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Alzheimer’s disease is the most common type of dementia, reaching 60–80% of case totals, and is one of the major global causes of the elderly population’s decline in functionality concerning daily life activities. Epidemiological research has already indicated that, in addition to several others metabolic factors, diabetes mellitus type 2 is a risk factor of Alzheimer’s disease. Many molecular pathways have been described, and at the same time, there are clues that suggest the connection between type 2 diabetes mellitus and Alzheimer’s disease, through specific genes, autophagy, and even inflammatory pathways. A systematic review with meta-analysis was conducted, and its main goal was to reveal the multilevel connection between these diseases.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide, with a vast majority of confirmed cases presenting with respiratory symptoms. Potential neurological manifestations and their pathophysiological mechanisms have not been thoroughly established. In this narrative review, we sought to present the neurological manifestations associated with coronavirus disease 2019 (COVID-19). Case reports, case series, editorials, reviews, case-control and cohort studies were evaluated, and relevant information was abstracted. Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications of COVID-19, due to many shared characteristics between these viruses and SARS-CoV-2. Studies from the current pandemic are accumulating and report COVID-19 patients presenting with dizziness, headache, myalgias, hypogeusia and hyposmia, but also with more serious manifestations including polyneuropathy, myositis, cerebrovascular diseases, encephalitis and encephalopathy. However, discrimination between causal relationship and incidental comorbidity is often difficult. Severe COVID-19 shares common risk factors with cerebrovascular diseases, and it is currently unclear whether the infection per se represents an independent stroke risk factor. Regardless of any direct or indirect neurological manifestations, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. In particular, the majority of stroke services worldwide have been negatively influenced in terms of care delivery and fear to access healthcare services. The effect on healthcare quality in the field of other neurological diseases is additionally evaluated.

The process of memory entails the activation of numerous neural networks and biochemical pathways throughout the brain. The phenomenon of memory decline in relation to aging has been the subject of extensive research for several decades. The correlation between the process of aging and memory is intricate and has various aspects to consider. Throughout the aging process, there are various alterations that take place within the brain and, as expected, affect other functions that have already been linked to memory and its function such as involving microcirculation and sleep. Recent studies provide an understanding of how these mechanisms may be interconnected through the relatively new concept of the glymphatic system. The glymphatic system is strongly correlated to sleep processes. Sleep helps the glymphatic system remove brain waste solutes. Astrocytes expand and contract to form channels for cerebrospinal fluid (CSF) to wash through the brain and eliminate waste. However, the details have not been totally elusive, but the discovery of what we call the glymphatic system enables us to connect many pieces of physiology to understand how such factors are interconnected and the interplay between them. Thus, the purpose of this review is to discuss how the glymphatic system, sleep, memory, and aging are interconnected through a network of complex mechanisms and dynamic interactions.

The glymphatic system is a fluid-transport framework in which cerebrospinal fluid (CSF) enters the brain along perivascular routes, exchanges with interstitial fluid (ISF), and exits toward venous, perineural, and meningeal lymphatic pathways enabling waste clearance. Recent studies have clarified the anatomical components that regulate solute movement. The perivascular astrocyte endfeet, which are enriched in polarized aquaporin-4 (AQP4) expression, create a high-permeability water interface that facilitates CSF–ISF exchange. Multiscale physical drivers such as cardiac pulsation, arteriolar vasomotion, and brain-state changes during sleep regulate the timing and efficiency of the glymphatic transport. A broad spectrum of solutes is transported through this pathway, from small metabolites to extracellular proteins including amyloid-β and tau, as well as exogenous tracers and some lipid-associated species. Glymphatic redistribution may interface with other clearance systems, including the brain-to-blood efflux via blood–brain barrier (BBB) transport, intramural periarterial drainage (IPAD) that clears along vascular basement membranes and the meningeal lymphatic pathways that drain macromolecules to deep cervical lymph nodes. These different routes may be interconnected and may represent a waste clearance network with complementary roles assigned to different mechanisms. Moreover, state dependence (notably sleep) and vascular health modulate glymphatic flux, offering plausible links between glymphatic system dysfunction, aging and neurodegeneration. Methodological advances—from intrathecal contrast magnetic resonance imaging (MRI) to in vivo two-photon imaging and tracer-kinetic modeling—have provided new insights into the anatomical scaffold and kinetics of the glymphatic system. Advances in glymphatic anatomy, together with growing evidence implicating glymphatic dysfunction in neurodegeneration, point towards a unifying framework that is urgently needed. Our synthesis spans glymphatic structure, fluid routing, and the repertoire of transported solutes and links to complementary clearance routes, supporting a unified model in which glymphatic clearance represents an important contributor of cerebral homeostasis. Understanding glymphatic dysfunction may guide the establishment of diagnostic imaging biomarkers that have the potential to assist in therapeutic modulation of neurodegenerative diseases.

Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.

Biomarkers in cerebrospinal fluid (CSF) are useful in the differential diagnosis between frontotemporal dementia (FTD) and Alzheimer’s dementia (AD), but require lumbar puncture, which is a moderately invasive procedure that can cause anxiety to patients. Gradually, the measurement of blood biomarkers has been attracting great interest. Testing blood instead of CSF, in order to measure biomarkers, offers numerous advantages because it negates the need for lumbar puncture, it is widely available, and can be repeated, allowing the prediction of disease course. In this study, a systematic review of the existing literature was conducted, as well as meta-analysis with greater emphasis on the most studied biomarkers, p-tau and progranulin. The goal was to give prominence to evidence regarding the use of plasma biomarkers in clinical practice.

Introduction: Glycemic variability (GV) has been associated with worse prognosis in critically ill patients. We sought to evaluate the potential association between GV indices and clinical outcomes in acute stroke patients. Methods: Consecutive diabetic and nondiabetic, acute ischemic or hemorrhagic stroke patients underwent regular, standard-of-care finger-prick measurements and continuous glucose monitoring (CGM) for up to 96 h. Thirteen GV indices were obtained from CGM data. Clinical outcomes during hospitalization and follow-up period (90 days) were recorded. Hypoglycemic episodes disclosed by CGM but missed by finger-prick measurements were also documented. Results: A total of 62 acute stroke patients [48 ischemic and 14 hemorrhagic, median NIHSS score: 9 (IQR: 3–16) points, mean age: 65 ± 10 years, women: 47%, nondiabetic: 79%] were enrolled. GV expressed by higher mean absolute glucose (MAG) values was associated with a lower likelihood of neurological improvement during hospitalization before and after adjusting for potential confounders (OR: 0.135, 95% CI: 0.024–0.751, p = 0.022). There was no association of GV indices with 3-month clinical outcomes. During CGM recording, 32 hypoglycemic episodes were detected in 17 nondiabetic patients. None of these episodes were identified by the periodic blood glucose measurements and therefore they were not treated. Conclusions: Greater GV of acute stroke patients may be related to lower odds of neurological improvement during hospitalization. No association was disclosed between GV indices and 3-month clinical outcomes.

We investigated whether the acetylcholine receptor (AChR) cluster cell-based assay (CBA) is effective in detecting AChR antibodies in sera from myasthenia gravis (MG) patients with low antibody concentrations, as determined by radioimmunoprecipitation assay (RIPA). In this retrospective diagnostic cohort study, 193 RIPA-positive sera from MG patients were analyzed. Following initial assessment using the gold-standard RIPA, samples were tested with a commercially available fixed CBA (F-CBA) and an in-house live CBA (L-CBA) to detect clustered AChR antibodies. Patients were classified into three groups based on RIPA levels to evaluate the sensitivity of each CBA. A subset of the cohort was blindly retested in a second laboratory to confirm results. The sensitivity of L-CBA and F-CBA in detecting 36 sera with low AChR-antibody levels (1.0-2.8 nM) was relatively high for L-CBA (83.33%, 95% CI: 71.16%, 95.51%) and low for F-CBA (45.71%, 95% CI: 29.21% to 62.22%). Both CBAs were 100% sensitive for sera with AChR-RIPA values > 3 nM. Antibodies of RIPA+/CBA- sera could be immunoadsorbed on AChR-transfected cells equally well as those from RIPA+/CBA+ sera, indicating that CBA negativity was due to low antibody concentrations. Overall, while AChR L-CBA demonstrates good sensitivity for detecting low concentrations of AChR antibodies, F-CBA performs less reliably in such cases. Since clustered AChR-CBAs can also identify antibodies that are not detectable by RIPA, we recommend that both RIPA and CBA be used together in the routine diagnosis of MG whenever possible. When available, L-CBA should be preferred over F-CBA due to its higher sensitivity.

A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS. We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate in each subgroup and the overall estimates. DMDs for RRMS were found to have a significantly lower risk of disability progression compared to placebo (RR = 0.72, 95%CI: 0.66-0.79; p<0.001), with no evidence of heterogeneity or publication bias. In subsequent subgroup analyses, neither dichotomization of DMDs as \"first\" and \"second\" line RRMS therapies [(RR = 0.72, 95% CI = 0.65-0.80) vs. (RR = 0.72, 95% = 0.57-0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64-0.87) vs. RR = 0.74 (95% CI = 0.66-0.83); p = 0.92] had a differential effect on the risk of disability progression. Either considerable (5-20%) or significant (>20%) rates of loss to follow-up were reported in many study protocols, while financial and/or other support from pharmaceutical industries with a clear conflict of interest on the study outcomes was documented in all included studies. Available DMD are effective in reducing disability progression in patients with RRMS, independently of the route of administration and their classification as \"first\" or \"second\" line therapies. Attrition bias needs to be taken into account in the interpretation of these findings.

Background and aims: Tenecteplase has recently emerged as an alternative thrombolytic agent in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO), possibly superior in achieving early reperfusion compared with alteplase. We aimed to compare the safety and efficacy of intravenous tenecteplase with intravenous alteplase for AIS patients with LVO in everyday clinical practice settings. Methods: We prospectively evaluated patients with AIS due to LVO, treated with intravenous thrombolysis (IVT) with or without mechanical thrombectomy in two tertiary stroke centers. Patients were treated with standard-dose alteplase (0.9 mg/kg) or 0.25 mg/kg tenecteplase. Safety outcomes included prevalence of symptomatic intracranial hemorrhage (sICH) and mortality. Efficacy outcomes included averted thrombectomy, major neurological improvement at 24 h (defined as decrease in baseline NIHSS score of 8 points or greater) and functional status on discharge and on 3 months assessed by modified Rankin Scale (mRS). Results: Nineteen AIS patients with LVO received tenecteplase and 39 received alteplase. We observed a non-significant higher rate of averted thrombectomies (32% versus 18%, p = 0.243) and a non-significant higher rate of sICH (16% versus 5%, p = 0.201) in the tenecteplase group. The rate of 24 h major neurological improvement was higher in the tenecteplase group (64% versus 33%, p = 0.046) but this was marginally attenuated in multivariable analyses (adjusted OR 10.22, 95% CI: 0.73–142.98; p = 0.084). Discharge mRS, 3-months mRS, and 3-month functional independence (mRS scores of 0–2) did not differ (p > 0.2) between the two groups. The rates of 3-month mortality (11% versus 18%, p = 0.703) were similar in the two groups. No independent association between thrombolytic agent and safety or efficacy outcomes emerged in multivariable regression analyses. Conclusion: The present pilot observational study highlights that AIS patients with LVO treated with 0.25 mg/kg bolus administration of tenecteplase had increased likelihood to achieve early neurological improvement compared with AIS patients treated with alteplase, but this association was attenuated after adjustment for potential confounders. There were no significant differences in 3-month functional or safety outcomes between the two groups. This preliminary real-world observation requires independent confirmation in larger, multicenter studies.