Detection of tau in Gerstmann-Sträussler-Scheinker disease ( PRNP  F198S) by [ 18 F]Flortaucipir PET

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Abstract

This study aimed to determine the pattern of [ ¹⁸F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [ ¹⁸F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [ ¹⁸F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer’s disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [ ¹⁸F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem. Scans were processed to generate standardized uptake value ratio (SUVR) images. Regional [ ¹⁸F]flortaucipir SUVR was extracted and compared between GSS patients, EOADs, and CNs. Neuropathology and tau immunohistochemistry were carried out post- mortem on a GSS patient who died 9 months after the [ ¹⁸F]flortaucipir scan. The GSS patients were at different stages of disease progression. Patient A was mildly to moderately affected, suffering from cognitive, psychiatric, and ataxia symptoms. Patient B was moderately to severely affected, suffering from ataxia and parkinsonism accompanied by psychiatric and cognitive symptoms. The [ ¹⁸F]flortaucipir scans showed uptake in frontal, cingulate, and insular cortices, as well as in the striatum and thalamus. Uptake was greater in Patient B than in Patient A. Both GSS patients showed greater uptake in the striatum and thalamus than the EOADs and greater uptake in all evaluated regions than the CNs. Thioflavin S fluorescence and immunohistochemistry revealed that the anatomical distribution of tau pathology is consistent with that of [ ¹⁸F]flortaucipir uptake. In GSS patients, the neuroanatomical localization of pathologic tau, as detected by [ ¹⁸F]flortaucipir, suggests correlation with the psychiatric, motor, and cognitive symptoms. The topography of uptake in PRNP F198S GSS is strikingly different from that seen in AD. Further studies of the sensitivity, specificity, and anatomical patterns of tau PET in diseases with tau pathology are warranted.

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An autoradiographic evaluation of AV-1451 Tau PET in dementia

Val Lowe, Geoffry L. Curran, Ping Fang … (2016)

Background It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates. Methods Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections. Results AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. “Off-target” binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin. Conclusions Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of “off-target” binding. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0315-6) contains supplementary material, which is available to authorized users.

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V Menon (2015)

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Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias.

P Vitali, E Maccagnano, Dannette Johnson … (2011)

Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI have high sensitivity and specificity for Creutzfeldt-Jakob disease (CJD). No studies, however, have demonstrated how MRI can distinguish CJD from nonprion causes of rapidly progressive dementia (npRPD). We sought to determine the diagnostic accuracy of MRI for CJD compared to a cohort of npRPD subjects. Two neuroradiologists blinded to diagnosis assessed DWI and FLAIR images in 90 patients with npRPD (n = 29) or prion disease (sporadic CJD [sCJD], n = 48, or genetic prion disease [familial CJD, n = 6, and Gerstmann-Sträussler-Scheinker, n = 7]). Thirty-one gray matter regions per hemisphere were assessed for abnormal hyperintensities. The likelihood of CJD was assessed using our previously published criteria. Gray matter hyperintensities (DWI > FLAIR) were found in all sCJD cases, with certain regions preferentially involved, but never only in limbic regions, and rarely in the precentral gyrus. In all sCJD cases with basal ganglia or thalamic DWI hyperintensities, there was associated restricted diffusion (apparent diffusion coefficient [ADC] map). This restricted diffusion, however, was not seen in any npRPD cases, in whom isolated limbic hyperintensities (FLAIR > DWI) were common. One reader's sensitivity and specificity for sCJD was 94% and 100%, respectively, the other's was 92% and 72%. After consensus review, the readers' combined MRI sensitivity and specificity for sCJD was 96% and 93%, respectively. Familial CJD had overlapping MRI features with sCJD. The pattern of FLAIR/DWI hyperintensity and restricted diffusion can differentiate sCJD from other RPDs with a high sensitivity and specificity. MRI with DWI and ADC should be included in sCJD diagnostic criteria. New sCJD MRI criteria are proposed.

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Author and article information

Contributors

Shannon L. Risacher: 317-963-7513 , srisache@iupui.edu

Bernardino Ghetti: bghetti@iupui.edu

Andrew J. Saykin: asaykin@iu.edu

Journal

Journal ID (nlm-ta): Acta Neuropathol Commun

Journal ID (iso-abbrev): Acta Neuropathol Commun

Title: Acta Neuropathologica Communications

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-5960

Publication date (Electronic): 29 October 2018

Publication date PMC-release: 29 October 2018

Publication date Collection: 2018

Volume: 6

Electronic Location Identifier: 114

Affiliations

[1 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Radiology and Imaging Sciences, , Indiana University School of Medicine, ; 355 West 16th Street, Suite 4100, Indianapolis, IN 46202 USA

[2 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Indiana Alzheimer Disease Center, , Indiana University School of Medicine, ; Indianapolis, IN USA

[3 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Neurology, , Indiana University School of Medicine, ; Indianapolis, IN USA

[4 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Psychiatry, , Indiana University School of Medicine, ; Indianapolis, IN USA

[5 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Pathology and Laboratory Medicine, , Indiana University School of Medicine, ; Indianapolis, IN USA

[6 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Medical and Molecular Genetics, , Indiana University School of Medicine, ; Indianapolis, IN USA

Article

Publisher ID: 608

DOI: 10.1186/s40478-018-0608-z

PMC ID: 6205777

PubMed ID: 30373672

SO-VID: 47c66d42-687b-4bfc-a0f8-5d38acca5dcf

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 26 September 2018

Date accepted : 28 September 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;

Award ID: P30 AG010133

Award ID: R01 AG19771

Award ID: K01 AG049050

Award Recipient : Shannon L. Risacher

Funded by: Alzheimer's Association

Award ID: n/a

Award Recipient : Shannon L. Risacher

Funded by: IU Health-IUSM Strategic Research Initiative

Award ID: n/a

Award Recipient : Shannon L. Risacher

Funded by: Indiana Clinical and Translational Sciences Institute

Award ID: n/a

Award Recipient : Shannon L. Risacher

Funded by: FundRef http://dx.doi.org/10.13039/100004312, Eli Lilly and Company;

Award ID: n/a

Funded by: FundRef http://dx.doi.org/10.13039/100006976, Lilly Endowment;

Award ID: n/a

Funded by: FundRef http://dx.doi.org/10.13039/501100008982, National Science Foundation;

Award ID: CNS-0521433

Custom metadata

Keywords: positron emission tomography (pet),[18f]flortaucipir/av-1451/t-807,gerstmann-sträussler-scheinker disease (gss),tau,prion protein (prp),prnp f198s mutation

Data availability:

Keywords: positron emission tomography (pet), [18f]flortaucipir/av-1451/t-807, gerstmann-sträussler-scheinker disease (gss), tau, prion protein (prp), prnp f198s mutation