Dataset Information

Binding of [¹⁸F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.

ABSTRACT: Purpose: In vivo tau-PET tracer retention in the anterior temporal lobe of patients with semantic variant primary progressive aphasia (SV PPA) has consistently been reported. This is unexpected as the majority of these patients have frontotemporal lobar degeneration TDP (FTLD-TDP).

Methods: We conducted an in vitro [¹⁸F]AV1451 autoradiography binding study in five cases with a clinical diagnosis of SV PPA constituting the range of pathologies (i.e., three FTLD-TDP, one Alzheimer's disease (AD), and one Pick's disease (PiD)). Binding was compared with two controls without neurodegeneration, two typical AD, one corticobasal syndrome with underlying AD, and one frontotemporal dementia behavioral variant with FTLD-TDP. The effect of blocking with the authentic reference material and with the MAO-B inhibitor deprenyl was assessed. Immunohistochemistry was performed on adjacent cryosections.

Results: Absence of specific [¹⁸F]AV1451 binding was observed for all three SV PPA FTLD-TDP cases. The absence of binding in controls as well as the successful blocking with authentic AV1451 in cases with tauopathy demonstrated specificity of the [¹⁸F]AV1451 signal for tau. The specific [¹⁸F]AV1451 binding was highest in AD, followed by PiD. This binding colocalized with the respective tau lesions and could not be blocked by deprenyl. Similar pilot findings were obtained with [¹⁸F]THK5351.

Conclusion: In vitro autoradiography showed no [¹⁸F]AV1451 binding in SV PPA due to FTLD-TDP, while specific binding was present in SV PPA due to AD and PiD. The discrepancy between in vitro and in vivo findings remains to be explained. The discordance is not related to [¹⁸F]AV1451 idiosyncrasies as [¹⁸F]THK5351 findings were similar.

SUBMITTER: Schaeverbeke J

PROVIDER: S-EPMC7300115 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Binding of [<sup>18</sup>F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.

Schaeverbeke Jolien J Celen Sofie S Cornelis Julie J Ronisz Alicja A Serdons Kim K Van Laere Koen K Thal Dietmar Rudolf DR Tousseyn Thomas T Bormans Guy G Vandenberghe Rik R

European journal of nuclear medicine and molecular imaging 20191218 8

<h4>Purpose</h4>In vivo tau-PET tracer retention in the anterior temporal lobe of patients with semantic variant primary progressive aphasia (SV PPA) has consistently been reported. This is unexpected as the majority of these patients have frontotemporal lobar degeneration TDP (FTLD-TDP).<h4>Methods</h4>We conducted an in vitro [<sup>18</sup>F]AV1451 autoradiography binding study in five cases with a clinical diagnosis of SV PPA constituting the range of pathologies (i.e., three FTLD-TDP, one Al ...[more]

PMID: 31848674

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Project description:BackgroundSemantic variant primary progressive aphasia (svPPA) is a subtype of primary progressive aphasia characterized by two-way anomia and disturbance in word comprehension, with focal atrophy in the left temporal lobe. [18F]THK-5351 was originally developed to trace tau protein. However, it has recently been suggested that [18F]THK-5351 binds to monoamine oxidase B in astrocytes, which reflects gliosis. Herein, the authors present two cases involving patients with early-stage svPPA who underwent [18F]THK-5351 positron emission tomography (PET) imaging, and examined whether [18F]THK-5351 PET imaging is more sensitive to neurodegenerative lesions than conventional imaging modalities such as magnetic resonance imaging (MRI) and cerebral blood flow (CBF)-single photon emission computed tomography (SPECT).Case presentationTwo patients, 64- and 79-year-old men, without notable medical or family history, exhibited disturbances in word comprehension and mild anomia with fluent speech and spared repetition. In both cases, surface dyslexia was observed but prosopagnosia was absent. Although mild depression was detected in 1 of the 2 patients, no behavioral disorders were present in either case. In both cases, MRI revealed atrophy in the anterior and inferior portions of the left temporal lobe. Technetium-99-ethyl cysteinate dimer ([99mTc]ECD) SPECT revealed hypoperfusion in the left temporal lobe. Alzheimer's disease was ruled out by [11C]Pittsburgh Compound-B (PiB) PET scan. Both patients fulfilled the diagnostic criteria for svPPA. Because of mild language deficits and lack of right temporal atrophy, they were considered to be at an early stage of the disease. In both cases, [18F]THK-5351 retention was observed in bilateral temporal lobes, predominantly on the left side. Comparison of different imaging modalities suggested that [18F]THK-5351 was more sensitive in detecting neurodegenerative change in the right temporal lobe than MRI and [99mTc]ECD SPECT.Conclusions[18F]THK-5351 retention was clearly demonstrated at an early stage of svPPA. Results of the present study suggest that [18F]THK-5351 PET imaging may facilitate very early diagnosis of the disease.

Project description:The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by semantic memory deficits with relatively preserved motor speech, syntax, and phonology. There is consistent evidence linking focal neurodegeneration of the anterior temporal lobes (ATL) to the semantic deficits observed in svPPA. Less is known about large-scale functional connectivity changes in this syndrome, particularly regarding the interplay between affected and spared language networks that leads to the unique cognitive dissociations typical of svPPA. Using whole-brain, seed-based connectivity on task-free Magnetic Resonance Imaging (MRI) data, we studied connectivity of networks anchored to three left-hemisphere regions crucially involved in svPPA symptomatology: ATL just posterior to the main atrophic area, opercular inferior frontal gyrus, and posterior inferior temporal lobe. First, in 32 healthy controls, these seeds isolated three networks: a ventral semantic network involving anterior middle temporal and angular gyri, a dorsal articulatory-phonological system involving inferior frontal and supramarginal regions, and a third functional connection between posterior inferior temporal and intraparietal regions likely involved in linking visual and linguistic processes. We then compared connectivity strength of these three networks between 16 svPPA patients and the 32 controls. In svPPA, decreased functional connectivity in the ventral semantic network correlated with weak semantic skills, while connectivity of the network seeded from the posterior inferior temporal lobe, though not significantly different between the two groups, correlated with pseudoword reading skills. Increased connectivity between the inferior frontal gyrus and the superior portion of the angular gyrus suggested possible adaptive changes. Our findings have two main implications. First, they support a functional subdivision of the left IPL based on its connectivity to specific language-related regions. Second, the unique neuroanatomical and linguistic profile observed in svPPA provides a compelling model for the functional interplay of these networks, being either up- or down- regulated in response to disease.

Project description:Data are mixed on whether patients with semantic variant primary progressive aphasia exhibit a category-selective semantic deficit for animate objects. Moreover, there is little consensus regarding the neural substrates of this category-selective semantic deficit, though prior literature has suggested that the perirhinal cortex and the lateral posterior fusiform gyrus may support semantic memory functions important for processing animate objects. In this study, we investigated whether patients with semantic variant primary progressive aphasia exhibited a category-selective semantic deficit for animate objects in a word-picture matching task, controlling for psycholinguistic features of the stimuli, including frequency, familiarity, typicality and age of acquisition. We investigated the neural bases of this category selectivity by examining its relationship with cortical atrophy in two primary regions of interest: bilateral perirhinal cortex and lateral posterior fusiform gyri. We analysed data from 20 patients with semantic variant primary progressive aphasia (mean age = 64 years, S.D. = 6.94). For each participant, we calculated an animacy index score to denote the magnitude of the category-selective semantic deficit for animate objects. Multivariate regression analysis revealed a main effect of animacy (β = 0.52, t = 4.03, P < 0.001) even after including all psycholinguistic variables in the model, such that animate objects were less likely to be identified correctly relative to inanimate objects. Inspection of each individual patient's data indicated the presence of a disproportionate impairment in animate objects in most patients. A linear regression analysis revealed a relationship between the right perirhinal cortex thickness and animacy index scores (β = -0.57, t = -2.74, P = 0.015) such that patients who were more disproportionally impaired for animate relative to inanimate objects exhibited thinner right perirhinal cortex. A vertex-wise general linear model analysis restricted to the temporal lobes revealed additional associations between positive animacy index scores (i.e. a disproportionately poorer performance on animate objects) and cortical atrophy in the right perirhinal and entorhinal cortex, superior, middle, and inferior temporal gyri, and the anterior fusiform gyrus, as well as the left anterior fusiform gyrus. Taken together, our results indicate that a category-selective semantic deficit for animate objects is a characteristic feature of semantic variant primary progressive aphasia that is detectable in most individuals. Our imaging findings provide further support for the role of the right perirhinal cortex and other temporal lobe regions in the semantic processing of animate objects.

Project description:PurposeTo assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology.MethodsThe study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction.ResultsPatients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results.Conclusion[18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment.

Dataset Information

Binding of [¹⁸F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.

Publications

Binding of [<sup>18</sup>F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.

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Dataset Information

Binding of [18F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.

Publications

Binding of [<sup>18</sup>F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Binding of [¹⁸F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.