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Neurology(R) Neuroimmunology &... Jul 2024AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have...
BACKGROUND AND OBJECTIVES
AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have overlapping clinical manifestations. Yet, important differences exist in these diseases, particularly in B-cell depletion (BCD) efficacy. Yet, the biology driving these differences remains unclear. Our study aims to clarify biological pathways distinguishing these diseases beyond autoantibodies and investigate variable BCD effects through proteomic comparisons.
METHODS
In a retrospective study, 1,463 serum proteins were measured in 53 AQP4-NMOSD, 25 MOGAD, 18 SN-NMOSD, and 49 healthy individuals. To identify disease subtype-associated signatures, we examined serum proteins in patients without anti-CD20 B-cell depletion (NoBCD). We then assessed the effect of BCD treatment within each subtype by comparing proteins between BCD-treated and NoBCD-treated patients.
RESULTS
In NoBCD-treated patients, serum profiles distinguished the 3 diseases. AQP4-NMOSD showed elevated type I interferon-induced chemokines (CXCL9 and CXCL10) and TFH chemokine (CXCL13). MOGAD exhibited increased cytotoxic T-cell proteases (granzyme B and granzyme H), while SN-NMOSD displayed elevated Wnt inhibitory factor 1, a marker for nerve injury. Across all subtypes, BCD-treated patients showed reduction of B-cell-associated proteins. In AQP4-NMOSD, BCD led to a decrease in several inflammatory pathways, including IL-17 signaling, cytokine storm, and macrophage activation. By contrast, BCD elevated these pathways in patients with MOGAD. BCD had no effect on these pathways in SN-NMOSD.
DISCUSSION
Proteomic profiles show unique biological pathways that distinguish AQP4-NMOSD, MOGAD, or SN-NMOSD. Furthermore, BCD uniquely affects inflammatory pathways in each disease type, providing an explanation for the disparate therapeutic response in AQP4-NMOSD and MOGAD.
Topics: Humans; Neuromyelitis Optica; Myelin-Oligodendrocyte Glycoprotein; Female; Middle Aged; Male; Adult; Retrospective Studies; Proteomics; B-Lymphocytes; Aquaporin 4; Autoantibodies; Aged
PubMed: 38885457
DOI: 10.1212/NXI.0000000000200268 -
SAGE Open Medical Case Reports 2024FLAMES, or fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (anti-myelin oligodendrocyte glycoprotein)-associated...
A burning encephalitis: Fluid-attenuated inversion recovery-hyperintense lesions in Anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures in anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures-A case report and review of the literature.
FLAMES, or fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (anti-myelin oligodendrocyte glycoprotein)-associated encephalitis with seizures, represents a rarely documented syndrome characterized by ambiguous features. Positioned within the spectrum of inflammatory demyelinating diseases of the central nervous system, it is regarded as a distinct subset of myelin oligodendrocyte glycoprotein antibody-associated disease, the latest classification in this domain. Myelin oligodendrocyte glycoprotein antibody-associated disease exhibits a diverse clinical spectrum, spanning from solitary optic neuritis or myelitis to multifocal central nervous system demyelination, manifesting as acute disseminated encephalomyelitis, or cortical encephalitis accompanied by seizures, delineating the fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures syndrome. We present a compelling case study of a 30-year-old individual with a history of recurrent seizures initially diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. However, the disease's progression more closely resembled self-resolving cerebral cortical encephalitis linked with myelin oligodendrocyte glycoprotein antibodies. In addition, we undertake a systematic review of literature cases to explore the diagnostic significance of magnetic resonance angiography, fluid-attenuated inversion recovery, and specialized markers such as diffusion-weighted imaging and perfusion in discerning fluid-attenuated inversion recovery-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein-associated encephalitis with seizures syndrome and elucidating its distinctive characteristics.
PubMed: 38881971
DOI: 10.1177/2050313X241261021 -
Clinical Proteomics Jun 2024Multiple sclerosis (MS) is a clinically and biologically heterogenous disease with currently unpredictable progression and relapse. After the development and success of...
BACKGROUND
Multiple sclerosis (MS) is a clinically and biologically heterogenous disease with currently unpredictable progression and relapse. After the development and success of neurofilament as a cerebrospinal fluid (CSF) biomarker, there is reinvigorated interest in identifying other markers of or contributors to disease. The objective of this study is to probe the predictive potential of a panel of brain-enriched proteins on MS disease progression and subtype.
METHODS
This study includes 40 individuals with MS and 14 headache controls. The MS cohort consists of 20 relapsing remitting (RR) and 20 primary progressive (PP) patients. The CSF of all individuals was analyzed for 63 brain enriched proteins using a method of liquid-chromatography tandem mass spectrometry. Wilcoxon rank sum test, Kruskal-Wallis one-way ANOVA, logistic regression, and Pearson correlation were used to refine the list of candidates by comparing relative protein concentrations as well as relation to known imaging and molecular biomarkers.
RESULTS
We report 30 proteins with some relevance to disease, clinical subtype, or severity. Strikingly, we observed widespread protein depletion in the disease CSF as compared to control. We identified numerous markers of relapsing disease, including KLK6 (kallikrein 6, OR = 0.367, p < 0.05), which may be driven by active disease as defined by MRI enhancing lesions. Other oligodendrocyte-enriched proteins also appeared at reduced levels in relapsing disease, namely CNDP1 (carnosine dipeptidase 1), LINGO1 (leucine rich repeat and Immunoglobin-like domain-containing protein 1), MAG (myelin associated glycoprotein), and MOG (myelin oligodendrocyte glycoprotein). Finally, we identified three proteins-CNDP1, APLP1 (amyloid beta precursor like protein 1), and OLFM1 (olfactomedin 1)-that were statistically different in relapsing vs. progressive disease raising the potential for use as an early biomarker to discriminate clinical subtype.
CONCLUSIONS
We illustrate the utility of targeted mass spectrometry in generating potential targets for future biomarker studies and highlight reductions in brain-enriched proteins as markers of the relapsing remitting disease stage.
PubMed: 38880880
DOI: 10.1186/s12014-024-09494-5 -
NeuroImage Jun 2024A new MRI technique is presented for three-dimensional fast simultaneous whole brain mapping of myelin water fraction (MWF), T, proton density (PD), R*, magnetic...
A new MRI technique is presented for three-dimensional fast simultaneous whole brain mapping of myelin water fraction (MWF), T, proton density (PD), R*, magnetic susceptibility (QSM), and B transmit field (B). Phantom and human (N = 9) datasets were acquired using a dual-flip-angle blipped multi-gradient-echo (DFA-mGRE) sequence with a stack-of-stars (SOS) trajectory. Images were reconstructed using a subspace-based algorithm with a locally low-rank constraint. A novel joint-sparsity-constrained multicomponent T*-T spectrum estimation (JMSE) algorithm is proposed to correct for the T saturation effect and B/B inhomogeneities in the quantification of MWF. A tissue-prior-based B estimation algorithm was adapted for B correction in the mapping of T and PD. In the phantom study, measurements obtained at an acceleration factor (R) of 12 using prospectively under-sampled SOS showed good consistency (R > 0.997) with Cartesian reference for R*/T/M. In the in vivo study, results of retrospectively under-sampled SOS with R = 6, 12, 18, showed good quality (structure similarity index measure > 0.95) compared with those of fully-sampled SOS. Besides, results of prospectively under-sampled SOS with R = 12 showed good consistency (intraclass correlation coefficient > 0.91) with Cartesian reference for T/PD/B/MWF/QSM/R*, and good reproducibility (coefficient of variation < 7.0%) in the test-retest analysis for T/PD/B/MWF/R*. This study has demonstrated the feasibility of simultaneous whole brain multiparametric mapping with a two-minute scan using the DFA-mGRE SOS sequence, which may overcome a major obstacle for neurological applications of multiparametric MRI.
PubMed: 38880311
DOI: 10.1016/j.neuroimage.2024.120689 -
Cell Death & Disease Jun 2024Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq,...
Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive cancer characterized by a poor prognosis and resistance to chemotherapy. In this study, utilizing scRNA-seq, we discovered that the tetra-transmembrane protein mal, T cell differentiation protein 2 (MAL2), exhibited specific enrichment in ICC cancer cells and was strongly associated with a poor prognosis. The inhibition of MAL2 effectively suppressed cell proliferation, invasion, and migration. Transcriptomics and metabolomics analyses suggested that MAL2 promoted lipid accumulation in ICC by stabilizing EGFR membrane localization and activated the PI3K/AKT/SREBP-1 axis. Molecular docking and Co-IP proved that MAL2 interacted directly with EGFR. Based on constructed ICC organoids, the downregulation of MAL2 enhanced apoptosis and sensitized ICC cells to cisplatin. Lastly, we conducted a virtual screen to identify sarizotan, a small molecule inhibitor of MAL2, and successfully validated its ability to inhibit MAL2 function. Our findings highlight the tumorigenic role of MAL2 and its involvement in cisplatin sensitivity, suggesting the potential for novel combination therapeutic strategies in ICC.
Topics: Cholangiocarcinoma; Humans; ErbB Receptors; Lipid Metabolism; Bile Duct Neoplasms; Cell Line, Tumor; Animals; Cisplatin; Signal Transduction; Cell Proliferation; Single-Cell Analysis; Myelin and Lymphocyte-Associated Proteolipid Proteins; Mice; Gene Expression Regulation, Neoplastic; Sequence Analysis, RNA; Apoptosis; Male
PubMed: 38866777
DOI: 10.1038/s41419-024-06775-7 -
Reviews in the Neurosciences Jun 2024Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other... (Review)
Review
Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other sensory and autonomic symptoms. A variety of medical disorders can cause SFN; however, more than 50% of cases are idiopathic (iSFN). Some investigations suggest an autoimmune etiology, backed by evidence of the efficacy of IVIG and plasma exchange. Several studies suggest that autoantibodies directed against nervous system antigens may play a role in the development of neuropathic pain. For instance, patients with CASPR2 and LGI1 antibodies often complain of pain, and and studies support their pathogenicity. Other antibodies have been associated with SFN, including those against TS-HDS, FGFR3, and Plexin-D1, and new potential targets have been proposed. Finally, a few studies reported the onset of SFN after COVID-19 infection and vaccination, investigating the presence of potential antibody targets. Despite these overall findings, the pathogenic role has been demonstrated only for some autoantibodies, and the association with specific clinical phenotypes or response to immunotherapy remains to be clarified. The purpose of this review is to summarise known autoantibody targets involved in neuropathic pain, putative attractive autoantibody targets in iSFN patients, their potential as biomarkers of response to immunotherapy and their role in the development of iSFN.
PubMed: 38865989
DOI: 10.1515/revneuro-2024-0027 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2024To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to...
OBJECTIVE
To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to investigate the therapeutic efficacy of ursolic acid (UA) in treating demyelination and the ensuing abnormalities in ISF drainage in SZ.
METHODS
Female C57BL/6J mice, aged 6-8 weeks and weighing (20±2) g, were randomly divided into three groups: control, SZ model, and UA treatment. The control group received intraperitoneal injection (ip) of physiological saline and intragastric administration (ig) of 1% carboxymethylcellulose sodium (CMC-Na). The SZ model group was subjected to ip injection of 2 mg/kg dizocilpine maleate (MK-801) and ig administration of 1% CMC-Na. The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801. The treatment group received UA pretreatment via ig administration for one week, followed by a two-week drug intervention for all the three groups. Behavioral assessments, including the open field test and prepulse inhibition experiment, were conducted post-modeling. Subsequently, changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions. Immunofluorescence analysis was employed to examine alterations in aquaporin 4 (AQP4) polarity distribution in the brain and changes in protein expression. Myelin reflex imaging using Laser Scanning Confocal Microscopy (LSCM) was utilized to study modifications in myelin within the mouse brain. Quantitative data underwent one-way ANOVA, followed by TukeyHSD for post hoc pairwise comparisons between the groups.
RESULTS
The open field test revealed a significantly longer total distance [(7 949.39±1 140.55) cm . (2 831.01±1 212.72) cm, < 0.001] and increased central area duration [(88.43±22.06) s . (56.85±18.58) s, =0.011] for the SZ model group compared with the controls. The UA treatment group exhibited signifi-cantly reduced total distance [(2 415.80±646.95) cm . (7 949.39±1 140.55) cm, < 0.001] and increased central area duration [(54.78±11.66) s . (88.43±22.06) s, =0.007] compared with the model group. Prepulse inhibition test results demonstrated a markedly lower inhibition rate of the startle reflex in the model group relative to the controls ( < 0.001 for both), with the treatment group displaying significant improvement ( < 0.001 for both). Myelin sheath analysis indicated significant demyelination in the model group, while UA treatment reversed this effect. Fluorescence tracing exhibited a significantly larger tracer diffusion area towards the rostral cortex and reflux area towards the caudal thalamus in the model group relative to the controls [(13.93±3.35) mm . (2.79±0.94) mm, < 0.001 for diffusion area; (2.48±0.38) mm . (0.05±0.12) mm, < 0.001 for reflux area], with significant impairment of drainage in brain regions. The treatment group demonstrated significantly reduced tracer diffusion and reflux areas [(7.93±2.48) mm . (13.93±3.35) mm, < 0.001 for diffusion area; (0.50±0.30) mm . (2.48±0.38) mm, < 0.001 for reflux area]. Immunofluorescence staining revealed disrupted AQP4 polarity distribution and reduced AQP4 protein expression in the model group compared with the controls [(3 663.88±733.77) μm . (13 354.92±4 054.05) μm, < 0.001]. The treatment group exhibited restored AQP4 polarity distribution and elevated AQP4 protein expression [(11 104.68±3 200.04) μm . (3 663.88±733.77) μm, < 0.001].
CONCLUSION
UA intervention ameliorates behavioral performance in SZ mice, Thus alleviating hyperactivity and anxiety symptoms and restoring sensorimotor gating function. The underlying mechanism may involve the improvement of demyelination and ISF drainage dysregulation in SZ mice.
Topics: Animals; Mice; Triterpenes; Schizophrenia; Mice, Inbred C57BL; Female; Disease Models, Animal; Demyelinating Diseases; Extracellular Fluid; Ursolic Acid; Dizocilpine Maleate; Aquaporin 4
PubMed: 38864135
DOI: 10.19723/j.issn.1671-167X.2024.03.016 -
Communications Biology Jun 2024Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse...
Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer's disease and in human Alzheimer's disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related.
Topics: Klotho Proteins; MicroRNAs; Animals; Aging; Alzheimer Disease; Brain; Mice; Glucuronidase; Humans; Longevity; Mice, Knockout; RNA, Transfer; Male; Neurons; Mice, Inbred C57BL
PubMed: 38862813
DOI: 10.1038/s42003-024-06407-y -
Translational Psychiatry Jun 2024There is growing evidence of a shared pathogenesis between Alzheimer's disease and depression. Therefore, we aimed to further investigate their shared disease...
There is growing evidence of a shared pathogenesis between Alzheimer's disease and depression. Therefore, we aimed to further investigate their shared disease mechanisms. We made use of publicly available brain-specific eQTL data and gene co-expression networks of previously reported genetic loci associated with these highly comorbid disorders. No direct genetic overlap was observed between Alzheimer's disease and depression in our dataset, but we did detect six shared brain-specific eQTL genes: SRA1, MICA, PCDHA7, PCDHA8, PCDHA10 and PCDHA13. Several pathways were identified as shared between Alzheimer's disease and depression by conducting clustering pathway analysis on hippocampal co-expressed genes; synaptic signaling and organization, myelination, development, and the immune system. This study highlights trans-synaptic signaling and synaptoimmunology in the hippocampus as main shared pathomechanisms of Alzheimer's disease and depression.
Topics: Alzheimer Disease; Humans; Genetic Predisposition to Disease; Hippocampus; Comorbidity; Quantitative Trait Loci; Gene Regulatory Networks; Depression; Depressive Disorder
PubMed: 38862462
DOI: 10.1038/s41398-024-02968-y -
Cureus May 2024Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune disorder characterized by recurrent episodes of demyelination affecting the...
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune disorder characterized by recurrent episodes of demyelination affecting the central nervous system. The following case report showcases a thorough analysis of a 21-year-old female patient presenting with MOGAD, outlining her clinical presentation, diagnostic workup, treatment protocol, and long-term management outcomes. Through a multidisciplinary approach, we aim to augment the understanding of this complex neurological entity and steer optimal therapeutic interventions.
PubMed: 38854354
DOI: 10.7759/cureus.59840