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Autism Spectrum disorders (ASD) are diagnosed more often in males than in females, by a ratio of about 3:1; this is likely to be due to a difference in risk burden between the sexes and/or to "compensatory skills" in females, that may delay the diagnosis of ASD. Identifying specific risk factors for ASD in females may be important in facilitating early diagnosis. We investigated whether HLA- class I: -A, -B, -C and class II -DRB1 alleles, which have been suggested to play a role in the development of ASD, can be considered as sex-related risk/protective markers towards the ASD. We performed HLA allele genotyping in 178 Italian children with ASD, 94 healthy siblings, and their parents. HLA allele distribution was compared between children with ASD, sex-matched healthy siblings, and a cohort of healthy controls (HC) enrolled in the Italian bone marrow donor registry. Allele transmission from parents to children with ASD and their siblings was also assessed. Our findings suggest that HLA-A*02 , B*38 , and C*12 alleles are more frequently carried by females with ASD compared to both HC and healthy female siblings, indicating these alleles as potential risk factors for ASD in females. Conversely, the HLA-A*03 allele was more commonly transmitted to healthy female siblings, suggesting it might have a protective effect. Additionally, the HLA-B*44 allele was found to be more prevalent in boys with ASD, indicating it is a potential risk factor for male patients. This is the first Italian study of sex-related HLA association with ASD. If confirmed, these results could facilitate early ASD diagnosis in female patients, allowing earlier interventions, which are crucial in the management of neurodevelopmental disorders.

Activation of the purinergic receptor P2X7 (P2X7R) is believed to be deleterious in autoimmune diseases and it was hypothesized to play a role in the pathogenesis of MS. P2X7R is an ATP-gated non-selective cationic channel; its activation can be driven by high concentrations of ATP and leads to the generation of large, cytolytic conductance pores. P2X7R activation can also result in apoptosis as a consequence of the activation of the caspase cascade via P2X7R-dependent stimulation of the NLRP3 inflammasome. We measured P2X7R in oligodendrocyte derived extracellular vesicles (ODEVs) in MS patients and in healthy subjects. Sixty-eight MS patients (50 relapsing-remitting, RR-MS, 18 primary progressive, PP-MS) and 57 healthy controls (HC) were enrolled. ODEVs were enriched from serum by a double step immunoaffinity method using an anti OMGp (oligodendrocyte myelin glycoprotein) antibody. P2X7R concentration was measured in ODEVs lysates by ELISA. One-way Anova test showed that P2X7R in ODEVs is significantly higher in PP-MS (mean: 1742.89 pg/mL) compared both to RR-MS (mean: 1277.33 pg/mL) (p < 0.001) and HC (mean: 879.79 pg/mL) (p < 0.001). Comparison between RR-MS and HC was also statistically significant (p < 0.001). Pearson's correlations showed that P2RX7 in ODEVs was positively correlated with EDSS (p = 0.002, r = 0.38, 0.15-0.57 95% CI) and MSSS (p = 0.004, r = 0.34, 0.12-0.54 95% CI) scores, considering MS patients together (PP-MS + RR-MS) and with disease duration in PP-MS group (p = 0.02, r = 0.53, 0.09-0.80 95% CI). Results suggest that ODEVs-associated P2X7R levels could be a biomarker for MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder affecting about 10 million people worldwide with a prevalence of about 2% in the over-80 population. The disease brings in also a huge annual economic burden, recently estimated by the Michael J Fox Foundation for Parkinson's Research to be USD 52 billion in the United States alone. Currently, no effective cure exists, but available PD medical treatments are based on symptomatic prescriptions that include drugs, surgical approaches and rehabilitation treatment. Due to the complex biology of a PD brain, the design of clinical trials and the personalization of treatment strategies require the identification of accessible and measurable biomarkers to monitor the events induced by treatment and disease progression and to predict patients' responsiveness. In the present review, we strive to briefly summarize current knowledge about PD biomarkers, focusing on the role of extracellular vesicles as active or involuntary carriers of disease-associated proteins, with particular attention to those research works that envision possible clinical applications.

Background: Nordic walking (NW) has several potential benefits for individuals with cardiovascular (CV) disease, type 2 diabetes, and obesity and/or overweight. NW improves cardiovascular health, including exercise capacity and blood pressure control. NW enhances glycemic control and insulin sensitivity in diabetes, and aids in weight management and body composition improvement. NW offers additional advantages, such as improvement in muscular strength, joint mobility, physical activity levels, and psychological well-being., Methods: This open-label study with 3 arms will aim to evaluate the efficacy, safety, and adherence to exercise prescription in obese and/or overweight diabetic patients with CV complications. The primary objective will be to assess the CV performance of participants after a 6-month and a 12-month follow-up period, following a 3-month NW intervention, compared with standard rehabilitation, and with cardiological counseling (control group) training lasting 3 months., Results: The results of the study will provide valuable insights into the comparative effectiveness of a NW intervention vs standard rehabilitation and control group training in improving CV performance in obese and/or overweight diabetic patients with CV complications. Additionally, safety and adherence data will help inform the feasibility and sustainability of the exercise prescription over an extended period., Conclusions: These findings may have implications for the development of tailored exercise programs for this specific patient population, with the aim of optimizing CV health outcomes., Clinical Trials Registration: NCT05987410., (© 2024 The Authors.)

Autism spectrum disorders (ASD) can present with different onset and timing of symptom development; children may manifest symptoms early in their first year of life, i.e., early onset (EO-ASD), or may lose already achieved skills during their second year of life, thus showing a regressive-type onset (RO-ASD). It is still controversial whether regression represents a neurobiological subtype of ASD, resulting from distinct genetic and environmental causes. We focused this study on the 25 kD synaptosomal-associated protein ( SNAP-25 ) gene involved in both post-synaptic formation and adhesion and considered a key player in the pathogenesis of ASD. To this end, four single nucleotide polymorphisms (SNPs) of the SNAP-25 gene, rs363050, rs363039, rs363043, and rs1051312, already known to be involved in neurodevelopmental and psychiatric disorders, were analyzed in a cohort of 69 children with EO-ASD and 58 children with RO-ASD. Both the rs363039 G allele and GG genotype were significantly more frequently carried by patients with EO-ASD than those with RO-ASD and healthy controls (HC). On the contrary, the rs1051312 T allele and TT genotype were more frequent in individuals with RO-ASD than those with EO-ASD and HC. Thus, two different SNAP-25 alleles/genotypes seem to discriminate between EO-ASD and RO-ASD. Notably, rs1051312 is located in the 3' untranslated region (UTR) of the gene and is the target of microRNA (miRNA) regulation, suggesting a possible epigenetic role in the onset of regressive autism. These SNPs, by discriminating two different onset patterns, may represent diagnostic biomarkers of ASD and may provide insight into the different biological mechanisms towards the development of better tailored therapeutic and rehabilitative approaches.

Better knowledge about the possible role of genetic factors in modulating the response to multiple sclerosis (MS) treatment, including rehabilitation, known to promote neural plasticity, could improve the standard of care for this disease. Vitamin D receptor ( VDR ) gene polymorphisms are associated with MS risk, probably because of the role played by vitamin D in regulating inflammatory and reparative processes. The aim of this study was to evaluate the association of the most important functional VDR SNPs ( TaqI ( T / C ), ApaI ( A / C ), and FokI ( C / T )) with functional outcome in MS patients undergoing multidisciplinary inpatient rehabilitation (MDR) treatment, in order to determine whether genetic profiling might be useful to identify subjects with a higher chance of recovery. To this end, 249 MS inpatients with a diagnosis of either progressive (pMS; n = 155) or relapsing remitting (RRMS; n = 94) disease who underwent MDR treatment (average duration = 5.1 weeks) were genotyped for VDR SNPs by real-time allelic discrimination. The rehabilitation outcome was assessed using the modified Barthel Index (mBI), Expanded Disability Status Scale (EDSS), and pain numerical rating scores (NRS) at the beginning and the end of MDR treatment. A positive correlation was observed in RRMS patients between the VDR TaqI major allele (TT) and mBI increase (i.e., better functional recovery), as assessed by the linear and logistic regression analysis adjusted for gender, age, disease duration, time of hospitalization, HLA-DRB1*15.01 positivity, and number of rehabilitative interventions (Beta = 6.35; p = 0.0002). The VDR-1 TaqI , ApaI , FokI : TCC haplotype was also associated with mBI increase in RRMS patients (Beta = 3.24; p = 0.007), whereas the VDR-2 : CAC haplotype was correlated with a lower mBI increase (Beta = -2.18 p = 0.04) compared with the other haplotypes. VDR TaqI major allele (TT), as well as the VDR-1 TaqI , ApaI , FokI : TCC haplotype could be associated with a better rehabilitation outcome in RRMS patients.

Introduction: Autism spectrum disorder (ASD) is accompanied by complex immune alterations and inflammation, and the possible role played by Natural Killer (NK) in such alterations is only barely understood., Methods: To address this question we analysed activating and inhibitory NK receptors, as well as NK cells phenotype and function in a group of mothers of children who developed ASD (ASD-MO; N=24) comparing results to those obtained in mothers of healthy children who did not develop (HC-MO; N=25)., Results: Results showed that in ASD-MO compared to HC-MO: 1) NK cells expressing the inhibitory receptor ILT2 are significantly decreased; 2) the activating HLA-G14bp+ polymorphism is more frequently observed and is correlated with the decrease of ILT2-expressing cells; 3) the CD56 bright and CD56 dim NK subsets are increased; 4) IFNγ and TNF production is reduced; and 5) perforin- and granzymes-releasing NK cells are increased even in unstimulated conditions and could not be upregulated by mitogenic stimulation., Discussion: Results herein reinforce the hypothesis that ASD relatives present traits similar to, but not as severe as the defining features of ASD (Autism endophenotype) and identify a role for NK cells impairment in generating the inflammatory milieu that is observed in ASD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saresella, Marventano, Piancone, Bolognesi, Hernis, Zanzottera, La Rosa, Agliardi, Giraldo, Chiappedi, Guerini and Clerici.)

The vitamin D/Vitamin D receptor (VDR) axis is crucial for human health as it regulates the expression of genes involved in different functions, including calcium homeostasis, energy metabolism, cell growth and differentiation, and immune responses. In particular, the vitamin D/VDR complex regulates genes of both innate and adaptive immunity. Autoimmune diseases are believed to arise from a genetic predisposition and the presence of triggers such as hormones and environmental factors. Among these, a role for Vitamin D and molecules correlated to its functions has been repeatedly suggested. Four single nucleotide polymorphisms (SNPs) of the VDR gene, ApaI , BsmI , TaqI , and FokI , in particular, have been associated with autoimmune disorders. The presence of particular VDR SNP alleles and genotypes, thus, was observed to modulate the likelihood of developing diverse autoimmune conditions, either increasing or reducing it. In this work, we will review the scientific literature suggesting a role for these different factors in the pathogenesis of autoimmune conditions and summarize evidence indicating a possible VDR SNP involvement in the onset of these diseases. A better understanding of the role of the molecular mechanisms linking Vitamin D/VDR and autoimmunity might be extremely useful in designing novel therapeutic avenues for these disorders.

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson's Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs' STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs' oligomeric α-Syn and RBDSQ total score was found ( p = 0.032). Regression analysis confirmed a significant association between NDEVs' oligomeric α-Syn concentration and RBD symptoms ( p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs' oligomeric α-Syn and SNARE complex components' serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype.

Approximately 15% of multiple sclerosis (MS) patients develop a progressive form of disease from onset; this condition (primary progressive-PP) MS is difficult to diagnose and treat, and is associated with a poor prognosis. Extracellular vesicles (EVs) of brain origin isolated from blood and their protein cargoes could function as a biomarker of pathological conditions. We verified whether MBP and MOG content in oligodendrocytes-derived EVs (ODEVs) could be biomarkers of MS and could help in the differential diagnosis of clinical MS phenotypes. A total of 136 individuals (7 clinically isolated syndrome (CIS), 18 PPMS, 49 relapsing remitting (RRMS)) and 70 matched healthy controls (HC) were enrolled. ODEVs were enriched from serum by immune-capture with anti-MOG antibody; MBP and MOG protein cargoes were measured by ELISA. MBP concentration in ODEVs was significantly increased in CIS (p < 0.001), RRMS (p < 0.001) and PPMS (p < 0.001) compared to HC and was correlated with disease severity measured by EDSS and MSSS. Notably, MBP concentration in ODEVs was also significantly augmented in PPMS compared to RRMS (p = 0.004) and CIS (p = 0.03). Logistic regression and ROC analyses confirmed these results. A minimally invasive blood test measuring the concentration of MBP in ODEVs is a promising tool that could facilitate MS diagnosis.

The early differential diagnosis of Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), is challenging because of an overlap of clinical features and the lack of reliable biomarkers. Neural-derived extracellular vesicles (NDEVs) isolated from blood provide a window into the brain's biochemistry and may assist in distinguishing between PD and APS. We verified in a case-control study whether oligomeric α-Synuclein and Tau aggregates isolated from NDEVs could allow the differential diagnosis of these conditions. Blood sampling and clinical data, including disease duration, motor severity, global cognition, and levodopa equivalent daily dose (LEDD), were collected from patients with a diagnosis of either PD (n = 70), PSP (n = 21), or CBD (n = 19). NDEVs were isolated from serum by immunocapture using an antibody against the neuronal surface marker L1CAM; oligomeric α-Synuclein and aggregated Tau were measured by ELISA. NDEVs analyses showed that oligomeric α-Synuclein is significantly augmented in PD compared to APS, whereas Tau aggregates are significantly increased in APS compared to PD (p < 0.0001). ROC analyses showed that these two biomarkers have a "good" power of classification (p < 0.0001 for both proteins), with high sensitivity and specificity, with NDEVs concentration of Tau aggregates and oligomeric α-Synuclein being respectively the best biomarker for PD/PSP and PD/CBD diagnostic differentiation. Logistic and multiple regression analysis confirmed that NDEVs-derived oligomeric α-Synuclein and Tau aggregates differentiate PD from CBD and PSP (p < 0.001). Notably, a positive correlation between NDEVs oligomeric α-Synuclein and disease severity (disease duration, p = 0.023; Modified H&Y, p = 0.015; UPDRS motor scores, p = 0.004) was found in PD patients and, in these same patients, NDEVs Tau aggregates concentration inversely correlated with global cognitive scores (p = 0.043). A minimally invasive blood test measuring the concentration of α-synuclein and Tau aggregates in NDEVs can represent a promising tool to distinguish with high sensitivity and specificity PD from CBD or PSP patients. Optimization and validation of these data will be needed to confirm the diagnostic value of these biomarkers in distinguishing synucleinopathies from taupathies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to progressive physical disability. Recent evidence has suggested that P2X7 receptor (P2X7R)-mediated purinergic signalling pathways play a role in MS-associated neuroinflammation, possibly contributing to disease pathogenesis. To evaluate possible associations between P2X7R polymorphisms and MS disease severity, we performed an association study of five non-synonymous SNPs coding variants of the P2X7R gene: rs1718119 Ala348Thr, rs2230911 Thr357Ser, rs2230912 Gln460Arg, rs3751143 Glu496Ala, and rs28360457 Arg307Gln, modulating P2X7R expression in 128 MS patients (relapsing remitting MS, RRMS: n = 94; secondary progressive, SPMS: n = 34). All patients were genotyped, and multiple sclerosis severity score (MSSS) was evaluated in every case; 189 healthy subjects were enrolled as well as controls. Results showed that P2X7R rs1718119(A) 348Thr and rs22390912(G) 464Arg, two SNPs of minor allele frequency (MAF) known to confer gain of function to the P2X7R protein, were associated with significantly higher MSSS in RRMS patients alone (SMRR (p < 0.001, p = 0.01, respectively)). Interestingly, two whole haplotypes resulted in having significant association with MSSS in these same patients. Thus: (1) the P2X7R-4 “ACGAG” haplotype, characterized by the co-presence of the rs1718119-rs2230912 AG MAF alleles, was associated with higher MSSS (Beta: 1.11 p = 0.04), and (2) the P2X7R-1 “GCAAG” complementary haplotype, which contains the rs1718119 and rs2230912 GA wild-type alleles, was more frequently carried by patients with lower MSSS and less severe disease (Beta: −1.54 p < 0.001). Although being preliminary and needing confirmation in an ampler cohort, these results suggest that 348Thr and 464Arg variants have a role as modulators of disease severity in RRMS patients.

Autism spectrum disorders (ASD) are characterized by a wide spectrum of clinical, behavioral, and cognitive manifestations. It is, therefore, crucial to investigate possible biomarkers associated with specific ASD phenotypes. Ample literature suggests a possible role for vitamin D (VD) in influencing ASD clinical phenotypes. We analyzed three vitamin D binding protein gene (DBP) functional polymorphisms (rs2282679, rs7041, and rs4588), which are involved in the modulation of vitamin D serum concentration in 309 ASD children and 831 healthy controls. Frequency comparisons of single nucleotide polymorphisms (SNPs) alleles, genotypes, and GC isoforms (GC1f, G1s, and GC2)—generated by the combination of rs7041 and rs4588 alleles—were correlated with ASD diagnostic, behavioral, and functioning scales. The GC1f isoform was significantly more frequent in ASD compared with controls (18.6% vs. 14.5% pc = 0.02). Significantly higher scores for item 15 of the Childhood Autism Rating Scale (CARS) and lower ones for the Children’s Global Assessment Scale (CGAS) functioning scales were seen in ASD carrying the GC1f isoform. In GC phenotype analysis, a gradient of severity for overall CARS scores and CARS item 15 was observed, with scores decreasing according to the presence of GC1f-GC1f > GC1f-GC1s > GC1s-GC1s > GC1f-GC2 > GC2-GC2 isoforms. Similarly, lower CGAS scores were seen in carriers of the GC1f-GC1f isoform, whereas higher scores were present in those carrying GC2-GC2 (p = 0.028). This is the first study to evaluate possible relationships between GC variants and the different aspects of ASD in Italian ASD children. Results, although needing to be validated in ampler cohorts, suggest that the GC1f isoform could be a marker of severity in ASD that may be useful in establishing the intensity of therapeutic and rehabilitative protocols.

Competing Interests: None

HLA allelic distribution was analysed in a cohort of 96 Northern Italian subjects (53M/43F) (mean age 59.9 ± 13.3 years) from Lombardy who developed COVID-19 during the first two pandemic waves to investigate possible correlations between HLA molecules and disease severity. An important role of HLA- B and HLA-C loci in modulating the clinical severity of COVID-19 disease was identified. In particular, the HLA-B07 supertype was observed to be associated with a significant risk for severe disease; conversely, the HLA-B27 supertype and C*12:02 allele played a protective role as they were associated with milder disease. These associations were confirmed after applying a multinomial regression analysis to adjust the correlation for age, gender and comorbidities with COVID-19 severity. Though the power of results is limited by the small sample size, data herein contribute to shedding light on the role played by genetic background in COVID-19 infection.

Vitamin D modulates immune responses and its deficiency has been observed in more than 60% of bronchiectasis patients. Vitamin D binding protein (DBP) is coded by the GC gene, is involved in the transport of vitamin D, and includes a number of isoforms based on single nucleotide polymorphisms (SNPs) in the coding region at rs7041 and rs4855. We evaluated the possible clinical impact of DBP polymorphisms and isoforms in an observational, cross-sectional study conducted in 116 bronchiectasis patients, who were genetically characterized for rs4588 and rs7041 SNPs. Results showed that the GC1f isoform (rs7041/rs4588 A/G) correlated with a more severe disease (18.9% vs. 6.3%, p = 0.038), a higher incidence of chronic infections (63.6% vs. 42%, p = 0.041), and a lower BACI score (0.0 (0.0, 2.5) vs. 3.0 (0.0, 3.0), p = 0.035). Moreover, blood concentration of vitamin D was higher in patients carrying GC1s (median (IQR): 20.5 (14.3, 29.7 vs. 15.8 (7.6, 22.4), p = 0.037)). Patients carrying GC1f isoform have a more severe disease, more chronic infections and lower asthmatic comorbidity in comparison to those without the GC1f isoform. Presence of the GC1s isoform (rs7041/rs4588 C/G) seems to be associated to a milder clinical phenotype with increased vitamin D levels and lower comorbidities score.

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes-particularly mRNA transport-or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.

The etiology of Parkinson's disease (PD) is presumably multifactorial and likely involves interactions between genetic and environmental factors, as well as mitochondrial dysfunction, oxidative stress and inflammation. Among environmental factors, Vitamin D was reported to associate with the risk of PD. Vitamin D activity is mediated by its binding to the vitamin D Receptor (VDR), a transcriptional factor for almost 3% of human genes. We genotyped for ApaI, BsmI, TaqI, FokI and rs1989969 VDR single nucleotide polymorphisms (SNPs) a cohort of 406 PD and 800 healthy controls (HC) and found a strong association between the FokI (rs2228570) VDR SNP and PD. Thus, the TT genotype and the T allele resulted associated with PD in the overall analyzed PD population. Gender-based stratification of data indicated that results were maintained for FokI TT genotype and T allele in male PD patients, whereas the FokI T allele alone was confirmed as a risk factor for PD in females. Co-segregation analyses indicated the TaqI ApaI FokI rs1989969 GCTG as a "risk" haplotype for PD. In a subgroup of patients and controls neural Vitamin D and VDR concentration was analyzed in extravesicles (NDEVs) isolated from peripheral blood: no differences emerged between PD and HC. NDEVs results will need to be validated in ampler cohort but we can speculate that, if at neuronal level the amounts of Vitamin D and of VDR are comparable, than the bioavailability of vitamin D and the efficacy of the vitamin D/VDR axis is differentially modulated in PD by VDR SNPs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Blood-based biomarkers are needed to be used as easy, reproducible, and non-invasive tools for the diagnosis and prognosis of chronic neurodegenerative disorders including Parkinson's Disease (PD). In PD, aggregated toxic forms of α-Synuclein (α-Syn) accumulate within neurons in the brain and cause neurodegeneration; α-Syn interaction with SNARE proteins also results in synaptic disfunction. We isolated neural derived extravesicles (NDEs) from peripheral blood of 32 PD patients and 40 healthy controls (HC) and measured the concentrations of oligomeric α-Syn and of the presinaptic SNARE complex proteins: STX-1A, VAMP-2 and SNAP-25. Oligomeric α-Syn was significantly augmented whereas STX-1A and VAMP-2 were significantly reduced in NDEs of PD patients compared to HC (p < 0.001 in all cases). ROC curve analyses confirmed the discriminatory ability of NDEs oligomeric α-Syn, STX-1A and VAMP-2 levels to distinguish between PD patients and HC. Oligomeric α-Syn NDEs concentration also positively correlated with disease duration and severity of PD. These results are promising and confirm that NDEs cargoes likely reflect core pathogenic intracellular processes in their originating brain cells and could serve as novel easily accessible bio-markers. Further studies are needed to confirm results and eventually for testing rehabilitation programs and drug treatments effects., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)