¹⁸F-FAHA PET signatures of histone deacetylase activity in the transgenic mouse model of Alzheimer’s disease

Objectives Epigenetic aberrations have been characterized in neurodegenerative diseases including Alzheimer's disease (AD). Several histonedeacetylase (HDAC) inhibitors have been proved effective to restore cognition and recovery memory in transgenic (Tg) AD animal models. For further understanding the deacetylation condition of the brain with AD, ¹⁸F-6-(fluoroacetamido)-1-hexanoicanilide (FAHA) was used to assess the HDAC activity in Tg AD mouse model.

Methods Transgenic mice of J20 line, which overexpress mutant human amyloid protein precursor (APP), were studied at 19-20 months. Static PET-scans were acquired with¹⁸F-FDG (0.74 MBq) and ¹¹C-Pittsburgh Compound B (¹¹C-PIB, 37 MBq). Then a 60-min dynamic PET scan was performed with ¹⁸F-FAHA (0.37 MBq). Image-derived cardiac input functions estimated from each experiment were used for quantification. The ¹⁸F-FAHA parametric images were analysed using a simplified-three compartment model (S3CM) to assess the HDAC activity.

Results The cerebral accumulation of FDG in the APP+ mice decreased when compared with that of non-Tg (APP-) mice. The amyloid imaging of the APP+ mice showed ¹¹C-PIB retention in the cortex at 20 m. The static images of FAHA did not demonstrate the difference of the HADC activity between two groups, whereas the quantification method using S3CM showed a monotonic increasing of the HADC activity in APP+ mice but not in APP- mice. The ¹⁸F-FAHA parametric images of the APP+ mice revealed increasing K_i and k₃ of the brain from 0.024 to 0.037, and from 0.032 to 0.61, respectively, in contrast to no change in non-Tg mice. Furthermore, the quantitative results exhibited a discrepancy between the k₃ and K_i images, indicating that a tissue with high perfusion needs not to be a tissue with high HDAC activity.

Conclusions The quantitative FAHA PET imaging showed a great potential for assessing the HDAC activity of brain in the Tg AD animals. A combined interpretation of the k₃ and K_i images is a feasible approach to analyse the HDAC activity in AD