18F-flortaucipir uptake patterns in clinical subtypes of primary progressive aphasia

doi:10.1016/j.neurobiolaging.2018.11.017

Neurobiology of Aging

Volume 75, March 2019, Pages 187-197

https://doi.org/10.1016/j.neurobiolaging.2018.11.017 Get rights and content

Highlights

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We compared ¹⁸F-flortaucipir uptake and structural changes in PPA subtypes.
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Increased ¹⁸F-flortaucipir uptake corresponds to areas related to language functions.
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Cortical thinning in each PPA subtype corresponded to increased ¹⁸F-flortaucipir uptake.
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¹⁸F-flortaucipir uptake and cortical atrophy were distinct in each subtype of PPA.

Abstract

We analyzed ¹⁸F-flortaucipir uptake patterns and structural changes in patients with subtypes of primary progressive aphasia (PPA) using ¹⁸F-flortaucipir positron emission tomography and volumetric magnetic resonance imaging. We enrolled 34 consecutive patients with PPA (10 nonfluent/agrammatic PPA [nfvPPA], 18 semantic variant PPA [svPPA], and 6 logopenic variant PPA [lvPPA], as well as 20 healthy controls, and 20 patients with Alzheimer's disease. ¹⁸F-flortaucipir uptake was increased in the frontal cortex and underlying white matter, and subcortical nuclei in the 10 nfvPPA and 8 nfvPPA-amyloid-β (Aβ)− subgroup patients. In the svPPA patients (both the 13 svPPA-Aβ− and 5 svPPA-Aβ+), uptake generally increased in the widespread neocortex with left anterior temporal predominance. ¹⁸F-flortaucipir uptake patterns in the 6 lvPPA and the 5 lvPPA-Aβ+ subgroup patients were similar to those seen in the patients with Alzheimer's disease with mild predominance in the left lateral temporal cortex. Cortical thinning in each PPA subtype corresponded with increased ¹⁸F-flortaucipir uptake. ¹⁸F-flortaucipir uptake patterns and cortical atrophy were distinct and corresponded to areas related to the specific language functions that are impaired in each subtype of PPA.

Introduction

Primary progressive aphasia (PPA) is a clinical syndrome characterized by predominant language dysfunction but with other cognitive functions relatively preserved (Mesulam, 2001). PPA can be classified into 3 subtypes based on characteristics of language impairment, which include the nonfluent/agrammatic variant PPA (nfvPPA), semantic variant PPA (svPPA), and logopenic variant PPA (lvPPA) (Gorno-Tempini et al., 2004, Gorno-Tempini et al., 2011).

PPA clinical syndromes are linked to underlying frontotemporal lobar degeneration (FTLD) tau, TAR DNA-binding protein 43 (TDP43), and Alzheimer's disease (AD) pathology (Grossman, 2010). FTLD-tau pathology is predominantly observed in nfvPPA, whereas svPPA and lvPPA are highly suggestive of TDP43 and AD pathologies, respectively. Although postmortem studies have shown proportional variability of these pathologies in the different PPA subtypes, with the exception of svPPA, which has a smaller proportion of FTLD-tau (0%–17%) or AD (10%–33%) tau pathology, over 75% of patients with nfvPPA harbor FTLD-tau (50%–100%) or AD (13%–41%) tau pathology, and approximately 85% of patients with lvPPA exhibit FTLD-tau (0%–29%) or AD (54%–77%) tau or TDP43 (14%–27%) pathology (Chare et al., 2014, Harris et al., 2013, Josephs et al., 2006, Josephs et al., 2014, Kertesz et al., 2005, Knibb et al., 2006, Mesulam et al., 2008, Rohrer et al., 2010, Rohrer et al., 2011).

The development of tau radiotracers has enabled in vivo visualization of tau pathology in various neurodegenerative diseases (Cho et al., 2017, Johnson et al., 2016, Passamonti et al., 2017, Smith et al., 2016). ¹⁸F-flortaucipir (formerly called ¹⁸F-AV-1451 or ¹⁸F-T807) has been the most widely used tau radiotracer. It strongly binds to paired helical filament tau predominantly found in patients with AD and weakly binds to straight filament tau found in non-AD tauopathies (Marquie et al., 2015), while even weakly binding to TDP43 pathology (Lowe et al., 2016).

Recently, the possibility of binding to monoamine oxidase-B has been raised, which can colocalize with neurodegeneration (Bevan-Jones et al., 2017).

Therefore, ¹⁸F-flortaucipir may be helpful for observing AD tau pathology, whereas the binding to FTLD-tau pathology in most patients with nfvPPA and the binding to TDP43 pathology in some patients with svPPA are difficult to accurately identify by ¹⁸F-flortaucipir.

Although ¹⁸F-flortaucipir binding patterns in small numbers of patients with lvPPA and svPPA have been reported in separate studies (Bevan-Jones et al., 2017, Makaretz et al., 2018, Nasrallah et al., 2018, Ossenkoppele et al., 2016, Xia et al., 2017), to date, only one study with ¹⁸F-flortaucipir positron emission tomography (PET) has collectively analyzed binding patterns in different PPA subtypes (Josephs et al., 2018). However, the results may have been mixed due to AD pathology, and distinct ¹⁸F-flortaucipir uptake patterns might still be determinable. In this study, we sought to investigate ¹⁸F-flortaucipir uptake patterns and structural changes in PPA using volumetric and cortical thickness analysis. We also sought to investigate differences according to amyloid-positivity.

Section snippets

Participants

From May 2015 to Jan 2017, we prospectively recruited 34 consecutive patients with PPA at Gangnam Severance Hospital (7 patients) and at Samsung Medical Center (27 patients). By using the clinical diagnostic criteria for the diagnosis of PPA and its variants, patients with PPA were clinically diagnosed and classified into one of 3 variants (10 nfvPPA, 18 svPPA, and 6 lvPPA patients) (Gorno-Tempini et al., 2011). None of the patients had their clinical diagnosis changed during the follow-up

Demographic characteristics

Demographic characteristics and neuropsychological tests results of the 5 diagnostic groups are presented in Table 1. There was no difference across groups in terms of age, gender, education, or duration of disease. Apolipoprotein E ε4 genotype was more prevalent in the patients with AD than the controls. Global cognition scales and all neuropsychological test results were observed to differ between the groups (p < 0.05); however, after post hoc comparisons, there was no difference between the

Discussion

In this study, we identified distinct ¹⁸F-flortaucipir uptake patterns for the subtypes of PPA. The frontal cortex and its associated subcortical white matter, and subcortical nuclei were the primary areas with increased ¹⁸F-flortaucipir uptake in nfvPPA and nfvPPA-Aβ− patients. Patients with svPPA and its subgroups (svPPA-Aβ− and svPPA-Aβ+) showed increased ¹⁸F-flortaucipir uptake in the widespread neocortex with clear left anterior temporal predominance. The ¹⁸F-flortaucipir uptake patterns

Conclusions

In summary, the uptake patterns of ¹⁸F-flortaucipir and cortical atrophy were distinct and corresponded to areas related to the specific language functions that are distinctly impaired in each subtype of PPA; increased uptake in the frontal cortex and underlying white matter, and subcortical gray matter in nfvPPA, in the left anterior temporal cortex in svPPA, and in the left temporoparietal cortex in lvPPA. However, because pathological heterogeneities exist in such patients, the

Disclosure

The authors report no disclosures relevant to the article.

Acknowledgements

This study was financially supported by a faculty research grant of Yonsei University College of Medicine, South Korea for (2018-32-0036), National Research Foundation of Korea, South Korea grant funded by the Korean government (MSIP) (No. 2015R1C1A2A01054507, 2017R1A2B2006694, and 2017R1A2B2005081), and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, South Korea (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea

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A striking uptake, particularly in the temporoparietal cortex, was reported in L/PhvPPA, while the patterns, involving, respectively, the left prefrontal and subcortical gray matter structures or the anteromedial temporal lobes, were less severe in Nf/AvPPA and SvPPA (Josephs et al., 2018; Cho et al., 2019). A study with ([18F]AV1451) recently confirmed a severe deposition of tau protein in temporoparietal regions in L/PhvPPA patients (Nasrallah et al., 2018), similar to what is observed in AD dementia patients with an 18F-flortaucipir (Cho et al., 2019). A study of frontotemporal dementia syndromes, Tsai et al. (2019) reported elevated 18F-fluortaucipir binding in patients with Nf/Av-PPA in the left higher than in the right inferior frontal gyrus.
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Regular article18F-flortaucipir uptake patterns in clinical subtypes of primary progressive aphasia

Highlights

Abstract

Introduction

Section snippets

Participants

Demographic characteristics

Discussion

Conclusions

Disclosure

Acknowledgements

Neuropsychologia

Neuroimage

Neuron

Alzheimers Dement.

Neuropsychologia

Atrophy, hypometabolism and white matter abnormalities in semantic dementia tell a coherent story

Brain

Controlling the false discovery rate: a practical and powerful approach to multiple testing

J. R. Stat. Soc. B Stat. Methodol.

[(18)F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia

J. Neurol. Neurosurg. Psychiatry

New criteria for frontotemporal dementia syndromes: clinical and pathological diagnostic implications

J. Neurol. Neurosurg. Psychiatry

18F-AV-1451 binds to motor-related subcortical gray and white matter in corticobasal syndrome

Neurology

In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum

Ann. Neurol.

A cognitive battery for dementia: development and measurement characteristics

Psychol. Assess.

An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies

Acta Neuropathol.

Office of rare diseases neuropathologic criteria for corticobasal degeneration

J. Neuropathol. Exp. Neurol.

Automatically parcellating the human cerebral cortex

Cereb. Cortex.

Cognition and anatomy in three variants of primary progressive aphasia

Ann. Neurol.

Classification of primary progressive aphasia and its variants

Neurology

Primary progressive aphasia: clinicopathological correlations

Nat. Rev. Neurol.

Classification and pathology of primary progressive aphasia

Neurology

Multimodal predictors for Alzheimer disease in nonfluent primary progressive aphasia

Neurology

A dextral primary progressive aphasia patient with right dominant hypometabolism and tau accumulation and left dominant amyloid accumulation

Case Rep. Neurol.

Tau positron emission tomographic imaging in aging and early Alzheimer disease

Ann. Neurol.

Fluorodeoxyglucose F18 positron emission tomography in progressive apraxia of speech and primary progressive aphasia variants

Arch. Neurol.

Progranulin-associated PiB-negative logopenic primary progressive aphasia

J. Neurol.

Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech

Brain

[(18) F]AV-1451 tau-PET and primary progressive aphasia

Ann. Neurol.

The evolution and pathology of frontotemporal dementia

Brain

Regular article
¹⁸F-flortaucipir uptake patterns in clinical subtypes of primary progressive aphasia