Abstract
Objective: Our aim was to assess in vivo metabolic changes using [18F]FDG PET imaging in transgenic mice following injection of α-synuclein pre-formed fibrils.
Background: Slowing intracerebral spread of α-synuclein pathology is a promising strategy to treat Parkinson’s disease and other synucleinopathies. The α-synuclein fibril inoculation model is a powerful preclinical tool for testing effectiveness of such potential disease-modifying treatments. Generally, this model has been well-characterized, but in vivo imaging data is limited. Understanding how pathological α-synuclein affects glucose metabolism via FDG PET imaging is valuable, as this non-invasive method is translatable to clinical studies.
Design/Methods: We injected α-synuclein pre-formed fibrils (PFFs) or control (PBS) into the anterior olfactory nucleus (AON) of M83 mice (containing human α-synuclein with the A53T mutation). We performed whole brain FDG PET imaging at 12 or 16 weeks post-injection (wpi). All scans were registered to a standard stereotaxic space for statistical analysis.
Results: Several regions showed hypometabolism in the injected vs. contralateral hemisphere in the PFF groups. At 12 wpi, ipsilateral olfactory regions were significantly reduced, and by 16 wpi, as pathology spread, piriform and isocortex were also significantly reduced. Control groups showed no hemispheric differences, confirming changes were not caused by the surgery. There were also clear group differences. At both timepoints, left and right olfactory regions were significantly lower in the PFF-injected group compared to the PBS group. Group average maps and voxelwise analysis further revealed more widespread hypometabolism in the PFF group, particularly at 16 wpi. This functional impairment complements other deficits in this model, including regional brain atrophy, neuronal loss, olfactory deficit, and sleep disturbances.
Conclusions: Injection of α-synuclein PFFs leads to metabolic changes measurable using FDG PET, and, in lieu of an in vivo measure of α-synuclein pathology, FDG PET is potentially a valuable, translatable tool for use in investigating treatments for PD and other synucleinopathies.
Disclosure: Dr. Deduck has nothing to disclose. Dr. Brison has nothing to disclose. Dr. Zehntner has nothing to disclose. Dr. Luk has received royalty, license fees, or contractual rights payments from Biospective, Psychogenics. Dr. Bedell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee: Biospective Inc.. Dr. Bedell holds stock and/or stock options in Stock: Biospective Inc. which sponsored research in which Dr. Bedell was involved as an investigator.
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