Immunopathogenesis of multiple sclerosis: molecular and cellular mechanisms and new immunotherapeutic approaches.

Background: Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating autoimmune disease with increasing global prevalence. It predominantly affects females, especially those of European descent. The interplay between environmental factors and genetic predisposition plays a crucial role in MS etiopathogenesis.Methods: We searched recent relevant literature on reputable databases, which include, PubMed, Embase, Web of Science, Scopus, and ScienceDirect using the following keywords: multiple sclerosis, pathogenesis, autoimmunity, demyelination, therapy, and immunotherapy.Results: Various animal models have been employed to investigate the MS etiopathogenesis and therapeutics. Autoreactive T cells within the CNS recruit myeloid cells through chemokine expression, leading to the secretion of inflammatory cytokines driving the MS pathogenesis, resulting in demyelination, gliosis, and axonal loss. Key players include T cell lymphocytes (CD4+ and CD8+), B cells, and neutrophils. Signaling dysregulation in inflammatory pathways and the immunogenetic basis of MS are essential considerations for any successful therapy to MS. Data indicates that B cells and neutrophils also have significant roles in MS, despite the common belief that T cells are essential. High neutrophil-to-lymphocyte ratios correlate with MS severity, indicating their contribution to disease progression. Dysregulated signaling pathways further exacerbate MS progression.Conclusion: MS remains incurable, but disease-modifying therapies, monoclonal antibodies, and immunomodulatory drugs offer hope for patients. Research on the immunogenetics and immunoregulatory functions of gut microbiota is continuing to provide light on possible treatment avenues. Understanding the complex interplay between genetic predisposition, environmental factors, and immune dysregulation is critical for developing effective treatments for MS.

5Z-7-Oxozaenol attenuates cuprizone-induced demyelination in mice through microglia polarization regulation.

INTRODUCTION: Demyelination is a key factor in axonal degeneration and neural loss, leading to disability in multiple sclerosis (MS) patients. Transforming growth factor beta activated kinase 1 (TAK1) is a critical molecule involved in immune and inflammatory signaling pathways. Knockout of microglia TAK1 can inhibit autoimmune inflammation of the brain and spinal cord and improve the outcome of MS. However, it is unclear whether inhibiting TAK1 can alleviate demyelination. METHODS: Eight-week-old male c57bl/6j mice were randomly divided into five groups: (a) the control group, (b) the group treated with cuprizone (CPZ) only, (c) the group treated with 5Z-7-Oxozaenol (OZ) only, and (d) the group treated with both cuprizone and 15 µg/30 µg OZ. Demyelination in the mice of this study was induced by administration of CPZ (ig) at a daily dose of 400 mg/kg for consecutive 5 weeks. OZ was intraperitoneally administered at mentioned doses twice a week, starting from week 3 after beginning cuprizone treatment. Histology, rotarod test, grasping test, pole test, Western blot, RT-PCR, and ELISA were used to evaluate corpus callosum demyelination, behavioral impairment, oligodendrocyte differentiation, TAK1 signaling pathway expression, microglia, and related cytokines. RESULTS: Our results demonstrated that OZ protected against myelin loss and behavior impairment caused by CPZ. Additionally, OZ rescued the loss of oligodendrocytes in CPZ-induced mice. OZ inhibited the activation of JNK, p65, and p38 pathways, transformed M1 polarized microglia into M2 phenotype, and increased brain-derived neurotrophic factor (BDNF) expression to attenuate demyelination in CPZ-treated mice. Furthermore, OZ reduced the expression of proinflammatory cytokines and increases anti-inflammatory cytokines in CPZ-treated mice. CONCLUSION: These findings suggest that inhibiting TAK1 may be an effective approach for treating demyelinating diseases.

Exploring Potential Mechanisms Accounting for Iron Accumulation in the Central Nervous System of Patients with Alzheimer's Disease.

Elevated levels of iron occur in both cortical and subcortical regions of the CNS in patients with Alzheimer's disease. This accumulation is present early in the disease process as well as in more advanced stages. The factors potentially accounting for this increase are numerous, including: (1) Cells increase their uptake of iron and reduce their export of iron, as iron becomes sequestered (trapped within the lysosome, bound to amyloid ß or tau, etc.); (2) metabolic disturbances, such as insulin resistance and mitochondrial dysfunction, disrupt cellular iron homeostasis; (3) inflammation, glutamate excitotoxicity, or other pathological disturbances (loss of neuronal interconnections, soluble amyloid ß, etc.) trigger cells to acquire iron; and (4) following neurodegeneration, iron becomes trapped within microglia. Some of these mechanisms are also present in other neurological disorders and can also begin early in the disease course, indicating that iron accumulation is a relatively common event in neurological conditions. In response to pathogenic processes, the directed cellular efforts that contribute to iron buildup reflect the importance of correcting a functional iron deficiency to support essential biochemical processes. In other words, cells prioritize correcting an insufficiency of available iron while tolerating deposited iron. An analysis of the mechanisms accounting for iron accumulation in Alzheimer's disease, and in other relevant neurological conditions, is put forward.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Tumor or demyelination? Three tumefactive multiple sclerosis case reports and literature review.

OBJECTIVE: To investigate the clinical diagnosis and treatment of tumefactive multiple sclerosis (TMS). METHODS: Clinical data, laboratory and imaging examinations, and treatment of three patients with TMS were retrospectively analyzed. Data were further analyzed in relation to the literature. RESULTS: All three patients had acute or subacute onset with large lesions on imaging, which were difficult to differentiate from tumors. Two cases had relapses on follow-up and one case had a stereotactic biopsy. CONCLUSION: TMS is difficult to differentiate from brain tumors. It is necessary to improve the understanding of these diseases, to apply the correct diagnosis and treatment and to avoid unnecessary invasive surgery and inappropriate treatment.

Exploring the immune-modulating properties of boswellic acid in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a condition where the central nervous system loses its myelin coating due to autoimmune inflammation. The experimental autoimmune encephalomyelitis (EAE) simulates some aspects of human MS. Boswellic acids are natural compounds derived from frankincense extract, known for their anti-inflammatory properties. The purpose of this research was to investigate therapeutic potential of boswellic acids. Mice were divided into three groups: low-dose (LD), high-dose (HD), and control groups (CTRL). Following EAE induction, the mice received daily doses of boswellic acid for 25 days. Brain tissue damage, clinical symptoms, and levels of TGF-ß, IFN-γ, and IL-17 cytokines in cell cultured supernatant of lymphocytes were assessed. Gene expression of transcription factors in brain was measured using real-time PCR. The levels of brain demyelination were significantly lower in the treatment groups compared to the CTRL group. Boswellic acid reduced the severity and duration of EAE symptoms. Furthermore, boswellic acid decreased the amounts of IFN-γ and IL-17, also the expression of T-bet and ROR-γt in brain. On the contrary, it increased the levels of TGF-ß and the expression FoxP3 and GATA3. Our findings suggest that boswellic acids possess therapeutic potential for EAE by modulating the immune response and reducing inflammation.

Galectin-3 Plays a Role in Neuroinflammation in the Visual Pathway in Experimental Optic Neuritis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) featuring numerous neuropathologies, including optic neuritis (ON) in some patients. However, the molecular mechanisms of ON remain unknown. Galectins, ß-galactoside-binding lectins, are involved in various pathophysiological processes. We previously showed that galectin-3 (gal-3) is associated with the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the current study, we investigated the expression of gal-3 in the visual pathway in EAE mice to clarify its role in the pathogenesis of ON. Immunohistochemical analysis revealed upregulation of gal-3 in the visual pathway of the EAE mice during the peak stage of the disease, compared with naïve and EAE mice during the chronic stage. Gal-3 was detected mainly in microglia/macrophages and astrocytes in the visual pathway in EAE mice. In addition, gal-3+/Iba-1+ cells, identified as phagocytic by immunostaining for cathepsin D, accumulated in demyelinating lesions in the visual pathway during the peak disease stage of EAE. Moreover, NLRP3 expression was detected in most gal-3+/Iba-1+ cells. These results strongly suggest that gal-3 regulates NLRP3 signaling in microglia/macrophages and neuroinflammatory demyelination in ON. In astrocytes, gal-3 was expressed from the peak to the chronic disease stages. Taken together, our findings suggest a critical role of gal-3 in the pathogenesis of ON. Thus, gal-3 in glial cells may serve as a potential therapeutic target for ON.

Interruptible demyelination in avian riboflavin deficient neuropathy.

BACKGROUND AND AIMS: The evolution of demyelination in individual internodes remains unclear although it has been noticed the paranodal demyelination precedes internodal demyelination in neuropathies with diverse aetiologies. For therapeutic purpose, it is fundamental to know whether the demyelinating procedure in affected internodes can be interrupted. This study aimed to delineate the development of demyelination in individual internodes in avian riboflavin deficient neuropathy. METHODS: Newborn broiler meat chickens were maintained either on a routine diet containing 5.0 mg/kg riboflavin, a riboflavin deficient diet containing 1.8 mg/kg riboflavin, or initially a riboflavin deficient diet for 11 days and then routine diet plus riboflavin repletion from day 12. Evolution of demyelination in individual internodes was analyzed by teased nerve fibre studies from day 11 to 21. RESULTS: In riboflavin deficient chickens, demyelination was the predominant feature: it was mainly confined to the paranodal region at day 11; extended into internodal region, but less than half of the internodal length in most affected internodes at day 16; involved more than half or whole internode at day 21. In the internode undergoing demyelination, myelin degeneration of varying degrees was noticed in the cytoplasm of the Schwann cell wrapping the internode. Two days after riboflavin repletion, co-existence of remyelination and active demyelination within individual internodes was noticed. Remyelination together with preserved short original internodes was the characteristic feature 4 and 9 days after riboflavin repletion. CONCLUSION: Riboflavin repletion interrupts the progression from paranodal to internodal demyelination in riboflavin deficient chickens and promotes remyelination before complete internodal demyelination.

The Response of Osmotic Demyelination Syndrome to Plasmapheresis in a Patient Presenting with Catatonia after Correction of Hyponatraemia in Hyperemesis Gravidarum.

Osmotic demyelination syndrome (ODS) is a disorder characterised by the widespread development of demyelination in both pontine and extrapontine regions. It has been recognised as a complication arising from the rapid correction of hyponatraemia. This study presents the case of a 20-year-old Thai female patient at 10 weeks gestation, exhibiting an initial presentation of catatonia - an uncommon manifestation of ODS. The patient developed symptoms following the rapid correction of hyponatraemia in the context of hyperemesis gravidarum. Magnetic resonance imaging (MRI) of the brain revealed a trident or bat-wing-shaped pattern in T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences at the central pons. The patient underwent five cycles of plasmapheresis and received rehabilitation, leading to clinical improvement. LEARNING POINTS: Osmotic demyelination syndrome (ODS) is a rare but potentially devastating neurological complication, such as catatonia, resulting from the correction of hyponatraemia.Pregnancies complicated by hyperemesis gravidarum tend to exhibit hyponatraemia and hypokalaemia, which serve as contributing risk factors for ODS.Plasmapheresis is considered as an option in the treatment of ODS for the removal of inflammatory substances.

CNS Demyelination Syndromes Following COVID-19 Vaccination: A Case Series.

Background and Objectives: Although immunization against coronavirus disease 2019 (COVID-19) is ongoing, adverse reactions to these vaccinations have been observed in isolated cases. We aimed to report different neurological complications developed after COVID-19 vaccination. Materials and Methods: In our case series study, we report all cases of CNS demyelination following COVID-19 immunization. Clinical evaluation, brain MRI, and CSF analysis for oligoclonal bands and IgG index were performed for all patients. Other investigations were performed for selected patients, including spine MRI, EEG, VEP, and aquaporin-4. Results: Eighteen patients (eight males and ten females) with no history of COVID-19 infection had neurological manifestations (vertigo, ataxia, recurrent attacks of loss of consciousness, optic neuritis, and myelitis) starting within 14 days after Pfizer (n = 12) and AstraZeneca (n = 6) vaccination. MRI was obtained during the acute stage of the disease. The most common presenting symptoms were optic neuritis and hemiparesis. Sixteen patients had altered signal intensity and multiple variable-sized, round to ill-defined oval lesions suggestive of MS. Two showed findings compatible with transverse myelitis. Conclusion: This study identified CNS demyelination complications after COVID-19 vaccination. The COVID-19 vaccination could result in CNS complications, possibly connected to a post-vaccination inflammatory process. We recommend continuous post-marketing monitoring for adverse reactions in individuals who received the vaccines to establish a connection and guarantee the long-term safety of COVID-19 vaccines.

Frame navigation guided percutaneous balloon compression for intractable trigeminal neuralgia secondary to multiple sclerosis.

Background: Patients with multiple sclerosis (MS) are more likely to develop trigeminal neuralgia (TN) compared to the regular population, due to scarring of the nerve and development of a demyelination plaque. Despite treatment, approximately 10% of MS patients treated for TN experience symptom recurrence, including the development of MS-like symptoms such as optic neuritis and bilateral facial pain. Methods: A computed tomography (CT) scan was performed preoperatively on two patients diagnosed with multiple sclerosis (MS) who experienced secondary trigeminal neuralgia (TN). A precise reference frame was strapped firmly to the patient's forehead during the intraoperative procedure. Preliminary CT images were registered using the navigation system and the bony landmarks were set. Case description: Two patients diagnosed with multiple sclerosis (MS) who experienced refractory trigeminal neuralgia (TN) underwent percutaneous balloon compression. Initial conservative treatment and one dosage of Gamma Knife Radiosurgery (GKR) resulted in symptom control for a few weeks. Both patients had an acute recurrence of pain; thus, percutaneous retrogasserian balloon compression was performed. During follow-up, the patients reported a 70% decrease in pain after the procedure, with minimal recurrence of shooting episodes. Conclusion: Management of trigeminal neuralgia secondary to drug-resistant multiple sclerosis presents a persistent challenge. The percutaneous technique for retrogasserian balloon compression may offer a solution for some patients, but it presents unique challenges for neurosurgeons. Given the complexity of the pathogenesis, target identification, and the potential absence of neurovascular conflict, microvascular decompression remains a debated approach for this patient population. While stereotactic radiosurgery may be a promising alternative.

The level of cytokines in tears as a novel indicator of demyelinating diseases.

INTRODUCTION: A novel research objective is to identify new molecules in more readily accessible biological fluids that could be used in the diagnosis of multiple sclerosis (MS) and other demyelinating disorders. AIM: To compare the level of selected cytokines in tears between patients with MS or other demyelinating disorder and healthy controls. MATERIAL AND METHODS: 84 patients with diagnosed MS during remission or with other demyelinating disease of the CNS and 70 healthy controls were enrolled in the study. Tears were collected without any stimulation and stored till the day of assessment. The concentration of selected cytokines was measured by the Bio-Plex Pro Human cytokine screening panel 27 cytokines assay according to the manufacturer's instructions. Statistical analysis was performed with Statistica 13. RESULTS: IL-1b level was significantly lower in the study group compared to the control group [3,6 vs 8.71, p < 0.001]. The same pattern was observed for IL-6 [3,1 vs 5.26, p = 0.027] and IL-10 [1,7 vs 10.92, p < 0.001] (Table 1). In the study group, IL-1RA (p = 0.015), IL-5 (p = 0.04), IL-9 (p = 0.014), and IL-15 (p = 0.037) showed significant correlations with age. In the total sample, IL-1Ra (p = 0.016) and IFN-g (p = 0.041) were significantly correlated with age, while in the control group, IL-8 (p = 0.09), MIP-1a (p = 0.009), and RANTES (p = 0.031) showed significant correlations. CONCLUSIONS: Our results show that MS and other demyelination diseases lead to decrease in the overall level of cytokines in tears. Further research is needed to determine the role of tear fluid in the assessment of demyelinating disorders like MS.

Acute respiratory failure caused by brainstem demyelinating lesions in an older patient with an atypical relapsing autoimmune disorder.

An 84-year-old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high-intensity signal lesions on fluid-attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well-defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8-positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti-AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing-remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study.

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

The Mouse Model of Internal Capsule Demyelination: A Novel Tool for Investigating Motor Functional Changes Caused by Demyelination and for Evaluating Drugs That Promote Remyelination.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, characterized by remyelination failure and axonal dysfunction. Remyelination by oligodendrocytes is critical for improvement of neurological deficits associated with demyelination. Rodent models of demyelination are frequently used to develop and evaluate therapies for MS. However, a suitable mouse model for assessing remyelination-associated recovery of motor functions is currently unavailable. In this review, we describe the development of the mouse model of internal capsule (IC) demyelination by focal injection of lysolecithin into brain and its application in the evaluation of drugs for demyelinating diseases. This mouse model exhibits motor deficits and subsequent functional recovery accompanying IC remyelination. Notably, this model shows enhancement of functional recovery as well as tissue regeneration when treated with clemastine, a drug that promotes remyelination. The IC demyelination mouse model should contribute to the development of novel drugs that promote remyelination and ameliorate neurological deficits in demyelinating diseases.

Astrocyte Activation and Drug Target in Pathophysiology of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease, which is also referred to as an autoimmune disorder with chronic inflammatory demyelination affecting the core system that is the central nervous system (CNS). Demyelination is a pathological manifestation of MS. It is the destruction of myelin sheath, which is wrapped around the axons, and it results in the loss of synaptic connections and conduction along the axon is also compromised. Various attempts are made to understand MS and demyelination using various experimental models out of them. The most popular model is experimental autoimmune encephalomyelitis (EAE), in which autoimmunity against CNS components is induced in experimental animals by immunization with self-antigens derived from basic myelin protein. Astrocytes serve as a dual-edged sword both in demyelination and remyelination. Various drug targets have also been discussed that can be further explored for the treatment of MS. An extensive literature research was done from various online scholarly and research articles available on PubMed, Google Scholar, and Elsevier. Keywords used for these articles were astrocyte, demyelination, astrogliosis, and reactive astrocytes. This includes articles being the most relevant information to the area compiled to compose a current review.

Hand knob sign in osmotic demyelinating syndrome.

BACKGROUND: Osmotic demyelinating syndrome, commonly recognized as a consequence of the rapid correction of hyponatremia, has been known to cause motor, neuropsychiatric, or extrapyramidal symptoms. We reported a patient with an unusual presentation involving bilateral hand weakness, and pseudobulbar affect. The imaging was compatible with osmotic demyelinating syndrome with bilateral hand knob lesions, despite no history of overcorrection of hyponatremia. CASE PRESENTATION: A 44-year-old female presented with three weeks of emotional lability, spastic dysarthria, and bilateral hand weakness following ankle surgery and a mild head injury. Physical examination revealed weakness in the intrinsic hand muscles, leading to a claw-like deformity of the hands, although sensation remained unimpaired. Magnetic resonance imaging (MRI) of the brain revealed several hyperintensities on fluid-attenuated inversion recovery imaging involving various areas, including the hand knob area of the bilateral precentral gyri, caudate, lentiform nuclei, and pons, suggestive of osmotic demyelinating syndrome. Clinical improvement was observed following a trial of intravenous pulse methylprednisolone and plasmapheresis. CONCLUSIONS: Bilateral hand weakness is an unusual manifestation of osmotic demyelinating syndrome. The precentral gyrus, specifically in the hand knob area, is the vulnerable region that can result from osmotic demyelinating syndrome.

Fractal Analysis in Neurodegenerative Diseases.

Neurodegenerative diseases are defined by progressive nervous system dysfunction and death of neurons. The abnormal conformation and assembly of proteins is suggested to be the most probable cause for many of these neurodegenerative disorders, leading to the accumulation of abnormally aggregated proteins, for example, amyloid ß (Aß) (Alzheimer's disease and vascular dementia), tau protein (Alzheimer's disease and frontotemporal lobar degeneration), α-synuclein (Parkinson's disease and Lewy body dementia), polyglutamine expansion diseases (Huntington disease), or prion proteins (Creutzfeldt-Jakob disease). An aberrant gain-of-function mechanism toward excessive intraparenchymal accumulation thus represents a common pathogenic denominator in all these proteinopathies. Moreover, depending upon the predominant brain area involvement, these different neurodegenerative diseases lead to either movement disorders or dementia syndromes, although the underlying mechanism(s) can sometimes be very similar, and on other occasions, clinically similar syndromes can have quite distinct pathologies. Non-Euclidean image analysis approaches such as fractal dimension (FD) analysis have been applied extensively in quantifying highly variable morphopathological patterns, as well as many other connected biological processes; however, their application to understand and link abnormal proteinaceous depositions to other clinical and pathological features composing these syndromes is yet to be clarified. Thus, this short review aims to present the most important applications of FD in investigating the clinical-pathological spectrum of neurodegenerative diseases.

Automated whole slide morphometry of sural nerve biopsy using machine learning.

AIM: The morphometry of sural nerve biopsies, such as fibre diameter and myelin thickness, helps us understand the underlying mechanism of peripheral neuropathies. However, in current clinical practice, only a portion of the specimen is measured manually because of its labour-intensive nature. In this study, we aimed to develop a machine learning-based application that inputs a whole slide image (WSI) of the biopsied sural nerve and automatically performs morphometric analyses. METHODS: Our application consists of three supervised learning models: (1) nerve fascicle instance segmentation, (2) myelinated fibre detection and (3) myelin sheath segmentation. We fine-tuned these models using 86 toluidine blue-stained slides from various neuropathies and developed an open-source Python library. RESULTS: Performance evaluation showed (1) a mask average precision (AP) of 0.861 for fascicle segmentation, (2) box AP of 0.711 for fibre detection and (3) a mean intersection over union (mIoU) of 0.817 for myelin segmentation. Our software identified 323,298 nerve fibres and 782 fascicles in 70 WSIs. Small and large fibre populations were objectively determined based on clustering analysis. The demyelination group had large fibres with thinner myelin sheaths and higher g-ratios than the vasculitis group. The slope of the regression line from the scatter plots of the diameters and g-ratios was higher in the demyelination group than in the vasculitis group. CONCLUSION: We developed an application that performs whole slide morphometry of human biopsy samples. Our open-source software can be used by clinicians and pathologists without specific machine learning skills, which we expect will facilitate data-driven analysis of sural nerve biopsies for a more detailed understanding of these diseases.

The neurotropic schistosome vs experimental autoimmune encephalomyelitis: are there any winners?

The incidences of multiple sclerosis have risen worldwide, yet neither the trigger nor efficient treatment is known. Some research is dedicated to looking for treatment by parasites, mainly by helminths. However, little is known about the effect of helminths that infect the nervous system. Therefore, we chose the neurotropic avian schistosome Trichobilharzia regenti, which strongly promotes M2 polarization and tissue repair in the central nervous system, and we tested its effect on the course of experimental autoimmune encephalomyelitis (EAE) in mice. Surprisingly, the symptoms of EAE tended to worsen after the infection with T. regenti. The infection did not stimulate tissue repair, as indicated by the similar level of demyelination. Eosinophils heavily infiltrated the infected tissue, and the microglia number increased as well. Furthermore, splenocytes from T. regenti-infected EAE mice produced more interferon (IFN)-γ than splenocytes from EAE mice after stimulation with myelin oligodendrocyte glycoprotein. Our research indicates that the combination of increased eosinophil numbers and production of IFN-γ tends to worsen the EAE symptoms. Moreover, the data highlight the importance of considering the direct effect of the parasite on the tissue, as the migrating parasite may further tissue damage and make tissue repair even more difficult.