18 F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study

Abstract

Objective: ¹⁸ F-flortaucipir (formerly ¹⁸ F-AV1451 or ¹⁸ F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo ¹⁸ F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).

Methods: Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (¹¹ C-PiB or ¹⁸ F-florbetapir) and tau (¹⁸ F-flortaucipir). ¹⁸ F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after ¹⁸ F-flortaucipir.

Results: Clinical PSP patients showed bilaterally elevated ¹⁸ F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p < 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with ¹⁸ F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo ¹⁸ F-flortaucipir and postmortem tau neuropathology.

Interpretation: ¹⁸ F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622-634.

Figure 1. Example ¹⁸F-flortaucipir scans

¹⁸F-flortaucipir SUVR images are overlaid on native-space MRIs for five example subjects. Far left: A 74-year-old, female healthy control with relatively low subcortical off-target PET uptake for the control population. Second from left: A 68-year-old, male control subject with high off-target PET uptake. Middle: A 65-year-old, male PSP patient (PSPRS=41, MMSE=23) with low PET uptake among the PSP patients. Second from right: A 78-year-old, male PSP patient (PSPRS=20, MMSE=24) with high PET uptake. Far right: A 71-year-old, male PD patient (UPDRS=27) with average PET uptake among the PD patients.

Figure 2. Voxelwise contrasts of ¹⁸F-flortaucipir uptake

Voxelwise contrasts show regions where ¹⁸F-flortaucipir uptake was greater in PSP patients relative to controls (A) and PD patients (B). Models were adjusted for age as a nuisance covariate, and the resulting t-score maps are shown at FWE-corrected p<0.05 with no cluster size correction.

Figure 3. ¹⁸F-flortaucipir SUVRs in regions of interest

Violin plots show the distribution of ¹⁸F-flortaucipir SUVRs in eight ROIs for PSP patients (red), PD patients (orange) and control subjects (blue). Dots are used to depict individual subject SUVRs, and horizontal bars show the group means for each ROI. SUVRs in the figure are not corrected for partial volume effects. Significant Mann-Whitney U-tests between diagnostic groups are indicated at top: *** p<0.0001, ** p<0.001, * p<0.05. ROIs are listed left-to-right in ascending order of p-values for the PSP>control contrast. SUVR means and standard deviations for each ROI are listed in Table 2. GP = globus pallidus, STN = subthalamic nucleus, DN = dentate nucleus, PUT = putamen, RN = red nucleus, SN = substantia nigra, CAUD = caudate nucleus.

Figure 4. ¹⁸F-flortaucipir patterns in typical and variant PSP

¹⁸F-flortaucipir SUVR images are overlaid on native-space MRIs for six PSP-RS patients (A), three PSP-PAGF patients (B), and one PSP-CBS patient (C).

Figure 5. PET-to-autopsy comparisons

¹⁸F-flortaucipir SUVR images are shown alongside microscopic findings for a 64-year-old woman with PSP-RS due to CBD. (A) Coronal PET slices are shown from most posterior (top left) to most anterior (bottom right). (B) A ballooned neuron typical of CBD is shown on H&E stain. Hyperphosphorylated tau immunohistochemistry (CP13) shows neuronal cytoplasmic inclusions and WM thread pathology in the subthalamic nucleus (C), thalamus (D), globus pallidus interna (E), lentiform nucleus (F), superior frontal sulcus (G), precentral gyrus (H), angular gyrus (I), caudate nucleus (J), dentate nucleus (K), substantia nigra (L), pons (M), and midbrain tectum (N). Astrocytic plaques are visible in G-I. Scale bars: 50 μm (B, C, D, E, G, H, I, J, and K) and 500 μm (F, L, M, and N). aMCC = anterior midcingulate cortex, ANG = angular gyrus, CAL = calcarine cortex, DN = dentate nucleus, EC = entorhinal cortex, GP = globus pallidus, HF = hippocampal formation, IFG = inferior frontal gyrus, INS = insula, ITG = inferior temporal gyrus, MFG = middle frontal gyrus, mFP = medial frontal pole, MTG = middle temporal gyrus, PAG = periaqueductal gray, PCC = posterior cingulate cortex, PostCG = postcentral gyrus, PreCG = precentral gyrus, PUT = putamen, SFS = superior frontal sulcus, SN = substantia nigra, STN = subthalamic nucleus, THAL = thalamus.