Transactivation of PDGFRβ by dopamine D4 receptor does not require PDGFRβ dimerization

Growth factor-induced receptor dimerization and cross-phosphorylation are hallmarks of signal transduction via receptor tyrosine kinases (RTKs). G protein-coupled receptors (GPCRs) can activate RTKs through a process known as transactivation. The prototypical model of RTK transactivation involves ligand-mediated RTK dimerization and cross-phosphorylation. Here, we show that the platelet-derived growth factor receptor β (PDGFRβ) transactivation by the dopamine receptor D4 (DRD4) is not dependent on ligands for PDGFRβ. Furthermore, when PDGFRβ dimerization is inhibited and receptor phosphorylation is suppressed to near basal levels, the receptor maintains its ability to be transactivated and is still effective in signaling to ERK1/2. Hence, the DRD4-PDGFRβ-ERK1/2 pathway can occur independently of a PDGF-like ligand, PDGFRβ cross-phosphorylation and dimerization, which is distinct from other known forms of transactivation of RTKs by GPCRs

Erratum to: Exploring the effects of coexisting amyloid in subcortical vascular cognitive impairment

Medicine, Faculty ofScience, Faculty ofOther UBCNon UBCMedicine, Department ofPhysical Therapy, Department ofPhysics and Astronomy, Department ofRadiology, Department ofReviewedFacult

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

The Use of Random Forests to Identify Brain Regions on Amyloid and FDG PET Associated With MoCA Score

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.Purpose: The aim of this study was to evaluate random forests (RFs) to identify ROIs on 18F-florbetapir and 18F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score. Materials and Methods: Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a mul- ticenter prospective observational trial, had MoCA and 18F-florbetapir PET; 55 had 18F-FDG PET. Scans were processed using the MINC toolkit to gen- erate SUV ratios, normalized to cerebellar gray matter (18F-florbetapir PET), or pons (18F-FDG PET). SUV ratio data and MoCA score were used for su- pervised training of RFs programmed in MATLAB. Results: 18F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid in- creased with decreasing MoCA score. 18F-FDG PETs were randomly di- vided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. 18F-FDG decreased with decreasing MoCA score. Conclusions: Random forests help pinpoint clinically relevant ROIs associ- ated with MoCA score; amyloid increased and 18F-FDG decreased with de- creasing MoCA score, most significantly in the posterior cingulate gyrus.CIHR MITNEC C6 || Linda C Campbell Foundation || Lilly-Avid Radiopharmaceuticals

The use of random forests to classify amyloid brain PET

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.Purpose: To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification. Methods: The data set included 57 baseline 18F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for super- vised training of an RF classifier programmed in MATLAB. Results: A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence in- terval [CI], 42%–100%), specificity = 92% (CI, 64%–100%), and classification accuracy = 90% (CI, 68%–99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right an- terior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees). Conclusions: Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.CIHR MITNEC C6 || Linda C Campbell Foundation || Lilly-Avid Radiopharmaceuticals

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

The Impact of Aerobic Exercise on Fronto-Parietal Network Connectivity and Its Relation to Mobility: An Exploratory Analysis of a 6-Month Randomized Controlled Trial

Impaired mobility is a major concern for older adults and has significant consequences. While the widely accepted belief is that improved physical function underlies the effectiveness of targeted exercise training in improving mobility and reducing falls, recent evidence suggests cognitive and neural benefits gained through exercise may also play an important role in promoting mobility. However, the underlying neural mechanisms of this relationship are currently unclear. Thus, we hypothesize that 6 months of progressive aerobic exercise training would alter frontoparietal network (FPN) connectivity during a motor task among older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI)—and exercise-induced changes in FPN connectivity would correlate with changes in mobility. We focused on the FPN as it is involved in top-down attentional control as well as motor planning and motor execution. Participants were randomized either to usual-care (CON), which included monthly educational materials about VCI and healthy diet; or thrice-weekly aerobic training (AT), which was walking outdoors with progressive intensity. Functional magnetic resonance imaging was acquired at baseline and trial completion, where the participants were instructed to perform bilateral finger tapping task. At trial completion, compared with AT, CON showed significantly increased FPN connectivity strength during right finger tapping (p < 0.05). Across the participants, reduced FPN connectivity was associated with greater cardiovascular capacity (p = 0.05). In the AT group, reduced FPN connectivity was significantly associated with improved mobility performance, as measured by the Timed-Up-and-Go test (r = 0.67, p = 0.02). These results suggest progressive AT may improve mobility in older adults with SIVCI via maintaining intra-network connectivity of the FPN