SpringerLink
Log in

PET Imaging to Measure Neuroinflammation In Vivo

  • Protocol
  • First Online:
Biomarkers for Alzheimer’s Disease Drug Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2785))

Abstract

This paper provides an overview of the role of neuroinflammation in Alzheimer’s disease and other neurodegenerative diseases, highlighting the potential of anti-inflammatory treatments to slow or prevent decline. This research focuses on the use of positron emission tomography (PET) imaging to visualize and quantify molecular brain changes in patients, specifically microglial activation and reactive astrogliosis. We discuss the development and application of several PET radioligands, including first-generation ligands like PK11195 and Ro5-4864, as well as second- and third-generation ligands such as [11C]PBR28, [18F]DPA-714, [18F]GE-180, and [11C]ER176. These ligands target the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and upregulated in astrocytes. We also address the limitations of these ligands, such as low brain uptake, poor penetration of the blood-brain barrier, short half-life, and variable kinetic behavior. Furthermore, we demonstrate the impact of genetic polymorphisms on ligand binding.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Guo Q, Owen DR, Rabiner EA, Turkheimer FE, Gunn RN (2012) Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo. NeuroImage 60(2):902–910. https://doi.org/10.1016/j.neuroimage.2011.12.078

    Article  PubMed  Google Scholar 

  2. Kobayashi M, Jiang T, Telu S, Zoghbi SS, Gunn RN, Rabiner EA, Owen DR, Guo Q, Pike VW, Innis RB, Fujita M (2018) (11)C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than (11)C-( R)-PK11195. J Cereb Blood Flow Metab 38(3):393–403. https://doi.org/10.1177/0271678X17699223

    Article  CAS  PubMed  Google Scholar 

  3. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (2012) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 32(1):1–5. https://doi.org/10.1038/jcbfm.2011.147

    Article  CAS  PubMed  Google Scholar 

  4. Vettermann FJ, Harris S, Schmitt J, Unterrainer M, Lindner S, Rauchmann BS, Palleis C, Weidinger E, Beyer L, Eckenweber F, Schuster S, Biechele G, Ferschmann C, Milenkovic VM, Wetzel CH, Rupprecht R, Janowitz D, Buerger K, Perneczky R, Höglinger GU, Levin J, Haass C, Tonn JC, Niyazi M, Bartenstein P, Albert NL, Brendel M (2021) Impact of TSPO receptor polymorphism on [(18)F]GE-180 binding in healthy brain and pseudo-reference regions of Neurooncological and neurodegenerative disorders. Life (Basel) 11(6). https://doi.org/10.3390/life11060484

  5. Tondo G, Iaccarino L, Caminiti SP, Presotto L, Santangelo R, Iannaccone S, Magnani G, Perani D (2020) The combined effects of microglia activation and brain glucose hypometabolism in early-onset Alzheimer’s disease. Alzheimers Res Ther 12(1):50. https://doi.org/10.1186/s13195-020-00619-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hamelin L, Lagarde J, Dorothee G, Potier MC, Corlier F, Kuhnast B, Caille F, Dubois B, Fillon L, Chupin M, Bottlaender M, Sarazin M (2018) Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer’s disease. Brain 141(6):1855–1870. https://doi.org/10.1093/brain/awy079

    Article  PubMed  Google Scholar 

  7. Kreisl WC, Lyoo CH, Liow JS, Wei M, Snow J, Page E, Jenko KJ, Morse CL, Zoghbi SS, Pike VW, Turner RS, Innis RB (2016) (11)C-PBR28 binding to translocator protein increases with progression of Alzheimer’s disease. Neurobiol Aging 44:53–61. https://doi.org/10.1016/j.neurobiolaging.2016.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zou J, Tao S, Johnson A, Tomljanovic Z, Polly K, Klein J, Razlighi QR, Brickman AM, Lee S, Stern Y, Kreisl WC (2020) Microglial activation, but not tau pathology, is independently associated with amyloid positivity and memory impairment. Neurobiol Aging 85:11–21. https://doi.org/10.1016/j.neurobiolaging.2019.09.019

    Article  CAS  PubMed  Google Scholar 

  9. Nutma E, Fancy N, Weinert M, Tsartsalis S, Marzin MC, Muirhead RCJ, Falk I, Breur M, de Bruin J, Hollaus D, Pieterman R, Anink J, Story D, Chandran S, Tang J, Trolese MC, Saito T, Saido TC, Wiltshire KH, Beltran-Lobo P, Phillips A, Antel J, Healy L, Dorion M-F, Galloway DA, Benoit RY, Amossé Q, Ceyzériat K, Badina AM, Kövari E, Bendotti C, Aronica E, Radulescu CI, Wong JH, Barron AM, Smith AM, Barnes SJ, Hampton DW, van der Valk P, Jacobson S, Howell OW, Baker D, Kipp M, Kaddatz H, Tournier BB, Millet P, Matthews PM, Moore CS, Amor S, Owen DR (2023) Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases. Nat Commun 14(1):5247. https://doi.org/10.1038/s41467-023-40937-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, Hammers A, Tai YF, Fox N, Kennedy A, Rossor M, Brooks DJ (2008) Microglia, amyloid, and cognition in Alzheimer’s disease: an [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis 32(3):412–419. https://doi.org/10.1016/j.nbd.2008.08.001

    Article  CAS  PubMed  Google Scholar 

  11. Fan Z, Aman Y, Ahmed I, Chetelat G, Landeau B, Ray Chaudhuri K, Brooks DJ, Edison P (2015) Influence of microglial activation on neuronal function in Alzheimer’s and Parkinson’s disease dementia. Alzheimers Dement 11(6):608–621 e607. https://doi.org/10.1016/j.jalz.2014.06.016

    Article  PubMed  Google Scholar 

  12. Passamonti L, Tsvetanov KA, Jones PS, Bevan-Jones WR, Arnold R, Borchert RJ, Mak E, Su L, O’Brien JT, Rowe JB (2019) Neuroinflammation and functional connectivity in Alzheimer’s disease: interactive influences on cognitive performance. J Neurosci 39(36):7218–7226. https://doi.org/10.1523/JNEUROSCI.2574-18.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, Wakuda T, Sugihara G, Takebayashi K, Suda S, Iwata Y, Ueki T, Tsuchiya KJ, Suzuki K, Nakamura K, Ouchi Y (2011) In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 38(2):343–351. https://doi.org/10.1007/s00259-010-1612-0

    Article  CAS  PubMed  Google Scholar 

  14. Malpetti M, Passamonti L, Rittman T, Jones PS, Vazquez Rodriguez P, Bevan-Jones WR, Hong YT, Fryer TD, Aigbirhio FI, O’Brien JT, Rowe JB (2020) Neuroinflammation and Tau colocalize in vivo in progressive supranuclear palsy. Ann Neurol 88(6):1194–1204. https://doi.org/10.1002/ana.25911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nicastro N, Malpetti M, Mak E, Williams GB, Bevan-Jones WR, Carter SF, Passamonti L, Fryer TD, Hong YT, Aigbirhio FI, Rowe JB, O’Brien JT (2020) Gray matter changes related to microglial activation in Alzheimer’s disease. Neurobiol Aging 94:236–242. https://doi.org/10.1016/j.neurobiolaging.2020.06.010

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dani M, Wood M, Mizoguchi R, Fan Z, Walker Z, Morgan R, Hinz R, Biju M, Kuruvilla T, Brooks DJ, Edison P (2018) Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain 141(9):2740–2754. https://doi.org/10.1093/brain/awy188

    Article  PubMed  Google Scholar 

  17. Ismail R, Parbo P, Madsen LS, Hansen AK, Hansen KV, Schaldemose JL, Kjeldsen PL, Stokholm MG, Gottrup H, Eskildsen SF, Brooks DJ (2020) The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer’s disease: a longitudinal PET study. J Neuroinflammation 17(1):151. https://doi.org/10.1186/s12974-020-01820-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pascoal TA, Benedet AL, Ashton NJ, Kang MS, Therriault J, Chamoun M, Savard M, Lussier FZ, Tissot C, Karikari TK, Ottoy J, Mathotaarachchi S, Stevenson J, Massarweh G, Scholl M, de Leon MJ, Soucy JP, Edison P, Blennow K, Zetterberg H, Gauthier S, Rosa-Neto P (2021) Microglial activation and tau propagate jointly across Braak stages. Nat Med 27(9):1592–1599. https://doi.org/10.1038/s41591-021-01456-w

    Article  CAS  PubMed  Google Scholar 

  19. Terada T, Yokokura M, Obi T, Bunai T, Yoshikawa E, Ando I, Shimada H, Suhara T, Higuchi M, Ouchi Y (2019) In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer’s disease. J Neurol 266(9):2186–2196. https://doi.org/10.1007/s00415-019-09400-2

    Article  PubMed  Google Scholar 

  20. Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT (2011) Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179(3):1373–1384. https://doi.org/10.1016/j.ajpath.2011.05.047

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sheffield LG, Marquis JG, Berman NE (2000) Regional distribution of cortical microglia parallels that of neurofibrillary tangles in Alzheimer’s disease. Neurosci Lett 285(3):165–168. https://doi.org/10.1016/s0304-3940(00)01037-5

    Article  CAS  PubMed  Google Scholar 

  22. Finze A, Biechele G, Rauchmann BS, Franzmeier N, Palleis C, Katzdobler S, Weidinger E, Guersel S, Schuster S, Harris S, Schmitt J, Beyer L, Gnorich J, Lindner S, Albert NL, Wetzel CH, Rupprecht R, Rominger A, Danek A, Burow L, Kurz C, Tato M, Utecht J, Papazov B, Zaganjori M, Trappmann LK, Goldhardt O, Grimmer T, Haeckert J, Janowitz D, Buerger K, Keeser D, Stoecklein S, Dietrich O, Morenas-Rodriguez E, Barthel H, Sabri O, Bartenstein P, Simons M, Haass C, Hoglinger GU, Levin J, Perneczky R, Brendel M (2023) Individual regional associations between Abeta-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies. Mol Psychiatry. https://doi.org/10.1038/s41380-023-02188-8

  23. Rauchmann BS, Brendel M, Franzmeier N, Trappmann L, Zaganjori M, Ersoezlue E, Morenas-Rodriguez E, Guersel S, Burow L, Kurz C, Haeckert J, Tato M, Utecht J, Papazov B, Pogarell O, Janowitz D, Buerger K, Ewers M, Palleis C, Weidinger E, Biechele G, Schuster S, Finze A, Eckenweber F, Rupprecht R, Rominger A, Goldhardt O, Grimmer T, Keeser D, Stoecklein S, Dietrich O, Bartenstein P, Levin J, Hoglinger G, Perneczky R (2022) Microglial activation and connectivity in Alzheimer disease and aging. Ann Neurol 92(5):768–781. https://doi.org/10.1002/ana.26465

    Article  CAS  PubMed  Google Scholar 

  24. Hu W, Pan D, Wang Y, Bao W, Zuo C, Guan Y, Hua F, Yang M, Zhao J (2020) PET imaging for dynamically monitoring Neuroinflammation in APP/PS1 mouse model using [(18)F]DPA714. Front Neurosci 14:810. https://doi.org/10.3389/fnins.2020.00810

    Article  PubMed  PubMed Central  Google Scholar 

  25. James ML, Belichenko NP, Nguyen TV, Andrews LE, Ding Z, Liu H, Bodapati D, Arksey N, Shen B, Cheng Z, Wyss-Coray T, Gambhir SS, Longo FM, Chin FT (2015) PET imaging of translocator protein (18 kDa) in a mouse model of Alzheimer’s disease using N-(2,5-dimethoxybenzyl)-2-18F-fluoro-N-(2-phenoxyphenyl)acetamide. J Nucl Med 56(2):311–316. https://doi.org/10.2967/jnumed.114.141648

    Article  CAS  PubMed  Google Scholar 

  26. Liu B, Le KX, Park MA, Wang S, Belanger AP, Dubey S, Frost JL, Holton P, Reiser V, Jones PA, Trigg W, Di Carli MF, Lemere CA (2015) In vivo detection of age- and disease-related increases in Neuroinflammation by 18F-GE180 TSPO MicroPET imaging in wild-type and Alzheimer’s transgenic mice. J Neurosci 35(47):15716–15730. https://doi.org/10.1523/jneurosci.0996-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Biechele G, Blume T, Deussing M, Zott B, Shi Y, **ang X, Franzmeier N, Kleinberger G, Peters F, Ochs K, Focke C, Sacher C, Wind K, Schmidt C, Lindner S, Gildehaus FJ, Eckenweber F, Beyer L, von Ungern-Sternberg B, Bartenstein P, Baumann K, Dorostkar MM, Rominger A, Cumming P, Willem M, Adelsberger H, Herms J, Brendel M (2021) Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation. Theranostics 11(18):8964–8976. https://doi.org/10.7150/thno.64022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blume T, Focke C, Peters F, Deussing M, Albert NL, Lindner S, Gildehaus FJ, von Ungern-Sternberg B, Ozmen L, Baumann K, Bartenstein P, Rominger A, Herms J, Brendel M (2018) Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo muPET-study. J Neuroinflammation 15(1):307. https://doi.org/10.1186/s12974-018-1347-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Biechele G, Franzmeier N, Blume T, Ewers M, Luque JM, Eckenweber F, Sacher C, Beyer L, Ruch-Rubinstein F, Lindner S, Gildehaus FJ, von Ungern-Sternberg B, Cumming P, Bartenstein P, Rominger A, Hoglinger GU, Herms J, Brendel M (2020) Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases. J Neuroinflammation 17(1):374. https://doi.org/10.1186/s12974-020-02046-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Focke C, Blume T, Zott B, Shi Y, Deussing M, Peters F, Schmidt C, Kleinberger G, Lindner S, Gildehaus FJ, Beyer L, von Ungern-Sternberg B, Bartenstein P, Ozmen L, Baumann K, Dorostkar MM, Haass C, Adelsberger H, Herms J, Rominger A, Brendel M (2019) Early and longitudinal microglial activation but not amyloid accumulation predicts cognitive outcome in PS2APP mice. J Nucl Med 60(4):548–554. https://doi.org/10.2967/jnumed.118.217703

    Article  CAS  PubMed  Google Scholar 

  31. Tournier BB, Tsartsalis S, Ceyzériat K, Fraser BH, Grégoire MC, Kövari E, Millet P (2020) Astrocytic TSPO upregulation appears before microglial TSPO in Alzheimer’s disease. J Alzheimers Dis 77(3):1043–1056. https://doi.org/10.3233/jad-200136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bartos LM, Kunte ST, Beumers P, **ang X, Wind K, Ziegler S, Bartenstein P, Choi H, Lee DS, Haass C, von Baumgarten L, Tahirovic S, Albert NL, Lindner S, Brendel M (2022) Single cell radiotracer allocation via immunomagentic sorting (scRadiotracing) to disentangle PET signals at cellular resolution. J Nucl Med 63:1459. https://doi.org/10.2967/jnumed.122.264171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kolabas ZI, Kuemmerle LB, Perneczky R, Förstera B, Ulukaya S, Ali M, Kapoor S, Bartos LM, Büttner M, Caliskan OS, Rong Z, Mai H, Höher L, Jeridi D, Molbay M, Khalin I, Deligiannis IK, Negwer M, Roberts K, Simats A, Carofiglio O, Todorov MI, Horvath I, Ozturk F, Hummel S, Biechele G, Zatcepin A, Unterrainer M, Gnörich J, Roodselaar J, Shrouder J, Khosravani P, Tast B, Richter L, Díaz-Marugán L, Kaltenecker D, Lux L, Chen Y, Zhao S, Rauchmann BS, Sterr M, Kunze I, Stanic K, Kan VWY, Besson-Girard S, Katzdobler S, Palleis C, Schädler J, Paetzold JC, Liebscher S, Hauser AE, Gokce O, Lickert H, Steinke H, Benakis C, Braun C, Martinez-Jimenez CP, Buerger K, Albert NL, Höglinger G, Levin J, Haass C, Kopczak A, Dichgans M, Havla J, Kümpfel T, Kerschensteiner M, Schifferer M, Simons M, Liesz A, Krahmer N, Bayraktar OA, Franzmeier N, Plesnila N, Erener S, Puelles VG, Delbridge C, Bhatia HS, Hellal F, Elsner M, Bechmann I, Ondruschka B, Brendel M, Theis FJ, Erturk A (2023) Distinct molecular profiles of skull bone marrow in health and neurological disorders. Cell 186(17):3706–3725.e3729. https://doi.org/10.1016/j.cell.2023.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hartnell IJ, Woodhouse D, Jasper W, Mason L, Marwaha P, Graffeuil M, Lau LC, Norman JL, Chatelet DS, Buee L, Nicoll JAR, Blum D, Dorothee G, Boche D (2023) Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology. Brain. https://doi.org/10.1093/brain/awad309

  35. Ishizawa K, Dickson DW (2001) Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 60(6):647–657. https://doi.org/10.1093/jnen/60.6.647

    Article  CAS  PubMed  Google Scholar 

  36. Lant SB, Robinson AC, Thompson JC, Rollinson S, Pickering-Brown S, Snowden JS, Davidson YS, Gerhard A, Mann DM (2014) Patterns of microglial cell activation in frontotemporal lobar degeneration. Neuropathol Appl Neurobiol 40(6):686–696. https://doi.org/10.1111/nan.12092

    Article  CAS  PubMed  Google Scholar 

  37. Woollacott IOC, Toomey CE, Strand C, Courtney R, Benson BC, Rohrer JD, Lashley T (2020) Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration. J Neuroinflammation 17(1):234. https://doi.org/10.1186/s12974-020-01907-0

    Article  PubMed  PubMed Central  Google Scholar 

  38. Broce I, Karch CM, Wen N, Fan CC, Wang Y, Tan CH, Kouri N, Ross OA, Hoglinger GU, Muller U, Hardy J, International FTDGC, Momeni P, Hess CP, Dillon WP, Miller ZA, Bonham LW, Rabinovici GD, Rosen HJ, Schellenberg GD, Franke A, Karlsen TH, Veldink JH, Ferrari R, Yokoyama JS, Miller BL, Andreassen OA, Dale AM, Desikan RS, Sugrue LP (2018) Immune-related genetic enrichment in frontotemporal dementia: an analysis of genome-wide association studies. PLoS Med 15(1):e1002487. https://doi.org/10.1371/journal.pmed.1002487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JB, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernandez I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimon J, Lleo A, Blesa R, Waldo ML, Nilsson K, Nilsson C, Mackenzie IR, Hsiung GY, Mann DM, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JC, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EG, Seelaar H, Pijnenburg YA, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol 13(7):686–699. https://doi.org/10.1016/S1474-4422(14)70065-1

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, Group PSPGS, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Muller U, Schellenberg GD (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43(7):699–705. https://doi.org/10.1038/ng.859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pottier C, Ren Y, Perkerson RB 3rd, Baker M, Jenkins GD, van Blitterswijk M, DeJesus-Hernandez M, van Rooij JGJ, Murray ME, Christopher E, McDonnell SK, Fogarty Z, Batzler A, Tian S, Vicente CT, Matchett B, Karydas AM, Hsiung GR, Seelaar H, Mol MO, Finger EC, Graff C, Oijerstedt L, Neumann M, Heutink P, Synofzik M, Wilke C, Prudlo J, Rizzu P, Simon-Sanchez J, Edbauer D, Roeber S, Diehl-Schmid J, Evers BM, King A, Mesulam MM, Weintraub S, Geula C, Bieniek KF, Petrucelli L, Ahern GL, Reiman EM, Woodruff BK, Caselli RJ, Huey ED, Farlow MR, Grafman J, Mead S, Grinberg LT, Spina S, Grossman M, Irwin DJ, Lee EB, Suh E, Snowden J, Mann D, Ertekin-Taner N, Uitti RJ, Wszolek ZK, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Hodges JR, Piguet O, Geier EG, Yokoyama JS, Rissman RA, Rogaeva E, Keith J, Zinman L, Tartaglia MC, Cairns NJ, Cruchaga C, Ghetti B, Kofler J, Lopez OL, Beach TG, Arzberger T, Herms J, Honig LS, Vonsattel JP, Halliday GM, Kwok JB, White CL 3rd, Gearing M, Glass J, Rollinson S, Pickering-Brown S, Rohrer JD, Trojanowski JQ, Van Deerlin V, Bigio EH, Troakes C, Al-Sarraj S, Asmann Y, Miller BL, Graff-Radford NR, Boeve BF, Seeley WW, Mackenzie IRA, van Swieten JC, Dickson DW, Biernacka JM, Rademakers R (2019) Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD. Acta Neuropathol 137(6):879–899. https://doi.org/10.1007/s00401-019-01962-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Respondek G, Levin J, Hoglinger GU (2018) Progressive supranuclear palsy and multiple system atrophy: clinicopathological concepts and therapeutic challenges. Curr Opin Neurol 31(4):448–454. https://doi.org/10.1097/WCO.0000000000000581

    Article  PubMed  Google Scholar 

  43. Jabbari E, Koga S, Valentino RR, Reynolds RH, Ferrari R, MMX T, Rowe JB, Dalgard CL, Scholz SW, Dickson DW, Warner TT, Revesz T, Hoglinger GU, Ross OA, Ryten M, Hardy J, Shoai M, Morris HR, Group PSPG (2021) Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. Lancet Neurol 20(2):107–116. https://doi.org/10.1016/S1474-4422(20)30394-X

    Article  CAS  PubMed  Google Scholar 

  44. Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, West AB (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32(5):1602–1611. https://doi.org/10.1523/JNEUROSCI.5601-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord 21(1):89–93. https://doi.org/10.1002/mds.20668

    Article  PubMed  Google Scholar 

  46. Malpetti M, Kievit RA, Passamonti L, Jones PS, Tsvetanov KA, Rittman T, Mak E, Nicastro N, Bevan-Jones WR, Su L, Hong YT, Fryer TD, Aigbirhio FI, O’Brien JT, Rowe JB (2020) Microglial activation and tau burden predict cognitive decline in Alzheimer’s disease. Brain 143(5):1588–1602. https://doi.org/10.1093/brain/awaa088

    Article  PubMed  PubMed Central  Google Scholar 

  47. Palleis C, Sauerbeck J, Beyer L, Harris S, Schmitt J, Morenas-Rodriguez E, Finze A, Nitschmann A, Ruch-Rubinstein F, Eckenweber F, Biechele G, Blume T, Shi Y, Weidinger E, Prix C, Botzel K, Danek A, Rauchmann BS, Stocklein S, Lindner S, Unterrainer M, Albert NL, Wetzel C, Rupprecht R, Rominger A, Bartenstein P, Herms J, Perneczky R, Haass C, Levin J, Hoglinger GU, Brendel M (2021) In vivo assessment of Neuroinflammation in 4-repeat Tauopathies. Mov Disord 36(4):883–894. https://doi.org/10.1002/mds.28395

    Article  CAS  PubMed  Google Scholar 

  48. Malpetti M, Passamonti L, Jones PS, Street D, Rittman T, Fryer TD, Hong YT, Vasquez Rodriguez P, Bevan-Jones WR, Aigbirhio FI, O’Brien JT, Rowe JB (2021) Neuroinflammation predicts disease progression in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 92(7):769–775. https://doi.org/10.1136/jnnp-2020-325549

    Article  PubMed  Google Scholar 

  49. Gerhard A, Watts J, Trender-Gerhard I, Turkheimer F, Banati RB, Bhatia K, Brooks DJ (2004) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration. Mov Disord 19(10):1221–1226. https://doi.org/10.1002/mds.20162

    Article  PubMed  Google Scholar 

  50. Bevan-Jones WR, Cope TE, Jones PS, Kaalund SS, Passamonti L, Allinson K, Green O, Hong YT, Fryer TD, Arnold R, Coles JP, Aigbirhio FI, Larner AJ, Patterson K, O’Brien JT, Rowe JB (2020) Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain 143(3):1010–1026. https://doi.org/10.1093/brain/awaa033

    Article  PubMed  PubMed Central  Google Scholar 

  51. Malpetti M, Cope TE, Street D, Jones PS, Hezemans FH, Mak E, Tsvetanov KA, Rittman T, Bevan-Jones WR, Patterson K, Passamonti L, Fryer TD, Hong YT, Aigbirhio FI, O’Brien JT, Rowe JB (2023) Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia. Brain 146(8):3221–3231. https://doi.org/10.1093/brain/awad078

    Article  PubMed  PubMed Central  Google Scholar 

  52. Malpetti M, Rittman T, Jones PS, Cope TE, Passamonti L, Bevan-Jones WR, Patterson K, Fryer TD, Hong YT, Aigbirhio FI, O’Brien JT, Rowe JB (2021) In vivo PET imaging of neuroinflammation in familial frontotemporal dementia. J Neurol Neurosurg Psychiatry 92(3):319–322. https://doi.org/10.1136/jnnp-2020-323698

    Article  PubMed  Google Scholar 

  53. Bevan-Jones WR, Cope TE, Jones PS, Passamonti L, Hong YT, Fryer T, Arnold R, Coles JP, Aigbirhio FI, O’Brien JT, Rowe JB (2019) In vivo evidence for pre-symptomatic neuroinflammation in a MAPT mutation carrier. Ann Clin Transl Neurol 6(2):373–378. https://doi.org/10.1002/acn3.683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Miyoshi M, Shinotoh H, Wszolek ZK, Strongosky AJ, Shimada H, Arakawa R, Higuchi M, Ikoma Y, Yasuno F, Fukushi K, Irie T, Ito H, Suhara T (2010) In vivo detection of neuropathologic changes in presymptomatic MAPT mutation carriers: a PET and MRI study. Parkinsonism Relat Disord 16(6):404–408. https://doi.org/10.1016/j.parkreldis.2010.04.004

    Article  PubMed  Google Scholar 

  55. Bartos LM, Kirchleitner SV, Kolabas ZI, Quach S, Blobner J, Mueller SA, Ulukaya S, Hoeher L, Horvath I, Wind-Mark K, Holzgreve A, Ruf VC, Gold L, Kunze LH, Kunte ST, Beumers P, Antons M, Zatcepin A, Briel N, Hoermann L, Messerer D, Bartenstein P, Riemenschneider MJ, Lindner S, Ziegler S, Herms J, Lichtenthaler SF, Ertürk A, Tonn JC, Baumgarten LV, Albert NL, Brendel M (2023) Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution. bioRxiv. https://doi.org/10.1101/2023.01.26.522174

  56. Ohnishi A, Senda M, Yamane T, Mikami T, Nishida H, Nishio T, Akamatsu G, Ikari Y, Kimoto S, Aita K, Sasaki M, Shinkawa H, Yamamoto Y, Shukuri M, Mawatari A, Doi H, Watanabe Y, Onoe H (2016) Exploratory human PET study of the effectiveness of (11)C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer’s disease. Nucl Med Biol 43(7):438–444. https://doi.org/10.1016/j.nucmedbio.2016.04.005

    Article  CAS  PubMed  Google Scholar 

  57. Shukuri M, Mawatari A, Ohno M, Suzuki M, Doi H, Watanabe Y, Onoe H (2016) Detection of Cyclooxygenase-1 in activated microglia during amyloid plaque progression: PET studies in Alzheimer’s disease model mice. J Nucl Med 57(2):291–296. https://doi.org/10.2967/jnumed.115.166116

    Article  CAS  PubMed  Google Scholar 

  58. Lodder C, Scheyltjens I, Stancu IC, Botella Lucena P, Gutierrez de Rave M, Vanherle S, Vanmierlo T, Cremers N, Vanrusselt H, Brone B, Hanseeuw B, Octave JN, Bottelbergs A, Movahedi K, Dewachter I (2021) CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia. Acta Neuropathol Commun 9(1):108. https://doi.org/10.1186/s40478-021-01204-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Horti AG, Naik R, Foss CA, Minn I, Misheneva V, Du Y, Wang Y, Mathews WB, Wu Y, Hall A, LaCourse C, Ahn HH, Nam H, Lesniak WG, Valentine H, Pletnikova O, Troncoso JC, Smith MD, Calabresi PA, Savonenko AV, Dannals RF, Pletnikov MV, Pomper MG (2019) PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc Natl Acad Sci U S A 116(5):1686–1691. https://doi.org/10.1073/pnas.1812155116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhou X, Ji B, Seki C, Nagai Y, Minamimoto T, Fu**aga M, Zhang MR, Saito T, Saido TC, Suhara T, Kimura Y, Higuchi M (2021) PET imaging of colony-stimulating factor 1 receptor: a head-to-head comparison of a novel radioligand, (11)C-GW2580, and (11)C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. J Cereb Blood Flow Metab 41(9):2410–2422. https://doi.org/10.1177/0271678X211004146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Savonenko AV, Melnikova T, Wang Y, Ravert H, Gao Y, Koppel J, Lee D, Pletnikova O, Cho E, Sayyida N, Hiatt A, Troncoso J, Davies P, Dannals RF, Pomper MG, Horti AG (2015) Cannabinoid CB2 receptors in a mouse model of abeta amyloidosis: immunohistochemical analysis and suitability as a PET biomarker of neuroinflammation. PLoS One 10(6):e0129618. https://doi.org/10.1371/journal.pone.0129618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ahmad R, Postnov A, Bormans G, Versijpt J, Vandenbulcke M, Van Laere K (2016) Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 43(12):2219–2227. https://doi.org/10.1007/s00259-016-3457-7

    Article  CAS  PubMed  Google Scholar 

  63. Illes P (2020) P2X7 receptors amplify CNS damage in neurodegenerative diseases. Int J Mol Sci 21(17). https://doi.org/10.3390/ijms21175996

  64. Martin E, Amar M, Dalle C, Youssef I, Boucher C, Le Duigou C, Bruckner M, Prigent A, Sazdovitch V, Halle A, Kanellopoulos JM, Fontaine B, Delatour B, Delarasse C (2019) New role of P2X7 receptor in an Alzheimer’s disease mouse model. Mol Psychiatry 24(1):108–125. https://doi.org/10.1038/s41380-018-0108-3

    Article  CAS  PubMed  Google Scholar 

  65. McLarnon JG, Ryu JK, Walker DG, Choi HB (2006) Upregulated expression of purinergic P2X(7) receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus. J Neuropathol Exp Neurol 65(11):1090–1097. https://doi.org/10.1097/01.jnen.0000240470.97295.d3

    Article  CAS  PubMed  Google Scholar 

  66. Koole M, Schmidt ME, Hijzen A, Ravenstijn P, Vandermeulen C, Van Weehaeghe D, Serdons K, Celen S, Bormans G, Ceusters M, Zhang W, Van Nueten L, Kolb H, de Hoon J, Van Laere K (2019) (18)F-JNJ-64413739, a novel PET ligand for the P2X7 Ion Channel: radiation dosimetry, kinetic modeling, test-retest variability, and occupancy of the P2X7 antagonist JNJ-54175446. J Nucl Med 60(5):683–690. https://doi.org/10.2967/jnumed.118.216747

    Article  CAS  PubMed  Google Scholar 

  67. Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, Nordberg A (2012) 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. https://doi.org/10.2967/jnumed.110.087031

    Article  CAS  PubMed  Google Scholar 

  68. Rodriguez-Vieitez E, Carter SF, Chiotis K, Saint-Aubert L, Leuzy A, Scholl M, Almkvist O, Wall A, Langstrom B, Nordberg A (2016) Comparison of early-phase 11C-deuterium-l-Deprenyl and 11C-Pittsburgh compound B PET for assessing brain perfusion in Alzheimer disease. J Nucl Med 57(7):1071–1077. https://doi.org/10.2967/jnumed.115.168732

    Article  CAS  PubMed  Google Scholar 

  69. Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, Almkvist O, Farid K, Scholl M, Chiotis K, Thordardottir S, Graff C, Wall A, Langstrom B, Nordberg A (2016) Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease. Brain 139(Pt 3):922–936. https://doi.org/10.1093/brain/awv404

    Article  PubMed  PubMed Central  Google Scholar 

  70. Scholl M, Carter SF, Westman E, Rodriguez-Vieitez E, Almkvist O, Thordardottir S, Wall A, Graff C, Langstrom B, Nordberg A (2015) Early astrocytosis in autosomal dominant Alzheimer’s disease measured in vivo by multi-tracer positron emission tomography. Sci Rep 5:16404. https://doi.org/10.1038/srep16404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vilaplana E, Rodriguez-Vieitez E, Ferreira D, Montal V, Almkvist O, Wall A, Lleo A, Westman E, Graff C, Fortea J, Nordberg A (2020) Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease. Neurology 94(19):e2026–e2036. https://doi.org/10.1212/WNL.0000000000009405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chiotis K, Johansson C, Rodriguez-Vieitez E, Ashton NJ, Blennow K, Zetterberg H, Graff C, Nordberg A (2023) Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer’s disease with multi-modal PET and plasma GFAP. Mol Neurodegener 18(1):60. https://doi.org/10.1186/s13024-023-00647-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ballweg A, Klaus C, Vogler L, Katzdobler S, Wind K, Zatcepin A, Ziegler SI, Secgin B, Eckenweber F, Bohr B, Bernhardt A, Fietzek U, Rauchmann BS, Stoecklein S, Quach S, Beyer L, Scheifele M, Simmet M, Joseph E, Lindner S, Berg I, Koglin N, Mueller A, Stephens AW, Bartenstein P, Tonn JC, Albert NL, Kumpfel T, Kerschensteiner M, Perneczky R, Levin J, Paeger L, Herms J, Brendel M (2023) [(18)F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data. J Neuroinflammation 20(1):68. https://doi.org/10.1186/s12974-023-02749-2

    Article  PubMed  PubMed Central  Google Scholar 

  74. Harada R, Hayakawa Y, Ezura M, Lerdsirisuk P, Du Y, Ishikawa Y, Iwata R, Shidahara M, Ishiki A, Kikuchi A, Arai H, Kudo Y, Yanai K, Furumoto S, Okamura N (2021) (18)F-SMBT-1: a selective and reversible PET tracer for monoamine oxidase-B imaging. J Nucl Med 62(2):253–258. https://doi.org/10.2967/jnumed.120.244400

    Article  CAS  PubMed  Google Scholar 

  75. Villemagne VL, Harada R, Doré V, Furumoto S, Mulligan R, Kudo Y, Burnham S, Krishnadas N, Bozinovski S, Huang K, Lopresti BJ, Yanai K, Rowe CC, Okamura N (2022) First-in-humans evaluation of (18)F-SMBT-1, a novel (18)F-labeled monoamine oxidase-B PET tracer for imaging reactive Astrogliosis. J Nucl Med 63(10):1551–1559. https://doi.org/10.2967/jnumed.121.263254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wilson H, Dervenoulas G, Pagano G, Tyacke RJ, Polychronis S, Myers J, Gunn RN, Rabiner EA, Nutt D, Politis M (2019) Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson’s disease: an in vivo11C-BU99008 PET study. Brain 142(10):3116–3128. https://doi.org/10.1093/brain/awz260

    Article  PubMed  Google Scholar 

  77. Calsolaro V, Matthews PM, Donat CK, Livingston NR, Femminella GD, Guedes SS, Myers J, Fan Z, Tyacke RJ, Venkataraman AV, Perneczky R, Gunn R, Rabiner EA, Gentleman S, Parker CA, Murphy PS, Wren PB, Hinz R, Sastre M, Nutt DJ, Edison P (2021) Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using (11)C-BU99008 PET and its relationship with amyloid load. Mol Psychiatry 26(10):5848–5855. https://doi.org/10.1038/s41380-021-01193-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kumar A, Koistinen NA, Malarte ML, Nennesmo I, Ingelsson M, Ghetti B, Lemoine L, Nordberg A (2021) Astroglial tracer BU99008 detects multiple binding sites in Alzheimer’s disease brain. Mol Psychiatry 26(10):5833–5847. https://doi.org/10.1038/s41380-021-01101-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Maura Malpetti

  2. Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany

    Nicolai Franzmeier

  3. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Nicolai Franzmeier & Matthias Brendel

  4. Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany

    Matthias Brendel

  5. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Matthias Brendel

  6. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal and Gothenburg, Sweden

    Nicolai Franzmeier

Authors
  1. Maura Malpetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicolai Franzmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthias Brendel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Brendel .

Editor information

Editors and Affiliations

  1. Department of Psychiatry and Psychotherapy, LMU Klinikum, München, Germany

    Robert Perneczky

Rights and permissions

Reprints and permissions

Copyright information

© 2024 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Malpetti, M., Franzmeier, N., Brendel, M. (2024). PET Imaging to Measure Neuroinflammation In Vivo. In: Perneczky, R. (eds) Biomarkers for Alzheimer’s Disease Drug Development. Methods in Molecular Biology, vol 2785. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3774-6_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-3774-6_12

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-3773-9

  • Online ISBN: 978-1-0716-3774-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation