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In-vivo imaging of grey and white matter neuroinflammation in Alzheimer’s disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA

Molecular Psychiatry volume 20, pages 1579–1587 (2015)Cite this article

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Abstract

Our primary aim was to compare neuroinflammation in cognitively intact control subjects and patients with Alzheimer’s disease (AD) by using positron emission tomography (PET) with translocator protein 18kDa (TSPO)-specific radioligand [18F]-FEPPA. [18F]-FEPPA PET scans were acquired on a high-resolution research tomograph in 21 patients with AD (47– 81 years) and 21 control subjects (49–82 years). They were analyzed by using a 2-tissue compartment model with arterial plasma input function. Differences in neuroinflammation, indexed as [18F]-FEPPA binding were compared, adjusting for differences in binding affinity class as determined by a single polymorphism in the TSPO gene (rs6971). In grey matter areas, [18F]-FEPPA was significantly higher in AD compared with healthy control subjects. Large increases were seen in the hippocampus, prefrontal, temporal, parietal and occipital cortex (average Cohen’s d= 0.89). Voxel-based analyses confirmed significant clusters of neuroinflammation in the frontal, temporal and parietal cortex in patients with AD. In white matter, [18F]-FEPPA binding was elevated in the posterior limb of the internal capsule, and the cingulum bundle. Higher neuroinflammation in the parietal cortex (r= −0.7, P= 0.005), and posterior limb of the internal capsule (r= −0.8, P=0.001) was associated with poorer visuospatial function. In addition, a higher [18F]-FEPPA binding in the posterior limb of the internal capsule was associated with a greater impairment in language ability (r= −0.7, P=0.004). Elevated neuroinflammation can be detected in AD patients throughout the brain grey and white matter by using [18F]-FEPPA PET. Our results also suggest that neuroinflammation is associated with some cognitive deficits.

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References

  1. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000; 21: 383–421.

    Article  CAS  Google Scholar 

  2. Wegiel J, Wisniewski HM . The complex of microglial cells and amyloid star in three-dimensional reconstruction. Acta Neuropathol 1990; 81: 116–124.

    Article  CAS  Google Scholar 

  3. Luber-Narod J, Rogers J . Immune system associated antigens expressed by cells of the human central nervous system. Neurosci Lett 1988; 94: 17–22.

    Article  CAS  Google Scholar 

  4. McGeer PL, Itagaki S, McGeer EG . Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 1988; 76: 550–557.

    Article  CAS  Google Scholar 

  5. Kreutzberg GW . Mic roglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312–318.

    Article  CAS  Google Scholar 

  6. Chen MK, Guilarte TR . Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Ther 2008; 118: 1–17.

    Article  CAS  Google Scholar 

  7. Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S et al. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 2009; 35: 306–328.

    Article  CAS  Google Scholar 

  8. Venneti S, Wiley CA, Kofler J . Imaging microglial activation during neuroinflammation and Alzheimer's disease. J Neuroimmune Pharmacol 2009; 4: 227–243.

    Article  Google Scholar 

  9. 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: 461–467.

    Article  CAS  Google Scholar 

  10. Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE et al. Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis 2008; 32: 412–419.

    Article  CAS  Google Scholar 

  11. Schuitemaker A, Kropholler MA, Boellaard R, van der Flier WM, Kloet RW, van der Doef TF et al. Microglial activation in Alzheimer's disease: an (R)-[(1)(1)C]PK11195 positron emission tomography study. Neurobiol Aging 2013; 34: 128–136.

    Article  CAS  Google Scholar 

  12. Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 2009; 72: 56–62.

    Article  CAS  Google Scholar 

  13. Wiley CA, Lopresti BJ, Venneti S, Price J, Klunk WE, DeKosky ST et al. Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch Neurol 2009; 66: 60–67.

    Article  Google Scholar 

  14. Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B . Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging 2008; 35: 2304–2319.

    Article  Google Scholar 

  15. Wilson AA, Garcia A, Parkes J, McCormick P, Stephenson KA, Houle S et al. Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors. Nucl Med Biol 2008; 35: 305–314.

    Article  CAS  Google Scholar 

  16. Rusjan PM, Wilson AA, Bloomfield PM, Vitcu I, Meyer JH, Houle S et al. Quantitation of translocator protein binding in human brain with the novel radioligand [(18)F]-FEPPA and positron emission tomography. J Cereb Blood Flow Metab 2011; 31: 1807–1816.

    Article  CAS  Google Scholar 

  17. Kreisl WC, Jenko KJ, Hines CS, Hyoung Lyoo C, Corona W, Morse CL et al. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab 2013; 33: 53–58.

    Article  CAS  Google Scholar 

  18. Mizrahi R, Rusjan PM, Kennedy J, Pollock B, Mulsant B, Suridjan I et al. Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [(18)F]-FEPPA. J Cereb Blood Flow Metab 2012; 32: 968–972.

    Article  CAS  Google Scholar 

  19. Guo Q, Owen DR, Rabiner EA, Turkheimer FE, Gunn RN . Identifying improved TSPO PET imaging probes through biomathematics: The impact of multiple TSPO binding sites in vivo. Neuroimage 2012; 60: 902–910.

    Article  Google Scholar 

  20. 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: 1608–1618.

    Article  Google Scholar 

  21. Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 2011; 52: 24–32.

    Article  CAS  Google Scholar 

  22. Sexton CE, Kalu UG, Filippini N, Mackay CE, Ebmeier KP . A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 2010; 32, 2322. e5–e18.

    Google Scholar 

  23. Canu E, Agosta F, Spinelli EG, Magnani G, Marcone A, Scola E et al. White matter microstructural damage in Alzheimer's disease at different ages of onset. Neurobiol Aging 2013; 34: 2331–2340.

    Article  Google Scholar 

  24. Migliaccio R, Agosta F, Possin KL, Rabinovici GD, Miller BL, Gorno-Tempini ML . White matter atrophy in Alzheimer's disease variants. Alzheimers Dement 2012; 8, S78-87, e71–e72.

    Article  Google Scholar 

  25. Rose SE, Chen F, Chalk JB, Zelaya FO, Strugnell WE, Benson M et al. Loss of connectivity in Alzheimer's disease: an evaluation of white matter tract integrity with colour coded MR diffusion tensor imaging. J Neurol Neurosurg Psychiatry 2000; 69: 528–530.

    Article  CAS  Google Scholar 

  26. Duan JH, Wang HQ, Xu J, Lin X, Chen SQ, Kang Z et al. White matter damage of patients with Alzheimer's disease correlated with the decreased cognitive function. Surg Radiol Anat 2006; 28: 150–156.

    Article  Google Scholar 

  27. Zhang Y, Schuff N, Jahng GH, Bayne W, Mori S, Schad L et al. Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology 2007; 68: 13–19.

    Article  CAS  Google Scholar 

  28. Scheltens P, Barkhof F, Leys D, Wolters EC, Ravid R, Kamphorst W . Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging. Neurology 1995; 45: 883–888.

    Article  CAS  Google Scholar 

  29. Sjobeck M, Haglund M, Englund E . Decreasing myelin density reflected increasing white matter pathology in Alzheimer's disease – a neuropathological study. Int J Geriatr Psychiatry 2005; 20: 919–926.

    Article  Google Scholar 

  30. Sjobeck M, Englund E . Glial levels determine severity of white matter disease in Alzheimer's disease: a neuropathological study of glial changes. Neuropathol Appl Neurobiol 2003; 29: 159–169.

    Article  CAS  Google Scholar 

  31. Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y et al. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease. Eur J Nucl Med Mol Imaging 2011; 38: 343–351.

    Article  CAS  Google Scholar 

  32. Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease. Brain 2013; 136: 2228–2238.

    Article  Google Scholar 

  33. Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK et al. Increased binding of peripheral benzodiazepine receptor in Alzheimer's disease measured by positron emission tomography with [11C]DAA1106. Biol Psychiatry 2008; 64: 835–841.

    Article  CAS  Google Scholar 

  34. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.

    Article  CAS  Google Scholar 

  35. Folstein MF, Folstein SE, McHugh PR . ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.

    Article  CAS  Google Scholar 

  36. Smith T, Gildeh N, Holmes C . The Montreal Cognitive Assessment: validity and utility in a memory clinic setting. Can J Psychiatry 2007; 52: 329–332.

    Article  Google Scholar 

  37. Tombaugh TN . Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol 2004; 19: 203–214.

    Article  Google Scholar 

  38. Trenerry MR . Stroop Neuropsychological Screening Test Manual. Psychological Assessment Resources: Odessa, FL, 1989.

    Google Scholar 

  39. Wechsler D . Wechsler Adult Intelligence Scale– Third Edition (WAIS–III). Texas: Pearson Corp, San Antonio, 1997.

    Google Scholar 

  40. Duff K, Humphreys Clark JD, O'Bryant SE, Mold JW, Schiffer RB, Sutker PB . Utility of the RBANS in detecting cognitive impairment associated with Alzheimer's disease: sensitivity, specificity, and positive and negative predictive powers. Arch Clin Neuropsychol 2008; 23: 603–612.

    Article  Google Scholar 

  41. Morris JC . The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993; 43: 2412–2414.

    Article  CAS  Google Scholar 

  42. Gelinas I, Gauthier L, McIntyre M, Gauthier S . Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther 1999; 53: 471–481.

    Article  CAS  Google Scholar 

  43. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J . The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308–2314.

    Article  CAS  Google Scholar 

  44. Alexopoulos GS, Abrams RC, Young RC, Shamoian CA . Cornell Scale for Depression in Dementia. Biol Psychiatry 1988; 23: 271–284.

    Article  CAS  Google Scholar 

  45. Suridjan I, Rusjan PM, Voineskos AN, Selvanathan T, Setiawan E, Strafella AP et al. Neuroinflammation in healthy aging: a PET study using a novel Translocator Protein 18kDa (TSPO) radioligand, [(18)F]-FEPPA. Neuroimage 2014; 84: 868–875.

    Article  CAS  Google Scholar 

  46. Scheltens P, Barkhof F, Valk J, Algra PR, van der Hoop RG, Nauta J et al. White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer's disease. Evidence for heterogeneity. Brain 1992; 115: 735–748.

    Article  Google Scholar 

  47. Rusjan P, Mamo D, Ginovart N, Hussey D, Vitcu I, Yasuno F et al. An automated method for the extraction of regional data from PET images. Psychiatry Res 2006; 147: 79–89.

    Article  Google Scholar 

  48. Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.

    Article  CAS  Google Scholar 

  49. Duvernoy H . The Human Brain: Surface, Blood Supply and Three Dimensional Sectional Anatomy. SpringerWien: New York, 1999.

    Book  Google Scholar 

  50. Mori S, Oishi K, Jiang H, Jiang L, Li X, Akhter K et al. Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template. Neuroimage 2008; 40: 570–582.

    Article  Google Scholar 

  51. Suridjan I, Rusjan P, Kenk M, Verhoeff NP, Voineskos AN, Rotenberg D et al. Quantitative imaging of neuroinflammation in human white matter: a positron emission tomography (PET) study with translocator protein 18kDA (TSPO) radioligand, [18F]-FEPPA. Synapse 2014; 68: 536–547.

    Article  CAS  Google Scholar 

  52. Muller-Gartner HW, Links JM, Prince JL, Bryan RN, McVeigh E, Leal JP et al. Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab 1992; 12: 571–583.

    Article  CAS  Google Scholar 

  53. Bencherif B, Stumpf MJ, Links JM, Frost JJ . Application of MRI-based partial-volume correction to the analysis of PET images of mu-opioid receptors using statistical parametric mapping. J Nucl Med 2004; 45: 402–408.

    CAS  PubMed  Google Scholar 

  54. Turkheimer FE, Banati RB, Visvikis D, Aston JA, Gunn RN, Cunningham VJ . Modeling dynamic PET-SPECT studies in the wavelet domain. J Cereb Blood Flow Metab 2000; 20: 879–893.

    Article  CAS  Google Scholar 

  55. Lahiri DK, Nurnberger JI Jr . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.

    Article  CAS  Google Scholar 

  56. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A et al. An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 2011; 32: 1–5.

    Article  Google Scholar 

  57. Gulyas B, Makkai B, Kasa P, Gulya K, Bakota L, Varszegi S et al. A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system. Neurochem Int 2009; 54: 28–36.

    Article  CAS  Google Scholar 

  58. Diorio D, Welner SA, Butterworth RF, Meaney MJ, Suranyi-Cadotte BE . Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex. Neurobiol Aging 1991; 12: 255–258.

    Article  CAS  Google Scholar 

  59. Venneti S, Wang G, Nguyen J, Wiley CA . The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders. J Neuropathol Exp Neurol 2008; 67: 1001–1010.

    Article  Google Scholar 

  60. Wirths O, Breyhan H, Marcello A, Cotel MC, Bruck W, Bayer TA . Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging 2010; 31: 747–757.

    Article  CAS  Google Scholar 

  61. Ou-Yang MH, Van Nostrand WE . The absence of myelin basic protein promotes neuroinflammation and reduces amyloid beta-protein accumulation in Tg-5xFAD mice. J Neuroinflammation 2013; 10: 134.

    Article  Google Scholar 

  62. Bai F, Zhang Z, Watson DR, Yu H, Shi Y, Yuan Y et al. Abnormal integrity of association fiber tracts in amnestic mild cognitive impairment. J Neurol Sci 2009; 278: 102–106.

    Article  Google Scholar 

  63. Fellgiebel A, Schermuly I, Gerhard A, Keller I, Albrecht J, Weibrich C et al. Functional relevant loss of long association fibre tracts integrity in early Alzheimer's disease. Neuropsychologia 2008; 46: 1698–1706.

    Article  Google Scholar 

  64. Meng JZ, Guo LW, Cheng H, Chen YJ, Fang L, Qi M et al. Correlation between cognitive function and the association fibers in patients with Alzheimer's disease using diffusion tensor imaging. J Clin Neurosci 2012; 19: 1659–1663.

    Article  Google Scholar 

  65. Xie S, Xiao JX, Wang YH, Wu HK, Gong GL, Jiang XX . Evaluation of bilateral cingulum with tractography in patients with Alzheimer's disease. Neuroreport 2005; 16: 1275–1278.

    Article  Google Scholar 

  66. Fellgiebel A, Muller MJ, Wille P, Dellani PR, Scheurich A, Schmidt LG et al. Color-coded diffusion-tensor-imaging of posterior cingulate fiber tracts in mild cognitive impairment. Neurobiol Aging 2005; 26: 1193–1198.

    Article  Google Scholar 

  67. Arends YM, Duyckaerts C, Rozemuller JM, Eikelenboom P, Hauw JJ . Microglia, amyloid and dementia in alzheimer disease. A correlative study. Neurobiol Aging 2000; 21: 39–47.

    Article  CAS  Google Scholar 

  68. Vehmas AK, Kawas CH, Stewart WF, Troncoso JC . Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging 2003; 24: 321–331.

    Article  Google Scholar 

  69. Maeda J, Zhang MR, Okauchi T, Ji B, Ono M, Hattori S et al. In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer's disease and related disorders. J Neurosci 2011; 31: 4720–4730.

    Article  CAS  Google Scholar 

  70. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007; 53: 337–351.

    Article  CAS  Google Scholar 

  71. Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR . A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 2012; 26: 469–479.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Alzheimer’s society of Canada and the Scottish Rite Charitable Foundation. We thank Alan A. Wilson, Peter Bloomfield, Armando Garcia, Winston Stableford, Min Wong, Alvina Ng, Laura Nguyen and Wanna Mar for their assistance and expertise.

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Authors and Affiliations

  1. Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada

    I Suridjan, A N Voineskos, T Chow, P M Rusjan, N J Lobaugh, S Houle & R Mizrahi

  2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    I Suridjan, B G Pollock, N P L G Verhoeff, A N Voineskos, T Chow & R Mizrahi

  3. Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada

    B G Pollock, A N Voineskos & B H Mulsant

  4. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    B G Pollock, N P L G Verhoeff, A N Voineskos, T Chow, S Houle, B H Mulsant & R Mizrahi

  5. Centre for Mental Health, Baycrest Health Sciences, Toronto, ON, Canada

    N P L G Verhoeff & T Chow

  6. Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada

    T Chow & N J Lobaugh

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Suridjan, I., Pollock, B., Verhoeff, N. et al. In-vivo imaging of grey and white matter neuroinflammation in Alzheimer’s disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA. Mol Psychiatry 20, 1579–1587 (2015). https://doi.org/10.1038/mp.2015.1

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