Neuroimaging of inflammation: high fat-induced exacerbation of Alzheimer disease

Objectives: Failure of clinical trial on late-phase Alzheimer’s disease (AD) patients may indicate that successful treatment for AD is more feasible when it is initiated at early stage of AD. Metabolic manifestations have occurs prior to the cognitive dysfunction of AD patients. Hypothalamic impairment during early stage in AD transgenic mice could provide new targets on developing therapeutic interventions. Therefore, the research on the hypothalamic impairment and underlying mechanism of metabolic manifestation of AD is a critical topic in the field. MBH of hypothalamus which is neglected previously in AD research has become the brain area of our focus.

Methods: Male C57BL/6J wild type (WT) mice and APP/PS1 transgenic (AD) mice were fed with normal chew diet (NCD) until 10 weeks old. Then, HFD-STZ WT and AD groups were fed with high fat diet (HFD) with STZ (50 mg/kg., i.p.) up to 11 or 22 weeks of dietary manipulation while NCD mice were injected with vehicle (0.1 M citrate buffer, pH 4.5). In-vivo leptin sensitivity, plasma leptin and leptin resistance were performed to assess leptin sensitivity on feeding suppression in HFD AD and WT mice. Additionally, in vivo measurement of microglial activation as measured with [¹⁸F]- FEPPA PET. The animals were anesthetized with a mixture of 2% isoflurane and 98% oxygen and injected with ~300μCi/150 μL (i.v.). The dynamic PET/CT images were acquired in 2-dimensional mode for 30 minutes. In the post-acquisition frame rebinning, 18 frames of increasing length will be generated (fifteen 60s-frames, three 600s-frames). Images were reconstructed using an ordered subset expectation maximization (OSEM2D) algorithm using 16 subsets and 4 iterations and yielded the spatial resolution of 1.5 mm at full width at half maximum (FWHM) at the center of the field of view (FOV). The image pixel size in OSEM2D reconstructed images is 0.86 mm transaxially with a 0.77 mm slice thickness. The CT imaging data were corrected for attenuation with the manufacturer’s software. Image processing will be accomplished by PMOD3.7 software (PMOD Technologies Ltd., Zurich, Switzerland). Binding potential (BP) of [¹⁸F]-FEPPA was calculated from quantitative PET imaging using Logan Graphical Analyses. The therapeutic effect of Xuefu Zhuyu Decoction (XZ), a Chinese medicine has been used to invigorate blood circulation, removes stasis, was also evaluated.

Results: Our data strongly suggests that the reciprocal augmentation of metabolic stresses and AD pathology leads to both accelerated cognitive impairments and abnormal lipid deposition in the peripheral. By using in vivo PET imaging, we also found that severe neuroinflammation and Aβ burden and astrocytic activation were observed in high-fat diet AD mice when compared to normal chew diet WT group. Moreover, in the therapy group of XZ , we found that hyperglycemia, body weight were ameliorated and serum Aβ42 was attenuated by XZ in the HFD-STZ AD mice after treatment with XZ.

Conclusion: The results from this study could be used to improve in our understanding of the mechanism of leptin insensitivity in HFDSTZ AD mice and to evaluate [¹⁸F]- FEPPA as a potential tool for diagnostic imaging and predicting therapeutic response for AD. Research Support: National Research Institute of Chinese Medicine (grant no. NRICM-101-PP02) and the Ministry of Science and Technology (grant no.MOST-102- 2320-B-077-003; MOST-103-2320-B-077-004-MY3;and MOST-103-2311-B-010- 008).