title: PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disorder. Genetic studies have linked mutation of the gene SOD1 to ALS pathology as well as several other pathological processes including modulation of glutamatergic function and inflammatory processes. Since therapeutic approaches for ALS are focused on glutamatergic function, we investigated modulation of glutamate transport based on its receptor function as well as excitotoxicity-induced inflammatory response.
  
  
  METHODS
  In vivo positron emission tomography (PET) imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) using [(18)F]FPEB ([(18)F]3-fluoro-5-(2-pyridylethynyl)benzonitrile) and inflammatory response using [(11)C]PBR28 (peripheral benzodiazepine receptor ligand 28) were done in an early and a late phase of neurodegeneration in four ALS mice expressing SOD1-G93A gene and four control base mice (C57/BL6). Accumulation of [(18)F]FPEB and [(11)C]PBR28 were quantitated in several brain areas and spinal cord to determine degeneration-induced modulation. The studies were completed with immunohistochemical analyses of mGluR5 and inflammatory response.
  
  
  RESULTS
  These studies showed enhanced binding potential of [(18)F]FPEB in several brain areas including striatum, hippocampus, and frontal cortex. In the whole brain, the binding potential increased 49 ± 9 % from base mice to ALS-type mice and further enhanced 23 ± 4 % during disease progression. Also, in the spinal cord 6-22 %, enhanced accumulation of [(18)F]FPEB was observed during progression of the disease. The accumulation of [(11)C]PBR28 increased by 110 ± 33 % in the whole brain during progression of the disease indicating significant inflammatory process. [(11)C]PBR28 accumulation enhanced 89-264 % in the spinal cord and 204 % in the lungs. The end point immunohistochemical analyses verified the enhanced mGluR5 expression and inflammation.
  
  
  CONCLUSIONS
  These results confirm the role of glutamate and inflammation in ALS-type pathology. These data also support the hypothesis that excessive glutamate may contribute to inflammation in the chronic neurodegenerative processes in ALS.
authors.affiliation: Athinoula A Martinos Biomedical Imaging Center, Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, USA. abrownell@mgh.harvard.edu.
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Brownell
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Charlestown, Massachusett, USA. dkuruppu@partners.org.
authors.forename: Darshini
authors.initials: D
authors.lastname: Kuruppu
authors.affiliation: Athinoula A Martinos Biomedical Imaging Center, Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, USA. kkil@nmr.mgh.harvard.edu.
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
authors.affiliation: Athinoula A Martinos Biomedical Imaging Center, Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, USA. kjokivarsi@uef.fi.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Jokivarsi
authors.affiliation: Athinoula A Martinos Biomedical Imaging Center, Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, USA. ppoutiainen@partners.org.
authors.forename: Pekka
authors.initials: P
authors.lastname: Poutiainen
authors.affiliation: Athinoula A Martinos Biomedical Imaging Center, Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, USA. aijunzhu@nmr.mgh.harvard.edu.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusett, USA. mmaxwell@als.net.
authors.forename: Michelle
authors.initials: M
authors.lastname: Maxwell
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography / Q000379:methods; D064529:Receptor, Metabotropic Glutamate 5 / Q000096:biosynthesis* / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase