[18F]FDG PET/CT Studies in Transgenic Hualpha-Syn (A53T) Parkinson’s Disease Mouse Model of α-Synucleinopathy

Abstract

Transgenic mice line M83 that express the A53T mutant α–synuclein protein at six times the level of endogenous mice α–synuclein are a model of α-synucleinopathy found in Parkinson’s disease (PD). This Hualpha-Syn (A53T) PD model is useful in assessing non-motor deficits at earlier stages of onset of PD. We report findings on metabolic changes using [18F]FDG PET/CT in the Hualpha-Syn (A53T) PD mouse model in comparison to non-carrier mice. Whole-body PET/CT imaging of male and female mice were carried out 2 h after [18F]FDG ip administration under 3% isoflurane anesthesia. Brain images were analyzed with PET images coregistered to a mouse brain MRI template. Hualpha-Syn (A53T) mice had significantly lower [18F]FDG uptake in several brain regions compared to the no-carrier mice. Significant hind limb muscle and lower spinal cord [18F]FDG hypometabolism at 9 months of age in A53T PD mice was also indicative of neurodegenerative disease, with a progressive motoric dysfunction leading to death. Significant decrease (up to 30%) in [18F]FDG uptake were observed in 9-month old male and female Hualpha-Syn (A53) mice. This is consistent with the cortical hypometabolism in PD patients. Hualpha-Syn (A53) mice may thus be a suitable model for studies related to PD α-synucleinopathy for the discovery of new biomarkers.

Longitudinal trimodal imaging of midbrain-associated network degeneration in Parkinson’s disease

“…At follow-up, clusters encompassed large portions of the bilateral SN 29 , supporting our previous conclusion that they represent metabolic consequences of cell loss in high energy consuming populations. Hypometabolism in the midbrain or specifically SN has also been reported recently in FDG-PET studies in animal models of PD 30 , 31 . Strikingly, our results indicate shifts of hypometabolism towards the medial and ventral SN, which degenerate after the lateroventral parts 32 .…”

[18F]Nifene PET/CT Imaging in Mice: Improved Methods and Preliminary Studies of α4β2* Nicotinic Acetylcholinergic Receptors in Transgenic A53T Mouse Model of α-Synucleinopathy and Post-Mortem Human Parkinson’s Disease

“…The overall regional brain distribution of [ 18 F]nifene in the non-carrier and A53T PD mice was similar, except that the amounts of bound [ 18 F]nifene in the A53T PD mice was lower. Standard uptake values (SUV) of [ 18 F]nifene were computed for the various brain regions in the non-carrier mice and the A53T PD mice using our previously reported mouse brain template [ 23 ]. Ratio of SUV of A53T PD mice over the non-carrier mice for various brain regions are shown in Figure 7 G. Several brain regions exhibited greater than 20% reductions in [ 18 F]nifene binding in the A53T PD mice brains.…”

“…The Hualpha-Syn ((A53T) PD mice have been shown to accumulate α-synuclein aggregates in these brain regions and spinal cord, potentially affecting other neurotransmitter receptor systems [ 30 ], resulting in motoric and nonmotoric deficits. Our previous [ 18 F]FDG PET/CT studies in these Hualpha-Syn ((A53T) PD mice also observed significant metabolic deficits in these brain regions and spinal cord, contributing to hind limb muscle hypometabolism and leading to hind limb paralysis [ 23 ].…”

“…Several transgenic mice models of α-synucleinopathy allow the study of PD progression [ 22 ]. Using PET/CT studies in Hualpha-Syn(A53T) α-synuclein mutant mice, we recently reported [ 18 F]FDG brain deficits, limb muscle deficits and reduction of metabolic activity in regions of the spinal cord [ 23 ]. These findings are consistent with the increased α-synuclein expression in the Hualpha-Syn(A53T) transgenic mice and spontaneously develop neurodegenerative disease between nine to 16 months of age [ 24 , 25 ].…”

“…Similar to human PD, neuronal abnormalities include pathological accumulations of α-synuclein and ubiquitin and Lewy body inclusions in neurons, with profound deficits in their motor neurons resulting in paralysis [ 22 ]. Our preliminary findings suggested hypometabolism in the lower spinal cord suggesting degeneration as a probable cause for the paralysis [ 23 ]. The Hualpha-Syn(A53T) mice also develop fine, sensorimotor, and synaptic deficits before developing age-related gross motor and cognitive impairment [ 25 ].…”