Liquiritin ameliorates painful diabetic neuropathy in SD rats by inhibiting NLRP3-MMP-9-mediated reversal of aquaporin-4 polarity in the glymphatic system.

Background: Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain. Methods: This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques. Results: The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements. Conclusion: Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.

Update on the intriguing roles of AQP4 expression and redistribution in the progression and treatment of glioma.

Aquaporin 4 (AQP4) is abundant in the human brain and has an important role in brain homeostasis and diseases. AQP4 expression has been found to be associated with glioma malignancies. However, the complete understanding of the biological processes and curative importance of AQP4 in glioma remains unclear. The impact of AQP4 subcellular mislocalization on glioma progression and the precise mechanisms regarding AQP4 translocation in glioma need further investigation. In this review, we update recent findings about disturbed AQP4 expression in glioma and explore targeting AQP4 to modulate the glioma progression. Thereafter we discuss some possible mechanisms of action of AQP4 translocations in glioma. The present article offers an appropriate introduction to the potential involvement of AQP4 in the emergence and progression of glioma. Both comprehensive research into the mechanisms and systematically intervention studies focusing on AQP4 are essential. By embracing this strategy, we can obtain a new and insightful outlook on managing cancerous glioma. Although the observations summarized in this review should be confirmed with more studies, we believe that they could provide critical information for the design of more focused research that will allow for systematic and definitive evaluation of the role of AQP4 in glioma treatments.

Glymphotherapeutics for Alzheimer's disease: Time to move the needle.

Alzheimer's disease (AD), the most predominant neurodegenerative disease and a quintessential entity within the dementia umbrella, is a global public health crisis. While the lack of disease modifying therapies has been a weak point in AD treatment, the success of recently approved monoclonal antibody-based therapeutics (aducanumab and lecanemab) targeted at the removal of amyloid-beta (Aß) peptides in the brain is still under debate. There are multiple safety concerns about these approved neurotherapeutics including amyloid-related imaging abnormalities, stroke, meningitis, encephalitis, and even death. Novel paradigms focused on aquaporin-4-mediated neuro-perivascular Aß and Tau protein clearance pathway are garnering attention. In this paper, we argue that orchestrating the drug discovery focused on glymphatic clearance-facilitating drugs ("glymphotherapeutics") might be a potentially novel and viable strategy to mitigate the progression and improve the clinical outcomes of AD.

Radiological features in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease-diagnostic criteria and lesion dynamics.

The spectrum of acquired pediatric demyelinating syndromes has been expanding over the past few years, to include myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), as a distinct neuroimmune entity, in addition to pediatric-onset multiple sclerosis (POMS) and aquaporin 4-IgG-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD). The 2023 MOGAD diagnostic criteria require supporting clinical or magnetic resonance imaging (MRI) features in patients with low positive myelin oligodendrocyte glycoprotein IgG titers or when the titers are not available, highlighting the diagnostic role of imaging in MOGAD. In this review, we summarize the key diagnostic features in MOGAD, in comparison to POMS and AQP4+NMOSD. We describe the lesion dynamics both during attack and over time. Finally, we propose a guideline on timing of imaging in clinical practice.

Potential prognostic value of rheumatoid factor in anti-aquaporin 4-immunoglobin G-positive neuromyelitis optica spectrum disorders.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is the central nervous system demyelinating disease differentiated from multiple sclerosis by the presence of anti-aquaporin 4-antibody (AQP4-ab), which is sometimes accompanied by non-organ-specific autoantibodies. METHODS: We prospectively collected clinical information and profiles of non-organ-specific autoantibodies such as fluorescent antinuclear (FANA), anti-Sjögren's syndrome A (SSA)/Ro, anti-SS B (SSB)/La, anti-neutrophil cytoplasmatic (ANCA), lupus anticoagulant (LA), anti-cardiolipin (ACA), anti-double-stranded DNA (dsDNA), rheumatoid factor (RF), anti-thyroperoxidase, and anti-thyroglobulin antibodies in patients with NMOSD. Clinical characteristics and laboratory findings of patients with NMOSD with or without autoantibodies were analyzed. Cox proportional hazard models were used to identify independent risk factors predicting high disability in patients with NMOSD. RESULTS: A total of 158 patients with NMOSD (Female: Male = 146:12; age, 36.11 ± 14.7) were included. FANA was observed most frequently (33.3 %), followed by anti-SSA (28.6 %), anti-SSB (10.0 %), RF (8.5 %), anti-dsDNA (7.0 %), LA (4.7 %), ACA (4.8 %), and ANCA (2.4 %). High disability (Expanded Disability Status Scale (EDSS) score ≥ 6) was observed more frequently in patients with RF (45.5 %) than in those without RF (14.5 %) (p = 0.02). RF was a significant predictive factor for the high disability (hazard ratio [HR], 3.763; 95 % confidence interval [CI], 1.086-13.038; p = 0.037), age at onset (HR, 1.093; 95 % CI, 1.05-1.14; p ≤0.001), and annual relapse rate (ARR) (HR, 4.212; 95 % CI, 1.867-9.503; p = 0.001). CONCLUSION: Organ-specific and non-organ-specific autoantibodies are frequently observed in Korean patients with AQP4-ab-positive NMOSD. RF may be an independent predictor of high disability, along with age at onset and ARR.

Glymphatic System and Psychiatric Disorders: A Rapid Comprehensive Scoping Review.

BACKGROUND: Since discovering the glymphatic system, there has been a looming interest in exploring its relationship with psychiatric disorders. Recently, increasing evidence suggests an involvement of the glymphatic system in the pathophysiology of psychiatric disorders. However, clear data are still lacking. In this context, this rapid comprehensive PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) scoping review aims to identify and analyze current evidence about the relation between the glymphatic system and psychiatric disorders. METHODS: We conducted a comprehensive review of the literature and then proceeded to discuss the findings narratively. Tables were then constructed and articles were sorted according to authors, year, title, location of study, sample size, psychiatric disorder, the aim of the study, principal findings, implications. RESULTS: Twenty papers were identified as eligible, among which 2 articles on Schizophrenia, 1 on Autism Spectrum Disorders, 2 on Depression, 1 on Depression and Trauma-related Disorders, 1 on Depression and Anxiety, 2 on Anxiety and Sleep Disorders, 8 on Sleep Disorders, 2 on Alcohol use disorder and 1 on Cocaine Use Disorder. CONCLUSION: This review suggests a correlation between the glymphatic system and several psychiatric disorders: Schizophrenia, Depression, Anxiety Disorders, Sleep Disorders, Alcohol Use Disorder, Cocaine Use Disorder, Trauma-Related Disorders, and Autism Spectrum Disorders. Impairment of the glymphatic system could play a role in Trauma-Related Disorders, Alcohol Use Disorders, Cocaine Use Disorders, Sleep Disorders, Depression, and Autism Spectrum Disorders. It is important to implement research on this topic and adopt standardized markers and radio diagnostic tools.

Polyautoimmunity and multiple autoimmune syndrome in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: The coexistence of neuromyelitis optica spectrum disorders (NMOSD) with other autoimmune diseases (AID) has been increasingly reported. The prevalence and significance of this association are not fully understood. OBJECTIVES: This study aimed to compare the clinical and laboratory characteristics in NMOSD patients with and without AID. METHODS: Retrospective cross-sectional observational study was conducted involving adults meeting NMOSD criteria followed in a neuroimmunology clinic at a tertiary center. Descriptive analysis of clinical/paraclinical/treatment/outcome data collected from the medical records was compared between NMOSD patients with AID (polyautoimmunity) and those without AID. RESULTS: From a cohort of 46 NMOSD patients, 16 (34.8 %) patients, mostly women around 40 years of age, presented with polyautoimmunity: 10 anti-AQP4 positive, 4 anti-MOG positive, and 2 seronegative. Five different organ -specific AID, and six systemic AID were identified in the polyautoimmunity patients group, in addition to 6 cases of multiple autoimmune syndrome. The AID manifestation preceded NMOSD in 10 (62.5 %) patients, with a median interval of 7 years. The NMOSD with polyautoimmunity and NMOSD without AID groups had similar initial clinical manifestations with optic neuritis and/or myelitis being most frequent. Inflammatory CSF, namely elevated proteins, was more common in the polyautoimmunity group (13.0 % in NMOSD vs. 31.3 % in NMOSD+AID, p = 0.003). After a 10±6 years follow-up period, more patients with polyautoimmunity had a relapsing disease (75.0 % in NMOSD vs. 46.7 % in NMOSD+AID, p = 0.012) but no difference in the functional outcome evaluated by the EDSS score was identified. CONCLUSIONS: Polyautoimmunity was common in AQP4 positive NMOSD patients leading to a significantly higher risk of disease recorrence. The presence of polyautoimmunity and multiple autoimmune syndrome in NMOSD patients suggests the existence of common susceptibility factors or pathophysiological mechanisms, emphasizing the importance of a multidisciplinary approach to those patients.

A rare case of systemic lupus erythematosus-associated neuromyelitis optica spectrum disorder with cystic lesions and dual seropositivity for anti-AQP4 and anti-MOG antibodies.

Key Clinical Message: In patients with SLE, concurrent NMOSD can manifest with optic neuritis and transverse myelitis. AQP-4 antibody positivity confirms the diagnosis. Prompt treatment is critical to manage the acute symptoms and prevent relapses, as highlighted by a young patient's case with optic neuritis and extensive spinal cord lesions. Abstract: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder of the central nervous system that affects the optic nerve and spinal cord. It is associated with autoantibodies against aquaporin-4 (AQP-4) and/or myelin oligodendrocytes glycoproteins. It is diagnosed based on clinical, radiological, and serological criteria, and treated with immunosuppressants in the acute phase. Long-term immunosuppression is essential to prevent potential relapses. In this case report, we present the case of a 19-year-old female patient with systemic lupus erythematosus (SLE), who presented with blurriness and loss of vision in her left eye. Optical coherence tomography was normal, but a gadolinium-enhanced cervico-dorsal MRI showed multiple lesions extending from the brainstem to the C7-T1 junction suggestive of longitudinally extensive transverse myelitis (LETM), the largest of which was a cystic lesion at the cervico-spinal junction. A contrast injection also revealed left optic neuritis. Cerebrospinal fluid analysis showed elevated IgG and red blood cell count, but no oligoclonal bands. The patient tested positive for AQP-4 autoantibodies, confirming the diagnosis of NMOSD. Treatment with intravenous methylprednisolone led to partial improvement, but the patient experienced a relapse with severe neurological symptoms, including tetraplegia and bladder and bowel dysfunction. This case illustrates the importance of considering NMOSD in the differential diagnosis of patients with SLE who present with optic neuritis and/or myelitis, especially when MRI findings are suggestive of LETM. Early diagnosis and adherence to treatment are crucial to prevent further relapses and deleterious sequelae.

Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder.

Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund's adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats.

Absence of Aquaporin-4 (AQP4) Prolongs the Presence of a CD11c+ Microglial Population during Postnatal Corpus Callosum Development.

Aquaporin-4 (AQP4) expression is associated with the development of congenital hydrocephalus due to its structural role in the ependymal membrane. Gene expression analysis of periaqueductal tissue in AQP4-knockout (KO) mice at 11 days of age (P11) showed a modification in ependymal cell adhesion and ciliary protein expression that could alter cerebrospinal fluid homeostasis. A microglial subpopulation of CD11c+ cells was overexpressed in the periaqueductal tissue of mice that did not develop hydrocephalus, suggesting a possible protective effect. Here, we verified the location of this CD11c+ expression in the corpus callosum (CC) and cerebellum of AQP4-KO mice and analysed its time course. Immunofluorescence labelling of the CD11c protein in the CC and cerebellum of WT and KO animals at P3, P5, P7 and P11 confirmed an expanded presence of these cells in both tissues of the KO animal; CD11c+ cells appeared at P3 and reached a peak at P11, whereas in the WT animal, they appeared at P5, reached their peak at P7 and were undetectable by P11. The gene expression analysis in the CC samples at P11 confirmed the presence of CD11c+ microglial cells in this tissue. Among the more than 4000 overexpressed genes, Spp1 stood out with the highest differential gene expression (≅600), with other genes, such as Gpnmb, Itgax, Cd68 and Atp6v0d2, also identified as overexpressed. Therefore, CD11c+ cells appear to be necessary for normal corpus callosum development during postnatal life, and the absence of AQP4 prolonged its expression in this tissue.

Neighborhood disadvantage, race, and clinical outcomes in neuromyelitis optica spectrum disorder.

BACKGROUND: Little is known about the relationship between neighborhood disadvantage and neuromyelitis optica spectrum disorder (NMOSD) outcomes. OBJECTIVE: The objective is to determine the impact of neighborhood disadvantage on time from symptom onset to diagnosis and annualized relapse rate (ARR). METHODS: Neighborhood disadvantage were captured with the Area Deprivation Index (ADI), a validated measure of neighborhood-level disadvantage. Negative binomial regression models assessed the impact of ADI on diagnostic delay (⩾3 months between symptom onset and diagnosis) and ARR. RESULTS: A total of 158 NMOSD patients were identified, a majority of whom were White (56.3%) and female (89.9%) with a mean age of 46 years at diagnosis. The ADI did not significantly affect odds of diagnostic delay (odds ratio (OR) = 0.99, p = 0.26). In univariable models, the ADI was not significantly associated with ARR (OR = 1.004, p = 0.29), but non-White race (OR = 1.541, p = 0.02) and time on immunosuppressive therapies (ISTs; OR = 0.994, p = 0.03) were. White patients used IST for an average of 81% of the follow-up period, compared to an average of 65% for non-White patients (p < 0.01). CONCLUSION: No significant relationship between neighborhood-level disadvantage and diagnostic delay or ARR in NMOSD patients was observed. Non-White patients had a higher ARR, which may be related to less IST use.

Pattern Visually Evoked Potentials (pVEPs) and Retinal Nerve Fiber Thickness in a Japanese Girl With Anti-myelin Oligodendrocyte Glycoprotein Antibody Seropositive Optic Neuritis.

We report our findings in a 5-year-old Japanese girl with unilateral optic neuritis who was seropositive for anti-myelin-oligodendrocyte glycoprotein (MOG) antibody. Functional and microstructural changes were assessed longitudinally for 3.5 years by serial recordings of the pattern visual evoked potentials (pVEPs) and optical coherence tomography (OCT) during the acute and chronic phases. On the initial visit, the best-corrected visual acuity (BCVA) in the right eye was light perception. She was treated with 450 mg of intravenous methylprednisolone pulses followed by a gradual tapering of the oral prednisolone. The visual acuity decreased to no light perception, and plasmapheresis combined with high-dose intravenous immunoglobulin therapy was performed. The BCVA quickly improved to 1.0, and no recurrence was detected for approximately four years. The implicit times of N75, P100, and N145 of the pVEPs and peripapillary retinal nerve fiber (pRNFL) thickness in the OCT images were measured during the course of the disease process. The pRNFL thickness of the right eye decreased and was less than one-half of the baseline value at one year and then stabilized. In contrast, the optic pathway function assessed by pVEPs improved. The implicit times of the N75 and P100 components of the right eye were shortened and stabilized at approximately one year. However, the implicit times in the right eye were still longer than that of the left eye. Our findings documented the course of the function and structures of an eye with anti-MOG antibody-positive optic neuritis. This information should be helpful for the understanding of the pathology and prognosis of this disease entity. Further analysis of the pVEPs and structural changes in more cases is needed.

Neuromyelitis Optica: A Deceiving Disorder of Demyelination.

Neuromyelitis optica (NMO), also known as Devic syndrome, is an autoimmune inflammatory and demyelinating disorder that affects the optic nerves and spinal cord. It is believed to be attributed to aquaporin-4 antibodies, a water channel expressed on astrocytes. It commonly presents with isolated or recurrent attacks of myelitis and optic neuritis. Intractable vomiting and hiccups may also be seen as symptoms. Acute treatment is often achieved with high-dose steroids and is imperative to prevent permanent central nervous system damage. Relapse prevention is achieved using long-term immunosuppression. This paper examines the case of an African-American female who presented with ascending lower extremity weakness.

Update on aquaporin-4 antibody detection: the early diagnosis of neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD.

AQP4 is upregulated in schizophrenia and Its inhibition attenuates MK-801-induced schizophrenia-like behaviors in mice.

BACKGROUND: The pathophysiology and molecular mechanisms of schizophrenia (SCZ) remain unclear, and the effective treatment resources are still limited. The goal of this study is to identify the expression of AQP4 in SCZ patients and explore whether AQP4 inhibition could ameliorate schizophrenia-like behaviors and its mechanisms. METHODS: Microarray datasets of PFC compared with healthy control were searched in the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were analyzed with the GEO2R online tool. The Venny online tool and metascape online software were used to identify common abnormally expressed genes and conduct cell type signature enrichment analysis. SCZ mouse models were induced with MK-801, an NMDA receptor antagonist (intraperitoneal injection, 0.1 mg/kg/day for 7 days), and C6 cell models were treated with 100 µM MK-801. RT-qPCR, Western Blotting, and immunofluorescence were employed to determine the expression of AQP4, proinflammatory cytokines, and GFAP. Open field tests and social interaction tests were performed to evaluate the schizophrenia-like behaviors. RESULTS: Bioinformatics analysis identified upregulation of AQP4 in the PFC of SCZ patients compared with healthy controls. Cell type signature enrichment analysis showed that all three DEGs lists were strongly enriched in the FAN EMBRYONIC CTX ASTROCYTE 2 category. Upregulation of AQP4 was also observed in MK-801-treated C6 cells and the PFC of MK-801-induced SCZ mouse model. Moreover, AQP4 inhibition with TGN-020 (an inhibitor of AQP4) improved anxiety-like behavior and social novelty preference defects in MK-801-treated mice. AQP4 inhibition also reduced the expression of IL-1ß, IL-6, and TNF-α in MK-801-treated C6 cells and mouse model. CONCLUSIONS: AQP4 is upregulated in the PFC of SCZ patients compared with healthy controls. AQP4 inhibition could alleviate the anxiety-like behavior and social novelty defects in MK-801-treated mice, this may be due to the role of AQP4 in the regulation of the expression of proinflammatory cytokines.

The Regulatory Role and Mechanism of Circadian Rhythm in Hemoglobin Co-cultured Neurovascular Unit.

Objective: Intracranial hemorrhage (ICH), the second most common subtype of stroke, exacerbates the disruption of the blood-brain barrier (BBB), leading to vasogenic edema, plasma protein extravasation, and infiltration of neurotoxic substances. The clearance capacity of the brain plays a crucial role in maintaining BBB homeostasis and facilitating patient recovery after hemorrhage. This study aimed to investigate the effect of circadian rhythms on BBB function, neuronal damage, and clearance capabilities. Methods: The transwell model and hemoglobin were co-cultured to simulate the BBB environment after ICH. After intervention with different light groups, neuronal apoptosis was determined, glial phagocytosis was analyzed, the expression of endogenous clearing-related proteins aquaporin 4 (AQP4) and low-density lipoprotein receptor-related protein 1 (LRP1) was detected by western blotting and immunofluorescence dual standard method, and the expression of the tight junction protein occludin and melatonin receptor 1A (MTNR1A) was quantitatively analyzed. Results: Circadian rhythms play a key role in maintaining the integrity of the BBB, reducing oxidative stress-induced neuronal damage, and improving microglial phagocytosis. Meanwhile, the expression of occludin and MTNR1A in neurovascular unit (NVU) co-cultured with hemoglobin improved the expression of AQP4 and LRP1, the key proteins in the NVU's endogenous brain clearance system. Conclusion: Circadian rhythm (alternating black and white light) protects the NVU BBB function after ICH, promotes the expression of proteins related to the clearance of the hematoma, provides new evidence for the clinical treatment of patients recovering from ICH, and improves the circadian rhythm to promote brain metabolism and hematoma clearance.

Explainable artificial intelligence identifies an AQP4 polymorphism-based risk score associated with brain amyloid burden.

Aquaporin-4 (AQP4) is hypothesized to be a component of the glymphatic system, a pathway for removing brain interstitial solutes like amyloid-ß (Aß). Evidence exists that genetic variation of AQP4 impacts Aß clearance, clinical outcome in Alzheimer's disease as well as sleep measures. We examined whether a risk score calculated from several AQP4 single-nucleotide polymorphisms (SNPs) is related to Aß neuropathology in older cognitively unimpaired white individuals. We used a machine learning approach and explainable artificial intelligence to extract information on synergistic effects of AQP4 SNPs on brain amyloid burden from the ADNI cohort. From this information, we formulated a sex-specific AQP4 SNP-based risk score and evaluated it using data from the screening process of the A4 study. We found in both cohorts significant associations of the risk score with brain amyloid burden. The results support the hypothesis of an involvement of the glymphatic system, and particularly AQP4, in brain amyloid aggregation pathology. They suggest also that different AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden.

[The diagnostic effectiveness of criteria for neuromyelitis optica spectrum disorders in the Russian clinical practice]. / Diagnosticheskaya effektivnost' kriteriev zabolevanii spektra optikoneiromielita v rossiiskoi klinicheskoi praktike.

OBJECTIVE: To compare the diagnostic criteria of 2006 (DC 2006) and 2015 (DC 2015) in the Russian population of patients with suspected neuromyelitis optica spectrum disorders (NMOSD), with the calculation of their sensitivity, specificity, accuracy and predictive value. MATERIAL AND METHODS: We reviewed medical records of suspected NMOSD patients who were therefore examined for the presence of serum autoantibodies targeting the aquaporin-4 water channel protein (AQP4-IgG) in 6 specialized Russian (Nizhny Novgorod and Moscow) medical centers. One hundred patients (78 female), aged 17 to 74 years (mean 38.1±13.3 years), were included. The follow-up period ranged from 4 to 108 months (mean 59.7±31.6 months). RESULTS: During the follow-up the diagnosis of NMOSD was confirmed in 32 people, and 68 patients had diagnoses different from NMOSD. At the disease onset, 68.8% of patients were seropositive for AQP4-IgG. The mean time for confirming NMOSD diagnosis was 15.2±14.2 months. At the disease onset, 36% of patients fulfilled the DC 2015, the diagnosis was subsequently confirmed in 77.8% out of them. 26% of the patients fulfilled the DC 2006, the diagnosis was subsequently confirmed in 84.6% out of them. The sensitivity of DC 2006/DC 2015 was 69%/88%, specificity 94%/88%, accuracy 86%/88%, negative predictive value 85%/94%, positive predictive value 86%/78%. CONCLUSION: The specificity, sensitivity and accuracy of modern diagnostic criteria for NMOSD In Russian patients is comparable to those obtained in foreign studies. DC 2015 helps to diagnose NMOSD earlier than DC 2006, but they have a lower specificity.

Prognostic factors associated with disability in a cohort of neuromyelitis optica spectrum disorder and MOG-associated disease from a nationwide Portuguese registry.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) and MOG-associated disease (MOGAD) are an increasingly recognized group of demyelinating disorders of the central nervous system. Previous studies suggest that prognosis is predicted by older age at onset, number of relapses, the severity of the first attack and autoantibody status. OBJECTIVE: To study prognostic factors associated with disability progression and additional relapses in the 3-year follow-up of a national NMOSD/MOGAD cohort. RESULTS: Out of 180 of the initial Portuguese cohort, data on 82 patients was available at the end of the follow-up period (2019-2022). Two patients died. Twenty (24.4%) patients had one or more attack in this period (25 attacks in total), mostly transverse myelitis (TM) (56.0%) or optic neuritis (32.0%). MOGAD was significantly associated with a monophasic disease course (p = 0.03), with milder attacks (p = 0.01), while AQP4 + NMOSD was associated with relapses (p = 0.03). The most common treatment modalities were azathioprine (38.8%) and rituximab (18.8%). AQP4 + NMOSD more frequently required chronic immunosuppressive treatment, particularly rituximab (p = 0.01). Eighteen (22.5%) had an EDSS ≥6 at the end of the follow-up. AQP4 + NMOSD (p < 0.01) and the occurrence of transverse myelitis (TM) during disease (p = 0.04) correlated with an EDSS≥6 at the end of the follow-up period. MOGAD was significantly associated with an EDSS<6 (p < 0.01), and MOG+ cases that reached an EDSS>6 were significantly older (64.0 ± 2.8 versus 31.0 ± 17.1, p = 0.017). A bivariate logistic regression model including the serostatus and TM attacks during disease history successfully predicted 72.2% of patients that progressed to an EDSS≥6. CONCLUSION: This study highlights that myelitis predict increased disability (EDSS≥6) in NMOSD/MOGAG and AQP4 positivity is associated with increased disability.