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COMPARATIVE ANALYSIS OF PIB IN VIVO WITH 6-CN-PIB AND Aβ-IMMUNOHISTOCHEMISTRY POSTMORTEM IN FAMILIAL ALZHEIMER DISEASE ASSOCIATED WITH THE PSEN1 I229F MUTATION

      Background: In AD, a correlation of in vivo [C-11]Pittsburgh Compound B (PiB) retention with postmortem measures of fibrillar Aβ pathology is essential for interpretation of PET imaging results.
      Methods: Structural magnetic resonance imaging (MRI) and Positron emission tomography (PET) with [C-11]PiB images of a familial AD (FAD) patient were acquired 12 months ante-mortem, using a standardized protocol to assess amyloid pathology in vivo. MRI and PET images were visually compared with those obtained postmortem using histopathology. The entire left cerebral hemisphere, sliced into 22 coronal slabs, and left cerebellar hemisphere, sliced into parasagittal sections, were processed postmortem and embedded in paraffin. Serial sections were stained for histology and Aβ 1-42 immunohistochemistry (IHC). Sections were also incubated in 10 μM 6-CN-PiB (a highly fluorescent derivative of PiB). High resolution low magnification images of complete coronal (cerebrum) or sagittal (cerebellum) sections were created and analyzed.
      Results: A 39 year old woman developed memory deficits at age 35. Genetic analysis revealed a I229F mutation in PSEN1 gene and she was diagnosed as having FAD. Significant [C-11]PiB PET uptake was observed bilaterally in frontal, parietal, and temporal lobes, as well as in the basal ganglia, but not in the cerebellum. By histopathology, Aβ immunoreactive deposits were severe in all gray matter structures of cerebrum and cerebellum. Cerebral cortical Aβ deposits consisted of cored, diffuse, and cotton wool plaques (CWP). 6-CN-PiB signal was strong in cored plaques, weak-to-moderate in diffuse plaques, and absent in CWPs. In the cerebellum, Aβ IHC detected a heavy burden of diffuse deposits in the parenchyma and in blood vessels, while 6-CN-PiB fluorescence was detected only in the leptomeningeal and parenchymal vessels and infrequently in small compact Aβ plaques.
      Conclusions: As progress in imaging techniques allows us to use new tracers for misfolded proteins accumulating in neurodegenerative disease, neuropathology becomes more relevant for defining the efficiency of tracers in identifying specific lesions. The relative contribution of different Aβ plaque types to [C-11]PiB PET retention in vivo is currently being investigated. Funding sources: P30AG010133, P01AG025204, U19AG032438.