Objective/Rationale:
No treatment has been proven to slow progression of Parkinson's disease. To develop such a treatment requires an objective measure of disease progression. Current clinically based measures and other biomarkers of PD progression are of highly limited utility. Neuroimaging biomarkers hold potential to provide unbiased measurements of PD progression. However, multiple issues complicate interpretation of currently available SPECT or PET markers, which has led to conflicting findings between neuroimaging-based and clincally based measures of disease severity. One key issue is whether any of the available PET markers truly reflects the reduction of the number of nigrostriatal neurons – the nerve cells that die in PD. We propose to compare three different PET tracers reflecting different characteristics of these neurons in a pre-clinical model: [11C]DTBZ , [11C]CFT, and [18F]FDOPA and determine which one provides the most faithful reflection of the decrease in the number of neurons.
Project Description:
We will use a pre-clinical model of PD that has been administered a toxin, MPTP, which destroys dopamine-producing neurons. Different models will receive different doses. Each model will have baseline PET measures of each of the three radiotracers [11C]DTBZ, [11C]CFT, and [18F]FDOPA and baseline measures of motor behavior using validated rating scales of parkinsonism. These measures will be repeated after a stable clinical condition has been reached, two months after MPTP administration. PET measures will be compared to in vitro counts in brain tissue of nigrostriatal neurons, measures of striatal dopamine content and behavioral ratings of parkinsonism. We then will determine which PET radiotracer provides the best correlation with the change in dopaminergic neurons or behavioral changes determined by ratings scales.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This study will provide a critical step in validation of a neuroimaging biomarker of PD progression. Such a validated biomarker is required to permit testing of any disease-modifying intervention in humans. Most importantly, these studies may help us to interpret previous studies that have used these radiotracers and found discordant results compared to clinical measures of disease progression.
Anticipated Outcome:
We anticipated identifying which of these three radiotracers is the most faithful representation of nigrostriatal dopamine neurons and which radiotracers may more closely reflect striatal dopamine content – one measure of the function of the terminals of these neurons.
Progress Report
We made substantial progress on our Validation of Biomarkers for Nigrostriatal Neurons project. A critical problem has been how to measure nigrostriatal dopamine neurons which can reflect the severity of Parkinson’s disease. Different approaches have included use of radiotracers that stick to different components of these neurons and some have thought that as the number of neurons decreases, as occurs in PD, the number of these sites per neuron may change to permit compensation. We have now found no evidence of such compensation. Further, we found that using PET to measure the uptake of these tracers in the striatum does not faithfully reflect the number of cell bodies of these neurons in the substantia nigra. We also found that the degree of parkinsonism correlates with the loss of cell bodies in the nigra rather than measures of dopamine in the striatum or measures of uptake of these different tracers in the striatum. Thus, a biomarker to measure PD severity or progression needs to reflect the number of nigral cell bodies rather than striatal dopamine. We are now making progress on how to make these direct measures using PET.
Presentations & Publications
Published/In press Manuscripts:
Tian L, Karimi M, Loftin SK, Brown CA, Xia H, Xu J, Mach RH, Perlmutter JS. No differential regulation of dopamine transporter (DAT) and vesicular monoamine transporter type 2 (VMAT2) in a [pre-clinical] model of Parkinson disease. PLoS ONE 7(2): e31439, 2012. PMCID: PMC3281061
Brown CA, Campbell MC, Karimi M, Tabbal SD, Loftin SK, Tian LL, Moerlein SM, Perlmutter JS. Dopaminergic dysfunction in the nucleus accumbens and ventral tegmental area predicts increased apathetic behavior in MPTP-treated [models]. Exp Neurol, Jul;236(1):190-7, 2012.
Tabbal SD, Tian L, Karimi M, Brown C, Xia H, Loftin SK, Perlmutter JS. Low nigrostriatal reserve for motor behavior in [pre-clinical models]. Exp Neurol 237(2):355-362, 2012 [Epub ahead of print]
Karimi MK, Tian L, Brown CA, Flores HP, Loftin SK, Videen TO, Moerlein SM, Perlmutter JS: Comparison of in vivo PET with in vitro measures of presynpatic nigrostriatal neurons. Ann Neurol (in press)
In process:
Tian L, Karimi M, Brown CA, Loftin S, Perlmutter JS. Absence of functional nigrostriatal regulation in a [pre-clinical model] of nigrostriatal injury. (in preparation)
Brown CA, Karimi MK, Tian LL, Flores H, Yi S, Tabbal SD, Loftin S, Moerlein SM, Perlmutter JS: Validation of PET Measures of Dopaminergic Nigral Neurons and Parkinsonism in MPTP-lesioned [pre-clinical models] (in preparation)
Presentations include:
Society of Neuroscience Annual Meeting in New Orleans October 2012:
Moerlein et al, “Validation of Nigrostriatal PET Measures: Critical Limits”
Tabbal et al, “Low nigrostriatal reserve for motor parkinsonism in [pre-clinical models]”
Perlmutter et al “Midbrain PET measures predict nigrostriatal integrity in a [pre-clinical model] of Parkinson disease”
Tian et al “Absence of functional nigrostriatal regulation in a [pre-clinical model] of nigrostriatal injury.”
American Neurological Association Meeting in Boston, October 2012
Perlmutter JS “Molecular imaging of networks: Facts and Fantasy”
December 2012
Researchers
-
Joel S. Perlmutter, MD