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Tau PET With ¹⁸F-THK-5351 Taiwan Patients With Familial Alzheimer's Disease With the APP p.D678H Mutation.

ABSTRACT: Background: Brain ¹⁸F-AV-45 amyloid positron emission tomography (PET) in Taiwanese patients with familial Alzheimer's disease with the amyloid precursor protein (APP) p.D678H mutation tends to involve occipital and cerebellar cortical areas. However, tau pathology in patients with this specific Taiwan mutation remains unknown. In this study, we aimed to study the Tau PET images in these patients. Methods: Clinical features, brain magnetic resonance imaging/computed tomography (MRI/CT), and brain ¹⁸F-THK-5351 PET were recorded in five patients with the APP p.D678H mutation and correlated with brain ¹⁸F-AV-45 PET images. We also compared the tau deposition patterns among five patients with familial mild cognitive impairment (fMCI), six patients with sporadic amnestic mild cognitive impairment (sMCI), nine patients with mild to moderate dementia due to Alzheimer's disease (AD), and 12 healthy controls (HCs). All of the subjects also received brain ¹⁸F-AV-45 PET. Results: The nine patients with sAD and six patients with sMCI had a positive brain AV-45 PET scans, while the 12 HCs had negative brain AV-45 PET scans. All five patients with fMCI received a tau PET scan with the age at onset ranging from 46 to 53 years, in whom increased standard uptake value ratio (SUVR) of ¹⁸F-THK-5351 was noted in all seven brain cortical areas compared with the HCs. In addition, the SUVRs of ¹⁸F-THK-5351 were increased in the frontal, medial parietal, lateral parietal, lateral temporal, and occipital areas (P < 0.001) in the patients with sAD compared with the HCs. The patients with fMCI had a significant higher SUVR of ¹⁸F-THK-5351 in the cerebellar cortex compared to the patients with sMCI. The correlations between regional SUVR and Mini-Mental State Examination score and between regional SUVR and clinical dementia rating (sum box) scores within volumes of interest of Braak stage were statistically significant. Conclusion: Tau deposition was increased in the patients with fMCI compared to the HCs. Increased regional SUVR in the cerebellar cortical area was a characteristic finding in the patients with fMCI. As compared between amyloid and tau PET, the amyloid deposition is diffuse, but tau deposition is limited to the temporal lobe in the patients with fMCI.

SUBMITTER: Huang CC

PROVIDER: S-EPMC6538951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:IntroductionTau-targeted positron emission tomography (tau-PET) is a potential tool for the differential diagnosis of Alzheimer's disease (AD) and to clarify the distribution of tau deposition. In addition to the quantitative analysis of tau-PET scans, visual reading supports the assessment of tau loading for clinical diagnosis. This study aimed to propose a method for visually interpreting tau-PET using the [18F] Florzolotau tracer and investigate the performance and utility of the visual reading.Materials and methodsA total number of 46 individuals with 12 cognitively unimpaired subjects (CU), 20 AD patients with mild cognitive impairment (AD-MCI), and 14 AD with dementia (AD-D) patients with both [18F]Florbetapir amyloid PET and [18F]Florzolotau tau PET scans were included. Clinical information, cognitive assessment, and amyloid PET scan results were recorded. For visual interpretation, a modified rainbow colormap was created and a regional tau uptake scoring system was proposed to evaluate the degree of tracer uptake and its spatial distribution within five cortical regions. Each region was scored on a scale of [0, 2] as compared to the background, and that resulted in a global scale range of [0, 10]. Four readers interpreted [18F]Florzolotau PET using the visual scale. The global and regional standardized uptake value ratios (SUVr) were also calculated for analysis.ResultsThe result indicates the average global visual scores were 0 ± 0 in the CU group, 3.43 ± 3.35 in the AD-MCI group, and 6.31 ± 2.97 in the AD-D group (p < 0.001). The consensus among the four observers on image scores was high with an intraclass correlation coefficient of 0.880 (95% CI: 0.767-0.936). The average global visual score was significantly associated with global SUVr (r = 0.884, p < 0.0001) and with the CDR-sum of box (r = 0.677, p < 0.0001).ConclusionThe visual reading method generated a visual score of [18F]Florzolotau tau-PET with good sensitivity and specificity to identify AD-D or CU individuals from the other patients. The preliminary result also showed that the global visual scores are significantly and reliably correlated with global cortical SUVr, and associated well with the clinical diagnosis and cognitive performance.

Project description:BackgroundThe role and implementation of tau PET imaging for predicting subsequent cognitive decline in Alzheimer's disease (AD) remains uncertain. This study was designed to evaluate the relationship between baseline [18F]GTP1 tau PET and subsequent longitudinal change across multiple cognitive measures over 18 months.MethodsOur analyses incorporated data from 67 participants, including cognitively normal controls (n = 10) and β-amyloid (Aβ)-positive individuals ([18F] florbetapir Aβ PET) with prodromal (n = 26), mild (n = 16), or moderate (n = 15) AD. Baseline measurements included cortical volume (MRI), tau burden ([18F]GTP1 tau PET), and cognitive assessments [Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), 13-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. Cognitive assessments were repeated at 6-month intervals over an 18-month period. Associations between baseline [18F]GTP1 tau PET indices and longitudinal cognitive performance were assessed via univariate (Spearman correlations) and multivariate (linear mixed effects models) approaches. The utility of potential prognostic tau PET cut points was assessed with ROC curves.ResultsUnivariate analyses indicated that greater baseline [18F]GTP1 tau PET signal was associated with faster rates of subsequent decline on the MMSE, CDR, and ADAS-Cog13 across regions of interest (ROIs). In multivariate analyses adjusted for baseline age, cognitive performance, cortical volume, and Aβ PET SUVR, the prognostic performance of [18F]GTP1 SUVR was most robust in the whole cortical gray ROI. When AD participants were dichotomized into low versus high tau subgroups based on baseline [18F]GTP1 PET standardized uptake value ratios (SUVR) in the temporal (cutoff = 1.325) or whole cortical gray (cutoff = 1.245) ROIs, high tau subgroups demonstrated significantly more decline on the MMSE, CDR, and ADAS-Cog13.ConclusionsOur results suggest that [18F]GTP1 tau PET represents a prognostic biomarker in AD and are consistent with data from other tau PET tracers. Tau PET imaging may have utility for identifying AD patients at risk for more rapid cognitive decline and for stratification and/or enrichment of participant selection in AD clinical trials. Trial registration ClinicalTrials.gov NCT02640092 . Registered on December 28, 2015.

Project description:PurposeThe tau tracer [18F]AV1451, also known as flortaucipir, is a promising ligand for imaging tau accumulation in Alzheimer's disease (AD). Most of the previous studies have quantified tau load using standardized uptake value ratios (SUVr) derived from a static [18F]AV1451 scan. SUVr may, however, be flow dependent and, especially for longitudinal studies, should be validated against a fully quantitative approach. The objective of this study was to identify the optimal tracer kinetic model for measuring tau load using [18F]AV1451.ProceduresFollowing intravenous injection of 225 ± 16 MBq [18F]AV1451, 130 min dynamic PET scans were performed in five biomarker confirmed AD patients and five controls. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function. Next, regional time-activity curves were generated using PVElab software. These curves were analysed using several pharmacokinetic models.ResultsThe reversible single tissue compartment model (1T2k_VB) was the preferred model for all but one control. For AD patients, however, model preference shifted towards a reversible two tissue compartmental model (2T4k_VB). The simplified reference tissue model (SRTM) derived binding potential (BPND) showed good correlation (AD: r 2 = 0.87, slope = 1.06; controls: r 2 = 0.87, slope = 0.86) with indirect plasma input binding (distribution volume ratio-1). Standardized uptake value ratios (80-100 min) correlated well with DVR (r 2 = 0.93, slope = 1.07) and SRTM-derived BPND (r 2 = 0.84, slope = 0.95). In addition, regional differences in tracer binding between subject groups in different tau-specific regions were observed.ConclusionsModel preference of [18F]AV1451 appears to depend on subject status and, in particular, VT. The relationship between model preference and VT suggests that (higher) tau load may be reflected by a second tissue compartment. Nevertheless, consistent results can be obtained using a 2T4k_VB model. In addition, SRTM can be used to derive BPND.

Project description:BackgroundThe tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.MethodsWe performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.ResultsOn qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

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Tau PET With ¹⁸F-THK-5351 Taiwan Patients With Familial Alzheimer's Disease With the APP p.D678H Mutation.

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Tau PET With 18F-THK-5351 Taiwan Patients With Familial Alzheimer's Disease With the APP p.D678H Mutation.

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OmicsDI is part of the ELIXIR infrastructure

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Tau PET With ¹⁸F-THK-5351 Taiwan Patients With Familial Alzheimer's Disease With the APP p.D678H Mutation.