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The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding. This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023. Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD – autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive–compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001). Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease. Michael J Fox Foundation for Parkinson's Research.

Background There are limited data on the impact of imaging modality selection for the assessment of coronary artery disease (CAD) risk on downstream resource utilisation. This study sought to identify differences between patient populations in the US undergoing stress echocardiography, single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), positron emission tomography (PET) MPI, and coronary computed tomography angiography (cCTA) for the assessment of CAD risk, and associated physician referral patterns. Methods Claims and electronic health records data for 2.5 million US patients who received stress echocardiography, cCTA, SPECT MPI or PET MPI between January 2016 and March 2018, from the Decision Resources Group Real-World Evidence US Data Repository, were analysed. Patients were stratified into suspected and existing CAD cohorts, and further stratified by pre-test risk and presence and recency of interventions or acute cardiac events (within 1–2 years pre-index test). Linear and logistic regression were used to compare numeric and categorical variables. Results Physicians were more likely to refer patients to standalone SPECT MPI (77%) and stress echocardiography (18%) than PET MPI (3%) and cCTA (2%). Overall, 43% of physicians referred more than 90% of their patients to standalone SPECT MPI. Just 3%, 1% and 1% of physicians referred more than 90% of their patients to stress echocardiography, PET MPI or cCTA. At the aggregated imaging level, patients who underwent stress echocardiography or cCTA had similar comorbidity profiles. Comorbidity profiles were also similar for patients who underwent SPECT MPI and PET MPI. Conclusion Most patients underwent SPECT MPI at the index date, with very few undergoing PET MPI or cCTA. Patients who underwent cCTA at the index date were more likely to undergo additional imaging tests compared with those who underwent other imaging modalities. Further evidence is needed to understand factors influencing imaging test selection across patient populations.

Objective Reduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson’s disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson’s Progression Markers Initiative (PPMI) cohort. Methods We measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year‐3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome‐wide genotyping arrays, whole‐exome sequencing, whole‐genome sequencing, Sanger sequencing, and RNA‐sequencing. Results Fifty‐two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count‐corrected enzymatic activity. Members of the lower tertile had higher MDS‐Unified Parkinson’s Disease Rating Scale motor score in the “off” medication examination at year‐III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time. Interpretation GCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.

Adherens junctions are the primary cell-cell junction that maintains the integrity of the endothelium. Vascular leakage resulting from inflammation contributes to a variety of pathological conditions. This thesis investigates the role of protein kinase C-α (PKCα) phosphorylation of p120-catenin p120) on adherens junction stability and regulation of endothelial permeability during inflammation. Vascular endothelial cadherin (VEC) is the major structural protein comprising adherens junctions. VEC requires binding of p120 to maintain intact adherens junctions; the loss of bound p120 results in VEC internalization and disassembly of adherens junctions. PKCα, a serine/threonine kinase, phosphorylates p120 on S879. We found that phosphorylation of this site causes p120 to dissociate from VEC and results in increased endothelial permeability. p120 phosphorylated on S879 showed no colocalization with VEC, indicating that once p120 is phosphorylated on this site, it can no longer bind VEC. We created point mutations of p120 on S879, and expressed these mutants using a liposome-based cDNA transfection in endothelial cells and mouse lungs. The pro-inflammatory agents thrombin and LPS were used to stimulate increased permeability in endothelial cells, and similarly PAR-1 agonist peptide or LPS was used in mice. The phosphomimetic p120 (S879D) did not associate with VEC in endothelial cells, whereas the phosphodefective p120 (S879A) remained bound to VEC even after thrombin stimulation. Endothelial cells expressing phosphodefective p120 exhibited less interendothelial gap formation after thrombin stimulation, suggesting that expression of phosphodefective p120 protected against adherens junction disassembly. Mice expressing phosphodefective p120 showed less of an increase in lung vessel permeability and less edema formation following in vivo stimulation with PAR-1 agonist peptide as compared to mice expressing wild-type p120. This further confirms that phosphorylation of p120 on S879 by PKCα is a critical signaling mechanism involved in regulation of adherens junction stability and endothelial barrier function. We also created a peptide that blocked S879 phosphorylation in endothelial cells by competitively binding p120. Cells incubated with the blocking peptide showed significantly less monolayer disruption after thrombin stimulation, indicating that blocking S879 may be a potential therapeutic target used to block edema.

We describe the public release of \\(>2.3\\) petabytes of data from the FLAMINGO cosmological simulations. The suite consists of hydrodynamical simulations that include radiative cooling, star formation, stellar mass loss and the resulting chemical enrichment, supernova feedback, and two implementations of AGN feedback. Neutrinos are simulated explicitly using particles. Data products include snapshots, halo and galaxy catalogues, HEALPix all-sky lightcone maps, particle data for lightcone maps, and power spectra. The FLAMINGO set includes 22 hydrodynamical simulations. In addition, there are 16 gravity-only simulations, including the \\(10080^3\\) particles FLAMINGO-10k run, with initial conditions that match those of the corresponding hydrodynamical runs. The fiducial hydrodynamical simulations span three numerical resolutions that have each been calibrated to reproduce the present-day galaxy stellar mass function and gas fractions in low-redshift clusters. Other simulations systematically vary the galaxy stellar mass function, cluster gas fractions, cosmology (including neutrino masses), and/or the nature of dark matter, in volumes of 1Gpc\\(^3\\). The release includes hitherto unpublished simulations that use extra dark matter particles. While we provide a facility for downloading complete simulation outputs, we recognise that for many users this will not be possible due to limited local storage or network bandwidth. We implement a web service that enables users to explore available outputs and selectively download datasets or parts of datasets.