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Morphologic and functional changes in the unilateral 6-hydroxydopamine lesion rat model for Parkinson’s disease discerned with μSPECT and quantitative MRI

  • Nadja Van CampEmail author
  • Ruth Vreys
  • Koen Van Laere
  • Erwin Lauwers
  • Dirk Beque
  • Marleen Verhoye
  • Cindy Casteels
  • Alfons Verbruggen
  • Zeger Debyser
  • Luc Mortelmans
  • Jan Sijbers
  • Johan Nuyts
  • Veerle Baekelandt
  • Annemie Van der Linden
Research Article

Abstract

Object

In the present study, we aimed to evaluate the impact of neurodegeneration of the nigrostriatal tract in a rodent model of Parkinson’s disease on the different MR contrasts (T2, T1, CBF and CBV) measured in the striatum.

Material and methods

Animals were injected with 6-hydroxydopamine (6OHDA) in the substantia nigra resulting in massive loss of nigrostriatal neurons and hence dopamine depletion in the ipsilateral striatum. Using 7T MRI imaging, we have quantified T2, T1, CBF and CBV in the striata of 6OHDA and control rats. To validate the lesion size, behavioral testing, dopamine transporter μSPECT and tyrosine hydroxylase staining were performed.

Results

No significant differences were demonstrated in the absolute MRI values between 6OHDA animals and controls; however, 6OHDA animals showed significant striatal asymmetry for all MRI parameters in contrast to controls.

Conclusions

These PD-related asymmetry ratios might be the result of counteracting changes in both intact and affected striatum and allowed us to diagnose PD lesions. As lateralization is known to occur also in PD patients and might be expected in transgenic PD models as well, we propose that MR-derived asymmetry ratios in the striatum might be a useful tool for in vivo phenotyping of animal models of PD.

Keywords

Parkinson’s disease Rat Neurodegeneration SPECT MRI 

Abbreviations

6OHDA

6-Hydroxydopamine

CBF

Cerebral blood flow

CBV

Cerebral blood volume

DA

Dopamine

DAT

Dopamine transporter

FOV

Field of view

PD

Parkinson’s disease

ROI

Region of interest

SN

Substantia nigra

VOI

Volume of interest

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References

  1. 1.
    Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80(14): 4546–4550CrossRefPubMedGoogle Scholar
  2. 2.
    Mendez JS, Finn BW (1975) Use of 6-hydroxydopamine to create lesions in catecholamine neurons in rats. J Neurosurg 42(2): 166–173CrossRefPubMedGoogle Scholar
  3. 3.
    Schwarting R, Huston J (1996) Unilateral 6-hydroxydopamine lesions of meso-striatal dopamine neurons and their physiological sequelae. Prog Neurobiol 49(3): 215–266CrossRefPubMedGoogle Scholar
  4. 4.
    Huang Y, Cheung L, Rowe D, Halliday G (2004) Genetic contributions to Parkinson’s disease. Brain Res Brain Res Rev 46(1): 44–70CrossRefPubMedGoogle Scholar
  5. 5.
    Lauwers E, Beque D, Van Laere K, Nuyts J, Bormans G, Mortelmans L, Casteels C, Vercammen L, Bockstael O, Nuttin B, Debyser Z, Baekelandt V (2006) Non-invasive imaging of neuropathology in a rat model of alpha-synuclein overexpression. Neurobiol Aging 28(2): 248–257CrossRefPubMedGoogle Scholar
  6. 6.
    Lauwers E, Debyser Z, Van Dorpe J, De Strooper B, Nuttin B, Baekelandt V (2003) Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. Brain Pathol 13(3): 364–372PubMedCrossRefGoogle Scholar
  7. 7.
    Baekelandt V, Claeys A, Eggermont K, Lauwers E, De Strooper B, Nuttin B, Debyser Z (2002) Characterization of lentiviral vector-mediated gene transfer in adult mouse brain. Hum Gene Ther 13(7): 841–853CrossRefPubMedGoogle Scholar
  8. 8.
    Lo BC, Schneider BL, Bauer M, Sajadi A, Brice A, Iwatsubo T, Aebischer P (2004) Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci USA 101(50): 17510–17515CrossRefGoogle Scholar
  9. 9.
    Lo BC, Ridet JL, Schneider BL, Deglon N, Aebischer P (2002) alpha-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci USA 99(16): 10813–10818CrossRefGoogle Scholar
  10. 10.
    Boska MD, Hasan KM, Kibuule D, Banerjee R, McIntyre E, Nelson JA, Hahn T, Gendelman HE, Mosley RL (2007) Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson’s disease. Neurobiol Dis 26(3): 590–596CrossRefPubMedGoogle Scholar
  11. 11.
    Kondoh T, Bannai M, Nishino H, Torii K (2005) 6-Hydroxydopamine-induced lesions in a rat model of hemi-Parkinson’s disease monitored by magnetic resonance imaging. Exp Neurol 192(1): 194–202CrossRefPubMedGoogle Scholar
  12. 12.
    Pelled G, Bergman H, Goelman G (2002) Bilateral overactivation of the sensorimotor cortex in the unilateral rodent model of Parkinson’s disease—a functional magnetic resonance imaging study. Eur J Neurosci 15(2): 389–394CrossRefPubMedGoogle Scholar
  13. 13.
    Pelled G, Bergman H, Ben-Hur T, Goelman G (2005) Reduced basal activity and increased functional homogeneity in sensorimotor and striatum of a Parkinson’s disease rat model: a functional MRI study. Eur J Neurosci 21(8): 2227–2232CrossRefPubMedGoogle Scholar
  14. 14.
    Pelled G, Bergman H, Ben-Hur T, Goelman G (2007) Manganese-enhanced MRI in a rat model of Parkinson’s disease. J Magn Reson Imaging 26(4): 863–870CrossRefPubMedGoogle Scholar
  15. 15.
    Schwarting R, Huston J (1996) The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 50(2–3): 275–331CrossRefPubMedGoogle Scholar
  16. 16.
    Fischman AJ, Babich JW, Elmaleh DR, Barrow SA, Meltzer P, Hanson RN, Madras BK (1997) SPECT imaging of dopamine transporter sites in normal and MPTP-treated rhesus monkeys. J Nucl Med 38(1): 144–150PubMedGoogle Scholar
  17. 17.
    Booij J, Andringa G, Rijks LJ, Vermeulen RJ, De Bruin K, Boer GJ, Janssen AG, Van Royen EA (1997) 123I]FP-CIT binds to the dopamine transporter as assessed by biodistribution studies in rats and SPECT studies in MPTP-lesioned monkeys. Synapse 27(3): 183–190CrossRefPubMedGoogle Scholar
  18. 18.
    Scherfler C, Donnemiller E, Schocke M, Dierkes K, Decristoforo C, Oberladstatter M, Kolbitsch C, Zschiegner F, Riccabona G, Poewe W (2002) Evaluation of striatal dopamine transporter function in rats by in vivo beta-[123I]CIT pinhole SPECT. NeuroImage 17(1): 128–141CrossRefPubMedGoogle Scholar
  19. 19.
    Meissner W, Prunier C, Guilloteau D, Chalon S, Gross CE, Bezard E (2003) Time-course of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of Parkinson’s disease. Mol Neurobiol 28(3): 209–218CrossRefPubMedGoogle Scholar
  20. 20.
    Perese DA, Ulman J, Viola J, Ewing SE, Bankiewicz KS (1989) A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Res 494(2): 285–293CrossRefPubMedGoogle Scholar
  21. 21.
    Thomas J, Wang J, Takubo H, Sheng J, de Jesus S, Bankiewicz KS (1994) A 6-hydroxydopamine-induced selective Parkinsonian rat model: further biochemical and behavioral characterization. Exp Neurol 126(2): 159–167CrossRefPubMedGoogle Scholar
  22. 22.
    Perese DA, Ulman J, Viola J, Ewing SE, Bankiewicz KS (1989) A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Res 494(2): 285–293CrossRefPubMedGoogle Scholar
  23. 23.
    Ungerstedt U (1971) Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour. Acta Physiol Scand 367: 49–68Google Scholar
  24. 24.
    Votaw J, Byas-Smith M, Hua J, Voll R, Martarello L, Levey AI, Bowman FD, Goodman M (2003) Interaction of isoflurane with the dopamine transporter. Anesthesiology 98(2): 404–411CrossRefPubMedGoogle Scholar
  25. 25.
    Votaw JR, Byas-Smith MG, Voll R, Halkar R, Goodman MM (2004) Isoflurane alters the amount of dopamine transporter expressed on the plasma membrane in humans. Anesthesiology 101(5): 1128–1135CrossRefPubMedGoogle Scholar
  26. 26.
    Bequé D, Vanhove C, Andreyev A, Nuyts J, Defrise M (2004) Correction for imperfect camera motion and resolution recovery in pinhole SPECT. Conference proceedings of IEEE medical imaging conference, Rome, Italy M2-173Google Scholar
  27. 27.
    Bequé D, Nuyts J, Suetens P, Bormans P (2005) Optimization of geometrical calibration in pinhole SPECT. IEEE Trans Med Imaging 24(5): 667–675CrossRefPubMedGoogle Scholar
  28. 28.
    Casteels C, Vermaelen P, Nuyts J, Van Der LA, Baekelandt V, Mortelmans L, Bormans G, Van LK (2006) Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. J Nucl Med 47(11): 1858–1866PubMedGoogle Scholar
  29. 29.
    Hall S, Rutledge JN, Schallert T (1992) MRI, brain iron and experimental Parkinson’s disease. J Neurol Sci 113(2): 198–1208CrossRefPubMedGoogle Scholar
  30. 30.
    Kondoh T, Bannai M, Nishino H, Torii K (2005) 6-Hydroxydopamine-induced lesions in a rat model of hemi-Parkinson’s disease monitored by magnetic resonance imaging. Exp Neurol 192(1): 194–202CrossRefPubMedGoogle Scholar
  31. 31.
    Casteels C, Lauwers E, Bormans G, Baekelandt V, Van LK (2008) Metabolic-dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson’s disease. Eur J Nucl Med Mol Imaging 35(1): 124–134CrossRefPubMedGoogle Scholar
  32. 32.
    Araujo DM, Cherry SR, Tatsukawa KJ, Toyokuni T, Kornblum HI (2000) Deficits in striatal dopamine D(2) receptors and energy metabolism detected by in vivo microPET imaging in a rat model of Huntington’s disease. Exp Neurol 166(2): 287–297CrossRefPubMedGoogle Scholar
  33. 33.
    Booij J, Bruin K, de Win MML, Lavini C, den Heeten GJ, Habraken JBA (2003) Imaging of striatal dopamine transporters in rat brain with single pinhole SPECT and co-aligned MRI is highly reproducible. Nucl Med Biol 30(6): 643–649CrossRefPubMedGoogle Scholar
  34. 34.
    Baete K, Nuyts J, Laere KV, Van Paesschen W, Ceyssens S, De Ceuninck L, Gheysens O, Kelles A, Vanden Eynden J, Suetens P, Dupont P (2004) Evaluation of anatomy based reconstruction for partial volume correction in brain FDG-PET. NeuroImage 23(1): 305–317CrossRefPubMedGoogle Scholar
  35. 35.
    Kosta P, Argyropoulou MI, Markoula S, Konitsiotis S (2006) MRI evaluation of the basal ganglia size and iron content in patients with Parkinson’s disease. J Neurol 253(1): 26–32CrossRefPubMedGoogle Scholar
  36. 36.
    Vymazal J, Righini A, Brooks R, Canesi M, Mariani C, Leonardi M, Pezzoli G (1999) T1 and T2 in the brain of healthy subjects, patients with Parkinson disease, and patients with multiple system atrophy: relation to iron content. Radiology 211(2): 489–495PubMedGoogle Scholar
  37. 37.
    Ye F, Allen P, Martin W (1996) Basal ganglia iron content in Parkinson’s disease measured with magnetic resonance. Mov Disord 11(3): 243–249CrossRefPubMedGoogle Scholar
  38. 38.
    Brex PA, Parker GJ, Leary SM, Molyneux PD, Barker GJ, Davie CA, Thompson AJ, Miller DH (2000) Lesion heterogeneity in multiple sclerosis: a study of the relations between appearances on T1 weighted images, T1 relaxation times, and metabolite concentrations. J Neurol Neurosurg Psychiatry 68(5): 627–632CrossRefPubMedGoogle Scholar
  39. 39.
    Paxinos G (1995) The rat nervous system. 2 edn. Academic Press, CaliforniaGoogle Scholar
  40. 40.
    Hsu JL, Jung TP, Hsu CY, Hsu WC, Chen YK, Duann JR, Wang HC, Makeig S (2007) Regional CBF changes in Parkinson’s disease: a correlation with motor dysfunction. Eur J Nucl Med Mol Imaging 34(9): 1458–1466CrossRefPubMedGoogle Scholar
  41. 41.
    Yang J, Sadler TR, Givrad TK, Maarek JM, Holschneider DP (2007) Changes in brain functional activation during resting and locomotor states after unilateral nigrostriatal damage in rats. NeuroImage 36(3): 755–773CrossRefPubMedGoogle Scholar
  42. 42.
    Bezard E, Gross CE, Brotchie JM (2003) Presymptomatic compensation in Parkinson’s disease is not dopamine-mediated. Trends Neurosci 26(4): 215–221CrossRefPubMedGoogle Scholar
  43. 43.
    Dahlgren N, Lindvall O, Nobin A, Stenevi U (1981) Cerebral circulatory response to hypercapnia: effects of lesions of central dopaminergic and serotoninergic neuron systems. Brain Res 230(1–2): 221–233CrossRefPubMedGoogle Scholar
  44. 44.
    Lindvall O, Ingvar M, Stenevi U (1981) Effects of methamphetamine on blood flow in the caudate-putamen after lesions of the nigrostriatal dopaminergic bundle in the rat. Brain Res 211(1): 211–216CrossRefPubMedGoogle Scholar
  45. 45.
    Mraovitch S, Calando Y, Onteniente B, Peschanski M, Seylaz J (1993) Cerebrovascular and metabolic uncoupling in the caudate-putamen following unilateral lesion of the mesencephalic dopaminergic neurons in the rat. Neurosci Lett 157(2): 140–144CrossRefPubMedGoogle Scholar
  46. 46.
    Choi JK, Chen YI, Hamel E, Jenkins BG (2006) Brain hemodynamic changes mediated by dopamine receptors: Role of the cerebral microvasculature in dopamine-mediated neurovascular coupling. NeuroImage 30(3): 700–712CrossRefPubMedGoogle Scholar

Copyright information

© ESMRMB 2010

Authors and Affiliations

  • Nadja Van Camp
    • 1
    Email author
  • Ruth Vreys
    • 1
  • Koen Van Laere
    • 2
  • Erwin Lauwers
    • 3
  • Dirk Beque
    • 2
  • Marleen Verhoye
    • 1
    • 4
  • Cindy Casteels
    • 2
  • Alfons Verbruggen
    • 5
  • Zeger Debyser
    • 6
  • Luc Mortelmans
    • 2
  • Jan Sijbers
    • 4
  • Johan Nuyts
    • 2
  • Veerle Baekelandt
    • 3
  • Annemie Van der Linden
    • 1
  1. 1.Bio-Imaging LabUniversity of AntwerpAntwerpBelgium
  2. 2.Division of Nuclear Medicine and MoSAICUniversity Hospital Leuven and K.U. LeuvenLeuvenBelgium
  3. 3.Laboratory for Neurobiology and Gene TherapyLeuvenBelgium
  4. 4.VisielabUniversity of AntwerpAntwerpBelgium
  5. 5.Laboratory for RadiopharmacyK.U. LeuvenLeuvenBelgium
  6. 6.Laboratory for Molecular Virology and Gene therapy, Division of Molecular Medicine, Department of Molecular and Cellular MedicineK.U. LeuvenLeuvenBelgium

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