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BACKGROUND: Dissociation between macrocirculation and microcirculation is often observed in surgical patients. OBJECTIVE: To test the hypothesis that the analogue of mean circulatory filling pressure (Pmca) can monitor hemodynamic coherence during major non-cardiac surgery. METHODS: In this post-hoc analysis and proof-of-concept study, we used the central venous pressure (CVP), mean arterial pressure (MAP), and cardiac output (CO) to calculate Pmca. Efficiency of the heart (Eh), arterial resistance (Rart), effective arterial elastance (Ea), venous compartment resistance (Rven), oxygen delivery (DO2), and oxygen extraction ratio (O2ER) were also calculated. Sublingual microcirculation was assessed using SDF + imaging, and the De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and Consensus PPV (small) were determined. RESULTS: Thirteen patients were included, with a median age of 66 years. Median Pmca was 16 (14.9–18) mmHg and was positively associated with CO [p < 0.001; a 1 mmHg increase in Pmca increases CO by 0.73 L min - 1 (p < 0.001)], Eh (p < 0.001), Rart (p = 0.01), Ea (p = 0.03), Rven (p = 0.005), DO2 (p = 0.03), and O2ER (p = 0.02). A significant correlation was observed between Pmca and Consensus PPV (p = 0.02), but not with De Backer Score (p = 0.34) or Consensus PPV (small) (p = 0.1). CONCLUSION: Significant associations exist between Pmca and several hemodynamic and metabolic variables including Consensus PPV. Adequately powered studies should determine whether Pmca can provide real-time information on hemodynamic coherence.

Background: The calculated plasma volume status (cPVS) was validated as a surrogate of intravascular filling. The aim of this study is to assess the cPVS in relation to sublingual perfusion and organ injury. Methods: Pre- and postoperative cPVS were obtained by determining the actual and ideal plasma volume levels in surgical patients. The sublingual microcirculation was assessed using SDF imaging, and we determined the De Backer score, the Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Our primary outcome was the assessment of the distribution of cPVS and its association with intraoperative sublingual microcirculation and postoperative complications. Results: The median pre- and postoperative cPVS were −7.25% (IQR −14.29–−1.88) and −0.4% (IQR −5.43–6.06), respectively (p < 0.001). The mean intraoperative administered fluid volume was 2.5 ± 2.5 L (1.14 L h−1). No statistically significant correlation was observed between the pre- or postoperative cPVS and sublingual microcirculation variables. Higher preoperative (OR = 1.04, p = 0.098) and postoperative cPVS (OR = 1.057, p = 0.029) were associated with postoperative organ injury and complications (sepsis (30%), anemia (24%), respiratory failure (13%), acute kidney injury (6%), hypotension (6%), stroke (3%)). Conclusions: The calculated PVS was associated with an increased risk of organ injury and complications in this cohort.

Severe sepsis and septic shock may impair microcirculatory perfusion and cause organ dysfunction. The aim of this pilot study was to assess a new microcirculation-guided resuscitation strategy in patients with septic shock undergoing emergency abdominal surgery.A microcirculation-guided treatment algorithm was developed and applied intraoperatively following restoration of systemic hemodynamics. Sublingual microcirculation was monitored with Sidestream DarkField (SDF +) imaging technique. The primary objective was to investigate the change in De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and Consensus PPV (small) and its association with venous-to-arterial carbon dioxide difference (v-aPCOThirteen consecutive patients were included in the study. Microcirculation-guided resuscitation resulted in an increase of 0.49 mmThe intraoperative use of microcirculation-guided resuscitation strategy may improve tissue perfusion and hemodynamic coherence in patients with septic shock.

Exogenous catecholamines may have pronounced side effects and affect physiological cascades. The aim of this study was to investigate the effect of vasopressors on mortality of critically ill patients with coronavirus disease 2019 (COVID-19). A systematic search of PubMed, Scopus, and ClinicalTrials.gov was conducted for relevant articles until December 2022. Eligibility criteria were randomized controlled and non-randomized trials. The primary outcome was in-hospital and 30-day mortality. The quality of studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS) tool, while paired meta-analysis was used to estimate the pooled risk ratios (RR) along with their 95% Confidence Interval (95% CI). Analyses of 22 studies (n = 8034) revealed that vasopressor use is associated with mortality compared to no vasopressor therapy [RR (95%CI): 4.30 (3.21, 5.75); p p p n = 3519) revealed that vasopressor use is associated with acute kidney injury [RR (95%CI): 3.17 (2.21, 4.54); p Graphical Abstract

BACKGROUND: The incidence of postoperative microcirculatory flow alterations and their effect on outcome have not been studied extensively. OBJECTIVE: This systematic review and meta-analysis were designed to investigate the presence of sublingual microcirculatory flow alterations during the immediate and early postoperative period and their correlation with complications and survival. METHODS: A systematic search of PubMed, Scopus, Embase, PubMed Central, and Google Scholar was conducted for relevant articles from January 2000 to March 2021. Eligibility criteria were randomized controlled and non-randomized trials. Case reports, case series, review papers, animal studies and non-English literature were excluded. The primary outcome was the assessment of sublingual microcirculatory alterations during the immediate and early postoperative period in adult patients undergoing surgery. Risk of bias was assessed with the Ottawa-Newcastle scale. Standard meta-analysis methods (random-effects models) were used to assess the difference in microcirculation variables. RESULTS: Thirteen studies were included. No statistically significant difference was found between preoperative and postoperative total vessel density (p = 0.084; Standardized Mean Difference (SMD): –0.029; 95%CI: –0.31 to 0.26; I2 = 22.55%). Perfused vessel density significantly decreased postoperatively (p = 0.035; SMD: 0.344; 95%CI: 0.02 to 0.66; I2 = 65.66%), while perfused boundary region significantly increased postoperatively (p = 0.031; SMD: –0.415; 95%CI: –0.79 to –0.03; I2 = 37.21%). Microvascular flow index significantly decreased postoperatively (p = 0.028; SMD: 0.587; 95%CI: 0.06 to 1.11; I2 = 86.09%), while no statistically significant difference was found between preoperative and postoperative proportion of perfused vessels (p = 0.089; SMD: 0.53; 95%CI: –0.08 to 1.14; I2 = 70.71%). The results of the non-cardiac surgery post-hoc analysis were comparable except that no statistically significant difference in perfused vessel density was found (p = 0.69; SMD: 0.07; 95%CI: –0.26 to 0.39; I2 = 0%). LIMITATIONS: The included studies investigate heterogeneous groups of surgical patients. There were no randomized controlled trials. CONCLUSIONS: Significant sublingual microcirculatory flow alterations are present during the immediate and early postoperative period. Further research is required to estimate the correlation of sublingual microcirculatory flow impairment with complications and survival.

Introduction: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker of the level of chronic systemic inflammation and the general condition of the patient. We aimed to investigate the impact of general anesthesia and major surgery on perioperative suPAR and C-reactive protein (CRP) levels. Methods: This study included patients undergoing elective major noncardiac surgery with an expected duration of ≥2 h under general anesthesia. Inclusion criteria were age ≥18 years and American Society of Anesthesiologists’ physical status I–IV. Blood was drawn 30 min prior to induction of anesthesia (preoperatively), as well as 30 min after emergence from anesthesia (postoperatively). Plasma suPAR levels were determined using the suPARnostic® Quick Triage lateral flow assay. CRP measurements were performed by particle-enhanced immunoturbidimetric assay. Results: The difference in preoperative and postoperative suPAR levels was not statistically significant (7.7 [5.28–10.4] ng/mL vs. 7.15 [5.68–9.8] ng/mL, p = 0.462). CRP levels increased significantly during surgery (0.81 [0.24–2.1] mg/dL vs. 5.76 [2.2–8.75] mg/dL, p < 0.001). No correlation was observed between CRP and suPAR levels, both preoperatively (rho = 0.127; p = 0.208) and postoperatively (rho = 0.017; p = 0.87). A statistically significant increase was also observed in postoperative white blood cell count (7.576 vs. 10.711, p < 0.001). Conclusion: General anesthesia and operative trauma did not affect perioperative suPAR levels despite the activation of systemic inflammatory response.

BackgroundApolipoprotein E-ε4 (APOEε4) genotype may be associated with the development of cognitive decline in idiopathic Parkinson’s disease i(PD), however its effect in genetic PD is understudied.ObjectivesIn the current work we aimed to assess the impact ofAPOEgenotype on cognition in iPD as well as in genetic PD with mutations in theAlpha-synuclein(SNCA) andGlycocerebrosidase(GBA1) genes.MethodsTwo independent PD cohorts were analyzed: The first cohort (Athens) included 50 iPD patients, 35 patients with the p.A53TSNCAmutation and 59 patients withGBA1mutations (13 mild /46 severe). The second cohort (Tübingen) included 292 patients withGBA1mutations (170 risk/ 52 mild/ 70 severe). All patients underwent cognitive testing and were genotyped forAPOE.ResultsIn the iPD subgroup, carriers of at least oneAPOEε4 exhibited lower Montreal Cognitive Assessment test (MoCA) score as compared to non-carriers (p=0.044). Notably, in the p.A53TSNCAsubgroup,APOEε4 carriers also had lower MoCA scores compared to non-carriers (p=0.039). There were noAPOEε4-related differences in the twoGBA1subgroups (Athens, p=0.729; Tübingen p=0.585).ConclusionsWe confirm the impact ofAPOEε4 on cognitive decline in iPD and for the first time report a similar effect in p.A53TSNCAmutation carriers, who represent the prototypical genetic synucleinopathy. Contrary, the lack of such an effect in two independent cohorts ofGBA1mutation carriers, who are thought to also manifest a predominant alpha-synuclein-driven cognitive decline, suggests differences in factors associated with cognitive dysfunction between different genetic forms of synucleinopathies.

Background: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. Methods: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. Results: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96–1.30]; p = 0.15; I2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006–1.42]; p = 0.042; I2 = 0%; 3 studies with 2107 participants). Conclusions: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies.

Background New noninvasive and affordable molecular approaches that will complement current practices and increase the accuracy of Parkinson's disease (PD) diagnosis are urgently needed. Circular RNAs (circRNAs) are stable noncoding RNAs that accumulate with aging in neurons and are increasingly shown to regulate all aspects of neuronal development and function. Objectives Τhe aims of this study were to identify differentially expressed circRNAs in blood mononuclear cells of patients with idiopathic PD and explore the competing endogenous RNA networks affected. Methods Eighty‐seven circRNAs were initially selected based on relatively high gene expression in the human brain. More than half of these were readily detectable in blood mononuclear cells using real‐time reverse transcription‐polymerase chain reaction. Comparative expression analysis was then performed in blood mononuclear cells from 60 control subjects and 60 idiopathic subjects with PD. Results Six circRNAs were significantly down‐regulated in patients with PD. The classifier that best distinguished PD consisted of four circRNAs with an area under the curve of 0.84. Cross‐linking immunoprecipitation‐sequencing data revealed that the RNA‐binding proteins bound by most of the deregulated circRNAs include the neurodegeneration‐associated FUS, TDP43, FMR1, and ATXN2. MicroRNAs predicted to be sequestered by most deregulated circRNAs have the Gene Ontology categories “protein modification” and “transcription factor activity” mostly enriched. Conclusions This is the first study that identifies specific circRNAs that may serve as diagnostic biomarkers for PD. Because they are highly expressed in the brain and are derived from genes with essential brain functions, they may also hint on the PD pathways affected. © 2021 Biomedical Research Foundation, Academy of Athens. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Age at onset is one of the most critical factors contributing to the clinical heterogeneity of Parkinson's disease (PD), and available evidence is rather conflicting.The aim of this study is to investigate the clinical differences between early-onset PD (EOPD) and mid-and-late-onset PD (MLOPD) in the Greek population, based on the existing data of the Hellenic Biobank of PD (HBPD).HBPD contains information of PD cases from two centers in Greece during 2006-2017. Patients with the A53T mutation in the SNCA gene or mutations in the GBA1 gene were excluded. Associations between clinical characteristics (motor and non-motor symptoms, side of onset, first symptom, motor complications) and MLOPD versus EOPD were explored with a single logistic regression model adjusting for gender, family history of PD, disease and dopaminergic therapy duration, disease severity (UPDRS III), levodopa equivalent daily dose, as well as each of the other clinical characteristics.675 patients (129 EOPD, 546 MLOPD) were included. EOPD was more frequently associated with dystonia (OR 0.19, 95% CI 0.08-0.50, p 0.01) and motor complications (0.23, 0.07-0.76, 0.02), compared to MLOPD. Bilateral onset (9.38, 1.05-84.04, 0.045) and autonomic dysfunction (2.31, 1.04-5.11, 0.04) were more frequently associated with MLOPD.EOPD and MLOPD display distinct clinical profiles, regarding motor and non-motor symptoms, side of onset and motor complications in the Greek population. These differences may reflect diverse pathophysiological backgrounds, potentially attributed to genetic or age-related epigenetic influences.

The present work investigated the dynamic changes in stressed volume (Vs) and other determinants of venous return using a porcine model of hyperdynamic septic shock. Septicemia was induced in 10 anesthetized swine, and fluid challenges were started after the diagnosis of sepsis-induced arterial hypotension and/or tissue hypoperfusion. Norepinephrine infusion targeting a mean arterial pressure (MAP) of 65 mmHg was started after three consecutive fluid challenges. After septic shock was confirmed, norepinephrine infusion was discontinued, and the animals were left untreated until cardiac arrest occurred. Baseline Vs decreased by 7% for each mmHg decrease in MAP during progression of septic shock. Mean circulatory filling pressure (Pmcf) analogue (Pmca), right atrial pressure, resistance to venous return, and efficiency of the heart decreased with time (p < 0.001 for all). Fluid challenges did not improve hemodynamics, but noradrenaline increased Vs from 107 mL to 257 mL (140%) and MAP from 45 mmHg to 66 mmHg (47%). Baseline Pmca and post-cardiac arrest Pmcf did not differ significantly (14.3 ± 1.23 mmHg vs. 14.75 ± 1.5 mmHg, p = 0.24), but the difference between pre-arrest Pmca and post-cardiac arrest Pmcf was statistically significant (9.5 ± 0.57 mmHg vs. 14.75 ± 1.5 mmHg, p < 0.001). In conclusion, the baseline Vs decreased by 7% for each mmHg decrease in MAP during progression of hyperdynamic septic shock. Significant changes were also observed in other determinants of venous return. A new physiological intravascular volume existing at zero transmural distending pressure was identified, termed as the rest volume (Vr).

Objective There is a pressing need to identify and validate, minimally invasive, molecular biomarkers that will complement current practices and increase the diagnostic accuracy in Parkinson’s disease (PD). Brain‐enriched miRNAs regulate all aspects of neuron development and function; importantly, they are secreted by neurons in amounts that can be readily detected in the plasma. Τhe aim of the present study was to validate a set of previously identified brain‐enriched miRNAs with diagnostic potential for idiopathic PD and recognize the molecular pathways affected by these deregulated miRNAs. Methods RT‐qPCR was performed in the plasma of 92 healthy controls and 108 idiopathic PD subjects. Statistical and in silico analyses were used to validate deregulated miRNAs and pathways in PD, respectively. Results miR‐22‐3p, miR‐124‐3p, miR‐136‐3p, miR‐154‐5p, and miR‐323a‐3p levels were found to be differentially expressed between healthy controls and PD patients. miR‐330‐5p, miR‐433‐3p, and miR‐495‐3p levels were overall higher in male subjects. Most of these miRNAs are clustered at Chr14q32 displaying CREB1, CEBPB, and MAZ transcription factor binding sites. Gene Ontology annotation analysis of deregulated miRNA targets revealed that “Protein modification,” “Transcription factor activity,” and “Cell death” terms were over‐represented. Kyoto Encyclopedia of Genes and Genome analysis revealed that “Long‐term depression,” “TGF‐beta signaling,” and “FoxO signaling” pathways were significantly affected. Interpretation We validated a panel of brain‐enriched miRNAs that can be used along with other measures for the detection of PD, revealed molecular pathways targeted by these deregulated miRNAs, and identified upstream transcription factors that may be directly implicated in PD pathogenesis.

Background Variations of α-synuclein levels have been reported in serum and plasma in Parkinson's Disease (PD) Patients. Methods Serum and plasma were obtained from PD patients without known mutations (GU-PD, n = 124)), carriers of the A53T/G209A point mutation in the α-synuclein gene (SNCA) (n = 29), and respective age-/sex-matched controls. Levels of total α-synuclein were assessed using an in-house ELISA assay. Results A statistically significant increase of α-synuclein levels was found in serum, but not plasma, from GU-PD patients compared to healthy controls. A statistically significant decrease of α-synuclein levels was found in serum and plasma from symptomatic A53T mutation carriers compared to healthy controls. Plasma α-synuclein levels were modestly negatively correlated with UPDRS part III score and disease duration in A53T-PD patients. Conclusion Increased α-synuclein levels in serum of GU-PD patients suggest a systemic deregulation of α-synuclein homeostasis in PD. The opposite results in A53T-PD highlight the complexity of α-synuclein homeostatic regulation in PD, and suggest the possibility of reduced expression of the mutant allele.

BackgroundThe role of blood uric acid and more recently bilirubin as biomarkers in symptomatic motor PD has been increasingly established in the literature.ObjectiveOur present study assessed the role of serum uric acid and total bilirubin as putative biomarkers in a prodromal PD cohort followed longitudinally.MethodsLongitudinal 5-year serum uric acid and total bilirubin measurement data of 65 Prodromal PD patients (including REM Sleep Behavior disorder (RBD), N=39 and Hyposmia, N=26) with an abnormal DATSCAN imaging were downloaded from the Parkinson’s Progression Markers Initiative (PPMI) database. This cohort was compared with 423 de novo sporadic PD patients and 196 healthy controls enrolled in the same study.ResultsAfter adjusting for age, sex and Body Mass Index (BMI), baseline and 5-year longitudinal serum uric acid levels were higher in the Prodromal cohort and RBD subgroup as compared to the motor PD cohort. This was also true for longitudinal measurements in the Hyposmic subgroup. In contrast, baseline and longitudinal serum total bilirubin did not differ between each prodromal group and the PD cohort.ConclusionsOur results are indicative of a role of serum uric acid (but probably not of total bilirubin) as a marker of neuroprotection, in a certain subgroup of premotor patients exhibiting exclusively non motor features (hyposmia or RBD). It is possible that an inherent antioxidant resistance of a subset of RBD or hyposmia patients with high serum uric acid level delayed or precluded the emergence of a motor PD phenotype as opposed to the PD cohort.

Background: several blood-based biomarkers have been proposed for predicting vancomycin-associated kidney injury (VIKI). However, no systematic analysis has compared their prognostic value. Objective: this systematic review and meta-analysis was designed to investigate the role of blood biomarkers and metabolomic profiling as diagnostic and prognostic predictors in pre-clinical studies of VIKI. Methods: a systematic search of PubMed was conducted for relevant articles from January 2000 to May 2022. Animal studies that administered vancomycin and studied VIKI were eligible for inclusion. Clinical studies, reviews, and non-English literature were excluded. The primary outcome was to investigate the relationship between the extent of VIKI as measured by blood biomarkers and metabolomic profiling. Risk of bias was assessed with the CAMARADES checklist the SYRCLE’s risk of bias tool. Standard meta-analysis methods (random-effects models) were used. Results: there were four studies for the same species, dosage, duration of vancomycin administration and measurement only for serum creatine and blood urea nitrogen in rats. A statistically significant increase was observed between serum creatinine in the vancomycin group compared to controls (pooled p = 0.037; Standardized Mean Difference: 2.93; 95% CI: 0.17 to 5.69; I2 = 92.11%). Serum BUN levels were not significantly different between control and vancomycin groups (pooled p = 0.11; SMD: 3.05; 95% CI: 0.69 to 6.8; I2 = 94.84%). We did not identify experimental studies using metabolomic analyses in animals with VIKI. Conclusions: a total of four studies in rodents only described outcomes of kidney injury as defined by blood biomarkers. Blood biomarkers represented included serum creatinine and BUN. Novel blood biomarkers have not been explored.

BackgroundHigher prevalence of motor and non-motor features has been observed in non-manifesting mutation carriers of Parkinson’s Disease (PD) compared to Healthy Controls (HC).ObjectivesThe aim was to detect the differences between GBA and LRRK2 mutation carriers without PD and HC on neuropsychiatric symptoms.MethodsThis is a cross-sectional retrospective study of non-manifesting GBA and LRRK2 mutation carriers and HC enrolled into Parkinson’s Progression Markers Initiative (PPMI). Data extracted from the PPMI database contained: demographics and performance in MoCA scale and MDS-UPDRS scale part 1A (neuropsychiatric symptoms). All six features were treated as both continuous (MDS-UPDRS individual scores) and categorical variables (MDS-UPDRS individual score>0 and MDS-UPDRS individual score=0). Logistic regression analyses were applied to evaluate the association between mutation carrying status and neuropsychiatric symptoms.ResultsWe found that non-manifesting mutation carriers as a whole (total N=654, GBA: n=285, LRRK2: n=369) were 2.3 times more likely to present apathy compared to HC, even after adjustment for covariates (adjusted OR=2.3, 95% CI=1.1-5.0, p-value=0.027). The effect was mainly driven by GBA mutation carriers (adjusted OR= 2.6, 95% CI=1.1-6.3, p=0.031), while the higher percentage of apathy for LRRK2 carriers compared to HC was marginally non-significant. Other neuropsychiatric symptoms, such as psychotic or depressive manifestations, did not differ between groups.ConclusionsSymptoms of apathy could be present in the premotor period of LRRK2 and, especially, GBA mutation carriers. Longitudinal data, including detailed neuropsychiatric evaluation and neuroimaging, would be essential to further investigate the pathophysiological basis of this finding.

INTRODUCTIONThe plasma suPAR level has previously been associated with postoperative complications and has been shown to be an independent predictor of coronary microvascular function and flow reserve. We investigated the association between preoperative suPAR levels and intraoperative sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.MethodsThis study included 100 patients undergoing major non-cardiac surgery between February 2019 and September 2020. The primary objective was to investigate the association between preoperative suPAR and intraoperative sublingual De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and Consensus PPV (small). Secondary objectives were to investigate the associations between these sublingual microcirculatory variables and (1) complications and (2) mean arterial pressure. EDTA blood was collected before induction of anesthesia and plasma suPAR levels were determined using the suPARnostic® quick triage lateral flow assay. Sublingual microcirculation was monitored with Sidestream DarkField (SDF+) imaging technique at 20 minutes after induction of anesthesia before surgical incision (baseline) and then every 30 minutes until emergence from anesthesia.ResultsA decrease of 0.7 mm-1 in the De Backer score, 2.5% in the Consensus PPV, and 2.8% in the Consensus PPV (small) from baseline measurement was observed for every 1 ng/ml increase of suPAR or 1 additional minute of intraoperative time. De Baker score did not change significantly from baseline (p=0.404), while Consensus PPV and Consensus PPV (small) decreased significantly from baseline (pConclusionPreoperative suPAR levels and prolonged operative duration were associated with intraoperative impairment of sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.

Graphical abstract, The progress of COVID-19 from moderate to severe may be precipitous, while the characteristics of the disease are heterogenous. The aim of this study was to describe the development of sinus bradycardia in critically ill patients with COVID-19 and its association with outcome in outbreak due to the SARS-CoV-2 B.1.1.7 Lineage. We leveraged the multi-center SuPAR in Adult Patients With COVID-19 (SPARCOL) study and identified patients who required admission to intensive care unit (ICU). Inclusion criteria were: (a) adult (≥18 years old) patients hospitalized primarily for COVID-19; (b) a confirmed SARS-CoV-2 infection diagnosed through reverse transcriptase polymerase chain reaction test of nasopharyngeal or oropharyngeal samples; and (c) at least one blood sample collected at admission and stored for suPAR, hs-CRP, and ferritin testing. All patients had continuous heart rate monitoring during hospitalization. In total, 81 patients were included. Of them, 17 (21 %) and 64 (79 %) were intubated and admitted to the ICU during the first and second wave, respectively. Two (12 %) and 62 (97 %) developed bradycardia before ICU admission, respectively (p < 0.001). Patients with bradycardia had increased suPAR (p < 0.001) and hs-CRP level (p < 0.001). Infusion of isoprenaline and/or noradrenaline was necessary to maintain an adequate rate and peripheral perfusion in all patients. Mortality was significantly higher in patients with bradycardia (p < 0.001). In conclusion, bradycardia was associated with poor outcome. As B.1.1.7 variant strain is spreading more rapidly in many countries, our findings help in the identification of patients who may require early admission to ICU.

Study objectiveTo systematically review the literature regarding the presence of sublingual microcirculatory alterations during the immediate and early postoperative period.DesignSystematic review and meta-analysis searching PubMed, Scopus, and Google Scholar.Patients/interventionsStudies comparing sublingual microcirculation before and after surgery.MeasurementThe primary outcome was to investigate the severity of microcirculatory alterations during the immediate and early postoperative period in adult patients undergoing non-cardiac and cardiac surgery.Main resultsAmong 17 eligible studies, 13 were finally analyzed. A non-statistically significant difference was found between preoperative and postoperative total vessel density (p=0.084; estimate: −0.029; 95% CI: −0.31 to 0.26; I2 = 22.55%, Q = 10.23, p=0.24). Perfused vessel density significantly decreased postoperatively (p=0.035; estimate: 0.344; 95% CI: 0.02 to 0.66; I2 = 65.66%, Q = 41.77, p2 = 37.21%, Q = 6.56, p=0.16). Microvascular flow index significantly decreased postoperatively (p=0.028; estimate: 0. 587; 95% CI: 0.06 to 1.11; I2 = 86.09%, Q = 96.28, p2 = 70.71%, Q = 18.99, p=0.002). The results in the non-cardiac surgery subgroup were comparable with the full group except that a statistically non-significant difference in PVD was found in the remaining seven studies (p=0.19; estimate: 0.26; 95% CI: −0.13 to 0.66; I2 = 71.94%, Q = 33.42, p=0.002). The other parameters did not differ significantly from their respective full group results.ConclusionsSignificant sublingual microcirculatory alterations are present during the immediate and early postoperative period.

Background: Previous studies have highlighted serum uric acid as a putative idiopathic Parkinson’s disease (iPD) biomarker. Only one study, so far, showed higher levels of serum uric acid in leucine-rich repeat kinase 2 (LRRK + 2) carriers compared to those who developed PD, however a longitudinal comparison between LRRK2 + PD and healthy controls (HC) has not been performed. Objective: The aim of this study was to determine whether there are longitudinal differences in serum uric acid between iPD, LRRK2 + PD and HC and their association with motor and non-motor features. Methods: Longitudinal data of uric acid of 282 de novo iPD, 144 LRRK2 + PD patients, and 195 age-matched HC were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database. We also used longitudinal Montreal Cognitive Assessment (MoCA), Movement Disorder Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS-III), Geriatric Depression Scale (GDS) scores, and DaTSCAN striatal binding ratios (SBRs). Results: Longitudinal uric acid measurements were significantly lower in LRRK2 + PD patients compared to HC up to 5 years follow-up. There was no significant impact or correlation of adjusted or unadjusted uric acid levels with MoCA, MDS-UPDRS III, or GDS scores, the presence of RBD or DAT-SCAN SBRs. Conclusion: LRRK2 + PD group had significantly lower uric acid concentrations compared to HC after adjusting for age, sex and baseline BMI up to 5 years follow-up. There were no significant associations between uric acid levels and indices of disease severity. These findings identify serum uric acid as a marker linked to LRRK2 + PD.

Purposeof review: To evaluate whether CSF and circulating neurofilament light chain (NFL), a marker of axonal damage, could discriminate Parkinson’s disease (PD) from atypical parkinsonian syndromes (APS).Recent findings:MEDLINE and SCOPUS were systematically searched, and fifteen studies were included (1035 PD patients,930 APS patients). CSF and circulating NFL levels were 1.26 and 1.53 standard deviations higher in APS compared to PD patients respectively [g=1.26 (95% CI 0.99-1.53);12 studies, 880 PD patients, 847 APS patients, g=1.53 (1.15-1.91);4 studies, 307 PD patients, 197 APS patients. Pooled areas under the curve were 0.941 (0.916-0.965) and 0.874 (0.802-0.946) for CSF and circulating NFL, corresponding to average sensitivities of 86% (79-90%) and 91% (86-95%), and specificity of 88% (82-92%) and 76% (62-85%), respectively.Summary:These results strongly support the high diagnostic accuracy of both CSF and circulating NFL in differentiating PD from APS, highlighting their usefulness as promising biomarkers.

Background: Multiple sclerosis (MS) treatment with B-cell targeted therapies, such as rituximab, ocrelizumab, ofatumumab and cladribine may be associated with an increased incidence of headache, thus proper management of a possible adverse effect may be necessary. We aimed to find, if any, and compare the association of B-cell targeted therapies with the incidence of headache in patients with multiple sclerosis. Methods: In a systematic based approach, the following databases were searched from inception till 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. No limits were applied to publication year, sex or race. Only randomized clinical trials (RCTs) enrolling patients with multiple sclerosis comparing B-cell targeted therapies (rituximab, ocrelizumab, ofatumumab, ublituximab or cladribine) with placebo, were selected for the systematic review and further metanalysis. Two reviewers independently extracted individual study data and evaluated studies for risk of bias using Cochrane Risk of Bias version 2 tool (ROB-II). PRISMA guidelines were followed at all stages of the systematic review. Random effects meta-analysis to derive confidence intervals and to assess heterogeneity were conducted. The primary outcome was all-cause headache during the administration of B-cell targeting therapy in patients with multiple sclerosis. Findings: Nine randomized clinical trials (3785 participants) were included. Compared with placebo, treatment with B-cell targeting therapies was not associated with a statistically significant increase in headache risk (RR 1·12 [95% CI 0·96 – 1·30]; p=0·15; I2 = 9·32%). In a subgroup analysis, cladribine was statistically significant for an increase in headache risk (RR 1·20 [95% CI 1·006 – 1·42]; p=0·042; I2 = 0%; 3 studies with 2107 participants). Interpretation: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Further sub-analyses revealed a significant association between cladribine alone and increased incidence of headache. Further research is needed to unravel the underlying pathogenetic mechanism of headache induction, as well as, to establish headache prevention strategies. Funding statement: The authors declare no funding applied for this study Declaration of Interests: T.M. has received travel grants from Merck and Sanofi-Genzyme. M.B. has received travel grants from Merck, Teva-Specifar, Genesis Pharma, Pfizer. N.P. declares no conflict of interest. K.P. declares no conflict of interest. A.L. declares no conflict of interest. G.V. declares no conflict of interest. N.G. declares no conflict of interest. N.F. has received honoraria, consultation fees and/or research grants from Actelion, Amgen, Biogen, Celgene, Genesis Pharma, Eli Lilly, Merck Serono, Novartis, Receptos, Roche, Sanofi-Genzyme and Teva-Specifar. D.D.M. has received consulting, research, speaking fees and/or travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, ElectroCore, Eli-Lily, Genesis Pharma, Merck-Serono, Merz, Mylan, Novartis, Roche, Sanofi Genzyme and Teva -Specifar

Study Objectives Τo assess whether REM Sleep Behavior Disorder (RBD) and other sleep abnormalities occur in carriers of the p.A53T alpha-synuclein gene (SNCA) mutation, using both subjective and objective measures. Methods We have assessed 15 p.A53T carriers (10 manifesting Parkinson’s Disease [PD-A53T] and 5 asymptomatic carriers) with simultaneous Video-PSG (polysomnography) recording, the Epworth Sleepiness Scale (ESS) for daytime sleepiness, the Athens Insomnia Scale (AIS), the RBD Screening Questionnaire (RBDSQ) for clinical features of RBD, the Montreal Cognitive Assessment (MOCA) for cognition and the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction. Results In our cohort, 90% of PD carriers had at least one sleep disorder and 40% had two: 4 RBD, 1 Periodic Limb Movements (PLM), 1 RBD plus PLM, 2 RBD plus moderate Obstructive Sleep Apnea (OSA), and 1 moderate OSA plus Restless Leg Syndrome. No asymptomatic carrier manifested a confirmed sleep disorder. 6/7 PD carriers with RBD had abnormal olfactory testing and 4/7 MOCA below cut off. There was a correlation of both impaired olfaction and cognition with RBD. Conclusions RBD occurs in the majority of PD-A53T, in contrast to most other genetic forms of PD, in which RBD is uncommon. The paucity of a sleep disorder in the asymptomatic carriers suggests that such carriers have not yet reached the prodromal phase when such sleep disorders manifest. Hyposmia in almost all subjects with RBD and cognitive decline in most of them are indicative of the general pattern of disease progression, which however is not uniform.

BackgroundNew noninvasive and affordable molecular approaches that will complement current practices and increase the accuracy of PD diagnosis are urgently needed. CircRNAs are highly stable non-coding RNAs that accumulate with aging in neurons and are increasingly shown to regulate all aspects of neuronal development and function.ObjectivesThe aims of the present study were to identify differentially expressed circRNAs in PBMCs of idiopathic PD patients and explore the competing endogenous RNA networks affected.MethodsEighty-seven circRNAs were initially selected based on relatively high gene expression in the human brain. Over half of these were readily detectable in PBMCs using RT-qPCR. Comparative expression analysis was then performed in PBMCs from sixty controls and sixty idiopathic subjects with PD.ResultsSix circRNAs derived from MAPK9, HOMER1, SLAIN1, DOP1B, REPS1, and PSEN1 transcripts were significantly downregulated in PD patients. The classifier that best distinguished PD consisted of four circRNAs with an AUC of 0.84. CLIP-Seq data revealed that the RNA binding proteins bound by most of the deregulated circRNAs include the neurodegeneration-associated FUS, TDP43, FMR1 and ATXN2. MicroRNAs predicted to be sequestered by most deregulated circRNAs had the GOslim categories ‘Protein modification’, ‘Transcription factor activity’ and ‘Cytoskeletal protein binding’ mostly enriched.ConclusionsThis is the first study that identifies circRNAs deregulated in the peripheral blood of PD patients. They may serve as diagnostic biomarkers and since they are highly expressed in the brain and are derived from genes with essential brain functions, they may also hint on the PD pathways affected.

Blood uric acid represents an important biomarker in sporadic Parkinson's disease (PD). Whether uric acid levels change in genetic forms of PD is beginning to be assessed. The aim of the present study was to evaluate differences in serum uric acid level among PD patients harboring mutations in the glucocerebrosidase (GBA1) gene, sporadic PD, and healthy controls followed longitudinally.Longitudinal 2-year serum uric acid measurement data of 120 GBA-PD patients have been downloaded from the Parkinson's Progression Markers Initiative (PPMI) database. This cohort was compared with 369 de novo sporadic PD patients and 195 healthy controls enrolled in the same study.Following adjustment for age, sex and BMI the GBA-PD cohort exhibited lower 2-year longitudinal uric acid level as compared to the controls (p = 0.016). Baseline uric acid measurements showed only a marginal difference (p = 0.119), but year 2 uric acid levels were lower in the GBA-PD cohort (p 0.001). There was no difference in baseline, year 2 and 2-year longitudinal serum uric acid in the GBA-PD cohort as compared to sporadic PD (p = 0.664, p = 0.117 and p = 0.315).This is the first study to assess serum uric acid in a GBA-PD cohort. Our findings suggest that low serum uric acid might be a progression biomarker in GBA-PD. However, more studies (ideally longitudinal) on the association between low serum uric acid and clinical data in GBA-PD are needed. These results are consistent with data from previous reports assessing uric acid as a biomarker in other genetic forms of PD.

Background There is a pressing need to identify and validate, minimally invasive, molecular biomarkers that will complement current practices and increase the diagnostic accuracy in Parkinson’s disease (PD). Brain-enriched miRNAs regulate all aspects of neuron development and function; importantly, they are secreted by neurons in amounts that can be readily detected in the plasma. Τhe aim of the present study was to validate a set of previously identified brain-enriched miRNAs with a diagnostic potential for idiopathic PD and recognize the molecular pathways affected by these deregulated miRNAs.Methods RT-qPCR was performed in the plasma of 92 healthy controls and 108 idiopathic PD subjects. Statistical and in silico analyses were used to validate deregulated miRNAs and pathways in PD, respectively.Results miR-22-3p, miR-124-3p, miR-136-3p, miR-154-5p and miR-323a-3p levels were found to be differentially expressed between healthy controls and PD patients. miR-330-5p, miR-433-3p and miR-495-3p levels were overall higher in male subjects. Most of these miRNAs are clustered at Chr14q32 displaying CREB1, CEBPB, and MAZ transcription factor binding sites. Gene Ontology (GO) annotation analysis of deregulated miRNA targets revealed that ‘Protein modification’, ‘Transcription factor activity’ and ‘Cell death’ terms were over-represented. Kyoto Encyclopedia of Genes and Genome (KEGG) analysis revealed that ‘Long-term depression’, ‘TGF-beta signaling’, and ‘FoxO signaling’ pathways were significantly affected.Conclusions We validated a panel of brain-enriched miRNAs that can be used along with other measures for the detection of PD, revealed molecular pathways targeted by these deregulated miRNAs, and identified upstream transcription factors that may be directly implicated in their regulation and thereafter PD pathogenesis.

Background Blood uric acid level represents an emerging biomarker in Parkinson's disease (PD). Whether uric acid levels change in genetic forms of PD is just beginning to be explored. Objective The aim of the present study was to assess differences in serum uric acid level among PD patients harboring the p.A53T mutation in the alpha-synuclein gene, idiopathic PD, and healthy controls. Methods Longitudinal 5-year serum uric acid measurement data of 369 de novo idiopathic PD patients and 174 age- and gender-matched healthy controls have been downloaded from the Parkinson's Progression Markers Initiative (PPMI) database. Furthermore, we assessed baseline serum uric acid measurements of 24 p.A53T alpha-synuclein PD patients enrolled in PPMI and followed in our site as compared to 24 age-, gender- and disease duration-matched sporadic PD patients and 24 healthy controls. Results Longitudinal serum uric acid measurements did not differ statistically between idiopathic PD patients and healthy controls (despite a trend for lower uric acid in the PD group) (p = 0.879). This was also true when male and female subgroups were assessed separately. The p.A53T SNCA mutation carrier PD group exhibited lower baseline serum uric acid level as compared to their matched healthy controls (p = 0.025). Conclusion In the present study we did not replicate the established lower serum uric acid measurements in PD patients as compared to controls using PPMI data, possibly due to the fact that PD patients in baseline visit were de novo and the average disease duration was shorter than that observed in most epidemiological PD studies. The faster progression rate and increased disease severity in p.A53T PD possibly correlate with the lower serum uric acid observed in this subgroup.

Background The p.A53T point mutation in the α-synuclein gene (SNCA) is a rare but highly relevant cause of autosomal dominant Parkinson's disease (PD). Objectives The objective of this study was to assess striatal dopaminergic denervation in a cohort of symptomatic carriers of the p.A53T SNCA mutation as compared to PD patients. Methods Data from the Parkinson's Progression Markers Initiative database of 11 symptomatic p.A53T SNCA mutation carriers who underwent 123I-FP-CIT SPECT [(123) I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane single photon emission computed tomography] imaging at our site were compared with those of 33 age-, sex-, and disease duration-matched PD patients. Results The p.A53T mutation carriers had significantly lower caudate nucleus binding ratio both contralaterally and ipsilaterally to the most affected side (P = .002 and P = .006) and a decreased contralateral caudate/putamen signal ratio (P = .007) as compared to PD. A similar degree of striatal asymmetry was observed in both subgroups. No correlation between scores in neuropsychological tests and caudate nucleus dopaminergic denervation could be demonstrated. Conclusions PD patients harboring the p.A53T SNCA mutation show evidence of a more severe nigrostriatal denervation, especially evident in the caudate nucleus. The lack of significant differences in the putaminal binding ratios may reflect a floor effect or a true preferential targeting of the caudate terminals in p.A53T SNCA-associated PD. © 2018 International Parkinson and Movement Disorder Society.

ObjectiveTo evaluate nonmotor symptoms in early SNCA/p.A53T Parkinson disease (PD) (A53T PD) compared to typical PD (tPD).MethodsThe presence of hyposmia, neuropsychiatric, dysautonomic, and sleep disturbances was assessed by standardized questionnaires and validated scales in 18 patients with A53T PD and 18 patients with tPD, matched for age, sex, and disease duration. All patients were enrolled into the Parkinson's Progression Markers Initiative study.ResultsThe levodopa equivalent daily dose was higher in the A53T PD (p = 0.018) group vs the tPD group. Scores on the University of Pennsylvania Smell Identification Test (p = 0.001), Benton Judgement of Line Orientation test (p = 0.001), Letter Number Sequencing Test (p = 0.002), and phonemic verbal fluency (p = 0.002) were lower in the A53T PD group vs the tPD group. In contrast, overall cognition, verbal memory, and semantic fluency were similar between groups.ConclusionThe observed selective cognitive impairment reflecting frontal-parietal network dysfunction, together with impaired olfaction, define a set of nonmotor dysfunctions related to A53T PD. These results have implications for the prognosis of patients with A53T PD. Moreover, as the archetypal α-synucleinopathy, such results may give insights into tPD.

Introduction It has been reported that early onset Parkinson's Disease (PD) patients have a less profound dopaminergic degeneration. The aim of the current study was to determine whether there are longitudinal differences in dopaminergic denervation [signal reduction in 123I-FP-CIT SPECT] in early versus mid and late onset PD. Methods DaTSCAN (123I-FP-CIT SPECT) imaging was acquired at Parkinson's Progression Markers Initiative (PPMI) imaging centers and sent to the imaging core for calculation of striatal binding ratios. Data from the PPMI database of 58 early de novo PD patients (age ≤ 50 years) were compared to those of 362 mid and late onset PD patients (age > 50 years). Results Although raw striatal binding ratios were higher in early onset versus mid/late onset PD, especially on the ipsilateral side, such differences were not observed, and were in fact reversed in the contralateral putamen, after age correction. The rate of signal decline was similar between the two groups. Interestingly, based on both raw and age-adjusted data, caudate nucleus and putamen asymmetry (contralateral/ipsilateral ratio) was more pronounced in early onset PD. Striatal asymmetry also significantly correlated with age at onset as a continuous variable. Conclusion Early onset PD patients exhibited similar rates of decline of dopaminergic denervation compared to mid/late onset PD. These results are not supportive of a more benign disease in this subgroup. The more pronounced asymmetry in early onset PD may however signify a qualitatively different pattern of neurodegeneration compared to mid/late onset PD.

BACKGROUND A minimally invasive test for early detection and monitoring of Parkinson's disease (PD) is a highly unmet need for drug development and planning of patient care. Blood plasma represents an attractive source of biomarkers. MicroRNAs (miRNAs) are conserved noncoding RNA molecules that serve as posttranscriptional regulators of gene expression. As opposed to ubiquitously expressed miRNAs that control house-keeping processes, brain-enriched miRNAs regulate diverse aspects of neuron development and function. These include neuron-subtype specification, axonal growth, dendritic morphogenesis, and spine density. Backed by a large number of studies, we now know that the differential expression of neuron-enriched miRNAs leads to brain dysfunction. OBJECTIVES The aim was to identify subsets of brain-enriched miRNAs with diagnostic potential for familial and idiopathic PD as well as specify the molecular pathways deregulated in PD. METHODS Initially, brain-enriched miRNAs were selected based on literature review and validation studies in human tissues. Subsequently, real-time reverse transcription polymerase chain reaction was performed in the plasma of 100 healthy controls and 99 idiopathic and 53 genetic (26 alpha-synucleinA53T and 27 glucocerebrosidase) patients. Statistical and bioinformatics analyses were carried out to pinpoint the diagnostic biomarkers and deregulated pathways, respectively. RESULTS An explicit molecular fingerprint for each of the 3 PD cohorts was generated. Although the idiopathic PD fingerprint was different from that of genetic PD, the molecular pathways deregulated converged between all PD subtypes. CONCLUSIONS The study provides a group of brain-enriched miRNAs that may be used for the detection and differentiation of PD subtypes. It has also identified the molecular pathways deregulated in PD. © 2019 International Parkinson and Movement Disorder Society.

Introduction The aim of this study is to investigate the association between environmental factors (smoking, coffee, pesticide exposure) and Parkinson's disease (PD) subtypes (early-onset, mid-and-late onset, familial and sporadic) in the Greek population. Methods The Hellenic Biobank of PD recorded information of PD cases and controls from two centers in Greece during 2006–2017. Patients with the A53T mutation in SNCA or GBA mutations were excluded. Associations of environmental factors with PD overall (and PD subtypes) versus controls were explored with logistic regression models adjusting for age, gender and each environmental factor. Results 686 patients and 356 controls were included. Smoking was associated with a reduced risk of PD overall (OR 0.48, 95% CI 0.35–0.67), mid-and-late onset (0.46, 0.32–0.66), familial (0.53, 0.34–0.83) and sporadic (0.46, 0.32–0.65), but not early-onset PD. There was an inverse linear association with pack-years of smoking, except for early-onset PD. Early-onset PD was the only PD subtype inversely associated with coffee consumption when dichotomously treated. Compared to never-coffee drinkers, only those at the upper tertile had lower odds for PD overall (0.52, 0.29–0.91), early-onset (0.16, 0.05–0.53) and familial PD (0.36, 0.17–0.75). No associations were found between pesticides and PD. Conclusions Our study shows that the well-known negative association of smoking with PD occurs across all PD subtypes in the Greek population, apart from early-onset PD. Early-onset PD was also most strongly inversely associated with coffee consumption, highlighting a potential distinct underlying physiopathology in this PD subset that may involve specific gene-environment interactions.

Background: Spontaneous intracranial hypotension (SIH) is a rare syndrome characterized by heterogeneity of presentation and prognosis, which can occasionally result in serious complications, such as the formation of subdural hematoma (SDH). This case series aims to emphasize that SIH remains a diagnostic and therapeutic challenge; it can present with a far broad clinical spectrum of symptoms, can lead to SDH and if conservative treatment fails, an epidural blood patch (EBP) is a viable treatment option. Although the exact aetiology of SIH is not known, it is believed to be due to cerebrospinal fluid (CBF) leak or a low CBF pressure. Case report: Three patients (two males and one female) with age ranging between 38-53 years old who presented with complaints not only of an orthostatic headache, but with a variety of symptoms of SIH, including the formation of two SDHs in one of them, were included in this series. These patients did not respond to conservative management and subsequently, given the clinical and radiological evidence of SIH, were referred to the Anaesthesia Department for an EBP. The exact site of the CSF leak was identified with imaging modalities, including magnetic resonance imaging (MRI) of the brain and spinal cord, prior to the EBP. All three patients were subjected to an EBP with an 18-gauge epidural needle placed into the middle epidural compartment at the T12–L3 level. A total of between 30–43 mL of autologous blood was collected from the patients’ left basilic vein and was injected into the epidural space under strict aseptic conditions. Two lumbar (L1–L2, L2–L3) and one thoracic (T11–T12) EBPs were performed on the three patients. All patients reported complete resolution of symptoms following the EBPs, while MRI imaging improved substantially. Discussion: This report describes three cases of SIH with CSF leak originating from the cervical, the thoracic and the lumbar level. The EBP restored CSF volume and relieved the patients' persistent symptoms. MRI helps in showing indirect signs of low volume of CSF, though it may not be possible to find the actual site of leak. In conclusion, EBP is a well-accepted and beneficial treatment modality for SIH when conventional measures fail.

Background G209A SNCA mutation carriers represent an important group of genetic PD. We describe motor and nonmotor features of G209A SNCA mutation carriers. Methods Longitudinal clinical assessments over 2 years were collected in 22 symptomatic and 8 asymptomatic G209A SNCA mutation carriers. Motor and nonmotor rating scales were administered. Correlations were performed between clinical variables and disease duration or age. Penetrance was calculated using Kaplan-Meier survival curves. Results Asymptomatic carriers did not manifest clear premotor symptoms, but symptomatic carriers often reported that olfactory dysfunction and rapid eye movement sleep behavior disorder preceded motor symptoms. Prominent motor decline and deterioration of autonomic and cognitive function occurred at follow-up; such nonmotor features correlated with disease duration, but not age. Disease penetrance was estimated at around 90%. Conclusions This study may help to inform clinical trials and provide the basis for studies of disease modifiers in genetic synucleinopathy cohorts. © 2016 International Parkinson and Movement Disorder Society

Background Reduced expression of lysosomal-associated membrane protein 2a and heatshock-cognate 70 proteins, involved in chaperone-mediated autophagy and of glucocerebrosidase, is reported in PD brains. The aim of this study was to identify systemic alterations in lysosomal-associated membrane protein 2a, heatshock cognate-70, and glucocerebrosidase levels/activity in peripheral blood mononuclear cells from PD patients. Methods Protein/mRNA levels were assessed in PD patients from genetically undetermined background, alpha-synuclein (G209A/A53T), or glucocerebrosidase mutation carriers and age-/sex-matched controls. Results Heatshock cognate 70 protein levels were reduced in all PD groups, whereas its mRNA levels were decreased only in the genetically undetermined group. Glucocerebrosidase protein levels were decreased only in the genetic PD groups, whereas increased mRNA levels and decreased activity were detected only in the glucocerebrosidase mutation group. Conclusions Reduced heatshock cognate-70 levels are suggestive of an apparent systemic chaperone-mediated autophagy dysfunction irrespective of genetic background. Glucocerebrosidase activity may serve as a screening tool to identify glucocerebrosidase mutation carriers with PD. © 2015 International Parkinson and Movement Disorder Society

Transcriptome analysis has identified a plethora of long non-coding RNAs (lncRNAs) expressed in the human brain and associated with neurological diseases. However, whether lncRNAs expression levels correlate with Parkinson’s disease (PD) pathogenesis remains unknown. Herein, we show that a number of lncRNA genes encompassing transcriptional units in close proximity to PD-linked protein-coding genes, including SNCA, LRRK2, PINK1, DJ-1, UCH-L1, MAPT and GBA1, are expressed in human dopaminergic cells and post-mortem material, such as cortex, Substantia Nigra and cerebellum. Interestingly, these lncRNAs are upregulated during neuronal differentiation of SH-SY5Y cells and of dopaminergic neurons generated from human fibroblast-derived induced pluripotent stem cells. Importantly, six lncRNAs are found under-expressed in the nigra and three in the cerebellum of PD patients compared to controls. Simultaneously, SNCA mRNA levels are increased in the nigra, while LRRK2 and PINK1 mRNA levels are decreased both in the nigra and the cerebellum of PD subjects compared to controls, indicating a possible correlation between the expression profile of the respective lncRNAs with their adjacent coding genes. Interestingly, all dysregulated lncRNAs are also detected in human peripheral blood mononuclear cells and four of them in exosomes derived from human cerebrospinal fluid, providing initial evidence for their potential use as diagnostic tools for PD. Our data raise the intriguing possibility that these lncRNAs may be involved in disease pathogenesis by regulating their neighboring PD-associated genes and may thus represent novel targets for the diagnosis and/or treatment of PD or related diseases.

The p.A53T point mutation in the α-synuclein gene (SNCA) is a rare but highly relevant cause of autosomal dominant Parkinson's disease (PD).The objective of this study was to assess striatal dopaminergic denervation in a cohort of symptomatic carriers of the p.A53T SNCA mutation as compared to PD patients.Data from the Parkinson's Progression Markers Initiative database of 11 symptomatic p.A53T SNCA mutation carriers who underwent 123I-FP-CIT SPECT [(123) I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane single photon emission computed tomography] imaging at our site were compared with those of 33 age-, sex-, and disease duration-matched PD patients.The p.A53T mutation carriers had significantly lower caudate nucleus binding ratio both contralaterally and ipsilaterally to the most affected side (P = .002 and P = .006) and a decreased contralateral caudate/putamen signal ratio (P = .007) as compared to PD. A similar degree of striatal asymmetry was observed in both subgroups. No correlation between scores in neuropsychological tests and caudate nucleus dopaminergic denervation could be demonstrated.PD patients harboring the p.A53T SNCA mutation show evidence of a more severe nigrostriatal denervation, especially evident in the caudate nucleus. The lack of significant differences in the putaminal binding ratios may reflect a floor effect or a true preferential targeting of the caudate terminals in p.A53T SNCA-associated PD. © 2018 International Parkinson and Movement Disorder Society.