Skip to main content

Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks

European Journal of Nuclear Medicine and Molecular Imaging volume 44, pages 533–547 (2017)Cite this article

Abstract

During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [18F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942–55. doi:10.1016/S0140-6736(10)61156-7.

    CAS  PubMed  Article  Google Scholar 

  2. Turner MR, Swash M. The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey. J Neurol Neurosurg Psychiatry. 2015;86(6):667–73. doi:10.1136/jnnp-2014-308946.

    PubMed  PubMed Central  Article  Google Scholar 

  3. Leigh PN, Abrahams S, Al-Chalabi A, Ampong MA, Goldstein LH, Johnson J. The management of motor neurone disease. J Neurol Neurosurg Psychiatry. 2003;74 Suppl 4:iv32–47.

    PubMed  PubMed Central  Google Scholar 

  4. Laferriere F, Polymenidou M. Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis. Swiss Med Wkly. 2015;145:w14054. doi:10.4414/smw.2015.14054.

    PubMed  Google Scholar 

  5. Talbot K. Motor neuron disease: the bare essentials. Pract Neurol. 2009;9(5):303–9. doi:10.1136/jnnp.2009.188151.

    PubMed  Article  Google Scholar 

  6. Fumagalli E, Funicello M, Rauen T, Gobbi M, Mennini T. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol. 2008;578(2-3):171–6. doi:10.1016/j.ejphar.2007.10.023.

    CAS  PubMed  Article  Google Scholar 

  7. Kretschmer BD, Kratzer U, Schmidt WJ. Riluzole, a glutamate release inhibitor, and motor behavior. Naunyn Schmiedebergs Arch Pharmacol. 1998;358(2):181–90.

    CAS  PubMed  Article  Google Scholar 

  8. Wang SJ, Wang KY, Wang WC. Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes). Neuroscience. 2004;125(1):191–201. doi:10.1016/j.neuroscience.2004.01.019.

    CAS  PubMed  Article  Google Scholar 

  9. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996;347(9013):1425–31.

    CAS  PubMed  Article  Google Scholar 

  10. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994;330(9):585–91. doi:10.1056/NEJM199403033300901.

    CAS  PubMed  Article  Google Scholar 

  11. Gordon PH, Cheung YK, Levin B, Andrews H, Doorish C, Macarthur RB, et al. A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotroph Lateral Scler. 2008;9(4):212–22. doi:10.1080/17482960802195632.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Beleza-Meireles A, Al-Chalabi A. Genetic studies of amyotrophic lateral sclerosis: controversies and perspectives. Amyotroph Lateral Scler. 2009;10(1):1–14. doi:10.1080/17482960802585469.

    CAS  PubMed  Article  Google Scholar 

  13. Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;364(6435):362. doi:10.1038/364362c0.

    CAS  PubMed  Google Scholar 

  14. Kwiatkowski Jr TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8. doi:10.1126/science.1166066.

    CAS  PubMed  Article  Google Scholar 

  15. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–11. doi:10.1126/science.1165942.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668–72. doi:10.1126/science.1154584.

    CAS  PubMed  Article  Google Scholar 

  17. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012;11(3):232–40. doi:10.1016/S1474-4422(12)70014-5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Chio A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, et al. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012;135(Pt 3):784–93. doi:10.1093/brain/awr366.

    PubMed  PubMed Central  Article  Google Scholar 

  19. Millecamps S, Boillee S, Le Ber I, Seilhean D, Teyssou E, Giraudeau M, et al. Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. J Med Genet. 2012;49(4):258–63. doi:10.1136/jmedgenet-2011-100699.

    CAS  PubMed  Article  Google Scholar 

  20. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002;59(7):1077–9.

    PubMed  Article  Google Scholar 

  21. Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry. 2011;82(5):476–86. doi:10.1136/jnnp.2010.212225.

    PubMed  Article  Google Scholar 

  22. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–56. doi:10.1016/j.neuron.2011.09.011.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005;65(4):586–90. doi:10.1212/01.wnl.0000172911.39167.b6.

    CAS  PubMed  Article  Google Scholar 

  24. Neary D, Snowden JS, Mann DM. Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). J Neurol Sci. 2000;180(1-2):15–20.

    CAS  PubMed  Article  Google Scholar 

  25. Canosa A, Pagani M, Cistaro A, Montuschi A, Iazzolino B, Fania P, et al. 18F-FDG-PET correlates of cognitive impairment in ALS. Neurology. 2016;86(1):44–9. doi:10.1212/WNL.0000000000002242.

    CAS  PubMed  Article  Google Scholar 

  26. Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7(11):616–30. doi:10.1038/nrneurol.2011.152.

    CAS  PubMed  Article  Google Scholar 

  27. Shaw PJ. Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry. 2005;76(8):1046–57. doi:10.1136/jnnp.2004.048652.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Lyras L, Evans PJ, Shaw PJ, Ince PG, Halliwell B. Oxidative damage and motor neurone disease difficulties in the measurement of protein carbonyls in human brain tissue. Free Radic Res. 1996;24(5):397–406.

    CAS  PubMed  Article  Google Scholar 

  29. Mitsumoto H, Santella RM, Liu X, Bogdanov M, Zipprich J, Wu HC, et al. Oxidative stress biomarkers in sporadic ALS. Amyotroph Lateral Scler. 2008;9(3):177–83. doi:10.1080/17482960801933942.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology. 2004;62(10):1758–65.

    CAS  PubMed  Article  Google Scholar 

  31. Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem. 2002;80(4):616–25.

    CAS  PubMed  Article  Google Scholar 

  32. Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998;18(9):3241–50.

    CAS  PubMed  Google Scholar 

  33. Vande Velde C, Miller TM, Cashman NR, Cleveland DW. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A. 2008;105(10):4022–7. doi:10.1073/pnas.0712209105.

    PubMed  PubMed Central  Article  Google Scholar 

  34. Wang W, Wang L, Lu J, Siedlak SL, Fujioka H, Liang J, et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med. 2016. doi:10.1038/nm.4130.

    Google Scholar 

  35. Perry TL, Krieger C, Hansen S, Eisen A. Amyotrophic lateral sclerosis: amino acid levels in plasma and cerebrospinal fluid. Ann Neurol. 1990;28(1):12–7. doi:10.1002/ana.410280105.

    CAS  PubMed  Article  Google Scholar 

  36. Shaw PJ, Forrest V, Ince PG, Richardson JP, Wastell HJ. CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration. 1995;4(2):209–16.

    CAS  PubMed  Article  Google Scholar 

  37. Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A. Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett. 1993;162(1-2):125–8.

    CAS  PubMed  Article  Google Scholar 

  38. Schmidt ML, Carden MJ, Lee VM, Trojanowski JQ. Phosphate dependent and independent neurofilament epitopes in the axonal swellings of patients with motor neuron disease and controls. Lab Invest. 1987;56(3):282–94.

    CAS  PubMed  Google Scholar 

  39. Zhang B, Tu P, Abtahian F, Trojanowski JQ, Lee VM. Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol. 1997;139(5):1307–15.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007;61(5):427–34. doi:10.1002/ana.21147.

    CAS  PubMed  Article  Google Scholar 

  41. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–3. doi:10.1126/science.1134108.

    CAS  PubMed  Article  Google Scholar 

  42. Brettschneider J, Arai K, Del Tredici K, Toledo JB, Robinson JL, Lee EB, et al. TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol. 2014;128(3):423–37. doi:10.1007/s00401-014-1299-6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Ludolph AC, Brettschneider J. TDP-43 in amyotrophic lateral sclerosis—is it a prion disease? Eur J Neurol. 2015;22(5):753–61. doi:10.1111/ene.12706.

    CAS  PubMed  Article  Google Scholar 

  44. Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 2011;10(3):253–63. doi:10.1016/S1474-4422(11)70015-1.

    CAS  PubMed  Article  Google Scholar 

  45. Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, et al. Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS One. 2012;7(6):e39216. doi:10.1371/journal.pone.0039216.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron D. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293–9.

    CAS  PubMed  Article  Google Scholar 

  47. Schrooten M, Smetcoren C, Robberecht W, Van Damme P. Benefit of the Awaji diagnostic algorithm for amyotrophic lateral sclerosis: a prospective study. Ann Neurol. 2011;70(1):79–83. doi:10.1002/ana.22380.

    PubMed  Article  Google Scholar 

  48. Galvin M, Madden C, Maguire S, Heverin M, Vajda A, Staines A, et al. Patient journey to a specialist amyotrophic lateral sclerosis multidisciplinary clinic: an exploratory study. BMC Health Serv Res. 2015;15:571. doi:10.1186/s12913-015-1229-x.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Chio A, Pagani M, Agosta F, Calvo A, Cistaro A, Filippi M. Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes. Lancet Neurol. 2014;13(12):1228–40. doi:10.1016/S1474-4422(14)70167-X.

    PubMed  Article  Google Scholar 

  50. Peretti-Viton P, Azulay JP, Trefouret S, Brunel H, Daniel C, Viton JM, et al. MRI of the intracranial corticospinal tracts in amyotrophic and primary lateral sclerosis. Neuroradiology. 1999;41(10):744–9.

    CAS  PubMed  Article  Google Scholar 

  51. Waragai M. MRI and clinical features in amyotrophic lateral sclerosis. Neuroradiology. 1997;39(12):847–51.

    CAS  PubMed  Article  Google Scholar 

  52. Cardenas-Blanco A, Machts J, Acosta-Cabronero J, Kaufmann J, Abdulla S, Kollewe K, et al. Structural and diffusion imaging versus clinical assessment to monitor amyotrophic lateral sclerosis. Neuroimage Clin. 2016;11:408–14. doi:10.1016/j.nicl.2016.03.011.

    PubMed  PubMed Central  Article  Google Scholar 

  53. Ciccarelli O, Behrens TE, Altmann DR, Orrell RW, Howard RS, Johansen-Berg H, et al. Probabilistic diffusion tractography: a potential tool to assess the rate of disease progression in amyotrophic lateral sclerosis. Brain. 2006;129(Pt 7):1859–71. doi:10.1093/brain/awl100.

    CAS  PubMed  Article  Google Scholar 

  54. Wong JC, Concha L, Beaulieu C, Johnston W, Allen PS, Kalra S. Spatial profiling of the corticospinal tract in amyotrophic lateral sclerosis using diffusion tensor imaging. J Neuroimaging. 2007;17(3):234–40. doi:10.1111/j.1552-6569.2007.00100.x.

    PubMed  Article  Google Scholar 

  55. Sheng L, Ma H, Zhong J, Shang H, Shi H, Pan P. Motor and extra-motor gray matter atrophy in amyotrophic lateral sclerosis: quantitative meta-analyses of voxel-based morphometry studies. Neurobiol Aging. 2015;36(12):3288–99. doi:10.1016/j.neurobiolaging.2015.08.018.

    PubMed  Article  Google Scholar 

  56. Agosta F, Canu E, Valsasina P, Riva N, Prelle A, Comi G, et al. Divergent brain network connectivity in amyotrophic lateral sclerosis. Neurobiol Aging. 2013;34(2):419–27. doi:10.1016/j.neurobiolaging.2012.04.015.

    PubMed  Article  Google Scholar 

  57. Jelsone-Swain LM, Fling BW, Seidler RD, Hovatter R, Gruis K, Welsh RC. Reduced interhemispheric functional connectivity in the motor cortex during rest in limb-onset amyotrophic lateral sclerosis. Front Syst Neurosci. 2010;4:158. doi:10.3389/fnsys.2010.00158.

    PubMed  PubMed Central  Article  Google Scholar 

  58. Zhou F, Xu R, Dowd E, Zang Y, Gong H, Wang Z. Alterations in regional functional coherence within the sensory-motor network in amyotrophic lateral sclerosis. Neurosci Lett. 2014;558:192–6. doi:10.1016/j.neulet.2013.11.022.

    CAS  PubMed  Article  Google Scholar 

  59. Filippini N, Douaud G, Mackay CE, Knight S, Talbot K, Turner MR. Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology. 2010;75(18):1645–52. doi:10.1212/WNL.0b013e3181fb84d1.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Quartuccio N, Van Weehaeghe D, Cistaro A, Jonsson C, Van Laere K, Pagani M. Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new? Q J Nucl Med Mol Imaging. 2014;58(4):344–54.

    CAS  PubMed  Google Scholar 

  61. Dalakas MC, Hatazawa J, Brooks RA, Di Chiro G. Lowered cerebral glucose utilization in amyotrophic lateral sclerosis. Ann Neurol. 1987;22(5):580–6. doi:10.1002/ana.410220504.

    CAS  PubMed  Article  Google Scholar 

  62. Ludolph AC, Langen KJ, Regard M, Herzog H, Kemper B, Kuwert T, et al. Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study. Acta Neurol Scand. 1992;85(2):81–9.

    CAS  PubMed  Article  Google Scholar 

  63. Hoffman JM, Mazziotta JC, Hawk TC, Sumida R. Cerebral glucose utilization in motor neuron disease. Arch Neurol. 1992;49(8):849–54.

    CAS  PubMed  Article  Google Scholar 

  64. Renard D, Collombier L, Castelnovo G, Fourcade G, Kotzki PO, LaBauge P. Brain FDG-PET changes in ALS and ALS-FTD. Acta Neurol Belg. 2011;111(4):306–9.

    PubMed  Google Scholar 

  65. Cistaro A, Valentini MC, Chio A, Nobili F, Calvo A, Moglia C, et al. Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset. Eur J Nucl Med Mol Imaging. 2012;39(2):251–9. doi:10.1007/s00259-011-1979-6.

    CAS  PubMed  Article  Google Scholar 

  66. Pagani M, Chio A, Valentini MC, Oberg J, Nobili F, Calvo A, et al. Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis. Neurology. 2014;83(12):1067–74. doi:10.1212/WNL.0000000000000792.

    CAS  PubMed  Article  Google Scholar 

  67. Van Laere K, Vanhee A, Verschueren J, De Coster L, Driesen A, Dupont P, et al. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurol. 2014;71(5):553–61. doi:10.1001/jamaneurol.2014.62.

    PubMed  Article  Google Scholar 

  68. Van Weehaeghe D, Ceccarini J, Delva A, Robberecht W, Van Damme P, Van Laere K. Prospective validation of 18F-FDG brain PET discriminant analysis methods in the diagnosis of amyotrophic lateral sclerosis. J Nucl Med. 2016. doi:10.2967/jnumed.115.166272.

    PubMed  Google Scholar 

  69. Pagani M, Oberg J, De Carli F, Calvo A, Moglia C, Canosa A, et al. Metabolic spatial connectivity in amyotrophic lateral sclerosis as revealed by independent component analysis. Hum Brain Mapp. 2016;37(3):942–53. doi:10.1002/hbm.23078.

    PubMed  Article  Google Scholar 

  70. Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. Amyotrophic lateral sclerosis—a model of corticofugal axonal spread. Nat Rev Neurol. 2013;9(12):708–14. doi:10.1038/nrneurol.2013.221.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Cistaro A, Pagani M, Montuschi A, Calvo A, Moglia C, Canosa A, et al. The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients. Eur J Nucl Med Mol Imaging. 2014;41(5):844–52. doi:10.1007/s00259-013-2667-5.

    CAS  PubMed  Article  Google Scholar 

  72. Elamin M, Phukan J, Bede P, Jordan N, Byrne S, Pender N, et al. Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology. 2011;76(14):1263–9. doi:10.1212/WNL.0b013e318214359f.

    CAS  PubMed  Article  Google Scholar 

  73. Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 2013;12(4):368–80. doi:10.1016/S1474-4422(13)70026-7.

    PubMed  Article  Google Scholar 

  74. Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A. 1994;91(22):10625–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Abe K, Yorifuji S, Nishikawa Y. Reduced isotope uptake restricted to the motor area in patients with amyotrophic lateral sclerosis. Neuroradiology. 1993;35(6):410–1.

    CAS  PubMed  Article  Google Scholar 

  76. Kew JJ, Leigh PN, Playford ED, Passingham RE, Goldstein LH, Frackowiak RS, et al. Cortical function in amyotrophic lateral sclerosis. a positron emission tomography study. Brain. 1993;116(Pt 3):655–80.

    PubMed  Article  Google Scholar 

  77. Waldemar G, Vorstrup S, Jensen TS, Johnsen A, Boysen G. Focal reductions of cerebral blood flow in amyotrophic lateral sclerosis: a [99mTc]-d, l-HMPAO SPECT study. J Neurol Sci. 1992;107(1):19–28.

    CAS  PubMed  Article  Google Scholar 

  78. Habert MO, Lacomblez L, Maksud P, El Fakhri G, Pradat JF, Meininger V. Brain perfusion imaging in amyotrophic lateral sclerosis: extent of cortical changes according to the severity and topography of motor impairment. Amyotroph Lateral Scler. 2007;8(1):9–15. doi:10.1080/14660820601048815.

    PubMed  Article  Google Scholar 

  79. Borasio GD, Linke R, Schwarz J, Schlamp V, Abel A, Mozley PD, et al. Dopaminergic deficit in amyotrophic lateral sclerosis assessed with [I-123] IPT single photon emission computed tomography. J Neurol Neurosurg Psychiatry. 1998;65(2):263–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Przedborski S, Dhawan V, Donaldson DM, Murphy PL, McKenna-Yasek D, Mandel FS, et al. Nigrostriatal dopaminergic function in familial amyotrophic lateral sclerosis patients with and without copper/zinc superoxide dismutase mutations. Neurology. 1996;47(6):1546–51.

    CAS  PubMed  Article  Google Scholar 

  81. Takahashi H, Snow BJ, Bhatt MH, Peppard R, Eisen A, Calne DB. Evidence for a dopaminergic deficit in sporadic amyotrophic lateral sclerosis on positron emission scanning. Lancet. 1993;342(8878):1016–8.

    CAS  PubMed  Article  Google Scholar 

  82. Lloyd CM, Richardson MP, Brooks DJ, Al-Chalabi A, Leigh PN. Extramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenil. Brain. 2000;123(Pt 11):2289–96.

    PubMed  Article  Google Scholar 

  83. Turner MR, Hammers A, Al-Chalabi A, Shaw CE, Andersen PM, Brooks DJ, et al. Distinct cerebral lesions in sporadic and ‘D90A’ SOD1 ALS: studies with [11C]flumazenil PET. Brain. 2005;128(Pt 6):1323–9. doi:10.1093/brain/awh509.

    CAS  PubMed  Article  Google Scholar 

  84. Wicks P, Turner MR, Abrahams S, Hammers A, Brooks DJ, Leigh PN, et al. Neuronal loss associated with cognitive performance in amyotrophic lateral sclerosis: an (11C)-flumazenil PET study. Amyotroph Lateral Scler. 2008;9(1):43–9. doi:10.1080/17482960701737716.

    CAS  PubMed  Article  Google Scholar 

  85. Turner MR, Hammers A, Al-Chalabi A, Shaw CE, Andersen PM, Brooks DJ, et al. Cortical involvement in four cases of primary lateral sclerosis using [(11)C]-flumazenil PET. J Neurol. 2007;254(8):1033–6. doi:10.1007/s00415-006-0482-7.

    PubMed  Article  Google Scholar 

  86. Turner MR, Rabiner EA, Hammers A, Al-Chalabi A, Grasby PM, Shaw CE, et al. [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain. 2005;128(Pt 4):896–905. doi:10.1093/brain/awh428.

    CAS  PubMed  Article  Google Scholar 

  87. Khandelwal PJ, Herman AM, Moussa CE. Inflammation in the early stages of neurodegenerative pathology. J Neuroimmunol. 2011;238(1-2):1–11. doi:10.1016/j.jneuroim.2011.07.002.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Hooten KG, Beers DR, Zhao W, Appel SH. Protective and toxic neuroinflammation in amyotrophic lateral sclerosis. Neurotherapeutics. 2015;12(2):364–75. doi:10.1007/s13311-014-0329-3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Alexianu ME, Kozovska M, Appel SH. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology. 2001;57(7):1282–9.

    CAS  PubMed  Article  Google Scholar 

  90. Hall ED, Oostveen JA, Gurney ME. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia. 1998;23(3):249–56.

    CAS  PubMed  Article  Google Scholar 

  91. McEnery MW, Snowman AM, Trifiletti RR, Snyder SH. Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A. 1992;89(8):3170–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, et al. Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis. Steroids. 1997;62(1):21–8.

    CAS  PubMed  Article  Google Scholar 

  93. Galiegue S, Tinel N, Casellas P. The peripheral benzodiazepine receptor: a promising therapeutic drug target. Curr Med Chem. 2003;10(16):1563–72.

    CAS  PubMed  Article  Google Scholar 

  94. Lavisse S, Garcia-Lorenzo D, Peyronneau MA, Bodini B, Thiriez C, Kuhnast B, et al. Optimized quantification of translocator protein radioligand (1)(8)F-DPA-714 uptake in the brain of genotyped healthy volunteers. J Nucl Med. 2015;56(7):1048–54. doi:10.2967/jnumed.115.156083.

  95. 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. 2010;30(9):1608–18. doi:10.1038/jcbfm.2010.63.

    PubMed  PubMed Central  Article  Google Scholar 

  96. Cagnin A, Gerhard A, Banati RB. In vivo imaging of neuroinflammation. Eur Neuropsychopharmacol. 2002;12(6):581–6.

    CAS  PubMed  Article  Google Scholar 

  97. Benavides J, Fage D, Carter C, Scatton B. Peripheral type benzodiazepine binding sites are a sensitive indirect index of neuronal damage. Brain Res. 1987;421(1-2):167–72.

    CAS  PubMed  Article  Google Scholar 

  98. Benavides J, Quarteronet D, Imbault F, Malgouris C, Uzan A, Renault C, et al. Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization. J Neurochem. 1983;41(6):1744–50.

    CAS  PubMed  Article  Google Scholar 

  99. Le Fur G, Guilloux F, Rufat P, Benavides J, Uzan A, Renault C, et al. Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3 isoquinolinecarboxamide. II. In vivo studies. Life Sci. 1983;32(16):1849–56.

    PubMed  Article  Google Scholar 

  100. Le Fur G, Perrier ML, Vaucher N, Imbault F, Flamier A, Benavides J, et al. Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide. I. In vitro studies. Life Sci. 1983;32(16):1839–47.

    PubMed  Article  Google Scholar 

  101. Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, et al. Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab. 2007;27(12):1975–86. doi:10.1038/sj.jcbfm.9600500.

    CAS  PubMed  Article  Google Scholar 

  102. Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage. 2005;24(2):591–5. doi:10.1016/j.neuroimage.2004.09.034.

    PubMed  Article  Google Scholar 

  103. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In vivo measurement of activated microglia in dementia. Lancet. 2001;358(9280):461–7. doi:10.1016/S0140-6736(01)05625-2.

    CAS  PubMed  Article  Google Scholar 

  104. Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000;123(Pt 11):2321–37.

    PubMed  Article  Google Scholar 

  105. Sitte HH, Wanschitz J, Budka H, Berger ML. Autoradiography with [3H]PK11195 of spinal tract degeneration in amyotrophic lateral sclerosis. Acta Neuropathol. 2001;101(2):75–8.

    CAS  PubMed  Google Scholar 

  106. Engelhardt JI, Tajti J, Appel SH. Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol. 1993;50(1):30–6.

    CAS  PubMed  Article  Google Scholar 

  107. Troost D, Van den Oord JJ, de Jong Vianney JM. Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 1990;16(5):401–10.

    CAS  PubMed  Article  Google Scholar 

  108. Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15(3):601–9. doi:10.1016/j.nbd.2003.12.012.

    CAS  PubMed  Article  Google Scholar 

  109. Zurcher NR, Loggia ML, Lawson R, Chonde DB, Izquierdo-Garcia D, Yasek JE, et al. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. Neuroimage Clin. 2015;7:409–14. doi:10.1016/j.nicl.2015.01.009.

    PubMed  PubMed Central  Article  Google Scholar 

  110. Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A, et al. Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J Nucl Med. 2009;50(3):468–76. doi:10.2967/jnumed.108.058669.

    CAS  PubMed  Article  Google Scholar 

  111. James ML, Fulton RR, Vercoullie J, Henderson DJ, Garreau L, Chalon S, et al. DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med. 2008;49(5):814–22. doi:10.2967/jnumed.107.046151.

    CAS  PubMed  Article  Google Scholar 

  112. Ory D, Planas A, Dresselaers T, Gsell W, Postnov A, Celen S, et al. PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide. Nucl Med Biol. 2015;42(10):753–61. doi:10.1016/j.nucmedbio.2015.06.010.

    CAS  PubMed  Article  Google Scholar 

  113. Arlicot N, Vercouillie J, Ribeiro MJ, Tauber C, Venel Y, Baulieu JL, et al. Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation. Nucl Med Biol. 2012;39(4):570–8. doi:10.1016/j.nucmedbio.2011.10.012.

    CAS  PubMed  Article  Google Scholar 

  114. Corcia P, Tauber C, Vercoullie J, Arlicot N, Prunier C, Praline J, et al. Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS One. 2012;7(12):e52941. doi:10.1371/journal.pone.0052941.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Sperlagh B, Vizi ES, Wirkner K, Illes P. P2X7 receptors in the nervous system. Prog Neurobiol. 2006;78(6):327–46. doi:10.1016/j.pneurobio.2006.03.007.

    CAS  PubMed  Article  Google Scholar 

  116. North RA. Molecular physiology of P2X receptors. Physiol Rev. 2002;82(4):1013–67. doi:10.1152/physrev.00015.2002.

    CAS  PubMed  Article  Google Scholar 

  117. Monif M, Reid CA, Powell KL, Smart ML, Williams DA. The P2X7 receptor drives microglial activation and proliferation: a trophic role for P2X7R pore. J Neurosci. 2009;29(12):3781–91. doi:10.1523/JNEUROSCI.5512-08.2009.

    CAS  PubMed  Article  Google Scholar 

  118. Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, et al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006;6:12. doi:10.1186/1471-2377-6-12.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. Apolloni S, Amadio S, Montilli C, Volonte C, D’Ambrosi N. Ablation of P2X7 receptor exacerbates gliosis and motoneuron death in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Hum Mol Genet. 2013;22(20):4102–16. doi:10.1093/hmg/ddt259.

    CAS  PubMed  Article  Google Scholar 

  120. Duan S, Anderson CM, Keung EC, Chen Y, Chen Y, Swanson RA. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci. 2003;23(4):1320–8.

    CAS  PubMed  Google Scholar 

  121. Duan S, Neary JT. P2X(7) receptors: properties and relevance to CNS function. Glia. 2006;54(7):738–46. doi:10.1002/glia.20397.

    PubMed  Article  Google Scholar 

  122. Guile SD, Alcaraz L, Birkinshaw TN, Bowers KC, Ebden MR, Furber M, et al. Antagonists of the P2X(7) receptor. from lead identification to drug development. J Med Chem. 2009;52(10):3123–41. doi:10.1021/jm801528x.

    CAS  PubMed  Article  Google Scholar 

  123. Gunosewoyo H, Coster MJ, Bennett MR, Kassiou M. Purinergic P2X(7) receptor antagonists: chemistry and fundamentals of biological screening. Bioorg Med Chem. 2009;17(14):4861–5. doi:10.1016/j.bmc.2009.05.083.

    CAS  PubMed  Article  Google Scholar 

  124. Gunosewoyo H, Coster MJ, Kassiou M. Molecular probes for P2X7 receptor studies. Curr Med Chem. 2007;14(14):1505–23.

    CAS  PubMed  Article  Google Scholar 

  125. Able SL, Fish RL, Bye H, Booth L, Logan YR, Nathaniel C, et al. Receptor localization, native tissue binding and ex vivo occupancy for centrally penetrant P2X7 antagonists in the rat. Br J Pharmacol. 2011;162(2):405–14. doi:10.1111/j.1476-5381.2010.01025.x.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Lord B, Ameriks MK, Wang Q, Fourgeaud L, Vliegen M, Verluyten W, et al. A novel radioligand for the ATP-gated ion channel P2X7: [(3)H] JNJ-54232334. Eur J Pharmacol. 2015;765:551–9. doi:10.1016/j.ejphar.2015.09.026.

    CAS  PubMed  Article  Google Scholar 

  127. Michel AD, Chambers LJ, Clay WC, Condreay JP, Walter DS, Chessell IP. Direct labelling of the human P2X7 receptor and identification of positive and negative cooperativity of binding. Br J Pharmacol. 2007;151(1):103–14. doi:10.1038/sj.bjp.0707196.

    CAS  PubMed  Article  Google Scholar 

  128. Romagnoli R, Baraldi PG, Pavani MG, Tabrizi MA, Moorman AR, Di Virgilio F, et al. Synthesis, radiolabeling, and preliminary biological evaluation of [3H]-1-[(S)-N, O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(o-tolyl)-piperazi ne, a potent antagonist radioligand for the P2X7 receptor. Bioorg Med Chem Lett. 2004;14(22):5709–12. doi:10.1016/j.bmcl.2004.07.095.

    CAS  PubMed  Article  Google Scholar 

  129. Michel AD, Clay WC, Ng SW, Roman S, Thompson K, Condreay JP, et al. Identification of regions of the P2X(7) receptor that contribute to human and rat species differences in antagonist effects. Br J Pharmacol. 2008;155(5):738–51. doi:10.1038/bjp.2008.306.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Ory D, Celen S, Gijsbers R, Van Den Haute C, Postnov A, Koole M, et al. Preclinical evaluation of a P2X7 receptor selective radiotracer: PET studies in a rat model with local overexpression of the human P2X7 receptor and in non-human primates. J Nucl Med. 2016. doi:10.2967/jnumed.115.169995.

    PubMed  Google Scholar 

  131. Janssen B, Vugts DJ, Funke U, Spaans A, Schuit RC, Kooijman E, et al. Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [(1)(1)C]A-740003 as a novel tracer of neuroinflammation. J Labelled Comp Radiopharm. 2014;57(8):509–16. doi:10.1002/jlcr.3206.

    CAS  PubMed  Article  Google Scholar 

  132. Abberley L, Bebius A, Beswick PJ, Billinton A, Collis KL, Dean DK, et al. Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X(7) receptor. Bioorg Med Chem Lett. 2010;20(22):6370–4. doi:10.1016/j.bmcl.2010.09.101.

    CAS  PubMed  Article  Google Scholar 

  133. Ali Z, Laurijssens B, Ostenfeld T, McHugh S, Stylianou A, Scott-Stevens P, et al. Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects. Br J Clin Pharmacol. 2013;75(1):197–207. doi:10.1111/j.1365-2125.2012.04320.x.

    CAS  PubMed  Article  Google Scholar 

  134. Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Isakson P. Distribution of COX-1 and COX-2 in normal and inflamed tissues. Adv Exp Med Biol. 1997;400A:167–70.

    CAS  PubMed  Article  Google Scholar 

  135. Yasojima K, Tourtellotte WW, McGeer EG, McGeer PL. Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy. Neurology. 2001;57(6):952–6.

    CAS  PubMed  Article  Google Scholar 

  136. Almer G, Guegan C, Teismann P, Naini A, Rosoklija G, Hays AP, et al. Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann Neurol. 2001;49(2):176–85.

    CAS  PubMed  Article  Google Scholar 

  137. Pompl PN, Ho L, Bianchi M, McManus T, Qin W, Pasinetti GM. A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2003;17(6):725–7. doi:10.1096/fj.02-0876fje.

    CAS  PubMed  Google Scholar 

  138. Kaur J, Tietz O, Bhardwaj A, Marshall A, Way J, Wuest M, et al. Design, synthesis, and evaluation of an (18)F-labeled radiotracer based on Celecoxib-NBD for positron emission tomography (PET) imaging of Cyclooxygenase-2 (COX-2). ChemMedChem. 2015;10(10):1635–40. doi:10.1002/cmdc.201500287.

    CAS  PubMed  Article  Google Scholar 

  139. Tietz O, Marshall A, Wuest M, Wang M, Wuest F. Radiotracers for molecular imaging of cyclooxygenase-2 (COX-2) enzyme. Curr Med Chem. 2013;20(35):4350–69.

    CAS  PubMed  Article  Google Scholar 

  140. 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. 1995;36(7):1255–62.

    CAS  PubMed  Google Scholar 

  141. Aquilonius SM, Jossan SS, Ekblom JG, Askmark H, Gillberg PG. Increased binding of 3H-l-deprenyl in spinal cords from patients with amyotrophic lateral sclerosis as demonstrated by autoradiography. J Neural Transm Gen Sect. 1992;89(1-2):111–22.

    CAS  PubMed  Article  Google Scholar 

  142. Farid K, Carter SF, Rodriguez-Vieitez E, Almkvist O, Andersen P, Wall A, et al. Case report of complex amyotrophic lateral sclerosis with cognitive impairment and cortical amyloid deposition. J Alzheimers Dis. 2015;47(3):661–7. doi:10.3233/JAD-141965.

    PubMed  Article  Google Scholar 

  143. 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. 2007;255(1-2):17–22. doi:10.1016/j.jns.2007.01.057.

    CAS  PubMed  Article  Google Scholar 

  144. Coffey RG, Yamamoto Y, Snella E, Pross S. Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochem Pharmacol. 1996;52(5):743–51.

    CAS  PubMed  Article  Google Scholar 

  145. Evens N, Vandeputte C, Coolen C, Janssen P, Sciot R, Baekelandt V, et al. Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer. Nucl Med Biol. 2012;39(3):389–99. doi:10.1016/j.nucmedbio.2011.09.005.

    CAS  PubMed  Article  Google Scholar 

  146. Ahmad R, Koole M, Evens N, Serdons K, Verbruggen A, Bormans G, et al. Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. Mol Imaging Biol. 2013;15(4):384–90. doi:10.1007/s11307-013-0626-y.

    PubMed  Article  Google Scholar 

  147. Mu L, Bieri D, Slavik R, Drandarov K, Muller A, Cermak S, et al. Radiolabeling and in vitro /in vivo evaluation of N-(1-adamantyl)-8-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide as a PET probe for imaging cannabinoid type 2 receptor. J Neurochem. 2013;126(5):616–24. doi:10.1111/jnc.12354.

    CAS  PubMed  Article  Google Scholar 

  148. Slavik R, Herde AM, Bieri D, Weber M, Schibli R, Kramer SD, et al. Synthesis, radiolabeling and evaluation of novel 4-oxo-quinoline derivatives as PET tracers for imaging cannabinoid type 2 receptor. Eur J Med Chem. 2015;92:554–64. doi:10.1016/j.ejmech.2015.01.028.

    CAS  PubMed  Article  Google Scholar 

  149. Slavik R, Grether U, Muller Herde A, Gobbi L, Fingerle J, Ullmer C, et al. Discovery of a high affinity and selective pyridine analog as a potential positron emission tomography imaging agent for cannabinoid type 2 receptor. J Med Chem. 2015;58(10):4266–77. doi:10.1021/acs.jmedchem.5b00283.

    CAS  PubMed  Article  Google Scholar 

  150. Sperlagh B, Illes P. P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci. 2014;35(10):537–47. doi:10.1016/j.tips.2014.08.002.

    CAS  PubMed  Article  Google Scholar 

  151. Aronica E, Catania MV, Geurts J, Yankaya B, Troost D. Immunohistochemical localization of group I and II metabotropic glutamate receptors in control and amyotrophic lateral sclerosis human spinal cord: upregulation in reactive astrocytes. Neuroscience. 2001;105(2):509–20.

    CAS  PubMed  Article  Google Scholar 

  152. Hamill TG, Krause S, Ryan C, Bonnefous C, Govek S, Seiders TJ, et al. Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers. Synapse. 2005;56(4):205–16. doi:10.1002/syn.20147.

    CAS  PubMed  Article  Google Scholar 

  153. Brownell AL, Kuruppu D, Kil KE, Jokivarsi K, Poutiainen P, Zhu A, et al. PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene. J Neuroinflammation. 2015;12(1):217. doi:10.1186/s12974-015-0439-9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  154. Giribaldi F, Milanese M, Bonifacino T, Anna Rossi PI, Di Prisco S, Pittaluga A, et al. Group I metabotropic glutamate autoreceptors induce abnormal glutamate exocytosis in a mouse model of amyotrophic lateral sclerosis. Neuropharmacology. 2013;66:253–63. doi:10.1016/j.neuropharm.2012.05.018.

    CAS  PubMed  Article  Google Scholar 

  155. Milanese M, Giribaldi F, Melone M, Bonifacino T, Musante I, Carminati E, et al. Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2014;64:48–59. doi:10.1016/j.nbd.2013.11.006.

    CAS  PubMed  Article  Google Scholar 

  156. Zanotti-Fregonara P, Barth VN, Liow JS, Zoghbi SS, Clark DT, Rhoads E, et al. Evaluation in vitro and in animals of a new 11C-labeled PET radioligand for metabotropic glutamate receptors 1 in brain. Eur J Nucl Med Mol Imaging. 2013;40(2):245–53. doi:10.1007/s00259-012-2269-7.

    CAS  PubMed  Article  Google Scholar 

  157. Zanotti-Fregonara P, Barth VN, Zoghbi SS, Liow JS, Nisenbaum E, Siuda E, et al. 11C-LY2428703, a positron emission tomographic radioligand for the metabotropic glutamate receptor 1, is unsuitable for imaging in monkey and human brains. EJNMMI Res. 2013;3(1):47. doi:10.1186/2191-219X-3-47.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  158. Zanotti-Fregonara P, Xu R, Zoghbi SS, Liow JS, Fujita M, Veronese M, et al. The PET radioligand 18F-FIMX images and quantifies metabotropic glutamate receptor 1 in proportion to the regional density of its gene transcript in human brain. J Nucl Med. 2016;57(2):242–7. doi:10.2967/jnumed.115.162461.

    CAS  PubMed  Article  Google Scholar 

  159. Crevecoeur J, Kaminski RM, Rogister B, Foerch P, Vandenplas C, Neveux M, et al. Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis. Neuropathol Appl Neurobiol. 2014;40(2):191–204. doi:10.1111/nan.12054.

    CAS  PubMed  Article  Google Scholar 

  160. Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000;57(1):65–73.

    CAS  PubMed  Article  Google Scholar 

  161. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18(9):1413–7. doi:10.1038/nm.2886.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Robinson JL, Molina-Porcel L, Corrada MM, Raible K, Lee EB, Lee VM, et al. Perforant path synaptic loss correlates with cognitive impairment and Alzheimer’s disease in the oldest-old. Brain. 2014;137(Pt 9):2578–87. doi:10.1093/brain/awu190.

    PubMed  PubMed Central  Article  Google Scholar 

  163. Sunico CR, Dominguez G, Garcia-Verdugo JM, Osta R, Montero F, Moreno-Lopez B. Reduction in the motoneuron inhibitory/excitatory synaptic ratio in an early-symptomatic mouse model of amyotrophic lateral sclerosis. Brain Pathol. 2011;21(1):1–15. doi:10.1111/j.1750-3639.2010.00417.x.

    CAS  PubMed  Article  Google Scholar 

  164. Gorrie GH, Fecto F, Radzicki D, Weiss C, Shi Y, Dong H, et al. Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. Proc Natl Acad Sci U S A. 2014;111(40):14524–9. doi:10.1073/pnas.1405741111.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Buckley K, Kelly RB. Identification of a transmembrane glycoprotein specific for secretory vesicles of neural and endocrine cells. J Cell Biol. 1985;100(4):1284–94.

    CAS  PubMed  Article  Google Scholar 

  166. Mendoza-Torreblanca JG, Vanoye-Carlo A, Phillips-Farfan BV, Carmona-Aparicio L, Gomez-Lira G. Synaptic vesicle protein 2A: basic facts and role in synaptic function. Eur J Neurosci. 2013;38(11):3529–39. doi:10.1111/ejn.12360.

    PubMed  Article  Google Scholar 

  167. Estrada S, Lubberink M, Thibblin A, Sprycha M, Buchanan T, Mestdagh N, et al. [(11)C]UCB-A, a novel PET tracer for synaptic vesicle protein 2A. Nucl Med Biol. 2016;43(6):325–32. doi:10.1016/j.nucmedbio.2016.03.004.

    CAS  PubMed  Article  Google Scholar 

  168. Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, et al. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016;57(5):777–84. doi:10.2967/jnumed.115.168179.

    PubMed  Article  Google Scholar 

  169. Warnock GI, Aerts J, Bahri MA, Bretin F, Lemaire C, Giacomelli F, et al. Evaluation of 18F-UCB-H as a novel PET tracer for synaptic vesicle protein 2A in the brain. J Nucl Med. 2014;55(8):1336–41. doi:10.2967/jnumed.113.136143.

    CAS  PubMed  Article  Google Scholar 

  170. Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8(348):348ra96. doi:10.1126/scitranslmed.aaf6667.

    PubMed  Article  Google Scholar 

  171. Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science. 1998;281(5384):1851–4.

    CAS  PubMed  Article  Google Scholar 

  172. Julien JP. Neurofilaments and motor neuron disease. Trends Cell Biol. 1997;7(6):243–9. doi:10.1016/S0962-8924(97)01049-0.

    CAS  PubMed  Article  Google Scholar 

  173. Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7(5):409–16. doi:10.1016/S1474-4422(08)70071-1.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  174. Zetterstrom P, Stewart HG, Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, et al. Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models. Proc Natl Acad Sci U S A. 2007;104(35):14157–62. doi:10.1073/pnas.0700477104.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. Hamilton RL, Bowser R. Alzheimer disease pathology in amyotrophic lateral sclerosis. Acta Neuropathol. 2004;107(6):515–22. doi:10.1007/s00401-004-0843-1.

    PubMed  Article  Google Scholar 

  176. Bryson JB, Hobbs C, Parsons MJ, Bosch KD, Pandraud A, Walsh FS, et al. Amyloid precursor protein (APP) contributes to pathology in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Hum Mol Genet. 2012;21(17):3871–82. doi:10.1093/hmg/dds215.

    CAS  PubMed  Article  Google Scholar 

  177. Yamakawa Y, Shimada H, Ataka S, Tamura A, Masaki H, Naka H, et al. Two cases of dementias with motor neuron disease evaluated by Pittsburgh compound B-positron emission tomography. Neurol Sci. 2012;33(1):87–92. doi:10.1007/s10072-011-0479-6.

    PubMed  Article  Google Scholar 

  178. Matias-Guiu JA, Pytel V, Cabrera-Martin MN, Galan L, Valles-Salgado M, Guerrero A, et al. Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis. Eur J Nucl Med Mol Imaging. 2016. doi:10.1007/s00259-016-3434-1.

    PubMed  Google Scholar 

  179. D’Amico E, Factor-Litvak P, Santella RM, Mitsumoto H. Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med. 2013;65:509–27. doi:10.1016/j.freeradbiomed.2013.06.029.

    PubMed  Article  CAS  Google Scholar 

  180. Manfredi G, Xu Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion. 2005;5(2):77–87. doi:10.1016/j.mito.2005.01.002.

    CAS  PubMed  Article  Google Scholar 

  181. Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A. Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med. 1997;38(7):1155–60.

    CAS  PubMed  Google Scholar 

  182. Vavere AL, Lewis JS. Cu-ATSM: a radiopharmaceutical for the PET imaging of hypoxia. Dalton Trans. 2007;43:4893–902. doi:10.1039/b705989b.

    Article  CAS  Google Scholar 

  183. Donnelly PS, Liddell JR, Lim S, Paterson BM, Cater MA, Savva MS, et al. An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copperII. Proc Natl Acad Sci U S A. 2012;109(1):47–52. doi:10.1073/pnas.1116227108.

    CAS  PubMed  Article  Google Scholar 

  184. Yoshii Y, Yoneda M, Ikawa M, Furukawa T, Kiyono Y, Mori T, et al. Radiolabeled Cu-ATSM as a novel indicator of overreduced intracellular state due to mitochondrial dysfunction: studies with mitochondrial DNA-less rho0 cells and cybrids carrying MELAS mitochondrial DNA mutation. Nucl Med Biol. 2012;39(2):177–85. doi:10.1016/j.nucmedbio.2011.08.008.

    CAS  PubMed  Article  Google Scholar 

  185. Ikawa M, Okazawa H, Arakawa K, Kudo T, Kimura H, Fujibayashi Y, et al. PET imaging of redox and energy states in stroke-like episodes of MELAS. Mitochondrion. 2009;9(2):144–8. doi:10.1016/j.mito.2009.01.011.

    CAS  PubMed  Article  Google Scholar 

  186. Ikawa M, Okazawa H, Kudo T, Kuriyama M, Fujibayashi Y, Yoneda M. Evaluation of striatal oxidative stress in patients with Parkinson’s disease using [62Cu]ATSM PET. Nucl Med Biol. 2011;38(7):945–51. doi:10.1016/j.nucmedbio.2011.02.016.

    CAS  PubMed  Article  Google Scholar 

  187. Ikawa M, Okazawa H, Tsujikawa T, Matsunaga A, Yamamura O, Mori T, et al. Increased oxidative stress is related to disease severity in the ALS motor cortex: a PET study. Neurology. 2015;84(20):2033–9. doi:10.1212/WNL.0000000000001588.

    CAS  PubMed  Article  Google Scholar 

  188. McAllum EJ, Lim NK, Hickey JL, Paterson BM, Donnelly PS, Li QX, et al. Therapeutic effects of CuII(atsm) in the SOD1-G37R mouse model of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14(7-8):586–90. doi:10.3109/21678421.2013.824000.

    CAS  PubMed  Article  Google Scholar 

  189. Soon CP, Donnelly PS, Turner BJ, Hung LW, Crouch PJ, Sherratt NA, et al. Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model. J Biol Chem. 2011;286(51):44035–44. doi:10.1074/jbc.M111.274407.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. Williams JR, Trias E, Beilby PR, Lopez NI, Labut EM, Bradford CS, et al. Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD. Neurobiol Dis. 2016;89:1–9. doi:10.1016/j.nbd.2016.01.020.

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Nuclear Medicine, Department of Imaging and Pathology, University Hospitals Leuven and KU Leuven, Leuven, Belgium

    Stefanie M. A. Willekens, Donatienne Van Weehaeghe & Koen Van Laere

  2. Department of Neurology, University Hospitals Leuven, Leuven, Belgium

    Philip Van Damme

  3. Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven, Belgium

    Philip Van Damme

  4. Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium

    Philip Van Damme & Koen Van Laere

  5. Laboratory of Neurobiology, VIB, Vesalius Research Center, Leuven, Belgium

    Philip Van Damme

Authors
  1. Stefanie M. A. Willekens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donatienne Van Weehaeghe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip Van Damme
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koen Van Laere
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefanie M. A. Willekens.

Ethics declarations

Funding

PVD and KVL hold a senior clinical investigator ship from FWO-Vlaanderen. PVD is supported by grants from the Opening the Future Fund (KU Leuven), the Interuniversity Attraction Poles (IUAP) program P7/16 of the Belgian Federal Science Policy Office, the Alzheimer Research Foundation (SAO-FRA), the Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND), the Fund for Scientific Research Vlaanderen (FWO-Vlaanderen), under the frame of E-RARE-2 (PYRAMID) and JPND (STRENGTH and RiMod-FTD), the IWT, the ALS liga België and the Thierry Latran foundation. For ALS and neuroinflammation research, KVL is supported by the European Union’s Seventh Framework Programme (FP7/2007–2013) under Grant Agreement no. HEALTH-F2-2011-278850 (INMiND).

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with animals or human participants, performed by any of the authors.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Willekens, S.M.A., Van Weehaeghe, D., Van Damme, P. et al. Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks. Eur J Nucl Med Mol Imaging 44, 533–547 (2017). https://doi.org/10.1007/s00259-016-3587-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-016-3587-y

Keywords

  • ALS
  • Neurodegeneration
  • PET
  • Targets
  • Radiotracers