[18F]FDDNP PET in Tauopathies: Correlation to post mortem Pathology in a Case of Progressive Supranuclear Palsy (PSP)

Author(s): Villegas, Brendon Josef | Advisor(s): Barrio, Jorge R | Abstract: This investigation of [18F]FDDNP was conducted in an effort to confirm the presence of disease in a patient with Progressive Supranuclear Palsy (PSP) and to correlate the ante mortem PET scan results to the post mortem pathology. The immunohistochemical and immunofluorescent staining of Paired Helical Filamentous (PHF) tau (AT8) and Amyloid Beta (6F/3D) misfolded proteins demonstrated a widespread deposition in the cortical and subcortical nuclei, the white matter, cerebellar white matter and the medulla oblongata. The in vitro autoradiography demonstrated a neocortical signal comprised of well-delineated amyloid beta in the nucleated layers I/II and hyperphosphorylated tau in the deeper layers III through VI. The autoradiography was well correlated with the immunohistochemical staining in adjacent tissue slides. The binding of the parametric [18F]FDDNP distribution volume ratio (DVR) correlated well (Spearman’s ρ = 0.962, p=.004) with the deposition of tau but not with the presence of amyloid beta (Spearman’s ρ =-0.829, p=.041). The [18F]FDDNP DVR signal appears to be primarily due to the large amount of bound hyperphosphorylated tau (p-tau) and the amyloid beta negligibly contributes to the total signal. Unlabeled FDDNP was shown to bind to tau in the form of globose tangles in the rostral ventromedial medulla as confirmed with both Thioflavin S and PHF-tau Immunofluorescence. The binding of [18F]FDDNP to the human neuroanatomy was investigated in two cohorts of distinct tauopathies and compared to the binding in two tau-negative cohorts against control patients. A cohort of PSP patients (n=12) with a mean age of 63.8 years and a cohort of Chronic Traumatic Encephalopathy (CTE) patients (n=14) with a mean age of 58.1 years are both characterized by the presence of various degrees of tau pathology in their brains. The cohort of Parkinson’s Disease (PD) patients (n=16) with a mean age of 63.2 years is initially characterized by clinical symptoms similar to PSP [18F]FDDNP is able to differentiate between PD and PSP with statistical significance (pl.05) in the striatum; particularly within the caudate nucleus. The Huntington’s Disease (HD) patients (n=15) with a mean age of 36.8 years display motor degeneration from a loss of striatal medium spiny neurons with no presence of amyloid beta or p-tau. It has further been demonstrated with statistical certainty that CTE is discernible from control patients in the amygdala, the midbrain, the caudate nucleus and the anterior cingulate gyrus (pl.05). On the other hand, the HD and PD cohort were both found to have decreased binding of [18F]FDDNP binding in caudate nucleus when compared to all the control patients (pl.05). In the tauopathy cases studied, [18F]FDDNP has successfully demonstrated its differential capability to discriminate between PSP, CTE and PD. The [18F]FDDNP DVR signal in the cases of PSP and CTE closely correlated with hyperphosphorylated tau deposition, as confirmed by the post mortem autopsy of a case with PSP.