In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease

Abstract

Objective: To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD).

Methods: In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63-74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC).

Results: All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528-13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2-3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08-1.36) were indistinguishable from CN persons (1.14, 0.84-1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60-3.04; p ≤ 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2).

Conclusion: Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia.

© 2018 American Academy of Neurology.

Figures

Figure 1. Selected neuroimaging findings in patients with CJD

Structural magnetic resonance brain images (T2-FLAIR [column I] and DWI [column II]) and [18F]-AV-1451 PET images (axial and coronal orientation, column III) are shown for each patient with CJD, coregistered at the level of the thalamus (cases A–E; presented in radiologic convention). Restricted diffusion within the cortical ribbon and deep gray nuclei was commonly observed (arrowheads) in patients with CJD, without corresponding increases in [18F]-AV-1451 retention. [18F]-AV-1451 retention was frequently observed within the choroid plexus and deep gray structures. Such off-target binding may have contributed to the qualitative appearance of focal (subcortical) retention in cases A and E. CJD = Creutzfeldt-Jakob disease; DWI = diffusion-weighted image; FLAIR = fluid attenuated inversion recovery.

Figure 2. [18F]-AV-1451 retention in AD- and CJD-specific regions of interest

Box/scatterplot showing [18F]-AV-1451 SUVRs in AD- and CJD-specific regions of interest in patients with CJD (teal), CN persons (orange), and participants with AD dementia (blue). AD summary values were computed using an average of AD-specific regions of interest, including the left and right inferior temporal cortex, amygdala, entorhinal cortex, and lateral occipital cortices. CJD-specific regions of interest included areas commonly involved on neuropathology: the lateral occipital, caudal middle frontal, superior temporal, fusiform and pericalcarine cortices, and the thalami. AD = Alzheimer disease; CJD = Creutzfeldt-Jakob disease; CN = cognitively normal; SUVR = standardized uptake ratio value ratio.

Figure 3. Selected neuropathologic findings in patients with CJD

H&E stained sections (column I) show spongiform change (arrows, panel G)—coarse in case A (panel A, temporal cortex), fine in case B (panel D, occipital cortex), case C (panel G, striatum), case D (panel J, cerebellum), and case E (panel M, H&E ×40, subiculum)—and astrogliosis (arrowheads, panel G) with variable anatomical distributions. Very rare neocortical balloon cells are present only in case E (arrow, panel M). IHC for β-amyloid peptide (column II; antibody 10D5) reveals diffuse amyloid plaques (arrowhead, panel E) and cored amyloid plaques (arrow, panel E); case A shows moderate diffuse plaques (panel B, temporal cortex); case B shows frequent diffuse and cored plaques (panel E, striatum); case C shows frequent diffuse plaques and no cored plaques (panel H, temporal cortex); case D shows only very rare diffuse plaques (panel K, temporal cortex); and case E shows frequent diffuse plaques and moderate cored plaques (panel N, frontal cortex). IHC for phosphorylated tau protein (column III; antibody PHF-1) highlights features of tauopathy: neurofibrillary tangles (arrows, panels C, F, and I), neuropil threads (arrowhead, panel C), and neuritic plaques (arrowhead, panel F). Tauopathy is modest in case A (panel C, inferior temporal isocortex), focally robust in case B (panel F, subiculum), almost absent in case C (panel I, parahippocampal gyrus); focally sparse to moderate in case D (panel L, CA1 area), and focally sparse in case E (panel O, parahippocampal gyrus). Scale bar (panel A) is equivalent to approximately: 40 μm (panel G); 100 μm (panels E and M); 200 μm (panels C, D, F, and J); 400 μm (panels A, I, L, and D); and 1,000 μm (panels B, H, K, and N). CJD = Creutzfeldt-Jakob disease; H&E = Hematoxylin & eosin; IHC = immunohistochemistry.