PET imaging of tau proteins
Tau (tubulin-associated unit) proteins include six isoforms produced by alternative mRNA splicing of the MAPT (microtubule-associated protein tau) gene. Tau proteins are natively unfolded and contain 352-441 amino acids, having up to 85 potential phosphorylation sites (serine, threonine and tyrosine). The relative activities of kinases and phosphatases, and conformation of the tau protein itself, determine the phosphorylation status. Tau proteins are involved in microtubule assembly and stabilization, and in regulation of motor-driven intracellular transport in neuronal axons. Increased phosphorylation leads to decreased binding to microtubules and subsequently disruption of microtubules. In addition to phosphorylation, tau proteins are regulated by also other post-translational modification such as glycation, nitration, acetylation, and proteolytic truncation.
Tau proteins are widely expressed in the central and peripheral nervous system, especially in neuronal axons, but also in the kidneys and lungs. Hyperphosphorylated tau proteins accumulate in the somatodendritic compartments of neurons, forming aggregates and eventually neurofibrillary tangles. These neurofibrillary tangles in the brain are found in several neurodegenerative diseases (tauopathies, proteinopathies), including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and traumatic brain injuries. In AD the tau proteins are surrounded by the more abundantly present amyloid β protein.
Neurofibrillary tangles, composed of tau, may not cause the neurodegeneration, but soluble tau oligomers are toxic to synapses, possibly by glutamate excitotoxicity and Ca2+ dysregulation (Forner et al., 2017).
Development of PET radiopharmaceuticals for tau protein aggregates has been hindered by the post-transitional modifications and resulting multiple 3D structures that the tau proteins can adopt in the aggregates. Another problem is the abundance of amyloid β in the aggregates; therefore most of the tau tracers are developed for other tauopathies than AD where amyloid β deposits are not present. Radiopharmaceutical must also be able to pass the blood-brain barrier, and show low or no specificity to α-synuclein.
Despite of the problems, several PET radiopharmaceuticals targeting abnormal conformations of the tau proteins have been developed (Villemagne et al., 2015), including [18F]THK523, [18F]THK5105, [18F]THK5117, [18F]THK5351, [18F]T807 (also known as [18F]AV-1451 and Flortaucipir), [18F]T808, and [11C]PBB3 and its 18F-labelled versions.
Tracer affinities to different tau aggregate types may vary, and therefore certain radiopharmaceuticals may be better suited for certain tauopathies (Bischof et al., 2017). [18F]THK523, [18F]THK5105, [18F]THK5117, and [18F]THK5351 are selective to the AD tau aggregates, and do not bind to α-synuclein deposits. [18F]THK5351 has lower nonspecific uptake in the white matter, and faster kinetics than the other THK tracers (Harada et al., 2016). However, [18F]THK5351 binds to MAO-B, which may limit its usability in studies of cortex and basal ganglia (Bischof et al., 2017). In vivo [18F]THK5117 uptake in the human brain did not correlate with biopsy verified tau pathology (Leinonen et al., 2018).
[18F]T807 and [18F]T808 seem to have good selectivity for AD and non-AD tau aggregates over amyloid β. However, [18F]T807 binds also to MAO-A and MAO-B with high affinity (Barrio, 2018).
Additionally, amyloid β tracer [18F]FDDNP binds to both extracellular amyloid β plaques and the intracellular neurofibrillary tangles.
Ariza M, Kolb HC, Moechars D, Rombouts F, Andrés JI. Tau positron emission tomography (PET) imaging: past, present, and future. J Med Chem. 2015; 58(11): 4365-4382. doi: 10.1021/jm5017544.
Bischof GN, Endepols H, van Eimeren T, Drzezga A. Tau-imaging in neurodegeneration. Methods 2017; 130: 114-123. doi: 10.1016/j.ymeth.2017.08.003.
Eisenmenger LB, Huo EJ, Hoffman JM, Minoshima S, Matesan MC, Lewis DH, Lopresti BJ, Mathis CA, Okonkwo DO, Mountz JM. Advances in PET imaging of degenerative, cerebrovascular, and traumatic causes of dementia. Semin Nucl Med. 2016; 46(1): 57-87. doi: 10.1053/j.semnuclmed.2015.09.003.
Fontaine SN, Sabbagh JJ, Baker J, Martinez-Licha CR, Darling A, Dickey CA. Cellular factors modulating the mechanism of tau protein aggregation. Cell Mol Life Sci. 2015; 72(10): 1863-1879. doi: 10.1007/s00018-015-1839-9.
Harada R, Okamura N, Furumoto S, Tago T, Maruyama M, Higuchi M, Yoshikawa T, Arai H, Iwata R, Kudo Y, Yanai K. Comparison of the binding characteristics of [18F]THK-523 and other amyloid imaging tracers to Alzheimer’s disease pathology. Eur J Nucl Med Mol Imaging 2013; 40(1): 125-132. doi: 10.1007/s00259-012-2261-2.
James OG, Doraiswamy PM, Borges-Neto S. PET imaging of tau pathology in Alzheimer’s disease and tauopathies. Front Neurol. 2015;6:38. doi: 10.3389/fneur.2015.00038.
Li Y, Tsui W, Rusinek H, Butler T, Mosconi L, Pirraglia E, Mozley D, Vallabhajosula S, Harada R, Furumoto S, Furukawa K, Arai H, Kudo Y, Okamura N, de Leon MJ. Cortical laminar binding of PET amyloid and tau tracers in Alzheimer disease. J Nucl Med. 2015; 56(2): 270-273. doi: 10.2967/jnumed.114.149229.
Mandelkow E-M, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012;2:a006247. doi: 10.1101/cshperspect.a006247.
Mietelska-Porowska A, Wasik U, Goras M, Filipek A, Niewiadomska G. Tau protein modifications and interactions: their role in function and dysfunction. Int J Mol Sci. 2014; 15(3):4671-4713. doi: 10.3390/ijms15034671.
Okamura N, Harada R, Furumoto S, Arai H, Yanai K, Kudo Y. Tau PET imaging in Alzheimer’s disease. Curr Neurol Neurosci Rep. 2014; 14(11): 500. doi: 10.1007/s11910-014-0500-6.
Shah M, Catafau AM. Molecular imaging insights into neurodegeneration: focus on tau PET radiotracers. J Nucl Med. 2014; 55(6): 871-874. doi: 10.2967/jnumed.113.136069.
Shokouhi S, Claassen D, Riddle WR. Imaging brain metabolism and pathology in Alzheimer’s disease with positron emission tomography. J Alzheimers Dis Parkinsonism 2014; 4:2. doi: 10.4172/2161-0460.1000143.
Thal DR, Attems J, Ewers M. Spreading of amyloid, tau, and microvascular pathology in Alzheimer’s disease: findings from neuropathological and neuroimaging studies. J Alzheimers Dis. 2014; 42(Suppl 4):S421-S429. doi: 10.3233/JAD-141461.
Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tau imaging: early progress and future directions. Lancet Neurol. 2015; 14: 114-124. doi: 10.1016/S1474-4422(14)70252-2.
Watanabe H, Ono M, Saji H. Novel PET/SPECT probes for imaging of tau in Alzheimer’s disease. ScientificWorldJournal 2015; 124192. doi: 10.1155/2015/124192.
Updated at: 2019-03-04
Created at: 2015-08-17
Written by: Vesa Oikonen