Dataset Information

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [¹⁸F]THK5351 uptake in progressive supranuclear palsy.

ABSTRACT:

Background

[¹⁸F]THK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). However, the interpretation of [¹⁸F]THK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD.

Objectives

To test the hypothesis that the MAO-B inhibitor, rasagiline reduces [¹⁸F]THK5351 uptake in PSP.

Methods

Six individuals (4: PSP; 2: cognitively unimpaired, CU) underwent [¹⁸F]THK5351 and [¹⁸F]AZD4694 to quantify baseline tau and amyloid deposition, respectively. Following a 10-day course of 1?mg rasagiline, all participants received a post-challenge [¹⁸F]THK5351 scan. The baseline and post-rasagiline challenge standardized uptake value (SUV) were generated normalized for patient weight and injected radioactivity.

Results

The post-rasagiline regional SUV was reduced on average by 69-89% in PSP, and 53-81% in CU. The distributions of post-rasagiline [¹⁸F]THK5351 SUV among PSP individuals were not consistent with the typical pattern of tau aggregates in PSP.

Conclusions

Similar to AD, the interpretation of [¹⁸F]THK5351 uptake in PSP is likely confounded by off-target binding to MAO-B binding sites. [¹⁸F]THK5351 is not sufficient in quantifying tau aggregates in PSP using the proposed rasagiline dosing regimen.

SUBMITTER: Ng KP

PROVIDER: S-EPMC6889764 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [<sup>18</sup>F]THK5351 uptake in progressive supranuclear palsy.

Ng Kok Pin KP Therriault Joseph J Kang Min Su MS Struyfs Hanne H Pascoal Tharick A TA Mathotaarachchi Sulantha S Shin Monica M Benedet Andrea L AL Massarweh Gassan G Soucy Jean-Paul JP Rosa-Neto Pedro P Gauthier Serge S

NeuroImage. Clinical 20191113

<h4>Background</h4>[<sup>18</sup>F]THK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). However, the interpretation of [<sup>18</sup>F]THK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD.<h4>Objectives</h4>To test the hypothesis that the MAO-B inhibitor, rasagiline reduces [<sup>18</sup> ...[more]

PMID: 31795034

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Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative movement disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells of the brain. These deposits are a key neuropathological finding, allowing a diagnosis of "definite PSP," which is usually established post mortem. To date criteria for clinical diagnosis of PSP in vivo do not include biomarkers of tau pathology. For intervention trials, it is increasingly important to (i) establish biomarkers for an early diagnosis and (ii) to develop biomarkers that correlate with disease progression of PSP. [18F]-THK5351 is a novel PET-ligand that may afford in vivo visualization and quantification of tau-related alterations. We investigated binding characteristics of [18F]-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. Eleven patients (68.4 ± 7.4 year; N = 6 female) with probable PSP according to current clinical criteria and nine healthy controls (71.7 ± 7.2 year; N = 4 female) underwent [18F]-THK5351 PET scanning. Voxel-wise statistical parametric comparison and volume-of-interest based quantification of standardized-uptake-values (SUV) were conducted using the cerebellar cortex as reference region. We correlated disease severity as measured with the help of the PSP Rating Scale (PSPRS) as well as several other clinical parameters with the individual PET findings. By voxel-wise mapping of [18F]-THK5351 uptake in the patient group we delineated typical distribution patterns that fit to known tau topology for PSP post mortem. Quantitative analysis indicated the strongest discrimination between PSP patients and healthy controls based on tracer uptake in the midbrain (+35%; p = 3.01E-7; Cohen's d: 4.0), followed by the globus pallidus, frontal cortex, and medulla oblongata. Midbrain [18F]-THK5351 uptake correlated well with clinical severity as measured by PSPRS (R = 0.66; p = 0.026). OCT and MRI delineated PSP patients from healthy controls by use of established discrimination thresholds but only OCT did as well correlate with clinical severity (R = 0.79; p = 0.024). Regional [18F]-THK5351 binding patterns correlated well with the established post mortem distribution of lesions in PSP and with clinical severity. The contribution of possible MAO-B binding to the [18F]-THK5351 signal needs to be further evaluated, but nevertheless [18F]-THK5351 PET may still serve as valuable biomarker for diagnosis of PSP.

Project description:PurposeThe pattern of flortaucipir tau PET uptake is topographically similar to the pattern of magnetic susceptibility in progressive supranuclear palsy (PSP); both with increased signal in subcortical structures such as the basal ganglia and midbrain, suggesting that they may be closely related. However, their relationship remains unknown since no studies have directly compared these two modalities in the same PSP cohort. We hypothesized that some flortaucipir uptake in PSP is associated with magnetic susceptibility, and hence iron deposition. The aim of this study was to evaluate the regional relationship between flortaucipir uptake and magnetic susceptibility and to examine the effects of susceptibility on flortaucipir uptake in PSP.MethodsFifty PSP patients and 67 cognitively normal controls were prospectively recruited and underwent three Tesla MRI and flortaucipir tau PET scans. Quantitative susceptibility maps were reconstructed from multi-echo gradient-echo MRI images. Region of interest (ROI) analysis was performed to obtain flortaucipir and susceptibility values in the subcortical regions. Relationships between flortaucipir and susceptibility signals were evaluated using partial correlation analysis in the subcortical ROIs and voxel-based analysis in the whole brain. The effects of susceptibility on flortaucipir uptake were examined by using the framework of mediation analysis.ResultsBoth flortaucipir and susceptibility were greater in PSP compared to controls in the putamen, pallidum, subthalamic nucleus, red nucleus, and cerebellar dentate (p<0.05). The ROI-based and voxel-based analyses showed that these two signals were positively correlated in these five regions (r = 0.36-0.59, p<0.05). Mediation analysis showed that greater flortaucipir uptake was partially explained by susceptibility in the putamen, pallidum, subthalamic nucleus, and red nucleus, and fully explained in the cerebellar dentate.ConclusionsThese results suggest that some of the flortaucipir uptake in subcortical regions in PSP is related to iron deposition. These findings will contribute to our understanding of the mechanisms underlying flortaucipir tau PET findings in PSP and other neurodegenerative diseases.

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

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [¹⁸F]THK5351 uptake in progressive supranuclear palsy.

Background

Objectives

Methods

Results

Conclusions

Publications

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [<sup>18</sup>F]THK5351 uptake in progressive supranuclear palsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [18F]THK5351 uptake in progressive supranuclear palsy.

Background

Objectives

Methods

Results

Conclusions

Publications

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [<sup>18</sup>F]THK5351 uptake in progressive supranuclear palsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [¹⁸F]THK5351 uptake in progressive supranuclear palsy.