Yeona Kang1,2, Sandra Milena Hurtado Rúa3, Ulrike W Kaunzner4, Jai Perumal4, Nancy Nealon4, Wenchao Qu1, Paresh J Kothari1, Timothy Vartanian4,5, Amy Kuceyeski1,5, Susan A Gauthier6,7,8. 1. Department of Radiology, Weill Cornell Medicine, New York, NY, 10021, USA. 2. Department of Mathematics, Howard University, Washington, D.C, 20059, USA. 3. Department of Mathematics and Statistics, College of Science and Health Professions, Cleveland State University, Cleveland, OH, 44115, USA. 4. Department of Neurology, Judith Jaffe Multiple Sclerosis Center, Weill Cornell Medicine, New York, NY, 10021, USA. 5. Feil Family Brain and Mind Institute, Weill Cornell, New York, NY, 10021, USA. 6. Department of Radiology, Weill Cornell Medicine, New York, NY, 10021, USA. sag2015@med.cornell.edu. 7. Department of Neurology, Judith Jaffe Multiple Sclerosis Center, Weill Cornell Medicine, New York, NY, 10021, USA. sag2015@med.cornell.edu. 8. Feil Family Brain and Mind Institute, Weill Cornell, New York, NY, 10021, USA. sag2015@med.cornell.edu.
Abstract
PURPOSE: The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABAA binding and the innate immune response is explored using positron emission tomography (PET) with [11C] flumazenil (FMZ) and [11C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages. PROCEDURES: Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABAA receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function. A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest. RESULTS: GABAA receptor binding was higher throughout the cortex in MS patients (5.72 ± 0.91) as compared with HC (4.70 ± 0.41) (p = 0.002). A significant correlation was found between FMZ binding and PK-PET within the cortex (r = 0.61, p < 0.001) and among the occipital (r = 0.61, p = 0.012), parietal (r = 0.49, p = 0.041), and cingulate (r = 0.32, p = 0.006) regions. CONCLUSIONS: A higher GABAA receptor density in MS subjects compared with HC was observed and correlated with innate immune activity. Our observations demonstrate that immune-driven GABAergic abnormalities may be present in MS.
PURPOSE: The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABAA binding and the innate immune response is explored using positron emission tomography (PET) with [11C] flumazenil (FMZ) and [11C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages. PROCEDURES: Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABAA receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function. A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest. RESULTS: GABAA receptor binding was higher throughout the cortex in MS patients (5.72 ± 0.91) as compared with HC (4.70 ± 0.41) (p = 0.002). A significant correlation was found between FMZ binding and PK-PET within the cortex (r = 0.61, p < 0.001) and among the occipital (r = 0.61, p = 0.012), parietal (r = 0.49, p = 0.041), and cingulate (r = 0.32, p = 0.006) regions. CONCLUSIONS: A higher GABAA receptor density in MS subjects compared with HC was observed and correlated with innate immune activity. Our observations demonstrate that immune-driven GABAergic abnormalities may be present in MS.
Authors: Rocío Serantes; Francisco Arnalich; María Figueroa; Marta Salinas; Eva Andrés-Mateos; Rosa Codoceo; Jaime Renart; Carlos Matute; Carmen Cavada; Antonio Cuadrado; Carmen Montiel Journal: J Biol Chem Date: 2006-03-27 Impact factor: 5.157
Authors: S Lamusuo; A Pitkänen; L Jutila; A Ylinen; K Partanen; R Kälviäinen; H M Ruottinen; V Oikonen; K Någren; P Lehikoinen; M Vapalahti; P Vainio; J O Rinne Journal: Neurology Date: 2000-06-27 Impact factor: 9.910
Authors: W Gordon Frankle; Raymond Y Cho; Rajesh Narendran; N Scott Mason; Shivangi Vora; Maralee Litschge; Julie C Price; David A Lewis; Chester A Mathis Journal: Neuropsychopharmacology Date: 2008-07-09 Impact factor: 7.853
Authors: Ikuo Odano; Christer Halldin; Per Karlsson; Andrea Varrone; Anu J Airaksinen; Raisa N Krasikova; Lars Farde Journal: Neuroimage Date: 2008-12-24 Impact factor: 6.556
Authors: Thomas Geeraerts; Jonathan P Coles; Franklin I Aigbirhio; John D Pickard; David K Menon; Tim D Fryer; Young T Hong Journal: Ann Nucl Med Date: 2011-04-02 Impact factor: 2.668
Authors: R B Banati; J Newcombe; R N Gunn; A Cagnin; F Turkheimer; F Heppner; G Price; F Wegner; G Giovannoni; D H Miller; G D Perkin; T Smith; A K Hewson; G Bydder; G W Kreutzberg; T Jones; M L Cuzner; R Myers Journal: Brain Date: 2000-11 Impact factor: 13.501
Authors: Y Kang; K Jamison; A Jaywant; K Dams-O'Connor; N Kim; N A Karakatsanis; T Butler; N D Schiff; A Kuceyeski; S A Shah Journal: Brain Commun Date: 2022-06-15