PET imaging a MPTP-induced mouse model of Parkinson's disease using the fluoropropyl-dihydrotetrabenazine analog [18F]-DTBZ (AV-133).

Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons in the nigrostriatal system. Numerous researchers in the past have attempted to track the progression of dopaminergic depletion in PD. We applied a quantitative non-invasive PET imaging technique to follow this degeneration process in an MPTP-induced mouse model of PD. The VMAT2 ligand (18)F-DTBZ (AV-133) was used as a radioactive tracer in our imaging experiments to monitor the changes of the dopaminergic system. Intraperitoneal administrations of MPTP (a neurotoxin) were delivered to mice at regular intervals to induce lesions consistent with PD. Our results indicate a significant decline in the levels of striatal dopamine and its metabolites (DOPAC and HVA) following MPTP treatment as determined by HPLC method. Images obtained by positron emission tomography revealed uptake of (18)F-DTBZ analog in the mouse striatum. However, reduction in radioligand binding was evident in the striatum of MPTP lesioned animals as compared with the control group. Immunohistochemical analysis further confirmed PET imaging results and indicated the progressive loss of dopaminergic neurons in treated animals compared with the control counterparts. In conclusion, our findings suggest that MPTP induced PD in mouse model is appropriate to follow the degeneration of dopaminergic system and that (18)F-DTBZ analog is a potentially sensitive radiotracer that can used to diagnose changes associated with PD by PET imaging modality.

PET imaging in rats to discern temporal onset differences between 6-hydroxydopamine and tau gene vector neurodegeneration models.

We attempted to monitor the nigrostriatal dopaminergic system in rats with positron emission tomography (PET) during the progression of two experimental disease states. One model was 6-hydroxydopamine (6-OHDA) lesioning and the other was direct gene transfer of the microtubule-associated protein tau to the substantia nigra using an adeno-associated virus vector (AAV9). The PET ligand was 6-[18F]fluoro-L-m-tyrosine (FMT), imaged prior to, and at two intervals after initiating dopaminergic neurodegeneration. The striatum was delineated with the aid of repeated PET imaging (FMT and sodium fluoride for bone), realignment to subsequent computed axial tomography scans, and registration to an atlas, which proved essential to tracking disease progression. The striata on the two sides of the brain were compared over time after unilateral lesioning treatments. 6-OHDA reduced uptake on the ipsilateral side relative to the untreated contralateral side at both 1 and 4 weeks after lesioning, while the AAV9 tau led to reduced uptake of the tracer in the striatum at 4 weeks, but not 1 week after treatment. The amplitude of the loss of FMT uptake in striatum at 4 weeks with either model was subtle relative to the postmortem histological analysis of the tissue, but the multi-modal imaging analysis yielded statistical effects that matched well with the histology in terms of the timing of the loss of dopaminergic markers. Live longitudinal imaging successfully tracked two distinct types of disease progression in individual rats, although the FMT is not a sensitive ligand to monitor the extent of the lesion.

Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study.

UNLABELLED: Although the pathophysiology underlying the pain of fibromyalgia syndrome (FMS) remains unknown, a variety of clinical and investigational findings suggests a dysregulation of dopaminergic neurotransmission. We therefore investigated presynaptic dopaminergic function in 6 female FMS patients in comparison to 8 age- and gender-matched controls as assessed by positron emission tomography with 6-[(18)F]fluoro-L-DOPA as a tracer. Semiquantitative analysis revealed reductions in 6-[(18)F]fluoro-L-DOPA uptake in several brain regions, indicating a disruption of presynaptic dopamine activity wherein dopamine plays a putative role in natural analgesia. Although the small sample size makes these findings preliminary, it appears that FMS might be characterized by a disruption of dopaminergic neurotransmission. PERSPECTIVE: An association between FMS and reduced dopamine metabolism within the pain neuromatrix provides important insights into the pathophysiology of this mysterious disorder.