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Nmdar antibodies positive encephalopathies and d-serine - Aviva Durrant, Uriel Heresco-Levy

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Watching at the "D" side: D-amino acids and their significance in neurobiology
June 05 -June 09, 2016 – Lake Como School of Advanced Studies

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Nmdar antibodies positive encephalopathies and d-serine - Aviva Durrant, Uriel Heresco-Levy

  1. 1. 1. Autoimmune-induced glutamatergic receptor dysfunctions (AGRDs) 2. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis 3. Schizophrenia and AGRD 4. Potential role of D-serine in autoimmune NMDAR encephalopathies
  2. 2. 1. Autoimmune-induced glutamatergic receptor dysfunctions (AGRDs) 2. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis 3. Schizophrenia and AGRD 4. Potential role of D-serine in autoimmune NMDAR encephalopathies
  3. 3.  inflammatory process grey matter: • • • • •
  4. 4. Paraneoplastic disorder • • •
  5. 5.  Clinical and immunological LE spectra more extensive than initially considered    
  6. 6. intracellular antigens extracellular antigens Target Antigen 65 kDa glutamic acid decarboxylase amphiphysin Leucine-rich glioma-inactive protein 1 (LG1) contactin-associated protein-like 2 (Contactin) DR2 GABAB receptor P/Q-type voltage-gated calcium channels NMDAR AMPAR mGLUR1 mGLUR5 Syndromes Stiff-person syndrome; cerebelitis Stiff-person syndrome Limbic encephalitis, seizures, hyponatraemia, myoclonus Encephalitis peripheral nerve hyperexcitability Psychosis w/ movement disorders Encephalitis w/ prominent seizures Lambert-Eaton myasthenic Syndrome cerebelitis Characteristic clinical syndrome Limbic encephalitis Hodgkin lymphoma Hodgkin lymphoma Antigen Function crucial for synthesis of GABA important for recycling synaptic vesicles secreted protein, regulates presynaptic Kv1 channels & postsynaptic AMPARs organizes Kv1 channels on myelinated axons -------------------------------------------------- mediates inhibitory neurotransmission- crucial for calcium influx into presynaptic terminals crucial for learning and memory crucial for learning and memory crucial for cerebellar function crucial for hippocampal function -
  7. 7. Disease Cerebral ischaemia & traumatic brain injury Pain Alzheimer’s disease Huntington’s disease Parkinson’s disease (dyskinesia) Depression White matter injury Autism spectrum disorders Cognitive impairments Schizophrenia Key NMDAR-subunit changes NMDARs excessively activated (especially extrasynaptic GLuN2B ) Increase GLU levels = neuronal death GLuN2B receptors (overexpression and altered phosphorylation state) GLuN2B NMDARs activation (causes amyloid-β (Aβ)-induced alterations: e.g. synaptic plasticity, synapse loss, Aβ- and tau-induced excitotoxicity) Extrasynaptic GLuN2B NMDARs activation (increases in mutant huntingtin protein-induced excitotoxicity) Enhanced synaptic GLuN2A expression and redistribution of GluN2B-containing receptors from synaptic to extrasynaptic locations NMDARs inhibitors (GluN2B) induce rapid (hours) and sustained (days) reduction in depressive symptoms NMDAR (GluN2C , GluN3A) activation leads to oligodendrocyte damage and loss of the myelin sheath Either reduced or enhanced NMDAR function is implicated Reduced NMDARs (GluN2B) expression Reduced NMDARs (and/or activity ) in GABAergic neurons leads to imbalance in neural network activity (loss of GLUN2A receptors) Potential Treatments GluN2B-selective antagonists GluN2B-selective antagonists NMDAR antagonists (memantine) or GluN2B-selective antagonists NMDAR antagonists or GluN2B-selective antagonists GluN2B-selective antagonists NMDAR antagonists (ketamine) or GluN2B-selective antagonists GluN2C- or GluN3A- selective antagonists NMDAR antagonists or NMDAR potentiators NMDAR potentiators NMDAR Potentiators: D-serine, glycine, GLYT1 inhibitors GluN2A-selective potentiators altered subunit expression trafficking localization or activity
  8. 8.      Summary: 1. Autoimmune-induced glutamatergic receptor dysfunctions (AGRDs)
  9. 9. 1. Autoimmune-induced glutamatergic receptor dysfunctions (AGRDs) 2. IgG - Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis 3. Schizophrenia and AGRD 4. Potential role of D-serine in autoimmune NMDAR encephalopathies
  10. 10. IgG antibodies against NR1 subunit of NMDAR Young women with behaviorial and personality changes that degenerated into severe neurological impairment. With removal of the teratoma & immune-suppressing meds, 3 out of 4 women recovered
  11. 11. TUMOR ASSOCIATION: • 94% (207/220) were ovarian teratomas • 2% (4/220) had extraovarian teratomas • 4% (9/220) had lung (2), breast (2), testicular or pacreatic cancer
  12. 12. IgG
  13. 13. Patients’ antibodies decrease NMDAR clusters
  14. 14. Patients’ antibodies do not affect other synaptic components
  15. 15. Fc Fab Fab Patients’ antibodies cross-link and internalize NMDAR
  16. 16. Patients’ antibodies decrease synaptic NMDAR currents NMDAR antagonist AMPA antagonist
  17. 17. Patients’ antibodies decrease NMDAR cluster density rodent hippocampus in vivo
  18. 18. Patients’ antibodies decrease NMDAR cluster density human hippocampus in vivo
  19. 19. 1. Autoimmune-induced glutamatergic receptor dysfunctions (AGRDs) 2. IgG - Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis 3. Schizophrenia and AGRD 4. Potential role of D-serine in autoimmune NMDAR encephalopathies
  20. 20.     
  21. 21. Reference Rhodes et al. (2011) Zandi et al. (2012) Haussleiter et al. (2012) Masdeu et al. (2012) Tsutsui et al. (2012) Cohort SCHZ ; control First-episode SCHZ psychosis FEP ; controls SCHZ & schizoaffective general psychiatric Antigen NR1 NR1 , NR2B NR1 , NR2B NR1 NMDAR Isotype IgG IgG IgG IgG IgG #s 0/7 ; 0/3 3/46 0/50 0/80 ; 0/40 4/51 3/5
  22. 22. Dahm et al. (2014) Muller et al. (2014) Pathmanan-Davel et al. (2015) SCHZ affective PD ischemia stroke ALS personality controls SCHZ MD personality controls FEP (43); controls (43) NR1 NR1 NR1 IgG, IgA, IgM IgG, IgA, IgM IgG, IgA, IgM 150/1378 (8,73,69) 37/310 (6,19,12) 48/258 (12,16,20) 101/442 (6,39,56) 7/29 (0,2,5) 1/42 (0,1,0) 170/1703 (20,76,74) 0/184 0/90 0/42 0/357 6/43 (5,1,1) 0/43 Steiner et al. (2013) Hammer et al. (2014) Doss et al. (2014) Acute SCHZ personality disorder MDD controls SCHZ PD affective controls dementia neurodegenerative psychiatric control NR1 , NR2B NR1 , NR2B NR1 , NR2B IgG,IgA, IgM IgG,IgA, IgM IgG,IgA, IgM 14/121 (4,6,4) 0/38 (0,0,0) 2/70 (0,2,0) 1/230 (0,0,1) 109/1081 (7,56,46) 43/263 (1,17,25) 27/148 (5,15,7) 166/1325 (5,78,83) 46/286 (5,14,27) 3/90 6/26 1/80; 2/47 Reference Cohort Antigen Isotype #s
  23. 23. Other ( IgA , IgM ) NMDAR antibodies
  24. 24. Multidisciplinary Case-specific
  25. 25. 1. Autoimmune-induced glutamatergic receptor dysfunctions (AGRDs) 2. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis 3. Schizophrenia and AGRD 4. Potential role of D-serine in autoimmune NMDAR encephalopathies
  26. 26. Kantrowitz 2010 Tsai 1998 Heresco-Levy 2005 Lane 2010 Weiser 2012 • lack of speech • flat affect • anhedonia • asociality • avolition • apathy
  27. 27. • hallucinations. • delusions. • bizarre or • disorganized behavior.
  28. 28. GLY , DSR , DCS , D-alanine, Sarcosine ( 26 studies , ~800 patients )     Pooled Effect size ( 95% CIs ) of clinical efficiency 
  29. 29. Kantrowitz et al., Schizophr Res, 2010 * * *
  30. 30. D-serine, 2.1 g Placebo D-serine, 2.1 gPlacebo
  31. 31. Attention / Vigilance Verbal learning
  32. 32. (Heresco-Levy et al., 2004)(Heresco-Levy et al., 2005)
  33. 33. (Heresco-Levy et al., 1999) (Heresco-Levy et al., 2004) (Heresco-Levy et al., 2005) (Kantrowitz et al., 2010)
  34. 34. Gelfin et al., Int J Neuropsychopharm, 2012, 15:543
  35. 35. Gelfin et al., Int J Neuropsychopharm, 2012, 15:543
  36. 36. Heresco-Levy et al., Movement Disorders, 2013, 28:419
  37. 37. A El Arfani et al., Neurochem Int, 2015, 88:88-96
  38. 38.      
  39. 39. Heresco-Levy et al., Biol Psych, 2015, 77:e27
  40. 40. Heresco-Levy et al., Biol Psych, 2015, 77:e27
  41. 41. , after a period of unexplained headaches had developed an acute psychosis characterized by grandiose and paranoid delusions, mystical thinking, elated affect and agitation. Following diagnosis, she never returned to her previous functional level, and Maintained on antipsychotic drugs with poor response. Medical neurological examinations and clinical laboratory consistently unremarkable. Abdomen ultrasound normal. Heresco-Levy et al., Biol Psych, 2014, in press
  42. 42. Heresco-Levy et al., Biol Psych, 2014, in press
  43. 43. Heresco-Levy et al., Biol Psych, 2014, in press * *
  44. 44.     

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