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18F-THK5351 Positron Emission Tomography Imaging in Neurodegenerative Tauopathies.

ABSTRACT: Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination-Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.

SUBMITTER: Ezura M

PROVIDER: S-EPMC8668184 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:ImportanceThe positron emission tomography (PET) tracer [18F]flortaucipir allows in vivo quantification of paired helical filament tau, a core neuropathological feature of Alzheimer disease (AD), but its diagnostic utility is unclear.ObjectiveTo examine the discriminative accuracy of [18F]flortaucipir for AD vs non-AD neurodegenerative disorders.Design, setting, and participantsIn this cross-sectional study, 719 participants were recruited from 3 dementia centers in South Korea, Sweden, and the United States between June 2014 and November 2017 (160 cognitively normal controls, 126 patients with mild cognitive impairment [MCI], of whom 65.9% were amyloid-? [A?] positive [ie, MCI due to AD], 179 patients with AD dementia, and 254 patients with various non-AD neurodegenerative disorders).ExposuresThe index test was the [18F]flortaucipir PET standardized uptake value ratio (SUVR) in 5 predefined regions of interest (ROIs). Cut points for tau positivity were determined using the mean +2 SDs observed in controls and Youden Index for the contrast AD dementia vs controls.Main outcomes and measuresThe reference standard was the clinical diagnosis determined at the specialized memory centers. In the primary analysis, the discriminative accuracy (ie, sensitivity and specificity) of [18F]flortaucipir was examined for AD dementia vs all non-AD neurodegenerative disorders. In secondary analyses, the area under the curve (AUC) of [18F]flortaucipir SUVR was compared with 3 established magnetic resonance imaging measures (hippocampal volumes and AD signature and whole-brain cortical thickness), and sensitivity and specificity of [18F]flortaucipir in MCI due to AD vs non-AD neurodegenerative disorders were determined.ResultsAmong 719 participants, the overall mean (SD) age was 68.8 (9.2) years and 48.4% were male. The proportions of patients who were amyloid-? positive were 26.3%, 65.9%, 100%, and 23.8% among cognitively normal controls, patients with MCI, patients with AD dementia, and patients with non-AD neurodegenerative disorders, respectively. [18F]flortaucipir uptake in the medial-basal and lateral temporal cortex showed 89.9% (95% CI, 84.6%-93.9%) sensitivity and 90.6% (95% CI, 86.3%-93.9%) specificity using the threshold based on controls (SUVR, 1.34), and 96.8% (95% CI, 92.0%-99.1%) sensitivity and 87.9% (95% CI, 81.9%-92.4%) specificity using the Youden Index-derived cutoff (SUVR, 1.27) for distinguishing AD dementia from all non-AD neurodegenerative disorders. The AUCs for all 5 [18F]flortaucipir ROIs were higher (AUC range, 0.92-0.95) compared with the 3 volumetric MRI measures (AUC range, 0.63-0.75; all ROIs P?<?.001). Diagnostic performance of the 5 [18F]flortaucipir ROIs were lower in MCI due to AD (AUC range, 0.75-0.84).Conclusions and relevanceAmong patients with established diagnoses at a memory disorder clinic, [18F]flortaucipir PET was able to discriminate AD from other neurodegenerative diseases. The accuracy and potential utility of this test in patient care require further research in clinically more representative populations.

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18F-THK5351 Positron Emission Tomography Imaging in Neurodegenerative Tauopathies.

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