Frequency of cognitive impairment in patients with neuromyelitis optica spectrum disorder in Mexico.

Background: Between 29% and 67% of neuromyelitis optica spectrum disorder patients have cognitive alterations. Objective: To assess the frequency of cognitive impairment in patients with neuromyelitis optica spectrum disorder in Mexico using the Brief International Cognitive Assessment for Multiple Sclerosis. Methods: We evaluated 40 neuromyelitis optica spectrum disorder patients and 40 healthy controls from Mexico. Results: 28 (70.0%) patients with neuromyelitis optica spectrum disorder had cognitive impairment in two or more cognitive domains. Student´s T test showed statistically poor performance by neuromyelitis optica spectrum disorder patients compared to healthy controls on all three neuropsychological test scores. This significant difference was observed on the Symbols Digit Modalities Test (t = 8.875; p ≤ 0.001); California Verbal Learning Test-II memory (t = 10.418; p ≤ 0.001); and Brief Visuospatial Memory Test Revised (t = 6.123; p ≤ 0.001). Conclusions: This study showed that 70% of neuromyelitis optica spectrum disorder patients exhibited cognitive impairment in two or more cognitive domains. Determining the frequency of cognitive impairment will guide the decision of Neuropsychologists in planning cognitive rehabilitation across various domains.

Validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in individuals with multiple sclerosis from Mexico.

BACKGROUND: Cognitive impairment is observed in 43-70 % of Multiple sclerosis (MS) patients. One of the most widely used batteries for cognitive assessment in this population is the Brief International Cognitive Assessment for MS (BICAMS). The objective of this study was to validate and assess the reliability of the BICAMS in a Mexican population with MS and to obtain and provide regression-based norms. METHODS: One hundred healthy controls (HCs) and 100 patients with multiple sclerosis participated in the present study, and groups were matched for age, years of education and sex. Subjects completed all three tests of the BICAMS. Test-retest measures were obtained from 30 patients to test reliability. RESULTS: The sample´s average age was 43.39 ± 6.03 years old, and the average years of education was 12.55 ± 2.52 years. Approximately 63 % of the participants were female. The groups did not differ in age, years of education, or sex. The MS group performed significantly worse than the HCs group on all three neuropsychological tests. A significant difference was observed for the SDMT (t = 10.166; p=<0.001), CVLT-II (t = 10.949; p=<0.001), and BVMT-R (t = 2.636; p = 0.009). For all comparisons, the effect size (d) for each test was calculated as follows: SDMT= 0.58 and CVLT-II= 0.61. The test-retest coefficients for each test were as follows: SDMT: r = 0.95; CVLT-II: r = 0.84; and BVMT-R = 0.81. CONCLUSION: The BICAMS can provide information on cognitive impairment in MS patients, and this information can be used by neuropsychologists for cognitive rehabilitation in different domains.

Genetic Basis of Inflammatory Demyelinating Diseases of the Central Nervous System: Multiple Sclerosis and Neuromyelitis Optica Spectrum.

Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.

Neuromyelitis optica spectrum disorder: pathophysiological approach.

Aim: To review the main pathological findings of Neuromyelitis Optica Spectrum Disorder (NMOSD) associated with the presence of autoantibodies to aquaporin-4 (AQP4) as well as the mechanisms of astrocyte dysfunction and demyelination. Methods: An comprehensive search of the literature in the field was carried out using the database of The National Center for Biotechnology Information from . Systematic searches were performed until July 2022. Results: NMOSD is an inflammatory and demyelinating disease of the central nervous system mainly in the areas of the optic nerves and spinal cord, thus explaining mostly the clinical findings. Other areas affected in NMOSD are the brainstem, hypothalamus, and periventricular regions. Relapses in NMOSD are generally severe and patients only partially recover. NMOSD includes clinical conditions where autoantibodies to aquaporin-4 (AQP4-IgG) of astrocytes are detected as well as similar clinical conditions where such antibodies are not detected. AQP4 are channel-forming integral membrane proteins of which AQ4 isoforms are able to aggregate in supramolecular assemblies termed orthogonal arrays of particles (OAP) and are essential in the regulation of water homeostasis and the adequate modulation of neuronal activity and circuitry. AQP4 assembly in orthogonal arrays of particles is essential for AQP4-IgG pathogenicity since AQP4 autoantibodies bind to OAPs with higher affinity than for AQP4 tetramers. NMOSD has a complex background with prominent roles for genes encoding cytokines and cytokine receptors. AQP4 autoantibodies activate the complement-mediated inflammatory demyelination and the ensuing damage to AQP4 water channels, leading to water influx, necrosis and axonal loss. Conclusions: NMOSD as an astrocytopathy is a nosological entity different from multiple sclerosis with its own serological marker: immunoglobulin G-type autoantibodies against the AQP4 protein which elicits a complement-dependent cytotoxicity and neuroinflammation. Some patients with typical manifestations of NMSOD are AQP4 seronegative and myelin oligodendrocyte glycoprotein positive. Thus, the detection of autoantibodies against AQP4 or other autoantibodies is crucial for the correct treatment of the disease and immunosuppressant therapy is the first choice.

Risk factors associated with permanent disability in neuromyelitis optica spectrum disorders.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. In NMOSD, a relapse results in increased disability. OBJECTIVE: To assess risk factors associated with permanent disability (PD) in patients with neuromyelitis optica spectrum disorders (NMOSD). METHODS: We evaluated 34 cases (who developed permanent disability) and 33 controls. The assessment included the following variables: sociodemographic data and characteristics of the disease. Logistic regression analysis was performed to adjust variables associated with PD. RESULTS: fifty-one percent developed PD during follow-up; 15 (22%) developed permanent visual disability, 13 (19%) developed permanent motor disability and 6 (9%) were restricted to wheelchair. Factors associated with PD in the crude analysis were: age at onset ≥ 50 years (OR 3.95, 95% IC 1.12-13.94, p= 0.032), time from onset to diagnosis ≥ 12 months (OR 3.30, 95% IC 1.13-9.64, p= 0.029), time from onset to treatment ≥ 60 months (OR 4.16, 95% IC 1.03-16.85, p= 0.045), EDSS ≥ 4.0 at the first appointment (OR 3.21, 95% IC 1.18-8.76, p= 0.022) and severe relapses during disease evolution (OR 5.72, 95% IC 1.98-16.57, p= 0.001). Factors associated with PD in the adjusted analysis were: age at onset ≥ 50 years (OR 5.82, 95% IC 1.30-26.05, p= 0.021), time from onset to diagnosis ≥ 12 months (OR 5.43, 95% IC 1.47-20.08, p= 0.011) and severe relapses during disease evolution (OR 6.65, 95% IC 1.98-22.31, p= 0.002). CONCLUSION: Half of patients with NMOSD may develop PD during disease evolution. Age of onset ≥ 50 years, delay to diagnosis ≥12 months and initial EDSS ≥ 4.0 constitute the strongest risk factors for PD.

Cognitive disorder and dementia in type 2 diabetes mellitus.

Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer's disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of ß-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.

Neuromyelitis optica spectrum disorder in Western Mexico.

BACKGROUND: Neuromyelitis Optica Spectrum Disorders (NMOSD) are a group of inflammatory diseases of the Central Nervous System (CNS) that primarily affect the optic nerve and spinal cord, usually with a severe and relapsing course. Due to the scarce information in non-Caucasian populations, we aimed to describe incidence, prevalence, and main clinical characteristics of NMOSD in a defined region in Mexico. MATERIALS AND METHODS: Descriptive, retrospective analysis of all reported cases of NMOSD attended in the neurology department of the UMAE-HE, CMNO, IMSS, the biggest third level hospital in Western Mexico. We searched the electronic medical records of the hospital for patients with a diagnosis of NMO, and reviewed all cases to confirm if they fulfilled NMOSD 2015 diagnostic criteria. Data were collected through a structured form. We described adjusted incidence and prevalence according to the WHO method, for the IMSS affiliated total population in Jalisco state in 2019. RESULTS: 67 NMOSD patients were included in the analysis of clinical data, with a mean age at onset of symptoms of 36 years ((Rivera et al., 2008-65). Most patients were female (74.6%). 53 patients living in Jalisco by the end of 2019 were included in the analysis of prevalence and incidence. Adjusted prevalence was 0.71/100,000 (95% CI 0.55-0.92), while adjusted incidence was 1.87/1,000,000 person-years (95% CI 1.11-3.16). In the full cohort, the first symptom of NMOSD was optic neuritis in 49.3% of the patients, followed by transverse myelitis (23.9%) and area postrema syndrome (10.4%). 62 patients relapsed in a mean follow-up of 2 years (0-7). 5 patients with less than 6 months of follow up had not relapsed. 55.2% of the patients were AQP4-IgG +, 14.9% AQP4-IgG -, and 29.9% unknown status. CONCLUSIONS: Although NMOSD prevalence is similar to other reports around the world, incidence is higher than in Caucasian populations. We believe that this high incidence is related to an increased awareness of the disease in the era of new NMOSD treatments. Recurrent disease is very frequent in our cohort.

Risk factors for mortality of adult patients with COVID-19 hospitalised in an emerging country: a cohort study.

OBJECTIVE: To describe mortality of in-hospital patients with COVID-19 and compare risk factors between survivors and non-survivors. DESIGN: Prospective cohort of adult inpatients. SETTING: Tertiary healthcare teaching hospital in Guadalajara, Mexico. PARTICIPANTS: All patients with confirmed COVID-19 hospitalised from 25 March to 7 September 2020 were included. End of study: 7 November 2020. PRIMARY OUTCOME MEASURES: Patient survival analysed by the Kaplan-Meier method and comparison of factors by the log-rank test. Mortality risk factors analysed by multivariate Cox's proportional-hazard model. RESULTS: One thousand ten patients included: 386 (38%) died, 618 (61%) alive at discharge and six (0.6%) remained hospitalised. There was predominance of men (63%) and high frequency of overweight-obesity (71%); hypertension (54%); diabetes (40%); and lung (9%), cardiovascular (8%) and kidney diseases (11%); all of them significantly more frequent in non-survivors. Overweight-obesity was not different between groups, but severity of disease (Manchester Triage System and quick Sequential Organ Failure Assessment) was significantly worse in non-survivors, who were also significantly older (65 vs 45 years, respectively) and had haematological, biochemical, coagulation and inflammatory biomarkers more altered than survivors. Mortality predictors were invasive mechanical ventilation (IMV; OR 3.31, p<0.0001), admission to intensive care unit (ICU; OR 2.18, p<0.0001), age (OR 1.02, p<0.0001), Manchester Triage System (urgent OR 1.44, p=0.02; immediate/very urgent OR 2.02, p=0.004), baseline C reactive protein (CRP; OR 1.002, p=0.009) and antecedent of kidney disease (OR 1.58, p=0.04) CONCLUSIONS: Mortality in hospitalised patients with COVID-19 in this emerging country centre seemed to be higher than in developed countries. Patients displayed a high frequency of risk factors for poor outcome, but the need for IMV, ICU admission, older age, more severe disease at admission, antecedent of kidney disease and higher CRP levels significantly predicted mortality.

Are electrophysiological and oligodendrocyte alterations an element in the development of multiple sclerosis at the same time as or before the immune response?

Efficient communication between the glial cells and neurons is a bi-directional process that is essential for conserving normal functioning in the central nervous system (CNS). Neurons dynamically regulate other brain cells in the healthy brain, yet little is known about the first pathways involving oligodendrocytes and neurons. Oligodendrocytes are the myelin-forming cells in the CNS that are needed for the propagation of action potentials along axons and additionally serve to support neurons by neurotrophic factors (NFTs). In demyelinating diseases, like multiple sclerosis (MS), oligodendrocytes are thought to be the victims. Axonal damage begins early and remains silent for years, and neurological disability develops when a threshold of axonal loss is reached, and the compensatory mechanisms are depleted. Three hypotheses have been proposed to explain axonal damage: 1) the damage is caused by an inflammatory process; 2) there is an excessive accumulation of intra-axonal calcium levels; and, 3) demyelinated axons evolve to a degenerative process resulting from the lack of trophic support provided by myelin or myelin-forming cells. Although MS was traditionally considered to be a white matter disease, the demyelination process also occurs in the cerebral cortex. Recent data supports the notion that initial response is triggered by CNS injury. Thus, the understanding of the role of neuron-glial neurophysiology would help provide us with further explanations. We should take in account the suggestion that MS is in part an autoimmune disease that involves genetic and environmental factors, and the pathological response leads to demyelination, axonal loss and inflammatory infiltrates.

Effect of fish oil on oxidative stress markers in patients with probable Alzheimer´s disease

High intake of omega-3 fatty acids has been associated with synaptic plasticity, neurogenesis and memory in several experimental models. To assess the efficacy of fish oil supplementation on oxidative stress markers in patients diagnosed with probable Alzheimer´s disease (AD) we conducted a double blind, randomized, placebo controlled clinical trial. AD patients who met the inclusive criteria were given fish oil (containing 0.45 g eicosapentaenoic acid and 1 g docosahexaenoic acid) or placebo daily for 12 months. Oxidative stress markers [lipoperoxides, nitric oxide catabolites levels, oxidized/reduced glutathione ratio, and membrane fluidity] and fatty acid profile in erythrocytes were assessed at enrollment, and 6 and 12 months after the start of the testing period. At the end of the trial, in patients who received fish oil, we detected a decrease in the omega 6/omega 3 ratio in erythrocyte membrane phospholipids. This change was parallel with decreases in plasma levels of lipoperoxides and nitric oxide catabolites. Conversely, the ratio of reduced to oxidized glutathione was significantly increased. In addition, membrane fluidity was increased significantly in plasma membrane samples. In conclusion fish oil administration has a beneficial effect in decreasing the levels of oxidative stress markers and improving the membrane fluidity in plasma(AU)

El alto consumo de ácidos grasos omega-3 se asocia con la plasticidad sináptica, neurogénesis y memoria en varios modelos experimentales. Para evaluar la eficacia de la suplementación con aceite de pescado en los marcadores de estrés oxidativo en pacientes con diagnóstico de la enfermedad de Alzheimer (EA) probable realizamos un ensayo clínico doble ciego, aleatorizado, controlado con placebo. A los pacientes con la EA que cumplían los criterios de inclusión se les administró aceite de pescado (que contenía 0,45 g de ácido eicosapentaenoico y 1 g de ácido docosahexaenoico) o placebo diariamente durante 12 meses. Los marcadores de estrés oxidativo plasmático [niveles de lipoperóxidos y catabolitos del óxido nítrico, cociente de glutatión reducido a glutatiónoxidado) y fluidez de la membrana] y el perfil de ácidos grasos en los eritrocitos se evaluaron al inicio, 6 meses y alos 12 meses. Al final del ensayo, en pacientes que recibieron aceite de pescado detectamos una disminución en el cociente de ácidos grasos omega 6/omega 3 en los fosfolípidos de la membrana eritrocitaria. Este cambio ocurrió en paralelo a la disminución de los niveles plasmáticos de lipoperóxidos y catabolitos del óxido nítrico. Por el contrario, el cociente de glutatión reducido a glutatión oxidado se incrementó significativamente. Además, la fluidez de la membrana aumentó significativamente en las muestras analizadas. En conclusión, la administración de aceite de pescado tiene un efecto beneficioso al disminuir los niveles de marcadores de estrés oxidativo plasmático y mejorar la fluidez de la membrana plasmática(AU)

Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the central nervous system (CNS). Neuroinflammation and oxidative stress are involved in the pathogenesis of MS, promoting tissue damage and demielinization. Current research findings suggest that melatonin has antioxidant and neuroprotective effects. The aim of this study was to evaluate the efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing-remitting multiple sclerosis (RRMS). 36 patients diagnose with RRMS treated with Interferon ß-1b (IFNß-1b) were enrolled in a double bind, randomized, placebo controlled trial. The experimental group received orally 25 mg/d of melatonin for 6 months. After melatonin administration, we observed a significant decrease in serum concentration of pro-inflammatory cytokines and oxidative stress markers; 18% for TNF-α (p <0.05), 34.8% for IL-1ß (p <0.05), 34.7% for IL-6 (p <0.05), 39.9% for lipoperoxides (LPO) (p <0.05) and 24% for nitric oxide catabolites (NOC) levels (p <0.05), compared with placebo group. No significant difference in clinical efficacy outcomes were found between groups. Melatonin treatment was well tolerated and we did not observe significant differences in rates of side effects between the two groups. We concluded that melatonin administration during 6 months period is effective in reducing levels of serum pro-inflammatory cytokines and oxidative stress markers in patients with RRMS. These data support future studies evaluating the safety and effectiveness of melatonin supplementation in RRMS patients.

Decreased serum levels of sCD40L and IL-31 correlate in treated patients with Relapsing-Remitting Multiple Sclerosis.

The CD40/CD40L system is a binding key for co-stimulation of immune cells. Soluble form of CD40L has been widely studied as marker of inflammatory and autoimmune diseases. Here we analyze serum concentrations of sCD40L, as well as 14 cytokines, in patients with Multiple Sclerosis (MS) treated with Glatiramer acetate or Interferon beta. In the healthy control group, we found in serum a highly positive correlation between sCD40L and Interleukin (IL)-31, an anti-inflammatory Th2 cytokine. Additionally, an important reduction in IL-31 and sCD40L serum levels, as well as a significant reduction in CD40 mRNA expression and complete depletion of CD40L mRNA, detected from peripheral blood cells, was found in treated patients with MS. Therefore, sCD40L and IL-31 must be taken into account as possible prognostic markers when analyzing the disease progress of MS in order to provide more personalized treatment.

Role of the blood-brain barrier in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with demyelination and axonal loss eventually leading to neurodegeneration. MS exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB). The BBB is a complex organization of cerebral endothelial cells, pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. In pathological conditions, lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Cytotoxic factors including pro-inflammatory cytokines, proteases, and reactive oxygen and nitrogen species accumulate and may contribute to myelin destruction. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in MS brains and parallel the release of inflammatory cytokines. In this review we establish the importance of the role of the BBB in MS. Improvements in our understanding of molecular mechanism of BBB functioning in physiological and pathological conditions could lead to improvement in the quality of life of MS patients.