Additional file 1 of Time course of neuroinflammation after human stroke – a pilot study using co-registered PET and MRI

Additional file 1: Supplemental Table 1. Patient Clinical Summary including Age, Vascular Territory, NIHSS on admission, and Time points of combined MRI and PET scans. Supplemental Table 2. Regional Standardized Uptake Value (SUV) values in different brain regions at session 1 and session 2. Supplemental Table 3. Regional Standardized Uptake Value (SUV) values in different brain regions at session 2. Supplemental Table 4. Patient data including specific activity and mass of [11C]PBR28 administered and Standardized Uptake Value (SUV) time

Functional roles of Rab interactors of LRRK2.

The heatmap shows the functional groups that included the Rab proteins presented in the LRRK2int. Blue squares represent the presence of a certain Rab interactor in a given functional group identified in the functional enrichment analysis for the general LRRK2int.</p

Tissue specific LRRK2_ints.

A) The network graphs represent the LRRK2ints with nodes color-coded for DEA ranks and dimension-coded based on the co-expression coefficients. The darker the colour, the higher the expression level of the interactor in a given tissue. The larger the node, the higher the co-expression coefficient calculated between LRRK2 and the interactor in a given tissue. B) For each of the 4 brain regions the LRRK2 interactors with a DEA rank>8 were extracted and the distribution of the DEA ranks was visualized. C) For each of the 4 brain regions the LRRK2 interactors with a co-expression coefficient≥0.7 were extracted and the distribution of the co-expression coefficients was visualized. D) Functional enrichment results for the tissue-specific LRRK2 interactors; GO:BPs were filtered for term size ≤80 to keep only specific terms and GO:BPs were grouped based on semantic similarity. The semantic class is reported on the x-axis, the p-value of the most significant term in the semantic class is reported on the y-axis, the dimension of the circle represent the number of GO:BPs terms grouped in the semantic class. For simplicity, the semantic classes containing only 1 GO:BP term were omitted from the graph.</p

Datasheet1_Validation of a rapid remote digital test for impaired cognition using clinical dementia rating and mini-mental state examination: An observational research study.docx

BackgroundThe Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE) are useful screening tools for mild cognitive impairment (MCI). However, these tests require qualified in-person supervision and the CDR can take up to 60 min to complete. We developed a digital cognitive screening test (M-CogScore) that can be completed remotely in under 5 min without supervision. We set out to validate M-CogScore in head-to-head comparisons with CDR and MMSE.MethodsTo ascertain the validity of the M-CogScore, we enrolled participants as healthy controls or impaired cognition, matched for age, sex, and education. Participants completed the 30-item paper MMSE Second Edition Standard Version (MMSE-2), paper CDR, and smartphone-based M-CogScore. The digital M-CogScore test is based on time-normalised scores from smartphone-adapted Stroop (M-Stroop), digit-symbols (M-Symbols), and delayed recall tests (M-Memory). We used Spearman's correlation coefficient to determine the convergent validity between M-CogScore and the 30-item MMSE-2, and non-parametric tests to determine its discriminative validity with a CDR label of normal (CDR 0) or impaired cognition (CDR 0.5 or 1). M-CogScore was further compared to MMSE-2 using area under the receiver operating characteristic curves (AUC) with corresponding optimal cut-offs.Results72 participants completed all three tests. The M-CogScore correlated with both MMSE-2 (rho = 0.54, p ConclusionDigital screening tests such as M-CogScore are desirable to aid in rapid and remote clinical cognitive evaluations. M-CogScore was significantly correlated with established cognitive tests, including CDR and MMSE-2. M-CogScore can be taken remotely without supervision, is automatically scored, has less of a ceiling effect than the MMSE-2, and takes significantly less time to complete.</p

Image_3.TIF

The deglycase and chaperone protein DJ-1 is pivotal for cellular oxidative stress responses and mitochondrial quality control. Mutations in PARK7, encoding DJ-1, are associated with early-onset familial Parkinson’s disease and lead to pathological oxidative stress and/or disrupted protein degradation by the proteasome. The aim of this study was to gain insights into the pathogenic mechanisms of selected DJ-1 missense mutations, by characterizing protein–protein interactions, core parameters of mitochondrial function, quality control regulation via autophagy, and cellular death following dopamine accumulation. We report that the DJ-1M26I mutant influences DJ-1 interactions with SUMO-1, in turn enhancing removal of mitochondria and conferring increased cellular susceptibility to dopamine toxicity. By contrast, the DJ-1D149A mutant does not influence mitophagy, but instead impairs Ca2+ dynamics and free radical homeostasis by disrupting DJ-1 interactions with a mitochondrial accessory protein known as DJ-1-binding protein (DJBP/EFCAB6). Thus, individual DJ-1 mutations have different effects on mitochondrial function and quality control, implying mutation-specific pathomechanisms converging on impaired mitochondrial homeostasis.</p

Co-expression analysis on the LRRK2_int.

A) Pair-wise Tukey’s test was performed to compare the co-expression coefficients (interactors vs LRRK2) across different tissues. Tissues were ranked according to the results. The bar graph shows that putamen, nucleus accumbens, caudate and hypothalamus are tissues with the highest ranks. Liver presents a rank of 0, meaning the co-expression coefficients of LRRK2 interactors are the lowest in comparison with any other tissues analysed. B) The heatmap was generated from the coefficient matrix derived from the co-expression analysis (Heatmap_Co-ex). Darker colour represents higher co-expression coefficient. The horizonal dendrogram of Heatmap_Co-ex was extracted as Den_Co-ex1, which shows the hierarchical clustering of tissues in which the LRRK2 interactors exhibited similar co-expression patterns with LRRK2. The vertical dendrogram of Heatmap_Co-ex was extracted as Den_Co-ex2, which shows the hierarchical clustering of interactors based on the similarity of their co-expression figures with LRRK2 across different tissues. Den_Co-ex2 was cut to generate 6 clusters of LRRK2 interactors (Cluster A-F, marked in green, blue, yellow, red, purple and turquoise, respectively). Interactors in Cluster D presents the highest level of overall co-expression behaviour with LRRK2 across different tissues (referred as Co-ex_ClusterLRRK2). Abbreviations: ACC: Anterior Cingulate Cortex; AMYG: Amygdala; CAU: caudate; CR: cerebellum; FC: frontal cortex; HP: hippocampus; HYPT: hypothalamus; NAc: nucleus accumbens; PUT: putamen; SN: substantia nigra; SPC: spinal cord c-1; Kidney_c: kidney cortex.</p

Top term in the Go:BP functional enrichment of the DEA Cluster_LRRK2.

Top term in the Go:BP functional enrichment of the DEA ClusterLRRK2.</p

Top terms in the GO:BP functional enrichment of the Co-ex_Cluster_LRRK2.

Top terms in the GO:BP functional enrichment of the Co-ex_ClusterLRRK2.</p

Additional file 3: Figure S2. of Pathogenic LRRK2 variants are gain-of-function mutations that enhance LRRK2-mediated repression of β-catenin signaling

Effects of loss of Lrrk2 on tibial cortical Zmax and Zmin. Images in Figures A and B show i) values for Zmax and Zmin, predicted resistance to fracture along the shortest and longest cross-sectional axes, respectively in female wild-type (WT) and Lrrk2 knockout (KO) mice; together with ii) the same data expressed as a graphical heat map along the tibial length; and iii) the points at which differences between genotypes for these parameters become statistically significant. (blue = n/s, yellow, p < 0.05, green p < 0.01, red, p < 0.001). (PDF 110 kb

Additional file 2: Figure S1. of Pathogenic LRRK2 variants are gain-of-function mutations that enhance LRRK2-mediated repression of β-catenin signaling

Effects of loss of Lrrk2 on tibial cortical Cross Sectional Area, Mean Cortical Thickness, and Ellipticity. Images in Figures A, B and C show i) values for cross-sectional area, mean cortical thickness and ellipticity, respectively in female wild-type (WT) and Lrrk2 knockout (KO) mice; together with ii) the same data expressed as a graphical heat map along the tibial length; and iii) the points at which differences between genotypes for these parameters become statistically significant. (blue = n/s, yellow, p < 0.05, green p < 0.01, red, p < 0.001). (PDF 131 kb