Use of FDG-PET and MR imaging with cognitive testing in AD therapeutic development

Objectives Alzheimer’s disease (AD) therapeutic investigations require preclinical assessment in transgenic mice. Imaging provides complementary evidence to support cognitive tests and histopathology that can be translated to clinical trials. This research investigated the therapeutic efficacy of a non-amyloid targeting microtubule-stabilizing drug paclitaxel with in vivo imaging and cognitive tests.

Methods Mice (3xTg-AD n=25) treated by intranasal lavage with paclitaxel (0.6mg/kg) (TgTAX) or saline (TgSAL) at 14 d intervals from 10-22wks (n=17) OR 47-58wks (n=8) and compared to WT (n=20). Therapeutic outcome was assessed by FDG-PET: mice (n=13) had 250µCi FDG ip with microPET after 60min uptake and 14T MRI: MEMRI of axonal transport: T1-weighted TR/TE: 5000ms/1.9ms, 0.140x0.140x0.25mm3 at 100min. and 280-350min after intranasal administration of MnCl_2, and DTI of white matter: 0.195x0.195x0.5mm³ FA/TR/TE: 90deg/8750ms/17.8ms, 30 directions. Water tread maze had 3 trials/day for 4 days, short-term memory test at day 5 and long-term at day 12. MEMRI of VOIs in the olfactory tract estimated drug effect on axonal transport. FDG-PET normalized to tracer dose and weight assessed global brain metabolism.

Results MEMRI indicated increased axonal transport in TgTAX vs TgSAL (p≤0.05). DTI fractional anisotropy was 16% decreased in 3xTg-AD vs WT at 6 mos (mn±sd 0.32±0.03 vs 0.38±0.02 p≤0.01) with no significant effect of drug. FDG-PET at 12mos found decreased brain metabolism in 3xTg-AD vs WT mice (18%, 114.2±15 vs 140.6±8, p≤0.05), but also did not distinguish drug vs saline. TgSAL mice exhibited short and long-term memory deficits compared to both WT and TgTAX at 12 mos (5 day 143.8±43s vs 64.2±59s and 91.5±77.4: day 12 138.3±52s vs 33.4±49s and 107.7±74 p≤0.05).

Conclusions The results indicate that microtubule stabilization may be a therapeutic option for AD. Preclinical testing in AD is critical to evaluate drugs for clinical trials. Cognitive and imaging tests must be able to distinguish disease from controls and detect outcome improvements from drug.

Research Support Support for this research was provided by the Alzheimer's Association.