Non-Amyloid PET Imaging Biomarkers for Neurodegeneration: Focus on Tau, Alpha-Synuclein and Neuroinflammation

Author(s): Ana M. Catafau, Santiago Bullich.

Journal Name: Current Alzheimer Research

Volume 14 , Issue 2 , 2017

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Abstract:

Clinical classifications of neurodegenerative disorders are often based on neuropathology. The term „proteinopathies“ includes disorders that have in common abnormal proteins as a hallmark, e.g. amyloidoses, tauopathies, synucleopathies, ubiquitinopathies. Different proteins can also co-exist in the same disease. To further complicate the pathophysiology scenario, not only different proteins, but also cells are believed to play an active role in neurodegeneration, in particular those participating in neuroinflammatory processes in the brain, such as activated microglia and astrocytes. In clinical practice, differentiating pathophysiology from clinical symptoms to allow accurate clinical classification of these disorders during life, becomes difficult in absence of biomarkers for these pathology hallmarks. PET imaging can be a useful tool in this context. Using PET tracers targeting misfolded proteins it will be possible to identify the presence or absence of the target, to depict the cerebral distribution and to quantify the protein load in different cerebral regions, as well as to monitor changes over time. Beta-amyloid is one of the proteins involved in neurodegenerative disorders, which is currently suitable to be imaged by means of PET. Research efforts are currently ongoing in order to identify new PET tracers targeting non-amyloid PET tracers for neurodegeneration. This article will focus on the investigational PET tracers targeting tau and alpha-synuclein as misfolded proteins, and activated microglia and astrocytes as cellular targets for neuroinflammation. An overview of target characteristics, development challenges, clinical relevance and current status of human PET imaging is provided.

Keywords: Astrocytes, alpha-synuclein, neurodegeneration, microglia, neuroinflammation, PET, tau.

[1]
Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y, et al. Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer disease: Phase 3 study. Alzheimers Dement 11(8): 964-74.(2015);
[2]
Sabri O, Seibyl J, Rowe C, Barthel H. Beta-amyloid imaging with florbetaben. Clin Transl Imaging 3(1): 13-26.(2015);
[3]
Catafau AM, Bullich S. Amyloid PET imaging: applications beyond Alzheimer’s disease. Clin Transl Imaging 3(1): 39-55.(2015);
[4]
Rabinovici GD, Miller BL. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 24(5): 375-98.(2010);
[5]
Chen-Plotkin AS, Lee VM, Trojanowski JQ. TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol 6(4): 211-20.(2010);
[6]
Morris JC, Blennow K, Froelich L, Nordberg A, Soininen H, Waldemar G, et al. Harmonized diagnostic criteria for Alzheimer’s disease: recommendations. J Intern Med 275(3): 204-13.(2014);
[7]
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13(6): 614-29.(2014);
[8]
Riedl L, Mackenzie IR, Forstl H, Kurz A, Diehl-Schmid J. Frontotemporal lobar degeneration: current perspectives. Neuropsychiatr Dis Treat 10: 297-310.(2014);
[9]
Bayer TA. Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders? Eur Neuropsychopharmacol 25(5): 713-24.(2015);
[10]
Delacourte A, David JP, Sergeant N, Buee L, Wattez A, Vermersch P, et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 52(6): 1158-65.(1999);
[11]
Delacourte A, Sergeant N, Wattez A, Maurage CA, Lebert F, Pasquier F, et al. Tau aggregation in the hippocampal formation: an ageing or a pathological process? Exp Gerontol 37(10-11): 1291-6.(2002);
[12]
Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85(3): 519-33.(2015);
[13]
Xu S, Brunden KR, Trojanowski JQ, Lee VM. Characterization of tau fibrillization in vitro. Alzheimers Dement 6(2): 110-7.(2010);
[14]
von Bergen M, Barghorn S, Muller SA, Pickhardt M, Biernat J, Mandelkow EM, et al. The core of tau-paired helical filaments studied by scanning transmission electron microscopy and limited proteolysis. Biochemistry 45(20): 6446-57.(2006);
[15]
Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tau imaging: early progress and future directions. Lancet Neurol 14(1): 114-24.(2015);
[16]
Fawaz MV, Brooks AF, Rodnick ME, Carpenter GM, Shao X, Desmond TJ, et al. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer’s disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection. ACS Chem Neurosci 5(8): 718-30.(2014);
[17]
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1(1) a006189(2011);
[18]
Okamura N, Harada R, Furumoto S, Arai H, Yanai K, Kudo Y. Tau PET imaging in Alzheimer’s disease. Curr Neurol Neurosci Rep 14(11): 500.(2014);
[19]
Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18(4): 351-7.(1997);
[20]
Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer’s disease. J Neural Transm Suppl 53: 127-40.(1998);
[21]
Duyckaerts C, Braak H, Brion JP, Buee L, Del Tredici K, Goedert M, et al. PART is part of Alzheimer disease. Acta Neuropathol 129(5): 749-56.(2015);
[22]
McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1): 43-64.(2013);
[23]
Rabinovici G, Schonhaut D, Baker S, Lazaris A, Ossenkoppele R, Lockhart S, et al. Preliminary Experience with [18F]AV1451 PET in Non-AD Neurodegenerative Syndromes.9th Human Amyloid Imaging (Conference Program and Abstracts) January 14-16. Miami, Florida, United States (2015).
[24]
Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer’s disease. J Neurosci 21(24): Rc189.(2001);
[25]
Shah M, Catafau AM. Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers. J Mol Med (Berl) 55(6): 871-4.(2014);
[26]
Smid LM, Kepe V, Vinters HV, Bresjanac M, Toyokuni T, Satyamurthy N, et al. Postmortem 3-D brain hemisphere cortical tau and amyloid-beta pathology mapping and quantification as a validation method of neuropathology imaging. J Alzheimers Dis 36(2): 261-74.(2013);
[27]
Kepe V, Bordelon Y, Boxer A, Huang SC, Liu J, Thiede FC, et al. PET imaging of neuropathology in tauopathies: progressive supranuclear palsy. J Alzheimers Dis 36(1): 145-53.(2013);
[28]
Villemagne VL, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Hodges J, Harada R, et al. In vivo evaluation of a novel tau imaging tracer for Alzheimer’s disease. Eur J Nucl Med Mol Imaging 41(5): 816-26.(2014);
[29]
Okamura N, Furumoto S, Harada R, Tago T, Yoshikawa T, Fodero-Tavoletti M, et al. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nucl Med 54(8): 1420-7.(2013);
[30]
Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14(1): 38-48.(2013);
[31]
Shah M, Seibyl J, Cartier A, Bhatt R, Catafau AM. Molecular imaging insights into neurodegeneration: focus on alpha-synuclein radiotracers. J Nucl Med 55(9): 1397-400.(2014);
[32]
Eberling JL, Dave KD, Frasier MA. alpha-synuclein imaging: a critical need for Parkinson’s disease research. J Parkinsons Dis 3(4): 565-7.(2013);
[33]
Marek K, Jennings D. Can we image premotor Parkinson disease? Neurology 72(7): S21-6.(2009);
[34]
Iranzo A, Valldeoriola F, Lomena F, Molinuevo JL, Serradell M, Salamero M, et al. Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol 10(9): 797-805.(2011);
[35]
Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson’s disease. Park Relat Disord 16(2): 79-84.(2010);
[36]
Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8(12): 1150-7.(2009);
[37]
Braak H, Del Tredici K. Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv Anat Embryol Cell Biol 201: 1-119.(2009);
[38]
Seibyl J, Russell D, Jennings D, Marek K. Neuroimaging over the course of Parkinson’s disease: from early detection of the at-risk patient to improving pharmacotherapy of later-stage disease. Semin Nucl Med 42(6): 406-14.(2012);
[39]
Mitchell D, Nash K, Hardick D, Kotzbaue P, Tu Z, Xu J, et al. Development of an Alpha-synuclein PET Tracer.9th Human Amyloid Imaging (Conference Program and Abstracts) January 14-16,. Miami, Florida, United States (2015).
[40]
Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet 358(9280): 461-7.(2001);
[41]
Venneti S, Lopresti BJ, Wiley CA. The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol 80(6): 308-22.(2006);
[42]
Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27(8): 402-9.(2006);
[43]
Chen MK, Guilarte TR. Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Ther 118(1): 1-17.(2008);
[44]
Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, et al. Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med 48(1): 158-67.(2007);
[45]
Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging 35(12): 2304-19.(2008);
[46]
Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage 40(1): 43-52.(2008);
[47]
Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M, et al. Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 30(9): 1608-18.(2010);
[48]
Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 52(1): 24-32.(2011);
[49]
Varley J, Brooks DJ, Edison P. Imaging neuroinflammation in Alzheimer’s and other dementias: Recent advances and future directions. Alzheimers Dement 11(9): 1110-20.(2015);
[50]
Varrone A, Oikonen V, Forsberg A, Joutsa J, Takano A, Solin O, et al. Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer’s disease patients and control subjects. Eur J Nucl Med Mol Imaging 42(3): 438-46.(2015);
[51]
Saura J, Bleuel Z, Ulrich J, Mendelowitsch A, Chen K, Shih JC, et al. Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry. Neuroscience 70(3): 755-74.(1996);
[52]
Tong J, Meyer JH, Furukawa Y, Boileau I, Chang LJ, Wilson AA, et al. Distribution of monoamine oxidase proteins in human brain: implications for brain imaging studies. J Cereb Blood Flow Metab 33(6): 863-71.(2013);
[53]
Fowler JS, Logan J, Shumay E, Alia-Klein N, Wang GJ, Volkow ND. Monoamine oxidase: radiotracer chemistry and human studies. J Labelled Comp Radiopharm 58(3): 51-64.(2015);
[54]
Fowler JS, Wang GJ, Logan J, Xie S, Volkow ND, MacGregor RR, et al. Selective reduction of radiotracer trapping by deuterium substitution: comparison of carbon-11-L-deprenyl and carbon-11-deprenyl-D2 for MAO B mapping. J Nucl Med 36(7): 1255-62.(1995);
[55]
Nag S, Varrone A, Toth M, Thiele A, Kettschau G, Heinrich T, et al. In vivo evaluation in cynomolgus monkey brain and metabolism of [(1)(8)F]fluorodeprenyl: a new MAO-B pet radioligand. Synapse (New York, NY) 66(4): 323-30.(2012);
[56]
Nag S, Lehmann L, Kettschau G, Heinrich T, Thiele A, Varrone A, et al. Synthesis and evaluation of [(1)(8)F]fluororasagiline, a novel positron emission tomography (PET) radioligand for monoamine oxidase B (MAO-B). Bioorg Med Chem 20(9): 3065-71.(2012);
[57]
Nag S, Lehmann L, Kettschau G, Toth M, Heinrich T, Thiele A, et al. Development of a novel fluorine-18 labeled deuterated fluororasagiline ([(18)F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B). Bioorg Med Chem 21(21): 6634-41.(2013);
[58]
Kumlien E, Nilsson A, Hagberg G, Langstrom B, Bergstrom M. PET with 11C-deuterium-deprenyl and 18F-FDG in focal epilepsy. Acta Neurol Scand 103(6): 360-6.(2001);
[59]
Engler H, Lundberg PO, Ekbom K, Nennesmo I, Nilsson A, Bergstrom M, et al. Multitracer study with positron emission tomography in Creutzfeldt-Jakob disease. Eur J Nucl Med Mol Imaging 30(1): 85-95.(2003);
[60]
Johansson A, Engler H, Blomquist G, Scott B, Wall A, Aquilonius SM, et al. Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET. J Neurol Sci 255(1-2): 17-22.(2007);
[61]
Hirvonen J, Kailajarvi M, Haltia T, Koskimies S, Nagren K, Virsu P, et al. Assessment of MAO-B occupancy in the brain with PET and [11C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther 85(5): 506-12.(2009);
[62]
Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53(1): 37-46.(2012);


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Article Details

VOLUME: 14
ISSUE: 2
Year: 2017
Page: [169 - 177]
Pages: 9
DOI: 10.2174/1567205013666160620111408
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