Abstract
This study investigated binding of [18F]AV-1451 to neuromelanin in the substantia nigra of patients with Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). [18F]AV-1451 is a positron emission tomography radiotracer designed to bind pathological tau. A post-mortem study using [18F]AV-1451 discovered off-target binding properties to neuromelanin in the substantia nigra. A subsequent clinical study reported a 30% decrease in [18F]AV-1451 binding in the midbrain of PD patients. A total of 12 patients and 10 healthy age-matched controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio (SUVR) from 60 to 90 min post-injection was calculated for the substantia nigra, using the cerebellar cortex as the reference region. The substantia nigra was delineated using automated region of interest software. An independent samples ANOVA and LSD post hoc testing were used to test for differences in [18F]AV-1451 SUVR between groups. Substantia nigra SUVR from 60 to 90 min was significantly greater in HC compared to both PSP and PD groups. Although the PD group had the lowest SUVR, there was no significant difference in substantia nigra uptake between PD and PSP. [18F]AV-1451 may be the first PET radiotracer capable of imaging neurodegeneration of the substantia nigra in parkinsonisms. Further testing must be done in PD and atypical parkinsonian disorders to support this off-target use of [18F]AV-1451.
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References
Armstrong RA, Cairns NJ (2013) Spatial patterns of the tau pathology in progressive supranuclear palsy. Neurol Sci 34:337–344. doi:10.1007/s10072-012-1006-0
Barret O, Alagille D, Sanabria S et al (2016) Kinetic modeling of the tau PET tracer 18F-AV-1451 in human healthy volunteers and Alzheimer’s disease subjects
Boileau I, Payer D, Chugani B et al (2013) The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [11C]-(+)-propyl-hexahydro-naphtho-oxazin and [11C]raclopride. Addiction 108:953–963. doi:10.1111/add.12066
Cho H, Choi JY, Hwang MS et al (2016) Subcortical 18 F-AV-1451 binding patterns in progressive supranuclear palsy. Mov Disord 00:1–7. doi:10.1002/mds.26844
Dauer W, Przedborski S (2003) Parkinson’s disease. Neuron 39:889–909. doi:10.1016/S0896-6273(03)00568-3
Defrise M, Liu X (1999) A fast rebinning algorithm for 3D positron emission tomography using John's equation. Inverse problems 15(4):1047. doi:10.1088/0266-5611/15/4/314
Dickson DW (1999) Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol 246:II6–II15. doi:10.1007/BF03161076
Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5):2283–2301. doi:10.1093/brain/114.5.2283
Goedert M, Trans P, Lond RS, Goedert M (1999) Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and alpha-synucleinopathies. Philos Trans R Soc B Biol Sci. doi:10.1098/rstb.1999.0466
Goetz CG, Tilley BC, Shaftman SR et al (2008) Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 23:2129–2170. doi:10.1002/mds.22340
Hansen AK, Knudsen K, Lillethorup TP et al (2016) In vivo imaging of neuromelanin in Parkinson’s disease using 18 F-AV-1451 PET. Brain aww098. doi: 10.1093/brain/aww098
Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334:345–348. doi:10.1038/334345a0
Kabani N, Collins D, Evans A (1998) A 3d neuroanatomical atlas. In: 4th Int Conf Funct Mapp Hum Brain, pp. 7–12
Kashihara K, Shinya T, Higaki F (2011) Neuromelanin magnetic resonance imaging of nigral volume loss in patients with Parkinson’s disease. J Clin Neurosci 18:1093–6. doi:10.1016/j.jocn.2010.08.043
Kastner A, Hirsch EC, Lejeune O et al (1992) Is the vulnerability of neurons in the substantia nigra of patients with Parkinson’s disease related to their neuromelanin content? J Neurochem 59:1080–1089. doi:10.1111/j.1471-4159.1992.tb08350.x
Kobylecki C, Jones M, Thompson JC et al (2015) Cognitive-behavioural features of progressive supranuclear palsy syndrome overlap with frontotemporal dementia. J Neurol 262:916–922. doi:10.1007/s00415-015-7657-z
Kordower JH, Olanow CW, Dodiya HB et al (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136:2419–2431. doi:10.1093/brain/awt192
Lang A, Lozano A (1998) Parkinson’s disease. N Engl J Med 15:1044–1053
Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066. doi:10.1016/S0140-6736(09)60492-X
Litvan I, Agid Y, Calne D et al (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47:1–9. doi:10.1212/WNL.47.1.1
Mann DMA, Yates PO (1983) Possible role of neuromelanin in the pathogensis of Parkinson’s disease. Mech Ageing Dev 21:193–203
Martin-Bastida A, Pietracupa S, Piccini P (2017) Neuromelanin in parkinsonian disorders: an update. Intern J Neurosci 1:1–8. doi:10.1080/00207454.2017.1325883
Marquie M, Normandin MD, Vanderburg CR et al (2015) Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol 78:787–800. doi:10.1002/ana.24517
Ohtsuka C, Sasaki M, Konno K et al (2014) Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging. Parkinsonism Relat Disord 20:755–60, doi:10.1016/j.parkreldis.2014.04.005
Rusjan P, Mamo D, Ginovart N et al (2006) An automated method for the extraction of regional data from PET images. Psychiatry Res 147:79–89. doi:10.1016/j.pscychresns.2006.01.011
Suzuki M, Desmond T, Albin R, Frey K (2002) Cholinergic vesicular transporters in progressive supranuclear palsy. Neurology 58:1013–1018
Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. In: 3-Dimensioanl proportional system: an approach to cerebral imaging
Togo T, Dickson DW (2002) Tau accumulation in astrocytes in progressive supranuclear palsy is a degenerative rather than a reactive process. Acta Neuropathol 104:398–402. doi:10.1007/s00401-002-0569-x
Whitwell JL, Lowe VL, Tosakulwong N et al (2017) [18F]AV-1451 tau positron emission tomography in progressive supranuclear palsy. Mov Disord 32:124–133. doi:10.1002/mds.26834
Williams DR, Lees AJ (2009) Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges
Williams DR, Holton JL, Strand C et al (2007) Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain 130:1566–1576. doi:10.1093/brain/awm104
Wooten D, Guehl NJ, Verwer EE et al (2016) Pharmacokinetic evaluation of the tau PET radiotracer [18F]T807 ([18F]AV-1451) in human subjects. J Nucl Med 807:1–27. doi:10.2967/jnumed.115.170910
Wray S, Saxton M, Anderton BH, Hanger DP (2008) Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N-terminally cleaved tau containing four microtubule-binding repeats. J Neurochem 105:2343–2352. doi:10.1111/j.1471-4159.2008.05321.x
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Dr. Lorraine Kalia (University of Toronto) and Dr. Elizabeth Slow (University of Toronto) supported patient recruitment for this study.
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SC: acquisition of data, analysis and interpretation of data, draft manuscript for intellectual content; SSC: analysis and interpretation of data, critical revision of manuscript for intellectual content; YK: acquisition of data, critical revision of manuscript for intellectual content; PR: analysis and interpretation of data, critical revision of manuscript for intellectual content; CG: critical revision of manuscript for intellectual content; JK: critical revision of manuscript for intellectual content; AEL: study concept and design, critical revision of manuscript for intellectual content; SH: study concept and design, critical revision of manuscript for intellectual content, study supervision; APS: study concept and design, critical revision of manuscript for intellectual content, study supervision
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Sarah Coakeley: Reports no disclosures; Sang Soo Cho: Reports no disclosures; Yuko Koshimori: Reports no disclosures; Pablo Rusjan: Reports no disclosures; Christine Ghadery: Reports no disclosures; Jinhee Kim: Reports no disclosures; Anthony E. Lang: Reports no disclosures; Sylvain Houle: Reports no disclosures; Antonio P. Strafella: Reports no disclosures
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Study funded by Canadian Institutes of Health Research (MOP-136778) and Parkinson’s Society Canada Fellowship (2015-741)
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Coakeley, S., Cho, S.S., Koshimori, Y. et al. [18F]AV-1451 binding to neuromelanin in the substantia nigra in PD and PSP. Brain Struct Funct 223, 589–595 (2018). https://doi.org/10.1007/s00429-017-1507-y
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DOI: https://doi.org/10.1007/s00429-017-1507-y