Autoimmune Neurological Disorders Research Articles

The Power of Antibodies: Advancing Biomarker-Based Disease Detection and Surveillance.

Antibodies have long served as fundamental tools in disease diagnosis and surveillance. Their utility as biomarkers has expanded beyond infectious diseases to encompass a wide range of health conditions. This review aims to explore recent advancements in antibody biomarker discovery and their applications in diagnosing and monitoring diverse health conditions. It also examines the role of antibody surveillance in public health and epidemiological studies. A comprehensive analysis of recent literature was conducted, focusing on studies that identify and characterize disease-specific antibodies. Particular attention was given to their relevance in autoimmune diseases, infections, cancers, and neurological disorders. The review highlights disease-specific antibody biomarkers and their clinical significance. It also discusses the utility and challenges of antibody-based surveillance in assessing disease prevalence, tracking immunity trends, and supporting One Health strategies. Recent advancements in antibody biomarker discovery demonstrate significant potential in improving early diagnosis, personalized treatment, and population-level health management. Antibody surveillance continues to play a pivotal role in guiding public health responses and understanding disease dynamics.

Serum Metabolites as Mediator Between Autoimmune Hyperthyroidism and Epilepsy: A Mendelian Randomization Analysis.

Epilepsy, a complex neurological condition, might intertwine with various immune system anomalies, including autoimmune hyperthyroidism. An overactive thyroid gland due to immune system misdirection could subtly influence epilepsy via mechanisms not fully understood. Our investigation leverages Mendelian randomization (MR) to dissect this association, aiming to illuminate the role of serum metabolites as a possible bridge connecting these conditions. A comprehensive MR analysis was conducted in three phases, using genetic variants from GWAS datasets. The first phase assessed the causal effect of autoimmune hyperthyroidism on epilepsy. The second phase examined the impact of 1400 serum metabolites on epilepsy. The final phase explored the mediation of these metabolites in the autoimmune hyperthyroidism-epilepsy pathway. The analysis employed inverse variance weighted (IVW) methods, along with sensitivity analyses including MR-Egger and weighted median approaches, to ensure robustness. Our Mendelian randomization analysis identifies a significant causal relationship from autoimmune hyperthyroidism to epilepsy. We observed that genetic predisposition towards autoimmune hyperthyroidism is associated with reduced risk of developing epilepsy (P = 0.037). Sensitivity analyses, such as culling analysis and funnel plot inspections, confirm the consistency and robustness of this finding. Further analysis revealed cAMP as a mediator in this causal pathway (P = 0.016), underscoring its role in the link between autoimmune hyperthyroidism and epilepsy. Conversely, no causal effect of epilepsy on the development of autoimmune hyperthyroidism was found, highlighting a unidirectional relationship. This study proposes that autoimmune hyperthyroidism may act as a protective factor against epilepsy, with this effect potentially mediated by serum metabolites, particularly cAMP. These findings provide novel insights into the interplay between autoimmune conditions, metabolic alterations, and neurological disorders, highlighting cAMP as a promising therapeutic target of epilepsy.

The Role of Killer Ig-like Receptors in Diseases from A to Z.

Killer Ig-like Receptors (KIRs) regulate immune responses, maintaining the balance between activation and inhibition of the immune system. KIRs are expressed on natural killer cells and some CD8 T cells and interact with HLA class I molecules, influencing various physiological and pathological processes. KIRs' polymorphism creates a variability in immune responses among individuals. KIRs are involved in autoimmune disorders, cancer, infections, neurological diseases, and other diseases. Specific combinations of KIRs and HLA are linked to several diseases' susceptibility, progression, and outcomes. In particular, the balance between inhibitory and activating KIRs can determine how the immune system responds to pathogens and tumors. An imbalance can lead to an excessive response, contributing to autoimmune diseases, or an inadequate response, allowing immune evasion by pathogens or cancer cells. The increasing number of studies on KIRs highlights their essential role as diagnostic and prognostic biomarkers and potential therapeutic targets. This review provides a comprehensive overview of the role of KIRs in all clinical conditions and diseases, listed alphabetically, where they are analyzed.

Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease.

Tryptophan is an essential amino acid critical for human health. It plays a pivotal role in numerous physiological and biochemical processes through its metabolism. The kynurenine (KYN) pathway serves as the principal metabolic route for tryptophan, producing bioactive metabolites, including KYN, quinolinic acid, and 3-hydroxykynurenine. Numerous studies are actively investigating the relationship between tryptophan metabolism and physiological functions. These studies are highlighting the interactions among metabolites that may exert synergistic or antagonistic effects, such as neuroprotective or neurotoxic, and pro-oxidative or antioxidant activities. Minor disruptions in the homeostasis of these metabolites can result in immune dysregulation, contributing to a spectrum of diseases. These diseases include neurological disorders, mental illnesses, cardiovascular conditions, autoimmune diseases, and chronic kidney disease. Therefore, understanding the physiological roles of the KYN pathway metabolites is essential for elucidating the contribution of tryptophan metabolism to health regulation. The present review emphasizes the physiological roles of KYN pathway metabolites and their mechanisms in disease development, aiming to establish a theoretical basis for leveraging dietary nutrients to enhance human health.

Circadian rhythmicity of symptomatic phenotypes in multiple sclerosis: the CircaMS study protocol and feasibility of biomarker collection

IntroductionMultiple sclerosis (MS) is a chronic autoimmune neurological disease with a variable prognosis and unpredictable course. Fatigue, pain and low mood are common symptoms that tend to fluctuate in people...

Stem Cells Biology: An Updated Review

Stem cells are partially differentiated cells in multicellular organisms that can change into various types of cells and increase indefinitely to produce more of the same stem cell which is considered as the earliest type of cell in a cell lineage. Treatment with those cells is regarded as an innovative approach in regenerative medicine, offering promising capabilities for healing and restoring damaged tissues and organs. Mesenchymal stem cells, derived from different sources like bone marrow, fat, and dental pulp, are highlighted for their self-renewal, immune-modulation, and regenerative abilities. Regenerative medicine is one of the more recent fields or methodologies that revolutionizes the path for upgrading human health and quality of life, relying on the use of stem cells. The process of using stem cells indicates marvelous capabilities for healing and restoring damaged tissues and organs. The current overview examines the science or biology of stem cells, showing their various sources, and their potential applications across a wide range of medical fields, carried by discussing multiple studies exploring the stem cells. The review further explores the potential of stem cell therapy for treating neurological disorders, autoimmune diseases, cardiovascular conditions, liver diseases, ophthalmic conditions, bone injuries, kidney disorders, and dental issues.

Digital Twin-Assisted Deep Learning with Model Fusion for Detecting Multiple Sclerosis in MRI Modalities

The advancement of technologies such as IoT, Big Data, Data Science, Augmented Reality/Virtual Reality, and cloud computing has transformed the manufacturing sector through the Digital Twin (DT), serving as a potent instrument for simulating concepts into practice. Recently, artificial intelligence has been merged with digital technology to conduct research in the healthcare sector, facilitating judgments on the planning of patients’ clinical courses and the allocation of available medical resources. DTs can be utilized in the medical industry to facilitate clinical decision-making, providing prognoses and personalized treatment for patients. Multiple sclerosis (MS) is an autoimmune neurological disorder that impacts the central nervous system, potentially resulting in neurological impairment and mortality if left untreated. [X1]. In this research study, magnetic resonance imaging (MRI) samples collected from the E-Health lab and IXI databases are used to construct the DT empowered with artificial intelligence for the diagnosis of MS in a robust manner. We propose a hybrid CNN-RNN model for detecting MS in two phases. In the first phase, the deep features of the MRI modalities are extracted by two transfer learning models, m-InceptionV3 and m-DenseNet121. In the second phase, the classification of extracted features to either healthy or MS is performed by the Long Short-Term Memory RNN model. Deep learning metrics like precision, recall, F1 score, and accuracy are used to validate the performance of the proposed model. The proposed model outperformed the other state-of-the-art models achieving a good performance of 99.67% in validation accuracy. This healthcare DT pipeline may assist in clinical decision-making for MS detection and planning post-MS rehabilitation. Received: 19 September 2024 | Revised: 26 November 2024 | Accepted: 2 January 2025 Conflicts of Interest The authors declare that they have no conflicts of interest to this work. Data Availability Statement The data that support the findings of this study are openly available in IXI Dataset at https://brain-development.org/ixi-dataset/. Author Contribution Statement Ramya Palaniappan: Conceptualization, Methodology, Software, Validation, Formal analysis, Writing – original draft, Writing – review & editing. Siva Rathinavelayutham: Investigation, Resources, Data curation, Visualization, Supervision, Project administration.

Phenotypic diversity in NAXE mutations.

NAD(P)HX epimerase (NAXE) gene mutations have been associated with early onset progressive encephalopathy. We present three patients with NAXE gene mutations and different initial manifestations. Patient(P)1 was a 30 month-old boy whose neurological regression started after an infection and progressed, ultimately leading to death one year later. His brain magnetic resonance imaging (MRI) findings were suggesting metabolic stroke. P2, nine year-old sister of P1, had mild developmental delay since birth, seizures after age 5 years and pellagra-like skin lesions. P3 was a 15 year old female presenting multifocal neurological signs progressing over months and leading to respiratory insufficiency. Her initial MRI was normal but inflammatory lesions appeared three months after the onset of symptoms. Laboratory investigations including biochemical, serological and metabolic tests, and brain biopsy were unrevealing. Clinical presentation of P1 and P3 initially suggested autoimmune neurological disease, but no response to immunotherapy was obtained. Two different types of variants c.641T > G; p.Ile214Ser and c.128C > A, p.Ser43* were detected in NAXE in these patients' two unrelated families. All patients were given mitochondrial cocktail including niacin. NAXE plays an important role in the electron donors for the mitochondrial respiratory chain. Mutations result in accumulation of toxic metabolites, disruption of energy production, and possibly cell death. P1-3 displayed different ages of onset, different clinical courses and MRI findings unreported previously, suggesting immune-mediated encephalitis and metabolic stroke in P1, and an inflammatory process in P3. NAXE mutations should be considered in progressive central nervous system symptoms.

Can patient self-evaluation of functional status be used for evaluation of impairment of motor function in Guillain-Barré syndrome? Mapping clinician- and patient-reported outcomes in a phase 3 study of eculizumab in Japan.

Guillain-Barré syndrome (GBS) is an autoimmune neurological disorder characterized by muscle weakness. In clinical trials, treatment benefit and disease severity are typically measured using clinician-reported outcome measures like the Hughes Functional Grading Scale (HFGS). However, patient-reported outcome measures, such as the Rasch-built Overall Disability Scale (R-ODS) may provide additional insight into the patient experience during treatment. In this study, exploratory analyses of clinical trial data were performed to investigate how existing clinician-reported outcomes and patient-reported outcomes can help to assess disease progression by providing an accurate measurement of functional status. Data were collected as part of a phase 3 study to assess the safety and efficacy of eculizumab in patients in Japan with severe GBS. The association between HFGS score and R-ODS total centile score (linear measure of limitations; 0, most severe activity and social participation limitations and 100, no limitations) was assessed using the Spearman rank-order correlation coefficient. Threshold values of R-ODS total centile score that could differentiate between patients with an HFGS score of ≤ 1 and > 1 were determined using receiver-operating characteristic curve analyses and mapping (Rasch measurement theory). A triangulation approach was used to establish a proposed value for R-ODS total centile score equivalent to an HFGS score of ≤ 1 or > 1. Overall, 57 patients were included in this analysis. These exploratory analyses revealed good correlation between R-ODS total centile and HFGS scores. Using the Rasch model, mapping of HFGS to R-ODS scores showed a good fit. Evaluation of the R-ODS threshold that could approximate the functional motor symptom categories based on HFGS (score of 0 or 1) revealed a range of values from 60 to 80. Based on a trial sample, a threshold of 60 was found to have 100% sensitivity and 87% specificity at week 4, and 93.8% sensitivity and 77.8% specificity at week 24. This study established thresholds for the R-ODS total centile score that could approximate classification of functional impairment in GBS based on the HFGS score. Given that the R-ODS reflects the patient perspective, it may be used to capture a more complete picture of GBS severity.

Traditional Chinese medicine provides candidates for mutiple seclorsis: A review based on the progress of MS and potent treatment medicine.

Traditional Chinese medicine provides candidates for mutiple seclorsis: A review based on the progress of MS and potent treatment medicine.

Sex differences in progressive multiple sclerosis brain gene expression in oligodendrocytes and OPCs.

Multiple sclerosis is a neurological autoimmune disease with sex-imbalanced incidence; in the USA, the disease is more likely to effect females at a ratio of 3:1. In addition, males are more likely to have a more severe disease course at time of diagnosis. Questions about both causes and downstream effects of this disparity remain. We aim to investigate gene expression differences at a cellular level while considering sex to discover fine-scale sex disparities. These investigations could provide new avenues for treatment targeting, or treatment planning based on sex. Public single-nuclei RNA-sequencing data from three publications of progressive MS including control brains were analysed using the Seurat R package. Differential gene and pathway expression was looked at both within a specific data set which has sub-lesion level sample dissection and across all studies to provide a broader lens. This allowed for the consideration of cell types and spatial positioning in relation to the interrogated lesion in some of the calculations. Our analysis showed expression changes in the female MS oligodendrocytes and oligodendrocyte progenitor cells compared to healthy controls, which were not observed in the corresponding male affected cells. Differentially up-regulated genes in females include increased HLA-A in the oligodendrocytes, and increased clusterin in the oligodendrocyte progenitor cells. There are also several mitochondrial genes in both the oligodendrocytes and oligodendrocyte progenitors which are up-regulated in females, including several directly involved in electron transport and which have previously been associated with neurodegenerative diseases. These results point to altered states in oligodendrocyte progenitors and oligodendrocytes that in combination with known physiological dissimilarities between sexes may denote different programming in males and females in response to the onset of demyelinating lesions. The potential for increased debris clearance mediated by clusterin and availability of oligodendrocyte progenitors in females may indicate an environment more primed for repair, potentially including remyelination. This could contribute to the disparity in etiology in females versus males.

Efficacy and safety of efgartigimod in patients with neurological autoimmune diseases.

Efficacy and safety of efgartigimod in patients with neurological autoimmune diseases.

Toward curing neurological autoimmune disorders: Biomarkers, immunological mechanisms, and therapeutic targets.

Toward curing neurological autoimmune disorders: Biomarkers, immunological mechanisms, and therapeutic targets.

Low-Cost Strategies for the Development of Neurocritical Care in Resource-Limited Settings.

This review explores low-cost neurocritical care interventions for resource-limited settings, including economical devices, innovative care models, and disease-specific strategies. Devices like inexpensive ventilators, wearable technology, smartphone-based ultrasound, brain4care, transcranial Doppler, and smartphone pupillometry offer effective diagnostic and monitoring capabilities. Initiatives such as intermediate care units, minimally equipped stroke units, and tele-neurocritical care have demonstrated benefits by reducing hospital stays, preventing complications, and improving clinical and economic outcomes. The review emphasizes locally applicable tailored approaches for diagnosing and managing conditions such as traumatic brain injury, neuroinfections, status epilepticus, autoimmune neurological disorders, and acute stroke as viable and affordable solutions.

P-70 THYMIC HYPERPLASIA AND GRAVES' DISEASE: IS THERE A HIDDEN AUTOIMMUNE DISORDER?

Abstract Introduction Thymic hyperplasia is reported in 10-38% of patients with Graves' disease. Clinical Case We present a case of a 45-year-old female with Graves' disease and thymic hyperplasia, exhibiting non-specific symptoms. The patient was diagnosed with Graves' disease at age 42 and treated with thiamazole. While she was taking thiamazol she was felt muscle pain, spasms, and pulsations. Her pituitary and adrenal hormones were within normal limits. Three months after diagnosis, she was hospitalized for recurrent transient ischemic attacks. Myasthenia gravis was suspected, but acetylcholine receptor antibody tests, though initially elevated, were later normal. The patient also experienced flushing, and neck and facial redness without a clear diagnosis. She developed erythematous changes on her thighs, arms, and cleavage. Mastocytosis was suspected, but skin biopsy and serum tryptase tests were negative. She also reported frequent nocturnal bowel movements. Tumor markers such as chromogranin A and glucagon were slightly elevated, but a Ga-68 Dotatoc PET CT scan showed no evidence of neuroendocrine tumors. After six months of remission, the patient discontinued thiamazole, leading to symptom resolution and normalization of anti-TRAb levels. However, her TSH receptor antibodies increased seasonally, from February to August, over the next two years, resulting in hyperthyroidism. Thyroid ultrasound revealed changes consistent with autoimmune thyroid disease. The patient declined thymectomy and thyroidectomy. Due to adverse reactions to thiamazole and propranolol, possibly linked to Myasthenia gravis, she was switched to propylthiouracil with a good response. The etiology of symptoms atypical for hyperthyroidism or thymic hyperplasia, such as facial muscle tingling, spasms, pulsations, and erythematous rash, may be related to other autoimmune or neurological conditions, including Stiff Person syndrome and Myastenia gravis. Additionally, the seasonal recurrence, from February to August, of Graves' disease over three consecutive years is notable. Given the high prevalence of thymic hyperplasia in Graves' disease, ruling out neurological autoimmune diseases is advisable, as specific symptoms can affect the quality of life and may be exacerbated by antithyroid therapy.

Effectiveness and safety of therapeutic plasma exchange in neurological disorders; measuring the response to treatment using Modified Rankin Scale – A single-center study

Abstract INTRODUCTION: Therapeutic plasma exchange (TPE) is commonly used as a treatment modality in varying neurological disorders. Response to TPE in neurological disorders is usually noted in “subjective” terms. We, measured response to treatment, objectively, using Modified Rankin Scale (MRS). MATERIALS AND METHODS: This was an observational prospective study in patients diagnosed with autoimmune neurological disorders (AND) who underwent TPE, in addition to intravenous immunoglobulin, and/or prednisolone. This study was carried out at a tertiary care center. Demographic data, procedure details including adverse reactions, and clinical responses were collated. Clinical response was assessed by applying MRS, in different neurological disorders, before (pre-TPE) and after TPE (post-TPE). Pre- and post-TPE clinical conditions were compared using the Wilcoxon matched-pairs signed-ranks test. RESULTS: Fifty-three patients were included, with 15 females and 38 males, who had a median age of 48 years. Seven different AND were; myasthenia gravis (n = 11), Guillain–Barre syndrome (n = 18), neuromyelitis Optica spectrum disorders (n = 6); chronic inflammatory demyelinating polyneuropathy (n = 5); autoimmune encephalitis (n = 6); transverse myelitis (n = 6); and multiple sclerosis (n = 1). Patients received a median of 5 cycles of TPE and a mean 1.5 plasma volume was exchanged. The improvement in the MRS scale was significant when post-TPE scores were compared with pre-TPE scores. The most common adverse reaction was shivering (n = 5; 1.85%), which was managed conservatively. CONCLUSION: TPE was shown to be an effective and safe treatment modality in providing relief to patients with neurological disorders.

Patterns of Tau pathology in patients with anti-IgLON5 disease visualized by Florzolotau (18F) PET.

Anti-IgLON5 disease is a rare autoimmune neurological disorder with prominent Tau protein deposits in the brainstem and hypothalamus. The aim of this study was to visualize the in vivo distribution patterns of Tau protein in patients with anti-IgLON5 disease using the second-generation Tau PET tracer, Florzolotau (18F) PET imaging. Patients diagnosed with anti-IgLON5 disease were enrolled consecutively. Age- and sex-matched healthy controls (HCs) were also enrolled. The uptake of Florzolotau (18F) and 18F-FDG was assessed using both visual and semi-quantitative analysis techniques. A total of 10 patients with anti-IgLON5 disease and 40 HCs were included in the study. All ten patients with anti-IgLON5 disease underwent Florzolotau (18F) PET scans, and five of them underwent 18F-FDG PET scans. Twenty HCs underwent Florzolotau (18F) PET scans, and the remaining 20 HCs underwent 18F-FDG PET scans. In patients with anti-IgLON5 disease, significant uptake of Florzolotau (18F) was observed predominantly in the midbrain, pons, cerebellum, caudate, and putamen. This uptake pattern was notably absent in the control group. Moreover, semi-quantitative analysis techniques demonstrated widespread hypometabolism in the cerebral cortex in patients with anti-IgLON5 disease. This study indicates distinct Tau protein deposition patterns in patients with anti-IgLON5 disease, potentially serving as imaging biomarkers.

Use of brain MRI and gene expression atlases to reconstruct the pathophysiology of autoimmune neurological disorders: The proof-of-concept of NMOSD

Background: The understanding of disease pathophysiology is pivotal for tailored treatments. The spatial distribution of brain damage relies on the regional antigen expression and the local balance of susceptibility and protective elements. Objective: As proof-of-concept, we investigated the spatial association between brain damage and gene expression in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD). Methods: In this multicenter cross-sectional study, 90 AQP4 + NMOSD patients and 94 age-matched healthy controls underwent a brain magnetic resonance imaging (MRI). We used T2-hyperintense lesion probability maps and white/gray matter atrophy as proxies of inflammation and neurodegeneration. The association with the expression of 266 candidate genes was obtained with the Multimodal Environment for Neuroimaging and Genomic Analysis platform. A functional-enrichment analysis investigated overrepresented biological processes. Results: In AQP4 + NMOSD, T2-hyperintense lesions were mainly periventricular; atrophy mostly involved the visual pathway. The expression of AQP4 and complement (C4a and C5) was associated with both inflammation and neurodegeneration. Complement activation and regulation/uptake of the insulin-like growth factor were the most relevant enriched pathways. Nonspecific pathways related to DNA synthesis and repair were associated with brain atrophy. Conclusions: Quantitative MRI and gene expression atlas identified the key elements of AQP4 + NMOSD pathophysiology. This analysis could help in understanding the pathophysiology of antibody-mediated autoimmune disorders.

The limbic and extra-limbic encephalitis associated with glutamic acid decarboxylase (GAD)-65 antibodies: an observational study.

We aimed to define the clinical features and outcomes of encephalitis associated with anti-GAD65 Abs. In addition, we reviewed cases published in the literature with GAD65 encephalitis. We retrospectively studied 482 consecutive patients attending a tertiary care center for evaluation of an autoimmune neurological disorder. Nineteen patients were enrolled (3.94% of the cohort). Twelve (63.16%) patients were females, and the mean age at onset of the cohort was 31.68 ± 13.88 years. The following clinical-neuroimaging syndromes were identified: limbic encephalitis (n = 10), limbic plus extra-limbic encephalitis (n = 6), meningoencephalitis (n = 1), extralimbic encephalitis (n = 1), and unclassified (n = 1). The mesial temporal lobes were the most frequently affected (n = 13, 68.42%) in the brain magnetic resonance imaging (MRI), followed by frontal lobes (21%), and insular lobes (21%). Epileptiform discharges (94.4%), mostly from temporal lobes, were the most common electroencephalogram (EEG) finding. Most patients received immunotherapy and were followed for a mean duration of 21 months. A total of 73 patients, including 54 from the literature and 19 presented from the current series, were analyzed. Limbic encephalitis was the predominant presentation, and most patients received immunotherapy. Outcomes varied considerably. Considering patients from the literature and this series (n = 70), mortality was 5.7%. Also, 82.8% of patients had persistent neurologic manifestations, including seizures and cognitive impairment following immunotherapy. Limbic encephalitis is the most common form of GAD65 encephalitis, while a smaller proportion of patients may have signs of extra-limbic involvement. Most patients have persistent manifestations following combined immunotherapy with a relatively low mortality rate.

New Posttranslational Modification Lactylation Brings New Inspiration for the Treatment of Rheumatoid Arthritis.

Lactic acid (LA) is an essential glycolytic metabolite and energy source in the body, which is present in high levels in the synovial fluid of patients with rheumatoid arthritis (RA) and is a reliable indicator for identifying inflammatory arthritis. LA not only acts as an inflammatory amplifier in RA, recent studies have found that novel posttranslational modification (PTM) lactylation mediated by LA may also play a key role in RA. Single-cell sequencing showed that the RA lactylation score of patients with RA was significantly increased, and core lactylation-promoting genes, including NDUFB3, NGLY1, and other genes, were found to be potential biomarkers of RA. More studies have shown that lactylation can regulate genes in various cells, such as fibroblast-like synoviocytes (FLSs) and macrophages, thus playing a special role in the development and occurrence of autoimmune diseases, neurological diseases, and cancer diseases. In this paper, we review the research on lactylation in RA-related cells and mechanisms and bring new insights into the pathogenesis, diagnosis, and treatment of RA.