PET of brain prion protein amyloid in Gerstmann-Sträussler-Scheinker disease

Abstract

In vivo amyloid PET imaging was carried out on six symptomatic and asymptomatic carriers of PRNP mutations associated with the Gerstmann-Sträussler-Scheinker (GSS) disease, a rare familial neurodegenerative brain disorder demonstrating prion amyloid neuropathology, using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP). 2-Deoxy-2-[F-18]fluoro-d-glucose PET ([F-18]FDG) and magnetic resonance imaging (MRI) scans were also performed in each subject. Increased [F-18]FDDNP binding was detectable in cerebellum, neocortex and subcortical areas of all symptomatic gene carriers in close association with the experienced clinical symptoms. Parallel glucose metabolism ([F-18]FDG) reduction was observed in neocortex, basal ganglia and/or thalamus, which supports the close relationship between [F-18]FDDNP binding and neuronal dysfunction. Two asymptomatic gene carriers displayed no cortical [F-18]FDDNP binding, yet progressive [F-18]FDDNP retention in caudate nucleus and thalamus was seen at 1- and 2-year follow-up in the older asymptomatic subject. In vitro FDDNP labeling experiments on brain tissue specimens from deceased GSS subjects not participating in the in vivo studies indicated that in vivo accumulation of [F-18]FDDNP in subcortical structures, neocortices and cerebellum closely related to the distribution of prion protein pathology. These results demonstrate the feasibility of detecting prion protein accumulation in living patients with [F-18]FDDNP PET, and suggest an opportunity for its application to follow disease progression and monitor therapeutic interventions.

Figures

Figure 1

[F‐18]FDDNP PET, MRI and [F‐18]FDG PET imaging results for four carriers of F198S mutation. [F‐18]FDDNP, [F‐18]FDG and MRI scans in the asymptomatic subject 10158 are comparable with those of the age‐matched control group. By contrast, asymptomatic subject 10142 shows increased [F‐18]FDDNP binding and mildly decreased [F‐18]FDG uptake in basal ganglia. Both symptomatic subjects 10136 and 10151 have increased [F‐18]FDDNP binding in basal ganglia and thalamus, which is paralleled by decreases in [F‐18]FDG uptake in the same areas. Consistent with pathology reports on presence of prion protein plaques in cerebellum, both subjects have increased [F‐18]FDDNP binding in the cerebellum. Cerebral cortex is affected to various degrees with variable patterns of binding. Warmer color images represent higher uptake.

Figure 2

[F‐18]FDDNP PET, MRI and [F‐18]FDG PET imaging results of longitudinal study of symptomatic P102L mutation carrier 10141 (A) and asymptomatic F198S mutation carrier 10142 (B), and imaging results for PRNP mutations A117V carrier 10308 (C). (A) Imaging results of the three‐point 27‐month longitudinal study of P102L mutation carrier 10141 from early symptomatic stage (baseline) to very affected stage (27‐month follow‐up). Cerebellum shows increased levels of [F‐18]FDDNP binding at all three stages; basal ganglia, thalamus and cerebral cortex show increased levels of binding at both follow‐up points. [F‐18]FDG also demonstrates progressive decline, most notably in basal ganglia and parieto‐temporal areas. (B) Results of the three‐time point 28‐month longitudinal study in asymptomatic F198S subject 10142. [F‐18]FDDNP demonstrates progressive involvement of basal ganglia and thalamus, paralleled by metabolic deficits ([F‐18]FDG) in similar areas. (C) Imaging results for the symptomatic A117V mutation carrier 10308. The brain is heavily affected as reflected in severe loss of white matter, cortical atrophy and enlargement of all ventricles (MRI). High [F‐18]FDDNP binding was observed in all cortical and subcortical areas with exception of cerebellum which shows no signal above control levels. This is paralleled by [F‐18]FDG uptake decrease in whole brain with the exception of cerebellum. Warmer colors represent higher uptake.

Figure 3

(A,B) Correlation of [F‐18]FDDNP DVR and [F‐18]FDG SUVR in striatum and thalamus of Gerstmann–Sträussler–Scheinker (GSS) subjects (black symbols) in comparison with normal controls (blue symbols), and Alzheimer's disease patients (red symbols). (C–E) Scatter plots of [F‐18]FDDNP DVR in striatum, thalamus and global cortices in the same GSS subjects. (F,G) Three‐dimensional plots of [F‐18]FDDNP DVR and [F‐18]FDG SUVR global cortices vs. memory measures (Buschke total), and striatum vs. motor symptoms (rated as normal, mild, moderate and severe). Statistics: Spearman rank correlations of [F‐18]FDDNP DVR values with [F‐18]FDG SUVR values in striatum (A) and thalamus (B) were significant at rS = −0.497 (P = 0.05) for striatum, and rS = −0.703 (P = 0.002) for thalamus. (C) Z scores (number of SDs from control group mean value) for global [F‐18]FDDNP DVR are: symptomatic subject 10136 = 3.1; symptomatic subject 10151 = 3.7; symptomatic subject 10141 = 2.1, 4.6 and 6.4 for scans 1, 2 and 3, respectively; symptomatic subject 10308 = 9.5; asymptomatic subject 10142 = 1.8, 3.0 and 2.3 for scans 1, 2 and 3, respectively; asymptomatic subject 10158 = −0.7. (D) Z scores for striatum [F‐18]FDDNP DVR are: symptomatic subject 10136 = 9.5; symptomatic subject 10151 = 12.6; symptomatic subject 10141 = 3.8, 7.5 and 9.2 for scans 1, 2 and 3, respectively; symptomatic subject 10308 = 12.0; asymptomatic subject 10142 = 5.5, 5.9 and 7.2 for scans 1, 2 and 3, respectively; asymptomatic subject 10158 = −0.3. (E) Z scores for thalamus [F‐18]FDDNP DVR are: symptomatic subject 10136 = 2.9; symptomatic subject 10151 = 10.7; symptomatic subject 10141 = 3.8, 4.9 and 5.3 for scans 1, 2 and 3, respectively; subject 10308 = 6.5; asymptomatic subject 10142 = 1.5, 2.4 and 3.4 for scans 1, 2 and 3, respectively; asymptomatic subject 10158 is −0.8. (F) The following statistical correlations are observed: [F‐18]FDG SUVR (global) vs. [F‐18]FDDNP DVR (global) is significant with Spearman coefficient rS = −0.803 (P < 0.001); [F‐18]FDDNP DVR (global) vs. Buschke total significant with Spearman coefficient rS = −0.83 (P = 0.04); and [F‐18]FDG SUVR (global) vs. Buschke total significant with Spearman coefficient rS = 0.89 (P = 0.02). (G) The following correlations are observed: [F‐18]FDG SUVR (striatum) vs. [F‐18]FDDNP DVR (striatum) is significant with Spearman coefficient rS = −0.497 (P < 0.05); [F‐18]FDDNP DVR vs. motor symptoms is significant with Spearman coefficient rS = −0.878 (P = 0.02); and [F‐18]FDG SUVR vs. motor symptoms was not significant with Spearman coefficient rS = 0.683 (P = 0.13). Z scores for [F‐18]FDDNP DVR and [F‐18]FDG SUVR are included in Supporting Table S3 for all cortical and subcortical structures analyzed. Values larger than 2.0 SD are bolded.

Figure 4

Results of in vitro FDDNP fluorescence microscopy studies and immunohistochemical labeling of prion protein (PrP) and tau pathology in brain samples from F198S mutation Gerstmann–Sträussler–Scheinker (GSS) patients. Panel 1a–i shows FDDNP fluorescent labeling (green signal) of the cerebral cortex (1a, 1d, 1g), striatum (1b, 1e, 1h) and cerebellum (1c, 1f, 1i) for the presymptomatic F198S mutation carrier (1a–1c), symptomatic GSS patient with the same mutation (1d–1f) and a normal control case (1g–1i). Intensely FDDNP fluorescent plaques with dense cores are present in all regions, but are particularly abundant in the cerebral and cerebellar cortex of both cases to a similar degree. The distinguishing feature between the GSS cases, also absent from the control brain, is the quantity of moderately labeled diffuse plaques lacking amyloid core: they are more abundant in all three regions of the symptomatic case (1d–1f). Panel 2a–c shows striatal labeling with FDDNP (green in 2a); IHC to prion protein (brown in 2b); and superimposed images of both signals, showing FDDNP in green, IHC signal transformed to red and the overlap of both signals in yellow to permit quantitative assessment of the signal overlap area (2c). The bottom row of images shows cortical FDDNP (green in 2d), IHC to tau (brown in 2e) and superimposed images of the two signals in 2f. High degree of signal overlap can be seen in FDDNP–PrP IHC superimposed images, while much less overlap is revealed by the superposition of FDDNP and tau IHC images. Size bar = 150 µm (1a–2c), 15 µm (2d–2f).