Semi-quantitative Assessment of Alzheimer's-like Pathology in Two Aged Polar Bears (Ursus maritimus).

Age-associated neurodegenerative changes, including amyloid ß (Aß) plaques, neurofibrillary tangles (NFTs), and amyloid angiopathy comparable to those seen in the brains of human patients with Alzheimer's disease (AD), have been reported in the brains of aged bears. However, the significance of these findings in bears is unclear due to the difficulty in assessing cognitive impairment and the lack of standardized approaches for the semiquantitative evaluation of Aß plaques and NFTs. In this study, we evaluate the neuropathologic changes in archival brain tissue of 2 aged polar bears (Ursus maritimus, ages 28 and 37) using the National Institute of Aging-Alzheimer Association (NIA-AA) consensus guidelines for the neuropathologic assessment of Alzheimer's Disease (AD). Both bears had an Aß (A) score of 3 of 3, Braak stage (B score) of 2 of 3, and neuritic plaque (C) score of 3 of 3. These findings are consistent with the neurodegenerative changes observed in brains of patients with AD. The application of NIA-AA consensus guidelines, as applied to the neuropathologic assessment of the aged bears in this report, demonstrates the use of standardized semiquantitative assessment systems for comparative, translational studies of aging in a vulnerable wildlife species.

Tracking Innate Immune Activation in a Mouse Model of Parkinson's Disease Using TREM1 and TSPO PET Tracers.

Parkinson's disease (PD) is associated with aberrant innate immune responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). Methods to investigate innate immune activation in PD are limited and have not yet elucidated key interactions between neuroinflammation and peripheral inflammation. Translocator protein 18 kDa (TSPO) PET is a widely evaluated imaging approach for studying activated microglia and peripheral myeloid lineage cells in vivo but has yet to be fully explored in PD. Here, we investigate the utility of TSPO PET in addition to PET imaging of triggering receptor expressed on myeloid cells 1 (TREM1)-a novel biomarker of proinflammatory innate immune cells-for detecting innate immune responses in the 6-hydroxydopamine mouse model of dopaminergic neuron degeneration. Methods: C57/BL6J and TREM1 knockout mice were stereotactically injected with 6-hydroxydopamine in the left striatum; control mice were injected with saline. At day 7 or 14 after surgery, mice were administered 18F-GE-180, 64Cu-TREM1 monoclonal antibody (mAb), or 64Cu-isotype control mAb and imaged by PET/CT. Ex vivo autoradiography was performed to obtain high-resolution images of tracer binding within the brain. Immunohistochemistry was conducted to verify myeloid cell activation and dopaminergic cell death, and quantitative polymerase chain reaction and flow cytometry were completed to assess levels of target in the brain. Results: PET/CT images of both tracers showed elevated signal within the striatum of 6-hydroxydopamine-injected mice compared with those injected with saline. Autoradiography afforded higher-resolution brain images and revealed significant TSPO and TREM1 tracer binding within the ipsilateral striatum of 6-hydroxydopamine mice compared with saline mice at both 7 and 14 d after toxin. Interestingly, 18F-GE-180 enabled detection of inflammation in the brain and peripheral tissues (blood and spleen) of 6-hydroxydopamine mice, whereas 64Cu-TREM1 mAb appeared to be more sensitive and specific for detecting neuroinflammation, in particular infiltrating myeloid cells, in these mice, as demonstrated by flow cytometry findings and higher tracer binding signal-to-background ratios in brain. Conclusion: TSPO and TREM1 PET tracers are promising tools for investigating different cell types involved in innate immune activation in the context of dopaminergic neurodegeneration, thus warranting further investigation in other PD rodent models and human postmortem tissue to assess their clinical potential.