Translocator Protein (18 kDa) Polymorphism (rs6971) in the Korean Population
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background and Purpose: The expression of the 18-kDA mitochondrial translocator protein (TSPO) in the brain is an attractive target to study neuroinflammation. However, the binding properties of TSPO ligands are reportedly dependent on genetic polymorphism of the TSPO gene (rs6971). The objective of this study is to investigate the rs6971 gene polymorphism in the Korean population. Methods: We performed genetic testing on 109 subjects including patients with mild cognitive impairment, Alzheimer’s disease (AD) dementia, non-AD dementia, and cognitively unimpaired participants. Magnetic resonance imaging scans and detailed neuropsychological tests were also performed, and 29 participants underwent 18F-DPA714 PET scans. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) was polymerase chain reaction amplified and sequenced using the Sanger method. The identified rs6971 genotype codes (C/C, C/T, or T/T) of the TSPO protein generated high-, mixed-, or low-affinity binding phenotypes (HABs, MABs, and LABs), respectively. Results: We found that 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). 18F-DPA-714 PET scans showed nonspecific binding to the thalamus and brainstem, and increased tracer uptake throughout the cortex in cognitively impaired patients. The participant with the MAB polymorphism had a higher DPA714 signal throughout the cortex. Conclusions: The majority of Koreans are HAB (aprox. 96%). Therefore, the polymorphism of the rs6971 gene would have a smaller impact on the availability of second-generation TSPO PET tracers.
Abstract
Background and Purpose: The expression of the 18-kDA mitochondrial translocator protein (TSPO) in the brain is an attractive target to study neuroinflammation. However, the binding properties of TSPO ligands are reportedly dependent on genetic polymorphism of the TSPO gene (rs6971). The objective of this study is to investigate the rs6971 gene polymorphism in the Korean population. Methods: We performed genetic testing on 109 subjects including patients with mild cognitive impairment, Alzheimer’s disease (AD) dementia, non-AD dementia, and cognitively unimpaired participants. Magnetic resonance imaging scans and detailed neuropsychological tests were also performed, and 29 participants underwent 18F-DPA714 PET scans. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) was polymerase chain reaction amplified and sequenced using the Sanger method. The identified rs6971 genotype codes (C/C, C/T, or T/T) of the TSPO protein generated high-, mixed-, or low-affinity binding phenotypes (HABs, MABs, and LABs), respectively. Results: We found that 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). 18F-DPA-714 PET scans showed nonspecific binding to the thalamus and brainstem, and increased tracer uptake throughout the cortex in cognitively impaired patients. The participant with the MAB polymorphism had a higher DPA714 signal throughout the cortex. Conclusions: The majority of Koreans are HAB (aprox. 96%). Therefore, the polymorphism of the rs6971 gene would have a smaller impact on the availability of second-generation TSPO PET tracers.
참고문헌 (26)
- Heneka MT, "Neuroinflammation in Alzheimer’s disease", Lancet Neurol, 14, pp.388~405 (2015)
- Sheedy FJ, "CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation", Nat Immunol, 14, pp.812~820 (2013)
- DPA714 PET, "J Neuroinflammation", 2018, 314~
- Owen DR, "Imaging brain microglial activation using positron emission tomography and translocator protein-specific radioligands", Int Rev Neurobiol, 101, pp.19~39 (2011)
- vinpocetine, "Curr Radiopharm", 2012, 19~28
- Gavish M, "Enigma of the peripheral benzodiazepine receptor", Pharmacol Rev, 51, pp.629~650 (1999)
- md. Maqusood Alam, "Recent Progress in the Development of TSPO PET Ligands for Neuroinflammation Imaging in Neurological Diseases", Nuclear Medicine and Molecular Imaging, 51(4), pp.283~296 (2017), 대한핵의학회
- Vivash L, "Imaging microglial activation with TSPO PET: lighting up neurologic diseases?", J Nucl Med, 57, pp.165~168 (2016)
- Owen DR, "An 18-kDa translocator protein(TSPO)polymorphism explains differences in binding affinity of the PET radioligand PBR28", J Cereb Blood Flow Metab, 32, pp.1~5 (2012)
- McKhann G, "Clinical diagnosis of Alzheimer’s disease : report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease", Neurology, 34, pp.939~944 (1984)
- Petersen RC, "Clinical practice. Mild cognitive impairment", N Engl J Med, 364, pp.2227~2234 (2011)
- Rascovsky K, "Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia", Brain, 134, pp.2456~2477 (2011)
- McKeith IG, "Diagnosis and management of dementia with Lewy bodies : fourth consensus report of the DLB Consortium", Neurology, 89, pp.88~100 (2017)
- Gilman S, "Second consensus statement on the diagnosis of multiple system atrophy", Neurology, 71, pp.670~676 (2008)
- McKee AC, "The first NINDS", NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy, 2016, pp.131, 75~86
- Greve DN, "Cortical surface-based analysis reduces bias and variance in kinetic modeling of brain PET data", Neuroimage, 92, pp.225~236 (2014)
- Greve DN, "Different partial volume correction methods lead to different conclusions : An(18)F-FDG-PET study of aging", Neuroimage, 132, pp.334~343 (2016)
- THK5351 and cerebral glucose hypometabolism in Alzheimer’s disease, "Neurobiol Aging", 2017, 210~219
- Owen DR, "TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis", Biochem J, 474, pp.3985~3999 (2017)
- Turkheimer FE, "The methodology of TSPO imaging with positron emission tomography", Biochem Soc Trans, 43, pp.586~592 (2015)
- Sherry ST, "dbSNP : the NCBI database of genetic variation", Nucleic Acids Res, 29, pp.308~311 (2001)
- International HapMap Consortium, "The International HapMap Project", Nature, 426, pp.789~796 (2003)
- Hamelin L, "Early and protective microglial activation in Alzheimer’s disease : a prospective study using 18F-DPA-714 PET imaging", Brain, 139, pp.1252~1264 (2016)
- Kreisl WC, "A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation", J Cereb Blood Flow Metab, 33, pp.53~58 (2013)
- PBR28 studies in humans and rodents, "Neuropsychopharmacology", 2018, 1832~1839
- -FEPPA, "J Cereb Blood Flow Metab", 2012, 968~972