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The process of finding new therapeutic indications for currently used drugs, defined as ‘repurposing’, is receiving growing attention. Chloroquine and hydroxychloroquine, with an original indication to prevent or cure malaria, have been successfully used to treat several infectious (HIV, Q fever, Whipple’s disease, fungal infections), rheumatological (systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, Sjögren’s syndrome), and other immunological diseases. Indeed, they have anti-inflammatory, immunomodulating, anti-infective, antithrombotic, and metabolic effects. Among the biological effects of chloroquine and hydroxychloroquine, it is important to highlight their antitumoral properties, likely due to their strong antiproliferative, antimutagenic, and inhibiting autophagy capacities. These effects make these drugs a possible option in the treatment of several tumors in association with radiotherapy and chemotherapy. Finally, the repurposing of chloroquine and hydroxychloroquine is currently being examined for neurological diseases such as neurosarcoidosis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to corticosteroids, and primary progressive multiple sclerosis. Several ongoing clinical trials have been testing these drugs in non-neoplastic and neoplastic diseases. Moreover, the well-demonstrated good tolerability of chloroquine and hydroxychloroquine make them safe even during pregnancy. Gastrointestinal and cutaneous manifestations are considered not to be serious, while retinal, neuromuscular, and cardiac toxicities are classified as serious adverse events.

This review analyzes the role of TNF-α and its increase in biological fluids in mild cognitive impairment, and Alzheimer’s disease (AD). The potential inhibition of TNF-α with pharmacological strategies paves the way for preventing AD and improving cognitive function in people at risk for dementia. We conducted a narrative review to characterize the evidence in relation to the involvement of TNF-α in AD and its possible therapeutic inhibition. Several studies report that patients with RA and systemic inflammatory diseases treated with TNF-α blocking agents reduce the probability of emerging dementia compared with the general population. Animal model studies also showed interesting results and are discussed. An increasing amount of basic scientific data and clinical studies underscore the importance of inflammatory processes and subsequent glial activation in the pathogenesis of AD. TNF-α targeted therapy is a biologically plausible approach for cognition preservation and further trials are necessary to investigate the potential benefits of therapy in populations at risk of developing AD.

Given the huge impact of the COVID-19 pandemic, it appears of paramount importance to assess the cognitive effects on the population returning to work after COVID-19 resolution. Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) represent promising biomarkers of neuro-axonal damage and astrocytic activation. In this cohort study, we explored the association between sNfL and sGFAP concentrations and cognitive performance in a group of 147 adult workers with a previous asymptomatic SARS-CoV-2 infection or mild COVID-19, one week and, in 49 of them, ten months after SARS-Cov2 negativization and compared them to a group of 82 age and BMI-matched healthy controls (HCs). sNfL and sGFAP concentrations were assessed using SimoaTM assay Neurology 2-Plex B Kit. COVID-19 patients were interviewed one-on-one by trained physicians and had to complete a list of questionnaires, including the Cognitive Failure Questionnaire (CFQ). At the first assessment (T0), sNfL and sGFAP levels were significantly higher in COVID-19 patients than in HCs (p < 0.001 for both). The eleven COVID-19 patients with cognitive impairment had significantly higher levels of sNfL and sGFAP than the others (p = 0.005 for both). At the subsequent follow-up (T1), sNfL and sGFAP levels showed a significant decrease (median sNfL 18.3 pg/mL; median sGFAP 77.2 pg/mL), although they were still higher than HCs (median sNfL 7.2 pg/mL, median sGFAP 63.5 pg/mL). Our results suggest an ongoing damage involving neurons and astrocytes after SARS-Cov2 negativization, which reduce after ten months even if still evident compared to HCs.

Background: Despite their potential usefulness as biomarkers, no study has investigated the interactions between cerebrospinal fluid (CSF) changes of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), growth differentiation factor 15 (GDF-15), transactive response DNA binding protein (TDP-43) and interleukin-6 (IL-6) and the core AD CSF biomarkers in the same cohort of AD patients. Objectives: The aim of this pilot study is to evaluate the CSF levels of these analytes in patients with AD and assess their clinical relevance in this neurological condition. Design: Cross-sectional study. Methods: We assessed the levels of NfL, GFAP, GDF-15, TDP-43 and IL-6 in the CSF samples of 52 early AD patients and evaluated their partial reciprocal correlations and those with Abeta42, p-Tau, t-Tau and Mini-Mental State Examination (MMSE), always adding age, sex and educational level as covariates. Results: MMSE score showed a positive correlation with the Aβ 1-42 concentrations (r = 0.485; p < 0.001), and a negative correlation with GDF-15 concentrations (r = −0.418; p = 0.002). IL-6 concentrations showed a positive correlation with NfL concentrations (r = 0.312; p = 0.026) and a negative correlation with TDP-43 concentrations (r = −0.322; p = 0.021). TDP-43 concentrations showed a positive correlation with GFAP (r = 0.33, p = 0.018). The mediation analysis suggests that the association between GDF-15 and MMSE is primarily mediated by Aβ 1-42. CSF GDF-15 concentrations were higher in AD patients with low Aβ 1-42 concentrations than those with high Aβ 1-42 concentrations (p < 0.001). Conclusion: Our findings highlight that CSF IL-6 levels correlate positively with markers of neuronal damage. CSF TDP-43 levels significantly correlated with GFAP, suggesting a potential link with reactive gliosis and astrocyte activation. In addition, while CSF GDF-15 levels negatively correlate with MMSE scores, mediation analysis revealed that this association is primarily indirect and mediated through Aβ 1-42 levels.

We previously identified IgG autoantibodies targeting epitopes within brainstem proteins-disabled homolog 1 ( ), apoptosis-inducing factor 1 ( ), and surfeit locus protein 1 ( )-as markers of severe acute COVID-19. This study investigates whether the same autoantibodies contribute to the pathophysiology of Post COVID Syndrome (PCS). Using a multiplexed bead-based immunoassay, we measured IgG levels against 18 synthetic peptides derived from , , and in serum samples from 45 PCS patients and 30 post-COVID controls without long-term symptoms. We employed generalized linear mixed models (GLMM) and nonlinear principal component analysis (CATPCA) to explore associations between antibody levels and clinical variables, including functional status (PCFS), respiratory symptoms, fatigue, cognitive impairment (as assessed by the Montreal Cognitive Assessment, MoCA), and mood. Higher IgG levels against the three autoantigens significantly predicted PCS at 3 months postinfection (t=2.21, p=0.03), whereas antibodies against a control peptide (polio) showed no such association. CATPCA identified a principal component capturing respiratory symptoms and functional impairment (PCFS), which was also significantly predicted by autoantibody levels (t=2.04, p=0.04). MoCA scores did not correlate with autoantibody levels, and subjective cognitive complaints were paradoxically linked to lower antibody titers and fewer physical symptoms. The findings from the present explorative study, although largely correlative, appear to suggest a sustained autoimmune response targeting neuronal and mitochondrial proteins in PCS, particularly associated with respiratory dysfunction and reduced functional capacity. The results also highlight potential limitations of standard cognitive screening tools like the MoCA in detecting subtle deficits in PCS. The identified autoantibodies may serve as biomarkers for persistent post-COVID disability. Future research replicating present results on larger samples and specifically investigating a causal link between occurrence of the Auto-Abs and PCS is needed for shaping future immunomodulatory therapeutic strategies.

We report an atypical case of Creutzfeldt-Jakob Disease (CJD) mimicking Frontotemporal Dementia (FTD) in a 68-year-old male. The patient initially presented with an anxious-depressive syndrome, progressing over 29 months to include dysexecutive syndrome, stereotyped speech, inertia, social withdrawal, verbal fluency impairments, and marked dyspraxia. Diagnostic imaging revealed signal alterations on MRI, while CSF analysis showed elevated T-TAU, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) levels. A second-generation RT-QuIC (SG-RT-QuIC) confirmed prion disease, with genetic testing identifying a codon 129 MV polymorphism and a deletion in the third octapeptide repeat. This case highlights the importance of integrating advanced diagnostic tools, such as SG-RT-QuIC and comprehensive genotyping, in evaluating atypical presentations of CJD. Early elevated GFAP levels highlight the usefulness of considering neuroinflammatory markers in slowly progressive forms of CJD.

Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy, also known as familial amyloid polyneuropathy (FAP), represents a progressive, heterogeneous, severe, and multisystemic disease caused by pathogenic variants in the TTR gene. This autosomal-dominant neurogenetic disorder has an adult onset with variable penetrance and an inconstant phenotype, even among subjects carrying the same mutation. Historically, ATTRv amyloidosis has been viewed as a non-inflammatory disease, mainly due to the absence of any mononuclear cell infiltration in ex vivo tissues; nevertheless, a role of inflammation in its pathogenesis has been recently highlighted. The immune response may be involved in the development and progression of the disease. Fibrillary TTR species bind to the receptor for advanced glycation end products (RAGE), probably activating the nuclear factor κB (NF-κB) pathway. Moreover, peripheral blood levels of several cytokines, including interferon (IFN)-gamma, IFN-alpha, IL-6, IL-7, and IL-33, are altered in the course of the disease. This review summarizes the current evidence supporting the role of the immune response in ATTRv amyloidosis, from the pathological mechanisms to the possible therapeutic implications.

BackgroundPain is one of the most disabling symptoms in multiple sclerosis. Chronic pain in multiple sclerosis is often neuropathic in nature, although a clear-cut distinction with nociceptive pain is not easy.ObjectiveThe aim of our study was to analyze the MRIs of multiple sclerosis patients with chronic pain in order to explore possible associations with lesion sites, on a voxel-by-voxel basis.Materials and methodsWe enrolled patients aged > 18 years with multiple sclerosis in accordance with the 2010 McDonald criteria. Patients meeting criteria for persistent pain (frequent or constant pain lasting > 3 months) were included in the “pain group”. The other patients were included in the “no pain group”. We outlined lesions on FLAIR MRI scans using a semi-automated edge finding tool. To detect the association between lesion localization and persistent pain, images were analysed with the voxel-based lesion symptom mapping methods implemented in the (nonparametric mapping software included into the MRIcron.ResultsWe enrolled 208 MS patients (140 F, mean age 55.2 ± 9.4 years; 176 RR, 28 progressive MS; mean EDSS 2.0 + 2.0). Pain group included 96 patients and no pain group 112 patients. Lesions of the right dorsolateral prefrontal area were significantly more prevalent in patients without pain, whereas periventricular posterior lesions were significantly more prevalent in patients with persistent pain.ConclusionOur data suggest a role of the right dorsolateral prefrontal cortex in the modulation of pain perception and in the occurrence of chronic pain in MS patients. Our data also support a hemispheric asymmetry in pain perception and modulation.

Background: The relationship between routine cerebrospinal fluid (CSF) testing and clinical and prognostic data in amyotrophic lateral sclerosis (ALS) remains unclear. Additionally, biochemical data have never been correlated with markers of neurodegeneration. The purpose of this study is to determine whether lumbar puncture may still have clinical utility in ALS. Methods: We collected the CSF profiles of 140 ALS subjects. CSF protein, albumin, IgG, IgG index, albumin quotient (QAlb), t-tau, p-tau, and Aβ42 were analyzed. Results: Approximately one-quarter of ALS patients had elevated levels of protein, albumin, and QAlb in the CSF, but these were not associated with clinical or survival data. Among the neurodegeneration markers, the percentage of patients with abnormal values ranged from 26.3% to 35.4%. The p-tau/t-tau ratio and Aβ42 were correlated with both the ALS progression rate and the time from diagnosis to death. Aβ42 was the prognostic marker most strongly associated with survival. Conclusions: The lack of correlation between biochemical CSF findings and the clinical and/or prognostic status of ALS suggests that these markers have no clinical value. However, neurodegeneration markers that are easily measurable in clinical laboratories, particularly Aβ42, may be useful at the time of diagnosis for predicting ALS survival and progression rate.