2 (PAD2), the predominant enzyme isoform that catalyzes this PTM in the central nervous system (CNS), are altered in mouse models of amyotrophic lateral sclerosis (ALS). We now demonstrate that PAD2 expression and PC are altered in human postmortem ALS spinal cord and motor cortex compared to controls, increasing in astrocytes while trending lower in neurons. Furthermore, PC is enriched in protein aggregates that contain the myelin proteins PLP and MBP in ALS. These results confirm our findings in ALS mouse models and suggest that altered PAD2 and PC contribute to neurodegeneration in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Citrulinación , Animales , Humanos , Ratones , Esclerosis Amiotrófica Lateral/metabolismo , Gliosis/metabolismo , Hidrolasas/genética , Hidrolasas/metabolismo , Proteínas de la Mielina/metabolismo , Vaina de Mielina/patología , Agregado de Proteínas , Arginina Deiminasa Proteína-Tipo 2/metabolismo , Desiminasas de la Arginina Proteica/metabolismo , Proteínas/metabolismo , Médula Espinal/patología
17.
Transl Res ; 268: 40-50, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38246342

RESUMEN

Traumatic brain injury (TBI) has a significant impact on cognitive function, affecting millions of people worldwide. Myelin loss is a prominent pathological feature of TBI, while well-functioning myelin is crucial for memory and cognition. Utilizing drug repurposing to identify effective drug candidates for TBI treatment has gained attention. Notably, recent research has highlighted the potential of clemastine, an FDA-approved allergy medication, as a promising pro-myelinating drug. Therefore, in this study, we aim to investigate whether clemastine can enhance myelination and alleviate cognitive impairment following mild TBI using a clinically relevant rat model of TBI. Mild diffuse TBI was induced using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Animals were treated with either clemastine or an equivalent volume of the vehicle from day 1 to day 14 post-injury. Following treatment, memory-related behavioral tests were conducted, and myelin pathology in the cortex and hippocampus was assessed through immunofluorescence staining and ProteinSimple® capillary-based immunoassay. Our results showed that TBI leads to significant myelin loss, axonal damage, glial activation, and a decrease in mature oligodendrocytes in both the cortex and hippocampus. The TBI animals also exhibited notable deficits in memory-related tests. In contrast, animals treated with clemastine showed an increase in mature oligodendrocytes, enhanced myelination, and improved performance in the behavioral tests. These preliminary findings support the therapeutic value of clemastine in alleviating TBI-induced cognitive impairment, with substantial clinical translational potential. Our findings also underscore the potential of remyelinating therapies for TBI.


Asunto(s)
Axones , Clemastina , Disfunción Cognitiva , Modelos Animales de Enfermedad , Vaina de Mielina , Ratas Sprague-Dawley , Animales , Clemastina/farmacología , Clemastina/uso terapéutico , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/patología , Axones/efectos de los fármacos , Axones/patología , Masculino , Ratas , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/complicaciones , Traumatismos Difusos del Encéfalo/efectos de los fármacos , Traumatismos Difusos del Encéfalo/patología , Hipocampo/efectos de los fármacos , Hipocampo/patología
18.
Acta Neuropathol Commun ; 12(1): 18, 2024 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-38291527

RESUMEN

In men, reduced levels of testosterone are associated with the prevalence and progression of multiple sclerosis (MS), a chronic and disabling demyelinating disorder. Testosterone has been shown to promote myelin repair. Here, we demonstrate that the cooperation between testosterone and CXCR4 signaling involving astrocytes is required for myelin regeneration after focal demyelination produced in the ventral mouse spinal cord by the infusion of lysolecithin. The testosterone-dependent remyelination of axons by oligodendrocytes was accompanied by an increase in astrocytes expressing CXCR4, its ligand CXCL12 and the androgen receptor (AR) within the demyelinated area. Depriving males of their testosterone or pharmacological inhibition of CXCR4, with the selective antagonist AMD3100, prevented the appearance of astrocytes expressing CXCR4, CXCL12 and AR within the demyelinated area and the concomitant recruitment of myelin forming oligodendrocytes. Conditional genetic ablation of either CXCR4 or AR in astrocytes also completely blocked the formation of new myelin by oligodendrocytes. Interestingly, the gain of function mutation in CXCR4 causing WHIM syndrome allows remyelination to take place, even in the absence of testosterone, but its potentiating effects remained observable. After testosterone deprivation or CXCR4 inhibition, the absence of astrocytes within the demyelinated area led to the incursion of Schwann cells, most likely derived from spinal nerves, and the formation of peripheral nerve type myelin. In patients with progressive MS, astrocytes expressing CXCR4 and AR surrounded myelin lesions, and their presence opposed the incursion of Schwann cells. These results highlight a mechanism of promyelinating testosterone signaling and the importance of normalizing its levels in combined myelin repair therapies.


Asunto(s)
Andrógenos , Vaina de Mielina , Humanos , Ratones , Masculino , Animales , Vaina de Mielina/patología , Andrógenos/farmacología , Células de Schwann , Oligodendroglía/patología , Testosterona , Médula Espinal/patología , Receptores CXCR4
19.
J Alzheimers Dis ; 97(1): 359-372, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38073386

RESUMEN

BACKGROUND: Patients with Alzheimer's disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD. OBJECTIVE: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD. METHODS: In this study, we used the magnetic resonance imaging (MRI) data from the OVERTURE study (NCT03556280), a randomized, controlled, clinical trial in which active treatment participants received daily, non-invasive, combined visual and auditory, 40 Hz stimulation for six months. A subset of OVERTURE participants who meet the inclusion criteria for detailed white matter (N = 38) and myelin content (N = 36) assessments are included in the analysis. White matter volume assessments were performed using T1-weighted MRI, and myelin content assessments were performed using T1-weighted/T2-weighted MRI. Treatment effects on white matter atrophy and myelin content loss were assessed. RESULTS: Combined visual and auditory gamma-sensory stimulation treatment is associated with reduced total and regional white matter atrophy and myelin content loss in active treatment participants compared to sham treatment participants. Across white matter structures evaluated, the most significant changes were observed in the entorhinal region. CONCLUSIONS: The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss. Furthermore, the entorhinal region MRI outcomes may have significant implications for early disease intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex.


Asunto(s)
Enfermedad de Alzheimer , Sustancia Blanca , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/patología , Sustancia Blanca/patología , Vaina de Mielina/patología , Imagen por Resonancia Magnética , Atrofia/patología
20.
Brain Pathol ; 34(2): e13184, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-37356965

RESUMEN

Autoimmune neuropathies are a heterogeneous group of rare and disabling diseases in which the immune system is thought to target antigens in the peripheral nervous system: they usually respond to immune therapies. Guillain-Barré syndrome is divided into several subtypes including "acute inflammatory demyelinating polyradiculoneuropathy," "acute motor axonal neuropathy," "acute motor sensory neuropathy," and other variants. Chronic forms such as chronic inflammatory demyelinating polyneuropathy (CIDP) and other subtypes and polyneuropathy associated with IgM monoclonal gammopathy; autoimmune nodopathies also belong to this group of auto-immune neuropathies. It has been shown that immunoglobulin G from the serum of about 30% of CIDP patients immunolabels nodes of Ranvier or paranodes of myelinated axons. Whatever the cause of myelin damage of the peripheral nervous system, the initial attack on myelin by a dysimmune process may begin either at the internodal area or in the paranodal and nodal regions. The term "nodoparanodopathy" was first applied to some "axonal Guillain-Barré syndrome" subtypes, then extended to cases classified as CIDP bearing IgG4 antibodies against paranodal axoglial proteins. In these cases, paranodal dissection develops in the absence of macrophage-induced demyelination. In contrast, the mechanisms of demyelination of other dysimmune neuropathies induced by macrophages are unexplained, as no antibodies have been identified in such cases. The main objective of this presentation is to show that the pathology illustrates, confirms, and may explain such mechanisms.


Asunto(s)
Síndrome de Guillain-Barré , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Síndrome de Guillain-Barré/patología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/patología , Axones/patología , Vaina de Mielina/patología , Inmunoglobulina G , Autoanticuerpos
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