8 research outputs found
Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis
BACKGROUND: [(18) F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [(18) F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques. METHODS: [(18) F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [(11)C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity. RESULTS: The different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BP(ND); r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BP(ND)) but not with the contralateral PET measures. EDVR and BP(ND) in the contralateral striatum were not different from controls and were not correlated with the denervation severity. CONCLUSIONS: The demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [(18) F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control
NEMA NU 4-2008 Comparison of preclinical PET imaging systems
The National Electrical Manufacturers Association (NEMA)
standard NU 4-2008 for performance measurements of smallanimal
tomographs was recently published. Before this standard,
there were no standard testing procedures for preclinical
PET systems, and manufacturers could not provide clear
specifications similar to those available for clinical systems
under NEMA NU 2-1994 and 2-2001. Consequently, performance
evaluation papers used methods that were modified ad
hoc from the clinical PET NEMA standard, thus making
comparisons between systems difficult. Methods: We acquired
NEMA NU 4-2008 performance data for a collection of commercial
animal PET systems manufactured since 2000: micro-
PET P4, microPET R4, microPET Focus 120, microPET Focus
220, Inveon, ClearPET, Mosaic HP, Argus (formerly eXplore
Vista), VrPET, LabPET 8, and LabPET 12. The data included
spatial resolution, counting-rate performance, scatter fraction,
sensitivity, and image quality and were acquired using settings
for routine PET. Results: The data showed a steady improvement
in system performance for newer systems as compared
with first-generation systems, with notable improvements in
spatial resolution and sensitivity. Conclusion: Variation in system
design makes direct comparisons between systems from
different vendors difficult. When considering the results from
NEMA testing, one must also consider the suitability of the
PET system for the specific imaging task at hand.This work was funded by the Natural Sciences and Engineering Research Council of Canada under Discovery Grant 341628-2007. No other potential conflict of interest relevant to this article was reported.En prens
Implementation of a motion compensation system for high resolution brain positron emission tomography
In this work we implement and validate a compensation method for subject
motion occurring during high resolution brain positron emission tomography
(PET). Head motion is acknowledged as a significant source of resolution
degradation in PET brain imaging; especially at the level of resolution, (2.5
mm)Âł , available in the tomograph currently installed at our research centre.
Several methods have been developed which are able to partially correct for
this motion, however none provide the level of correction accuracy as the
method implemented here.
An infrared motion tracking system was installed to collect subject motion
information during PET scanning. In order to apply these measurements to the
PET data, a method for aligning the two reference frames both temporally and
spatially was developed. Installation of the motion tracking system allowed an
in-depth analysis of typical subject motions encountered during scanning. This
permitted us to motivate the need for motion correction, and to identify
activities causing head motion which may be limited prior to scanning.
Motion corrections based on the acquired data were incorporated into a
statistical reconstruction algorithm. First, the position and orientation of each
motion impacted event was corrected back to a common reference position.
Second, compensation was applied for variations in the relationship between
the location of an emission event and the sensitivity of the detectors that
measured it due to motion. The consideration of variations in tomograph
sensitivity separates this motion correction method from those attempted
previously. Experimental validation using phantom data revealed that the
motion correction was able to compensate for translations ranging from a few
millimeters to a few centimeters. When applied to human data, differences in the quantitative results for images reconstructed with and without motion
correction were on the order of those changes we are attempting to study.
The motion correction algorithm was developed by a previous student in our
group (A. Rahmim), while implementation and testing of the tracking system,
and validation of the motion correction algorithm with phantom and human
studies was completed as part of this work. Routine application of this motion
correction scheme will improve the effective resolution of the tomograph,
allowing improved quantification.Science, Faculty ofPhysics and Astronomy, Department ofGraduat
Single Inflammatory Trigger Leads to Neuroinflammation in LRRK2 Rodent Model without Degeneration of Dopaminergic Neurons
Background: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system. Objective: To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design. Methods: Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra. Results: Longitudinal [C-11]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [C-11] PBR28 binding from baseline averaging 0.128 +/- 0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed. Conclusion: A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD
In vivo dopaminergic and serotonergic dysfunction inDCTN1gene mutation carriers
Photograph of a scene during a Kaw Nation Pow Wow
Behavioral deficits and striatal DA signaling in LRRK2 p.G2019S transgenic rats: a multimodal investigation including PET neuroimaging
Background: A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. Objective: Assess the behavioral consequences of LRRK2 p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from human LRRK2 mutation carriers. Methods: Rats overexpressing human LRRK2 p.G2019S were generated by BAC transgenesis and compared to non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was assayed for D2, DAT, dopamine and cAMP-regulated phosphoprotein (DARPP32) and tyrosine hydroxylase (TH) expression by Western blot, and TH by immunohistochemistry. Results: Transgenic rats had no abnormalities in measures of striatal dopamine function at 12 months. A behavioral phenotype was present, with LRRK2 p.G2019S rats performing significantly worse on the rotarod than non-transgenic littermates (26% reduction in average running duration at 6 months), but with normal performance in other motor tests. Conclusions: Neuroimaging using dopaminergic PET did not recapitulate prior studies in human LRRK2 mutation carriers. Consistently, LRRK2 p.G2019S rats do not develop overt neurodegeneration; however, they do exhibit behavioral abnormalities