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DETERMINATION OF NEURITIC VERSUS DIFFUSE PLAQUE CONTRIBUTION TO SIGNAL DERIVED FROM CN-FLUTEMETAMOL

      Background

      Specificity and sensitivity of Flutemetamol (Vizamyl™) PET are high for detecting neuritic amyloid-beta plaques (NP). Several false-positive results from the Flutemetamol clinical-pathological study, as well as high retention of Flutemetamol in the striatum from AD cases, indicate that this radiotracer may also detect diffuse plaques (DP). The fluorescent derivative of Flutemetamol (CN-Flutemetamol) labels both plaque types in AD brain tissue sections, although NP show brighter fluorescence than DP. The current study explores quantitatively this relation in brain areas affected differentially by NP and DP.

      Methods

      Tissue sections from the frontal cortex (FC, variable proportions of NP and DP) and caudate (CD, exclusively DP) from ten AD cases were processed using CN-Flutemetamol and analyzed for plaque load (% area occupied by plaques) and integrated density (a measure that integrates both size and fluorescence intensity of labeled plaques per defined field). A similar approach was used to assess total light output of individual NP and DP imaged using a DSU spinning disk confocal microscope.

      Results

      All plaques in both regions were labeled with CN-Flutemetamol. CN-Flutemetamol positive total plaque load was similar in CD and FC (CD = 3.79 ± 0.64; FC = 5.81 ± 1.18; t-test p = 0.15), however, the integrated density in FC was greater than in the CD (CD=5024 ± 490.3; FC=11742 ± 568.2; t-test p<0.0001). Confocal analysis yielded similar results with total light output of NP greatly exceeding that of DP.

      Conclusions

      For two regions with comparable plaque area coverage, but with different involvement of NP and DP, the region with a preponderance of NP yields greater overall CN-Flutemetamol fluorescence signal when area coverage and signal intensity are calculated as a single value (integrated density). These observations were confirmed by confocal image analysis of individual plaques, and they imply that in PET imaging studies, brain regions with high densities of NP exhibit greatest Flutemetamol retention. However, DP can contribute to Flutemetamol PET signal in regions with very high DP area coverage. Thus, Flutemetamol PET may correlate better with NIA-AA 2012 AD neuropathology criteria that incorporate both CERAD (NP) and Thal phases (all types of Aβ plaques).