BACKGROUND:Although subtle differences in cortico-striato-thalamo-cortical circuit structure and function are critical to the current understanding of the neurocircuitry in obsessive-compulsive disorder (OCD), emerging evidence suggests that the cerebellum may also be involved. However, much of this evidence comes from studies with small samples and notable methodological heterogeneity. METHODS:We conducted a mega-analysis of individual-participant data on cerebellar subregional volumes, comparing individuals with OCD and healthy controls (HCs) from the ENIGMA-OCD Working Group. Three-dimensional T1-weighted volumetric structural brain magnetic resonance imaging (MRI) scans from 1954 individuals with OCD and 2091 HCs across 22 sites (40 datasets) were processed using the ACAPULCO (Automatic Cerebellum Anatomical parcellation using U-Net Locally Constrained Optimization) pipeline to extract cerebellar parcellations. We harmonized the volume measures across sites using the ComBat algorithm. Multiple linear regression models were fitted to estimate group differences separately within the pediatric (<12 years), adolescent (12-17 years), and adult (from 18 years) samples, adjusting for age, gender, and intracranial volume. RESULTS:In adults with OCD (vs. HCs), we found significantly smaller volumes of the corpus medullare (d = -0.093, false discovery rate (FDR)-corrected p = .036), left VIIb (d = -0.085, pFDR = .039) and right VIIb (d = -0.091, pFDR = .036). None of the comparisons between children or adolescents with OCD versus HCs remained statistically significant after FDR correction. In all 3 age groups, cerebellar (subregional) volumes were significantly moderated by medication status. CONCLUSIONS:We report novel findings implicating specific cerebellar subregions across developmental stages of OCD and the key impact of medication status. Additional research on the functional significance of these findings may offer new translational leads.

Parkinson’s disease (PD) is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, only few studies assessed these biological frameworks in large patient samples across disease stages. Analyzing the largest imaging cohort in PD to date (n = 3,096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities, and gene expression. We found widespread cortical and subcortical atrophy in PD to be associated with advancing disease stage, longer time since diagnosis, and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in PD and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex, and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in PD. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in PD across disease stages and within individual patients are influenced by both network spread and local vulnerability.

Parkinson's disease is the second most common neurodegenerative disease. Despite this, there are no robust biomarkers to predict progression, and understanding of disease mechanisms is limited. We used the Subtype and Stage Inference algorithm to characterize Parkinson's disease heterogeneity in terms of spatiotemporal subtypes of macroscopic atrophy detectable on T1-weighted MRI-a successful approach used in other neurodegenerative diseases. We trained the model on covariate-adjusted cortical thicknesses and subcortical volumes from the largest known T1-weighted MRI dataset in Parkinson's disease, Enhancing Neuroimaging through Meta-Analysis consortium Parkinson's Disease dataset (n = 1100 cases). We tested the model by analyzing clinical progression over up to 9 years in openly-available data from people with Parkinson's disease from the Parkinson's Progression Markers Initiative (n = 584 cases). Under cross-validation, our analysis supported three spatiotemporal atrophy subtypes, named for the location of the earliest affected regions as: 'Subcortical' (n = 359, 33%), 'Limbic' (n = 237, 22%) and 'Cortical' (n = 187, 17%). A fourth subgroup having sub-threshold/no atrophy was named 'Sub-threshold atrophy' (n = 317, 29%). Statistical differences in clinical scores existed between the no-atrophy subgroup and the atrophy subtypes, but not among the atrophy subtypes. This suggests that the prime T1-weighted MRI delineator of clinical differences in Parkinson's disease is atrophy severity, rather than atrophy location. Future work on unravelling the biological and clinical heterogeneity of Parkinson's disease should leverage more sensitive neuroimaging modalities and multimodal data.

Fluctuations often complicate the course of Parkinson’s disease (PD). The third-generation catechol-O-methyltransferase inhibitor, opicapone, is safe and effective in patients with PD motor fluctuations, whether long-standing or earlier onset. Real-world data are needed to identify the most appropriate candidates for initiating and sustaining therapy with opicapone. To evaluate the long-term outcomes and identify predictors for safer and prolonged use of opicapone. This real-world, longitudinal, multicenter, retrospective study collected data on the demographics, medical history, motor subtype, motor severity, cognitive and psychiatric disorders at baseline when opicapone was introduced as add-on therapy and at the last follow-up. Discontinuation rates and main causes were recorded. Clinical features of patients who continued/discontinued were compared to identify predictors for drug discontinuation and define successful long-term outcomes. Of the 178 enrolled patients, 85

The integration of pharmacogenetics into personalized medicine enables the optimization of drug selection and dosage, maximizing therapeutic benefits while minimizing the risk of adverse drug reactions. The association between APOE alleles and ARIA, a known adverse reaction in Alzheimer’s disease patients treated with anti-amyloid monoclonal antibodies, has led to the inclusion of APOE genotyping among conventional pharmacogenetic tests. Given the dual role of APOE alleles, the widespread implementation of this genetic test requires caution and should be accompanied by appropriate genetic counselling. APOE genotyping is uniquely positioned at the intersection of pharmacogenetics and germline testing: it provides insight not only into drug safety (specifically the risk of Amyloid-Related Imaging Abnormalities) but also into familial risk for developing Alzheimer’s disease. Carriers of risk alleles, especially homozygotes, face the highest risk and require close monitoring. While APOE genotyping can inform treatment decisions, it also raises ethical concerns due to the broader implications of disclosing genetic risk information for neurodegenerative diseases. Identifying a high-risk APOE genotype in a patient substantially impacts family members. Therefore, patients considered for treatment with anti-amyloid monoclonal antibodies should receive comprehensive pre- and post-test genetic counseling that goes beyond traditional standards, as currently provided for other peculiar tests. Such counseling ensures that patients are adequately informed about potential outcomes, psychological impacts, and familial implications. It also supports ethical decision-making and facilitates truly informed consent, helping to prevent deterministic or overly simplistic interpretations of genetic risk.

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behavior disorder (iRBD), 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD, an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD.

Background/Objectives: Pausing is a multifaceted phenomenon relevant to motor and cognitive disorders, particularly Parkinson’s Disease (PD). Thus, examining pauses as a metric for linguistic planning and motor speech difficulties in PD patients has gained significant attention. Here, we examined the production of silent and filled pauses (indexing difficulties at various linguistic processing levels) during narrative tasks to investigate the interplay between pausing behavior and informativeness/productivity measures. Methods: Individuals’ pausing patterns during narratives were analyzed relative to their syntactic context (within and between sentences expressing motor and non-motor related content), in 29 patients in the mild-to-moderate stage of PD, and 29 age-matched healthy speakers. The interaction between communicative metrics (informativeness and productivity), motor symptoms, cognitive capabilities, and pausing behavior was explored to characterize the mechanisms underlying pause production and its influence on discourse content. Results: PD patients’ pausing profile was characterized by an overall reduced number of pauses, longer silent pauses and fewer/shorter filled pauses, particularly before words that extend or specify the semantic content of sentences. Contrary to what was observed in healthy speakers, both the duration of silent pauses and the total number and duration of filled pauses could explain a significant proportion of variance in informativeness measures. Silent pause duration significantly correlated with measures of lexical access, indicating that cognitive processes influence pause production, while motor speech and cognitive challenges may also interact. Conclusions: Current results have significant implications for understanding discourse difficulties linked to PD and for formulating intervention strategies to improve communication efficacy.

Parkinson’s disease (PD) is associated with extensive structural brain changes. Recent work has proposed that the spatial pattern of disease pathology is shaped by both network spread and local vulnerability. However, only few studies assessed these biological frameworks in large patient samples across disease stages. Analyzing the largest imaging cohort in PD to date (N = 3,096 patients), we investigated the roles of network architecture and local brain features by relating regional abnormality maps to normative profiles of connectivity, intrinsic networks, cytoarchitectonics, neurotransmitter receptor densities, and gene expression. We found widespread cortical and subcortical atrophy in PD to be associated with advancing disease stage, longer time since diagnosis, and poorer global cognition. Structural brain connectivity best explained cortical atrophy patterns in PD and across disease stages. These patterns were robust among individual patients. The precuneus, lateral temporal cortex, and amygdala were identified as likely network-based epicentres, with high convergence across disease stages. Individual epicentres varied significantly among patients, yet they consistently localized to the default mode and limbic networks. Furthermore, we showed that regional overexpression of genes implicated in synaptic structure and signalling conferred increased susceptibility to brain atrophy in PD. In summary, this study demonstrates in a well-powered sample that structural brain abnormalities in PD across disease stages and within individual patients are influenced by both network spread and local vulnerability.

BACKGROUND:The outcome of levodopa/carbidopa intestinal gel (LCIG) in Parkinson's disease carriers of GBA1 mutations (GBA-PD) remains uncertain. OBJECTIVE:To evaluate the safety and efficacy of LCIG in a large PD cohort, focusing on GBA1 variants. METHODS:This multicenter, retrospective, longitudinal "real-world" study included consecutive patients with advanced PD treated with LCIG at 31 Italian centers; data were collected at baseline, 1-, 5-year, and last-available follow-up. RESULTS:Data from 512 PD patients (59% male, mean age and disease duration at LCIG initiation 67.0 ± 8.0 and 12.9 ± 5.0 years, respectively) were analyzed. GBA1 genotyping was available for 306 patients (60%), of whom 40 (13%) had GBA1 mutations or risk variants. Mean follow-up on LCIG was 3.9 ± 2.9 years; 5-year follow-up data were available for 159 subjects. At baseline, GBA-PD had a younger age, shorter PD duration, worse cognition, and more hallucinations than noncarriers. At 1- and 5-year follow-up, LCIG improved motor and non-motor symptoms, OFF-time, and dyskinesias in the entire population. In GBA-PD, MDS-UPDRS parts I, II, and III scores did not change, while part IV score improved significantly less than in noncarriers; cognition and orthostatic hypotension symptoms worsened more rapidly. Multivariate analysis of predictors for adverse events and LCIG discontinuation found no significant contribution from GBA1 mutation status. CONCLUSIONS:GBA1 status does not increase the risk of adverse events or LCIG discontinuation. LCIG is a safe option for advanced GBA-PD, even in patients with cognitive impairment at baseline. However, GBA-PD experiences lower efficacy on motor disability and complications and faster cognitive decline than noncarriers.

Alzheimer's disease is a disabling neurodegenerative disorder for which no effective treatment currently exists. To predict the diagnosis of Alzheimer's disease could be crucial for patients' outcome, but current Alzheimer's disease biomarkers are invasive, time consuming or expensive. Thus, developing MRI-based computational methods for Alzheimer's disease early diagnosis would be essential to narrow down the phenotypic measures predictive of cognitive decline. Amnestic mild cognitive impairment (aMCI) is associated with higher risk for Alzheimer's disease, and here, we aimed to identify MRI-based quantitative rules to predict aMCI to possible Alzheimer's disease conversion, applying different machine learning algorithms sequentially. At baseline, T1-weighted brain images were collected for 104 aMCI patients and processed to obtain 146 volumetric measures of cerebral grey matter regions [regions of interest (ROIs)]. One year later, patients were classified as converters (aMCI-c = 32) or non-converters, i.e. clinically and neuropsychologically stable (aMCI-s = 72) based on cognitive performance. Feature selection was performed by random forest (RF), and the identified seven ROIs volumetric data were used to implement support vector machine (SVM) and decision tree (DT) classification algorithms. Both SVM and DT reached an average accuracy of 86% in identifying aMCI-c and aMCI-s. DT found a critical threshold volume of the right entorhinal cortex (EC-r) as the first feature for differentiating aMCI-c/aMCI-s. Almost all aMCI-c had an EC-r volume <1286 mm3, while more than half of the aMCI-s patients had a volume above the identified threshold for this structure. Other key regions for the classification between aMCI-c/aMCI-s were the left lateral occipital (LOC-l), the middle temporal gyrus and the temporal pole cortices. Our study reinforces previous evidence suggesting that the morphometry of the EC-r and LOC-l best predicts aMCI to Alzheimer's disease conversion. Further investigations are needed prior to deeming our findings as a broadly applicable predictive framework. However, here, a first indication was derived for volumetric thresholds that, being easy to obtain, may assist in early identification of Alzheimer's disease in clinical practice, thus contributing to establishing MRI as a useful non-invasive prognostic instrument for dementia onset.

Aim Acromegaly is a rare chronic disease, caused by the over-secretion of growth hormone (GH), that creates a pro-inflammatory state, but the exact mechanisms by which GH or insulin-like growth factor 1 (IGF-1) act on inflammatory cells are not fully understood. Aim of the study was to evaluate Interleukin-33 (IL33) and the skin perfusion of hands in patients with acromegaly (AP) and healthy controls (HC). Methods IL33 have been assessed in 40 AP and 40 HC. IL 33 was determined and skin perfusion of hands was assessed by laser speckle contrast analysis (LASCA) in both populations. Results IL33 was significantly higher in AP compared to HC [45.72 pg/ml (IQR 28.74–60.86) vs 14 pg/ml (IQR 6.5535); p < 0.05]. At LASCA, peripheral blood perfusion (PBP) was significantly lower in AP compared to HC [53.39 pU (IQR 40.94–65.44) vs 87 pU (IQR 80–98) p < 0.001]. The median values of ROI1, ROI2 and ROI3 were significantly lower in AP compared to HC [97.32 pU (IQR 50.89–121.69) vs 131 pU (IQR 108–135); p < 0.001], [58.68 pU (IQR 37.72–84.92) vs 83 pU (IQR 70–89), p < 0.05] and HC [52.16 (34.47–73.78) vs 85 (78–98), p < 0.001], respectively. The proximal–distal gradient (PDG) was observed in 18 of 40 (45%) AP. Conclusion Serum IL33 is higher in AP compared to HC; conversely a reduction of PBP of hands was present in AP compared to HC, probably due to endothelial dysfunction, strictly dependent on acromegaly and are not influenced by the choice of treatment.

Background: Systemic sclerosis (SSc) is characterized by progressive fibrosis and microvascular dysfunction that involves multiple organ systems, including kidneys. Kidney involvement, beyond the scleroderma renal crisis (SRC), is often asymptomatic and underdiagnosed, associated with subclinical renal vasculopathy characterized by abnormalities in renal microcirculation and mild changes of glomerular filtration rate (GFR). Kidney involvement is rare in isolated Sjögren's syndrome (SS) and reported between 5% and 14% in european patients and approximately 30% in asian patients. Objectives: The aim of the study was to assess renal involvement in SSc and SS and follow its progression over a three-year period. Methods: Patients with SSc (2013 EULAR criteria) and isolated SS (2016 ACR/EULAR criteria) were consecutively enrolled. Demographic and clinical characteristics at baseline (T0) were gathered including sex, age, body mass index (BMI), history of essential hypertension and diabetes, serum creatinine, and estimated GFR calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Exclusion criteria were presence of SRC, atherosclerosis renal artery stenosis and other secondary causes of hypertension, glomerulonephritis, urinary tract obstruction, urinary infections, heart failure, pulmonary arterial hypertension, malignancies. All patients were followed for three years (T1) with renal function assessment. Group comparisons were made using the Student's t-test or Mann-Whitney test for continuous variables and the chi-square test or Fisher's exact test for categorical variables. A significance level of p<0.05 was considered. Results: A total of 248 patients were enrolled, 127 SSc and 121 SS patients. Their features at baseline (T0) are summarized in Table 1. Table 2 summarizes the comparative analysis of renal function between SSc and SS patients at baseline and after 3 years. SS patients had similar median serum creatinine both at T0 and at T1 [0.78 mg/dl (IQR 0.68;0.84) vs 0.78 mg/dl (IQR 0.7;0.84), p>0.05], but a higher eGFR at T0 than at T1 [87.9 ml/min (IQR 72.6;102.3) vs 86.4 ml/min (IQR 72.7;96.7), p<0.05], with a variation of −2.1 ml/min (IQR −11.4;1.1). SSc patients had a statistically significant lower median serum creatinine at T0 than at T1 [0.7 mg/dl (IQR 0.6;0.8) vs 0.8 mg/dl (IQR 0.7;0.9), p<0.001], with a variation of 0.1 mg/dl (IQR 0;0.2), and a statistically significant higher median eGFR at T0 than at T1 [97 ml/min (IQR 85;108.5) vs 91 ml/min (IQR 73;103), p<0.001], with a variation of −3 ml/min (IQR −18;−1). In both SSc and SS eGFR median variation was statistically significant higher in patients affected by systemic arterial hypertension compared to those without [−12.2 ml/min (IQR −16.32;5.42) vs −1.8 ml/min (IQR −3;0.4), p<0.01 for SS patients and −18 ml/min (IQR −26; −12) vs −2 ml/min (IQR −7;2.25), p<0.001 for SSc].SSc patients had a significantly higher variation compared to SS patients both for median serum creatinine [0.1 mg/dl (IQR 0;0.2) vs 0 mg/dl (IQR −0.1;0.1), p<0.05] and median eGFR [−3 ml/min (IQR −18;−1) vs −2.1 ml/min (IQR −11.4;1.1), p<0.05]. Conclusion: In both SSc and SS patients, renal involvement exhibited a subclinical pattern (eGFR > 60 ml/min). This preliminary study also highlights slight differences in renal involvement and its progression between the two groups considered. In SSc patients, creatinine levels at T0 are, on average, lower than in pSS patients possibly linked to their reduced muscle mass. Over time, SSc patients tend to show a tendency toward eGFR reduction, for the continuous microvascular damage leading to chronic hypoxic-ischemic injury. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson's disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4-5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

OBJECTIVE: In this study, we aimed to evaluate the kidney involvement as-sessed by estimated glomerular filtration rate (eGFR), the associations with specific clinical disease variables and laboratory findings, and the predictive role of eGFR on clinical outcomes of patients admitted with COVID-19 in Internal Medicine ward in the first wave. PATIENTS AND METHODS: Clinical data of 162 consecutive patients hospitalized in the University Hospital Policlinico Umberto I in Rome, Italy, between December 2020 to May 2021 were collected and retrospectively analyzed. RESULTS: The median eGFR was significantly lower in patients with worse outcomes than in patients with favorable outcomes [56.64 ml/min/1.73 m2 (IQR 32.27-89.73) vs. 83.39 ml/min/1.73 m2 (IQR 69.59-97.08), p<0.001]. Patients with eGFR < 60 ml/ min/1.73 m(2) (n=38) were significantly older com-pared to patients with normal eGFR [82 years (IQR 74-90) vs. 61 years (IQR 53-74), p<0.001] and they had fever less frequently [39.5% vs. 64.2%, p<0.01]. Kaplan-Meier curves demonstrated that over-all survival was significantly shorter in patients with eGFR < 60 ml/min/1.73 m(2) (p<0.001). In mul-tivariate analysis, only eGFR < 60 ml/min/1.73 m2 [HR=2.915 (95% CI=1.110-7.659), p<0.05] and plate-let to lymphocyte ratio [HR=1.004 (95% CI=1.002-1.007), p<0.01] showed a significant predictive val-ue for death or transfer to intensive care unit (ICU). CONCLUSIONS: Kidney involvement on ad-mission was an independent predictor for death or transfer to ICU among hospitalized COVID-19 patients. The presence of chronic kidney dis-ease could be regarded as a relevant factor in risk stratification for COVID-19.

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by immune system dysregulation, endothelial dysfunction and fibrosis of skin and internal organs. Interstitial lung disease (ILD) is common in SSc and about 80% of patients will develop ILD during the disease course [1]. Although most patients have a stable or slowly progressive disease, showing a slow decline in lung function or a minimal increase in the extent of pulmonary fibrosis by high resolution computed tomography (HRCT), 25-30% of them will ultimately progress to respiratory failure or death [2]. Of the SSc-related deaths, 35% were attributed to ILD [3]. The underlying pathophysiologic mechanisms of SSc-ILD is still not completely understood [2]. The pathogenesis of SSc-ILD is initially characterized by an injury to alveolar epithelial and vascular endothelial cells which promotes the recruitment of inflammatory cells and the production of profibrotic mediators, in the attempt to repair the damage [4,5]. In this early inflammatory phase, profibrotic type 2 (Th2) cytokines, such as IL-4, IL-5, IL-13, play a key role [6,7]. Objectives Aim of the study was to evaluate the Th2 cytokines serum levels in SSc-ILD. Methods Serum levels of IL-4, IL-5, IL-11, IL-13, IL-21, IL-31 and CXCL-13 were measured by Bio-Plex Multiplex Immunoassays in 60 SSc patients and 20 healthy controls (HC). Pulmonary function tests with diffusion lung capacity for carbon monoxide (DLco) and high resolution computed tomography (HRCT) were performed in SSc patients. ILD is defined as fibrotic changes (ground glass, reticular and honeycombing), assessed by Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER) software, affecting at least 10% of the lungs. Results Serum levels of Th2 cytokines were higher in SSc patients than HC. A linear correlation was observed between ground glass and IL-13 (r=0.342, p<0.01), IL-21 (r=0.345, p<0.01), IL-31 (r=0.473, p<0.001), IL-4 (r=0.863, p<0.001), IL-5 (r=0.249, p<0.05) and peripheral blood eosinophils (r=0.463, p<0.001). We found a negative correlation between DLco and IL-4 (r=-0.511, p<0.001) and peripheral blood eosinophils (r=-0.446, p<0.001). In the logistic regression analysis, IL-4 is associated with DLco≤ 60% of the predicted [OR 1.039 (CI 95%: 1.015-1.064), p<0.001], mRSS [OR 1.138 (CI 95%: 1.023-1.266), p<0.05] and IL-4 [OR 1.017 (CI 95%: 1-1.034), p<0.05] were associated with ILD. Conclusion Th2 cytokines might have a key role in early phase of ILD in SSc patients. Future large studies are needed to confirm these findings. References [1]Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390:1685-99. https://doi.org/10.1016/S0140-6736(17)30933-9. [2]Hoffmann-Vold AM, Allanore Y, Alves M, et al. EUSTAR collaborators. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. 2021;80:219-27. https://doi.org/10.1136/annrheumdis-2020-217455. [3]Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69:1809-15. https://doi.org/10.1136/ard.2009.114264. [4]Kase K, Watanabe S, Saeki S, et al. Fractional analysis of bronchoalveolar lavage in systemic sclerosis-associated interstitial lung disease. J Thorac Dis 2021;13:4146-55. https://doi.org/10.21037/jtd-20-2596. [5]Distler O, Assassi S, Cottin V, et al. Predictors of progression in systemic sclerosis patients with interstitial lung disease. Eur Respir J. 2020;55:1902026. https://doi.org/10.1183/13993003.02026-2019. [6]Perelas A, Silver RM, Arrossi AV, Highland KB. Systemic sclerosis-associated interstitial lung disease. Lancet. Respir Med. 2020;8:304-20. https://doi.org/10.1016/S2213-2600(19)30480-1. [7]Volkmann ER, Tashkin DP. Treatment of Systemic Sclerosis-related Interstitial Lung Disease: A Review of Existing and Emerging Therapies. Ann Am Thorac Soc. 2016;13:2045-56. https://doi.org/10.1513/AnnalsATS.201606-426FR. Acknowledgements: NIL. Disclosure of Interests None Declared.

Objectives: The study aim was to evaluate the predictive role of the echocardiography-derived tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for pulmonary hypertension (PH) diagnosis and mortality in the European Scleroderma Trials and Research (EUSTAR) cohort. Methods: Eligible patients were systemic sclerosis (SSc) patients registered in the EUSTAR database with at least one visit recording TAPSE and sPAP data. Individual centres were required to provide TAPSE and sPAP data at 12 +/- 3 months before right heart catheterization (RHC). Logistic regression analysis was applied to analyse the predictive ability of TAPSE/sPAP ratio for PH diagnosis. Cox regression analysis was performed to evaluate TAPSE/sPAP ratio as a predictive factor for all-cause mortality. Results: 2555 SSc patients met the inclusion criteria for this study with 355 SSc patients having available RHC data at baseline. PH was confirmed by RHC in 195 SSc patients (54.9%). TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.251 (95% CI 0.084-0.753), p < 0.05] and FVC/DLCO [OR 2.568 (95% CI 1.227-5.375), p < 0.05] were significantly associated with PH diagnosis. In logistic regression analysis with echocardiographic parameters at 12 +/- 3 months before RHC, TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.265 (95% CI 0.102-0.685), p < 0.01] and FVC/DLCO [OR 2.529 (95% CI 1.358-4.711), p < 0.01] were associated with PH diagnosis. In multivariate Cox regression analysis, TAPSE/sPAP ratio <= 0.32 mm/mmHg [HR 0.310 (0.164-0.585), p < 0.001] was the most significant predictive factor for death. Conclusions: TAPSE/sPAP ratio < 0.55 mm/mmHg is a predictive risk factor for PH. TAPSE/sPAP ratio <= 0.32 mm/mmHg is a predictive risk marker for all-cause mortality.

Introduction:the interplay between neuropsychological and communicative abilities in Parkinson's disease (PD) has been relatively overlooked, and it is not entirely understood which difficulties are consequent to impaired motor control, and which have a linguistic/cognitive basis. Here, we examined narrative discourse in PD using a multi-level analysis procedure considering sentence-level (productivity, lexical-grammatical processing) and discourse-level processes (narrative organization, informativeness), and partialling out patients' motor speech impairments. The interaction between cognitive (i.e. linguistic and executive) and communication abilities was also investigated.Methods:Twenty-nine PD subjects in the mild stage of the disease were compared to 29 matched healthy comparators (HC) on quantitative measures of narrative discourse derived from two picture description tasks. Multivariate (considering articulation rate and educational attainment as covariates) and univariate (with group membership as independent variable) analyses of variance were conducted on separate linguistic domains. The contribution of executive/linguistic abilities to PD's narrative performance was explored by multiple regression analyses on narrative measures significantly differentiating patients from HC.Results:significant reductions in patients were observed on measures of productivity (less well-formed words, shorter sentences) and informativeness (fewer conceptual units, less informative elements, lower number of details) and these alterations were explained by variations in linguistic abilities (action and object naming) rather than executive abilities. Articulation rate and educational attainment did not impact the observed reduced productivity and under-informativeness.Conclusion:referential narrative discourse is altered in PD, regardless of motor impairments in speech production. The observed reductions in productivity/informativeness aspects of narratives were related to naming abilities and in particular to verbs processing, consistently with the neurocognitive model of motor language coupling. Since narratives are amenable to recurrent and automated analysis for the identification of linguistic patterns potentially anticipating the development of PD and the onset of cognitive deterioration, discourse abilities should be quantitatively and repeatedly profiled in the disorder.