Advances in the Role of Neuroimaging to Monitor Disease Progression in Parkinson’s Disease
slower rate of clinical progression compared with the placebo group when clinical assessments were performed after a wash-out period of two weeks. Although this probably reflects inadequate washout of symptomatic effects, a more rapid rate of decline in DAT binding was noted with β-CIT imaging in the L-dopa treatment group. In studies of fetal nigral transplantation,81–83
although there was a substantial
increase in striatal FD uptake post-transplantation, clinical improvement was disappointing. In one subject studied post-mortem after grafting, a marked disparity was noted between DA neuronal counts (that were highly asymmetric) and FD uptake (which was symmetrical).81 A randomized controlled trial of intraputaminal GDNF infusion in PD similarly failed to demonstrate significant clinical benefit despite increased FD uptake.87
This discrepancy between clinical progression and RTI findings could reflect many factors, including potential confounding effects of the dopaminergic medication or other therapy on the surrogate imaging markers rather than on the disease process itself. Levodopa may act to depress DAT binding and AADC activity relative to DA agonists. Also, if DA agonists are indeed neuroprotective or levodopa neurotoxic, this effect might be masked by the higher clinical efficacy of levodopa, especially when using short wash-out periods. Moreover, clinical progression was measured using UPRDS, which reflects a composite of dopaminergic and non-dopaminergic dysfunction in PD;6
the clinical
Clinical rating scales also remain vulnerable to both patient and evaluator subjectivity. In the case of cell-based therapy such as transplantation, grafts may survive, but fail to form synaptic connections with the host striatum. It has indeed been demonstrated that there is lag between improvement in FD uptake following transplant and clinical improvement, which corresponds to improved cerebral blood flow in supplementary motor and prefrontal cortex during performance of a motor task.88
sign that best reflects the severity of the nigrostriatal lesion is bradykinesia.9
Thus, assessment of the nigrostriatal
DA system alone may be inadequate to assess the overall disease progression in PD.
1. de Rijk MC, Launer LJ, Berger K, et al., Prevalence of Parkinson’s disease in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group, Neurology, 2000;54(11 Suppl. 5):S21–S3.
2. Calne DB, Snow BJ, Lee C, Criteria for diagnosing Parkinson’s disease, Ann Neurol, 1992;(32 Suppl.):S125–S27.
3. Hornykiewicz O, Biochemical aspects of Parkinson’s disease, Neurology, 1998;51(2 Suppl. 2):S2–S9.
4. Bernheimer H, Birkmayer W, Hornykiewicz O, et al., Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations, J Neurol Sci, 1973;20(4):415–55.
5. Fearnley JM, Lees AJ, Ageing and Parkinson’s disease: substantia nigra regional selectivity, Brain, 1991;114(Pt 5):2283–301.
6. Lang AE, Obeso JA, Time to move beyond nigrostriatal dopamine deficiency in Parkinson’s disease, Ann Neurol, 2004;55(6):761–5.
7. Snow BJ, Tooyama I, McGeer EG, et al., Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels, Ann Neurol, 1993;34(3):324–30.
8. Pate BD, Kawamata T, Yamada T, et al., Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices, Ann Neurol, 1993;34(3):331–8.
9. Vingerhoets FJ, Schulzer M, Calne DB, Snow BJ, Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion?, Ann Neurol, 1997;41(1):58–64.
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11. Sossi V, Fuente-Fernandez R, Holden JE, et al., Increase in dopamine turnover occurs early in Parkinson’s disease:
into putamen, 18F-dopa PET provided proof of mechanism by detecting increased DA storage capacity after treatment. Also, while not providing a direct readout of dopaminergic function, changes in glucose metabolism can also be used to infer re-establishment of physiological connections. This approach has been successfully applied to the study of glutamic acid decarboxylase (GAD) gene transfer in the STN.90
Despite the above concerns, functional imaging still offers an objective method of assessing disease progression in PD. In trials of implantation of fetal DA cells89
Further trials are therefore needed in order to determine the contribution of possible confounding factors and to better validate imaging outcomes as biomarkers of disease progression. Proper study design and analysis are required, and the PET data must be interpreted with caution and in the context of the clinical outcome.
Not only does the pattern of glucose metabolism revert to a more physiological profile following treatment, but it can be shown that the change is more in keeping with alteration of STN function as opposed to a simple lesion effect.91
Conclusions
It is increasingly recognized that biomarkers are needed to monitor the progression of PD, if new therapies directed at disease modification are to be developed and tested. RTI of striatal dopaminergic function is widely used but is imperfect as a biomarker in PD. However, the association between these measures and clinical change has not always been straightforward.92
At best, these techniques assess
At this point, while undeniably useful, RTI studies cannot be considered an adequate surrogate endpoint for clinical trials in PD. n
evidence from a new modeling approach to PET 18 F-fluorodopa data, J Cereb Blood F Metab, 2002;22(2):232–9.
12. Doudet DJ, Chan GL, Holden JE, et al., 6-[18F]Fluoro-L-DOPA PET studies of the turnover of dopamine in MPTP-induced parkinsonism in monkeys, Synapse, 1998;29(3):225–32.
13. DeJesus OT, Endres CJ, Shelton SE, et al., Evaluation of fluorinated m-tyrosine analogs as PET imaging agents of dopamine nerve terminals: comparison with 6-fluoroDOPA, J Nucl Med, 1997;38:630–6.
14. Doudet DJ, Chan GLY, Jivan S, et al., Evaluation of dopaminergic presynaptic integrity: 6-[18F]fluoro-L-dopa versus 6-[18F]fluoro- L-m-tyrosine, J Cereb Blood F Metab, 1999;19:278–87.
15. Jordan S, Eberling JL, Bankiewicz KS, et al., 6-[18F]fluoro-L-m- tyrosine: metabolism, positron emission tomography kinetics, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesions in primates, Brain Res, 1997;750(264):276.
16. Hersch SM, Yi H, Heilman CJ, et al., Subcellular localization and molecular topology of the dopamine transporter in the striatum and substantia nigra, J Comp Neurol, 1997;388(2):211–27.
17. Nirenberg MJ, Vaughan RA, Uhl GR, et al., The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons, J Neurosci, 1996;16(2):436–47.
18. Bezard E, Dovero S, Prunier C, et al., Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-lesioned macaque model of Parkinson’s disease, J Neurosci, 2001;21(17):6853–61.
19. Pirker W, Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it?, Mov Disord, 2003;18(Suppl. 7):S43–S51.
20. Seibyl JP, Marek KL, Quinlan D, et al., Decreased single-photon
emission computed tomographic [123I]beta-CIT striatal uptake correlates with symptom severity in Parkinson’s disease, Ann Neurol, 1995;38(4):589–98.
21. Nurmi E, Bergman J, Eskola O, et al., Reproducibility and effect of levodopa on dopamine transporter function measurements: a [18F]CFT PET study, J Cereb Blood F Metab, 2000;20(11):1604–9.
22. Seibyl JP, Marek K, Sheff K, et al., Test/retest reproducibility of iodine-123-betaCIT SPECT brain measurement of dopamine transporters in Parkinson’s patients, J Nucl Med, 1997;38(9):1453–9.
23. Volkow ND, Ding YS, Fowler JS, et al., A new PET ligand for the dopamine transporter: studies in the human brain, J Nucl Med, 1995;36(12):2162–8.
24. Vander Borght TM, Sima AA, Kilbourn MR, et al., [3H]methoxytetrabenazine: a high specific activity ligand for estimating monoaminergic neuronal integrity, Neuroscience, 1995;68(3):955–62.
25. Vanderborght T, Kilbourn M, Desmond T, et al., The vesicular monoamine transporter is not regulated by dopaminergic drug treatments, Eur J Pharmacol, 1995;294:577–83.
26. Wilson JM, Kish SJ, The vesicular monoamine transporter, in contrast to the dopamine transporter, is not altered by chronic cocaine self-administration in the rat, J Neurosci, 1996;16:3507–10.
27. de la Fuente-Fernandez R, Furtado S, Guttman M, et al., VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET, Synapse, 2003;49(1):20–8.
28. Fuente-Fernandez R, Sossi V, McCormick S, et al., Visualizing vesicular dopamine dynamics in Parkinson’s disease, Synapse, 2009;63(8):713–6.
29. Boileau I, Rusjan P, Houle S, et al., Increased vesicular monoamine transporter binding during early abstinence in
the function of nigrostriatal DA terminals, rather than the number or density of nigral neurons. The potential effects of sprouting, compensatory up- or down-regulation of the receptor/transporter under study, pharmacological influences on receptor/transporter expression, and, indeed, the effects of endogenous DA, are not fully resolved. Some of the most disabling features of advanced PD do not have a major dopaminergic basis and will accordingly not be captured by dopaminergic tracers.6,93
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