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Title: PANS: Stovetop Cookware or Chronic Mental Illness?

Biography:

Katie Hoeveler, MD, started her medical career as a pediatrician in a hospital-based practice in San Diego, CA.  She was drawn to the children with mental health challenges and became fascinated with brain pathology. Thus, she completed her Adult Psychiatry Residency and Child Psychiatry Fellowship as part of the Post Pediatric Portal Program at the Children’s Hospital of Philadelphia and the University of Pennsylvania.  She stayed on at CHOP as a Consult-Liaison Psychiatrist and then Medical Director of the brand new Medical Behavioral Unit. She was also an Assistant Professor of Clinical Psychiatry at the University of Pennsylvania. She started her private oractice in June 2019 and is part of a group of distinguished psychologists. She has researched and given presentations on all aspects of child psychiatry including anxiety, depression, and ADHD.

Abstract:

Statement of the Problem:  Pediatric Autoimmune Neuropsychiatric Syndrome, or PANS, is characterized by an abrupt onset of neuropsychiatric symptoms following a microbial infection.  Whether PANS is a distinct form of more typical cases of OCD or tic disorder is controversial, and many experts doubt the existence of PANS.  Two cases of PANS following Mycoplasma Pneumoniae infection- in the same family- inspired us to investigate the evidence in the literature for the existence of PANS and the evidence for a genetic component to susceptibility to PANS.

Methodology and Theoretic Orientation:  We performed a literature search in PubMed and in UptoDate. We used the key words “PANS NOT PANDAS,” to exclude PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection) which is a related, but separate, diagnosis. Given the relatively small number of articles on PANS, we included all articles in the literature review.  We analyzed the articles for evidence of the existence of PANS as a unique diagnosis, separate from other neuropsychiatric diagnoses.  We also analyzed the articles for evidence of a genetic component to susceptibility to PANS.

Findings: Of the 29 articles on PANS, five articles presented clear evidence for the existence of PANS, and two articles addressed the genetic susceptibility to PANS.  The remaining articles consisted of mainly of case reports and the treatment of PANS.  The first group of five articles documented a unique constellation of neuropsychiatric symptoms, following a bacterial infection, that is not otherwise better described by any other medical nor neuropsychiatric disorder.  The second group of two articles showed that there is significant autoimmunity (that gives rise to PANS) in first degree relatives suggesting a genetic component to susceptibility.

Conclusion and Significance: While our literature review and case reports present convincing evidence for the existence and heritability of PANS, more, larger cohort studies are needed.  In addition, it is crucial to increase visibility and awareness of PANS to pediatricians, child and adolescent psychiatrists, and psychologists.  Delaying diagnosis and treatments in PANS portend a significantly worse prognosis.

Title: Presenilin1 FAD mutants impair angiogenic functions of VEGFR2 in brain endothelial cells.

Biography:

Dr Anastasios Georgakopoulos is a Professor at the Center for Molecular Biology and Genetics of Neurodegeneration, department of Psychiatry at the Icahn School of Medicine at Mount Sinai, New York. He has extensive experience in research on the role of Presenilin1(PS1)/γ-secretase system on the function of various cell systems including neuronal and endothelial cells. PS1 mutants have been linked to the pathogenesis of Familial Alzheimer’s Disease (FAD). He has been working exclusively on the molecular biology of WT and mutant PS1 for over 24 years. He was the first to show that PS1 localizes at Cadherin-based adherens junctions at cell-cell contact sides and synapses. In addition, he found the interaction of PS1 with substrates of γ-secretase such as E- and N-cadherins and ephinB ligands and EphB receptors and the physiological role that these interactions have. He has published several articles on the above subjects. His laboratory studies mechanisms of VEGF/VEGFR2 and ephrinB/EphB-mediated angiogenesis and neuroprotection and the role that PS1/γ-secretase system has on their regulation aiming to discover methods to effectively treat and prevent neurodegenerative disorders like Alzheimer’s Disease.

Abstract:

Alzheimer’s disease (AD) is a multifactorial and progressive neurodegenerative disease where cerebrovascular abnormalities are commonly observed. Brain vascular alterations occur before the appearance of neuropathology in animal AD models. Various factors, including decreased sprouting angiogenesis, can cause the reduction in capillary density observed in AD brains. Angiogenesis is a reparative function of the brain in response to toxic insults and is regulated by endothelial cells (ECs) and angiogenic factors such as the Vascular Endothelial Growth factor (VEGF); impairment in this function would render the brain vulnerable to toxic insults and lead to neurodegeneration. The purpose of this study is to examine the effects of Presenilin1 (PS1) mutants linked to familial AD (FAD) in the VEGFinduced angiogenic signaling and functions of brain endothelial cells. Methodology and Theoretical Orientation: Primary cortical endothelial cells (pCECs) from brains of wild-type (WT) and knock-in (KI) mice expressing either PS1 M146V or PS1 I213T FAD mutant in heterozygous state were isolated and cultured. These mice constitute a “humanized” FAD model having the same genotype as human FAD patients. We performed in vitro angiogenesis assays including sprouting on beads, cell migration and tube formation using pCEC cultures. Processing of VEGFR2 was detected in HEK293 cells overexpressing VEGFR2 in the presence or absence of VEGF-A and γ-secretase inhibitor (RO4929097). The same processing was also analyzed by western blotting in PS1 M146V and I213T mutant pCECs treated with VEGF-A. The role of γ-secretase in VEGF-induced formation of angiogenic complexes between VE-cadherin and Rok-α kinase was detected in the presence or absence of RO4929097 with immunoprecipitation and western blotting. VEGF-induced phosphorylation of signaling molecules downstream of VEGFR2 such as ERK1/2 and Akt kinases and PLCγ1 was also examined in WT and both PS1 FAD mutant pCECs by western blotting. Findings: We found that VEGFR2 is processed by γ-secretase and that this processing together with VEGF-induced sprouting, tube formation, migration and angiogenic complexes between VE-cadherin and Rok-α kinase are decreased in the presence of γ-secretase inhibitor or by PS1 FAD mutants. Furthermore, the VEGF-induced phosphorylation of ERK1/2, Akt and PLCγ1 is decreased in PS1 FAD mutant pCECs. Conclusion & Significance: Our findings show that VEGFR2 is processed by γ-secretase, which promotes VEGF-induced angiogenic functions of brain ECs through activation of VEGFVEGFR2 downstream signaling. Our data also show that PS1 FAD mutants decrease both the VEGFR2 processing by γ-secretase and the VEGF-induced angiogenic signaling and functions of brain endothelial cells, providing a mechanism via which FAD mutants affect brain angiogenesis and promote neurodegeneration.