Immune responses to oligomeric α-synuclein in Parkinson's disease peripheral blood mononuclear cells.

Parkinson's disease displays clinical heterogeneity, presenting with motor and non-motor symptoms. Heterogeneous phenotypes, named brain-first and body-first, may reflect distinct α-synuclein pathology starting either in the central nervous system or in the periphery. The immune system plays a prominent role in the central and peripheral pathology, with misfolded α-synuclein being placed at the intersection between neurodegeneration and inflammation. Here, we characterized the inflammatory profile and immune-phenotype of peripheral blood mononuclear cells (PBMCs) from Parkinson's disease patients upon stimulation with α-synuclein monomer or oligomer, and investigated relationships of immune parameters with clinical scores of motor and non-motor symptoms. Freshly isolated PBMCs from 21 Parkinson's disease patients and 18 healthy subjects were exposed in vitro to α-synuclein species. Cytokine/chemokine release was measured in the culture supernatant by Multiplex Elisa. The immune-phenotype was studied by FACS-flow cytometry. Correlation analysis was computed between immune parameters and parkinsonian motor and non-motor scales. We found that Parkinson's disease patients exhibited a dysregulated PBMC-cytokine profile, which remained unaltered after exposure to α-synuclein species and correlated with both motor and non-motor severity, with a strong correlation observed with olfactory impairment. Exposure of PBMCs from healthy controls to α-synuclein monomer/oligomer increased the cytokine/chemokine release up to patient's values. Moreover, the PBMCs immune phenotype differed between patients and controls and revealed a prominent association of the Mos profile with olfactory impairment, and of NK profile with constipation. Results suggest that a deranged PBMC-immune profile may reflect distinct clinical subtypes and would fit with the recent classification of Parkinson's disease into peripheral-first versus brain-first phenotype.

Network analysis of gut microbial communities reveal key genera for a multiple sclerosis cohort with Mycobacterium avium subspecies paratuberculosis infection.

BACKGROUND: In gut ecosystems, there is a complex interplay of biotic and abiotic interactions that decide the overall fitness of an individual. Divulging the microbe-microbe and microbe-host interactions may lead to better strategies in disease management, as microbes rarely act in isolation. Network inference for microbial communities is often a challenging task limited by both analytical assumptions as well as experimental approaches. Even after the network topologies are obtained, identification of important nodes within the context of underlying disease aetiology remains a convoluted task. We therefore present a network perspective on complex interactions in gut microbial profiles of individuals who have multiple sclerosis with and without Mycobacterium avium subspecies paratuberculosis (MAP) infection. Our exposé is guided by recent advancements in network-wide statistical measures that identify the keystone nodes. We have utilised several centrality measures, including a recently published metric, Integrated View of Influence (IVI), that is robust against biases. RESULTS: The ecological networks were generated on microbial abundance data (n = 69 samples) utilising 16 S rRNA amplification. Using SPIEC-EASI, a sparse inverse covariance estimation approach, we have obtained networks separately for MAP positive (+), MAP negative (-) and healthy controls (as a baseline). Using IVI metric, we identified top 20 keystone nodes and regressed them against covariates of interest using a generalised linear latent variable model. Our analyses suggest Eisenbergiella to be of pivotal importance in MS irrespective of MAP infection. For MAP + cohort, Pyarmidobacter, and Peptoclostridium were predominately the most influential genera, also hinting at an infection model similar to those observed in Inflammatory Bowel Diseases (IBDs). In MAP- cohort, on the other hand, Coprostanoligenes group was the most influential genera that reduces cholesterol and supports the intestinal barrier. CONCLUSIONS: The identification of keystone nodes, their co-occurrences, and associations with the exposome (meta data) advances our understanding of biological interactions through which MAP infection shapes the microbiome in MS individuals, suggesting the link to the inflammatory process of IBDs. The associations presented in this study may lead to development of improved diagnostics and effective vaccines for the management of the disease.

Exploring the Association between Cathepsin B and Parkinson's Disease.

OBJECTIVE: The aim of this study is to investigate the association between Cathepsin B and Parkinson's Disease (PD), with a particular focus on determining the role of N-acetylaspartate as a potential mediator. METHODS: We used summary-level data from Genome-Wide Association Studies (GWAS) for a two-sample Mendelian randomization (MR) analysis, exploring the association between Cathepsin B (3301 cases) and PD (4681 cases). A sequential two-step MR approach was applied (8148 cases) to study the role of N-acetylaspartate. RESULTS: The MR analysis yielded that genetically predicted elevated Cathepsin B levels correlated with a reduced risk of developing PD (p = 0.0133, OR: 0.9171, 95% CI: 0.8563-0.9821). On the other hand, the analysis provided insufficient evidence to determine that PD affected Cathepsin B levels (p = 0.8567, OR: 1.0035, 95% CI: 0.9666-1.0418). The estimated effect of N-acetylaspartate in this process was 7.52% (95% CI = -3.65% to 18.69%). CONCLUSIONS: This study suggested that elevated Cathepsin B levels decreased the risk of developing PD, with the mediation effect of N-acetylaspartate. Further research is needed to better understand this relationship.

Neurological and Psychiatric Disorders in the COVID-19 Era.

Over the 4 last years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has determined the diffusion of the coronavirus disease 2019 (COVID-19) global outbreak [...].

Determinants of self-perceived quality of life in mildly disabled multiple sclerosis patients: a cross-sectional study.

INTRODUCTION: While the determinants influencing self-perceived health-related quality of life (spHRQoL) in persons with multiple sclerosis (pwMS) and severe physical impairment have been well investigated, their impact on pwMS with mild disability is poorly addressed. We aimed to investigate possible drivers of spHRQoL among Sardinian pwMS with an EDSS lower than 2.5. METHODS: A sample of 87 fully ambulatory (EDSS < 2.5) pwMS were included after screening for major cognitive impairment. spHRQoL was measured with the Italian version of 36-Item Short Form Health Survey (SF-36). The Physical Component Summary (PCS) and Mental Component Summary (MCS) were used as dependent variables for univariate analysis with Cognitive Behavioral Assessment (CBA) and specific individual factors as independent variables. Subsequent multivariate general linear models (GLMs) for PCS and MCS respectively were run after stepwise regression. Normative data referring to Italian population were used for comparison. RESULTS: As compared to normative data, no statistically significant difference was found for PCS, while MCS was reduced. Multivariate GLMs showed a significant association between lower PCS scores and presence of psychosomatic symptoms, older age and fatigue (p < 0.05). Furthermore, a significant association was shown between lower MCS scores and presence of anxiety (p < 0.001). CONCLUSION: Mood, presence of psychosomatic symptoms, fatigue and age can have a relevant impact on spHRQoL in people with mildly disabling MS and should be considered in the management of such individuals.

Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

INTRODUCTION/AIMS: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). METHODS: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. RESULTS: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). DISCUSSION: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

Epidemiology of aquaporin-4-IgG-positive NMOSD in Sardinia.

PURPOSE: The Italian Island of Sardinia (population, 1,578,146) is recognized for the high risk of multiple sclerosis (MS) but the epidemiological burden of other less common demyelinating diseases of the central nervous system (CNS), such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD), is unknown. In this study, we determined the incidence and prevalence of AQP4-IgG+NMOSD in Sardinia over a ten-year study period (2013-2022). METHODS: Patients with a diagnosis of AQP4-IgG+NMOSD (per 2015 IPND diagnostic criteria) were retrospectively identified using two sources: (1) Archives of the reference and only laboratory for AQP4-IgG testing in Sardinia; and (2) medical records of the four MS units in the island. Incidence (January 2013-December 2022) and prevalence (December 31, 2022) were calculated. RESULTS: A total of 45 cases were included: incident, 31; prevalent, 41. The median age (range) at disease presentation was 51 (6-78) years; female/male ratio was 9:1. The crude (95 % CI) incidence and prevalence were 1.9 (1.3-2.7) per million and 2.6 (1.9-3.5) per 100,000, respectively. Prevalence increased from 2013 (1.1 per 100,000) to 2022 (2.6 per 100,000); p = 0.002. After age-standardization to the world, incidence and prevalence (95 % CI) decreased to 1.3 (0.7-2) per million and 1.8 (1.3-2.3) per 100,000, respectively. Coexisting immune-mediated disorders, mostly autoimmune thyroiditis, were reported in 50 % of patients. CONCLUSIONS: The epidemiology of AQP4-IgG+NMOSD in Sardinia is overall in line with other Caucasian populations. The high MS risk in the island seems disease-specific and not associated with an increased risk of other CNS demyelinating disorders, confirming different pathophysiology.

Validity and reliability of the Questionnaire of Olfactory Disorders for Italian-speaking patients with olfactory dysfunction.

Objective: To translate and validate an Italian version of the Questionnaire of Olfactory Disorders (IT-QOD). Materials and methods: This is a prospective, multicentre study that involved patients with olfactory dysfunction (OD). Both cases and controls underwent administration of the IT-QOD, Sino-Nasal Outcome Test-22 (SNOT-22) and psychophysical evaluation of orthonasal and retronasal olfactory function. Results: The IT-QOD was administered to 96 patients and 38 controls. The Cronbach's alpha exceeded 0.90, indicating satisfactory internal consistency. The test-retest reliability was found to be high for both parosmia (rs = 0.944) and life quality (rs = 0.969). Patients with OD had significantly higher IT-QOD scores compared to healthy individuals (p < 0.001), indicating strong internal validity. The external validity was also satisfactory, as shown by the significant correlation with SNOT-22 (rs = -0.54) and the threshold, discrimination, and identification score (rs = -0.63). Conclusions: The IT-QOD was demonstrated to be reliable and valid to assess the impact of OD on the quality of life of Italian-speaking patients.

A top-down proteomic approach reveals a salivary protein profile able to classify Parkinson's disease with respect to Alzheimer's disease patients and to healthy controls.

Parkinson's disease (PD) is a complex neurodegenerative disease with motor and non-motor symptoms. Diagnosis is complicated by lack of reliable biomarkers. To individuate peptides and/or proteins with diagnostic potential for early diagnosis, severity and discrimination from similar pathologies, the salivary proteome in 36 PD patients was investigated in comparison with 36 healthy controls (HC) and 35 Alzheimer's disease (AD) patients. A top-down platform based on HPLC-ESI-IT-MS allowed characterizing and quantifying intact peptides, small proteins and their PTMs (overall 51). The three groups showed significantly different protein profiles, PD showed the highest levels of cystatin SA and antileukoproteinase and the lowest of cystatin SN and some statherin proteoforms. HC exhibited the lowest abundance of thymosin ß4, short S100A9, cystatin A, and dimeric cystatin B. AD patients showed the highest abundance of α-defensins and short oxidized S100A9. Moreover, different proteoforms of the same protein, as S-cysteinylated and S-glutathionylated cystatin B, showed opposite trends in the two pathological groups. Statherin, cystatins SA and SN classified accurately PD from HC and AD subjects. α-defensins, histatin 1, oxidized S100A9, and P-B fragments were the best classifying factors between PD and AD patients. Interestingly statherin and thymosin ß4 correlated with defective olfactory functions in PD patients. All these outcomes highlighted implications of specific proteoforms involved in the innate-immune response and inflammation regulation at oral and systemic level, suggesting a possible panel of molecular and clinical markers suitable to recognize subjects affected by PD.

Unraveling the prognostic significance and molecular characteristics of tumor-infiltrating B lymphocytes in clear cell renal cell carcinoma through a comprehensive bioinformatics analysis.

Introduction: Clear cell renal cell carcinoma (ccRCC) is a prevalent subtype of kidney cancer that exhibits a complex tumor microenvironment, which significantly influences tumor progression and immunotherapy response. In recent years, emerging evidence has underscored the involvement of tumor-infiltrating B lymphocytes (TIL-Bs), a crucial component of adaptive immunity, and their roles in ccRCC as compared to other tumors. Therefore, the present study endeavors to systematically explore the prognostic and molecular features of TIL-Bs in ccRCC. Methods: Initially, xCell algorithm was used to predict TIL-Bs in TCGA-KIRC and other ccRCC transcriptomic datasets. The Log-Rank test and Cox regression were applied to explore the relationship of B-cells with ccRCC survival. Then, we used WGCNA method to identify important modules related to TIL-Bs combining Consensus subcluster and scRNA-seq data analysis. To narrow down the prospective biomarkers, a prognostic signature was proposed. Next, we explored the feature of the signature individual genes and the risk-score. Finally, the potential associations of signature with clinical phenotypes and drugs were investigated. Results: Preliminary, we found ccRCC survival was negatively associated with TIL-Bs, which was confirmed by other datasets. Afterwards, ten co-expression modules were identified and a distinct ccRCC cluster was subsequently detected. Moreover, we assessed the transcriptomic alteration of B-cell in ccRCC and a relevant B-cell subtype was also pinpointed. Based on two core modules (brown, red), a 10-gene signature (TNFSF13B, SHARPIN, B3GAT3, IL2RG, TBC1D10C, STAC3, MICB, LAG3, SMIM29, CTLA4) was developed in train set and validated in test sets. These biomarkers were further investigated with regards to their differential expression and correlation with immune characteristics, along with risk-score related mutations and pathways. Lastly, we established a nomogram combined tumor grade and discovered underlying drugs according to their sensitivity response. Discussion: In our research, we elucidated the remarkable association between ccRCC and B-cells. Then, we detected several key gene modules, together with close patient subcluster and B-cell subtype,which could be responsible for the TIL-Bs in ccRCC. Moreover, we proposed a 10-gene signature and investigated its molecular features from multiple perspectives. Overall, understanding the roles of TIL-Bs could aid in the immunotherapeutic approaches for ccRCC, which deserve further research to clarify the implications for patient prognosis and treatment.

Neurological Consequences of COVID-19: A Systematic Review of the Pandemic's Impact on Neurology Training.

The COVID-19 pandemic had a significant impact on neurology training programs, leading to disruptions and changes that may have long-term implications for neurological education. The objective of this study was to investigate the impact of COVID-19 on neurological training programs, collecting available data relating to residents' experience worldwide. We performed a systematic search of the literature published on PubMed from January 2020 to March 2023, including studies referring to quantitative analysis of residents'/trainees' perspectives. Specifically, we included studies that examined how the pandemic has affected clinical and research activities, the use of telemedicine, the delivery of education and the psychological status of residents. Of the 95460 studies identified through database searching, 12 studies met the full criteria and underwent data extraction. In conclusion, the COVID-19 pandemic has had significant impacts on neurology training programs, highlighting the need for resilience and flexibility in medical education. Future research should focus on the long-term outcomes of these adaptations in the quality of neurology education and patient care.

Non-demyelinating disorders mimicking and misdiagnosed as NMOSD: a literature review.

BACKGROUND: Differentiating neuromyelitis optica spectrum disorder (NMOSD) from its mimics is crucial to avoid misdiagnosis, especially in the absence of aquaporin-4-IgG. While multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD) represent major and well-defined differential diagnoses, non-demyelinating NMOSD mimics remain poorly characterized. METHODS: We conducted a systematic review on PubMed/MEDLINE to identify reports of patients with non-demyelinating disorders that mimicked or were misdiagnosed as NMOSD. Three novel cases seen at the authors' institutions were also included. The characteristics of NMOSD mimics were analyzed and red flags associated with misdiagnosis identified. RESULTS: A total of 68 patients were included; 35 (52%) were female. Median age at symptoms onset was 44 (range, 1-78) years. Fifty-six (82%) patients did not fulfil the 2015 NMOSD diagnostic criteria. The clinical syndromes misinterpreted for NMOSD were myelopathy (41%), myelopathy + optic neuropathy (41%), optic neuropathy (6%), or other (12%). Alternative etiologies included genetic/metabolic disorders, neoplasms, infections, vascular disorders, spondylosis, and other immune-mediated disorders. Common red flags associated with misdiagnosis were lack of cerebrospinal fluid (CSF) pleocytosis (57%), lack of response to immunotherapy (55%), progressive disease course (54%), and lack of magnetic resonance imaging gadolinium enhancement (31%). Aquaporin-4-IgG positivity was detected in five patients by enzyme-linked immunosorbent assay (n = 2), cell-based assay (n = 2: serum, 1; CSF, 1), and non-specified assay (n = 1). CONCLUSIONS: The spectrum of NMOSD mimics is broad. Misdiagnosis frequently results from incorrect application of diagnostic criteria, in patients with multiple identifiable red flags. False aquaporin-4-IgG positivity, generally from nonspecific testing assays, may rarely contribute to misdiagnosis.

Olfactory Impairment Is the Main Predictor of Higher Scores at REM Sleep Behavior Disorder (RBD) Screening Questionnaire in Parkinson's Disease Patients.

INTRODUCTION: Olfactory impairment and REM sleep behavior disorder (RBD) are common non-motor symptoms in Parkinson's disease (PD) patients, often preceding the onset of the specific motor symptoms and, thus, crucial for strategies directed to anticipate PD diagnosis. In this context, the specific interaction between olfactory impairment and RBD has not been clearly defined. OBJECTIVE: The aim of this study was to determine the possible role of olfactory impairment and other clinical characteristics as possible predictors of higher scores at RBD screening questionnaire (RBDSQ) in a large population of PD patients. METHODS: In this study, 590 PD patients were included from the Parkinson's Progression Markers Initiative. Demographic and clinical features were registered. All participants completed motor and non-motor evaluations at the baseline visit. For motor assessments, the disease severity was evaluated by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) pars III. Regarding non-motor symptoms assessment, Montreal Cognitive Assessments (MoCA), University of Pennsylvania Smell Identification Test (UPSIT) and RBD screening questionnaire (RBDSQ) were registered. RESULTS: Among 590 PD patients included in this study, 111 patients with possible RBD were found (18.8%). RBD was less frequent in female PD patients (p ≤ 0.011). Among patients with or without possible RBD diagnosis, statistically significant differences in MDS-UPDRS III (23.3 ± 11.4 vs. 19.7 ± 9.1, respectively, p ≤ 0.002) and in UPSIT score (19.7 ± 8.3 vs. 22.6 ± 8.0, respectively, p ≤ 0.001) were found. Moreover, significant correlations between RBDSQ versus UPDRS III score and versus UPSIT score were observed. Multivariate linear regression analysis showed that UPSIT was the most significant predictor of higher scores at RBDSQ, while the other significant predictors were UPDRS III and age. CONCLUSIONS: The severity of olfactory impairment appears tightly correlated to RBD symptoms, highlighting the role of these biomarkers for PD patients. Additionally, according to this large study, our data confirmed that RBD in PD patients exhibits peculiar gender differences.

Gender-Related Differences in the Correlation between Odor Threshold, Discrimination, Identification, and Cognitive Reserve Index in Healthy Subjects.

BACKGROUND: Many studies suggested that olfactory function could be associated with semantic memory, executive function, and verbal fluency. However, the gender-related association between olfactory function and the cognitive domain is not well investigated. The aim of this study was to estimate gender-related differences in the relationship between olfactory function and each specific cognitive domain of the Cognitive Reserve Index (CRI) questionnaire, such as education, working activity, and leisure time in healthy subjects. METHODS: Two hundred and sixty-nine participants were recruited (158 women and 111 men), with a mean age of 48.1 ± 18.6 years. The CRI questionnaire and Sniffin' Sticks test were used to evaluate the cognitive reserve and the olfactory function, respectively. RESULTS: In all subjects, significant associations between the odor threshold versus CRI-Education, between the odor discrimina-tion and identification versus CRI-Working activity and CRI-Leisure Time, were found. In women, odor threshold, discrimination, and identification were associated with CRI-Leisure Time, while in men, only a significant association between odor threshold and CRI-Education was observed. CONCLUSIONS: Our data, showing significant gender-related associations between olfactory function and CRI scores, suggested the use of olfactory evaluation and cognitive reserve as an important screening tool for the early detection of mild cognitive impairment.

Autoimmune encephalitis misdiagnosis and mimics.

The diagnosis of autoimmune encephalitis (AE) requires reasonable exclusion of other conditions. The aim of this study is to characterize mimickers and misdiagnoses of AE, thus we performed an independent PubMed search for mimickers of AEs or patients with alternative neurological disorders misdiagnosed as AE. Fifty-eight studies with 66 patients were included. Neoplastic (n = 17), infectious (n = 15), genetic (n = 13), neurodegenerative (n = 8), and other neurological (n = 8) or systemic autoimmune (n = 5) disorders were misdiagnosed as AE. The lack of fulfillment of diagnostic criteria for AE, atypical neuroimaging findings, non-inflammatory CSF findings, non-specific autoantibody specificities and partial response to immunotherapy were major confounding factors.

Olfactory Impairment Correlates with Executive Functions Disorders and Other Specific Cognitive Dysfunctions in Parkinson's Disease.

INTRODUCTION: Olfactory and cognitive disorders represent important non-motor symptoms in Parkinson's disease (PD). No clear evidence was reported about association of specific cognitive domains and olfactory impairment. OBJECTIVE: The aim of this study was to evaluate the association between olfactory dysfunction and specific cognitive domains in PD patients compared to controls. METHODS: 178 PD patients and 98 controls were enrolled and evaluated for odor threshold (OT), discrimination (OD), identification (OI), and TDI score using the Sniffin' Sticks test. Cognitive function was evaluated using the Montreal Cognitive Assessment scale with six sub-scores: Orientation (OIS), Attention (AIS), Language (LIS), Visuospatial (VIS), Memory (MIS), and Executive index scores (EIS). RESULTS: Statistically significant correlations were observed between OT versus, LIS, and between TDI score versus EIS. Multivariate linear regression analysis, including age and sex which are well-known predictors of olfactory dysfunction, showed that, among specific cognitive domains, only LIS was significant predictor for OT, VIS was a significant predictor for OD, while both EIS and AIS were significant predictors for OI, and finally only EIS was significant predictor for TDI score. CONCLUSIONS: Olfactory disorders in PD patients appear commonly related to dysfunction of specific cognitive domains, with strict association between global olfactory impairment and executive function deficits.