18F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

PURPOSE: Human post mortem studies have described the topographical patterns of tau pathology in progressive supranuclear palsy (PSP). Recent advances in tau PET tracers are expected to herald the next era of PSP investigation for early detection of tau pathology in living brains. This study aimed to investigate whether 18F-Florzolotau PET imaging may capture the distribution patterns and regional vulnerability of tau pathology in PSP, and to devise a novel image-based staging system. METHODS: The study cohort consisted of 148 consecutive patients with PSP who had undergone 18F-Florzolotau PET imaging. The PSP rating scale (PSPrs) was used to measure disease severity. Similarities and differences of tau deposition among different clinical phenotypes were examined at the regional and voxel levels. An 18F-Florzolotau pathological staging system was devised according to the scheme originally developed for post mortem data. In light of conditional probabilities for the sequence of events, an 18F-Florzolotau modified staging system by integrating clusters at the regional level was further developed. The ability of 18F-Florzolotau staging systems to reflect disease severity in terms of PSPrs score was assessed by analysis of variance. RESULTS: The distribution patterns of 18F-Florzolotau accumulation in living brains of PSP showed a remarkable similarity to those reported in post mortem studies, with the binding intensity being markedly higher in Richardson's syndrome. Moreover, 18F-Florzolotau PET imaging allowed detecting regional vulnerability and tracking tau accumulation in an earlier fashion compared with post mortem immunostaining. The 18F-Florzolotau staging systems were positively correlated with clinical severity as reflected by PSPrs scores. CONCLUSIONS: 18F-Florzolotau PET imaging can effectively capture the distribution patterns and regional vulnerability of tau pathology in PSP. The 18F-Florzolotau modified staging system holds promise for early tracking of tau deposition in living brains.

In Vivo 18 F-Florzolotau Tau Positron Emission Tomography Imaging in Parkinson's Disease Dementia.

BACKGROUND: Tau pathology is observed during autopsy in many patients with Parkinson's disease dementia (PDD). Positron emission tomography (PET) imaging using the tracer 18 F-florzolotau has the potential to capture tau accumulation in the living brain. OBJECTIVE: The aim was to describe the results of 18 F-florzolotau PET/CT (computed tomography) imaging in patients with PDD. METHODS: Ten patients with PDD, 9 with Parkinson's disease with normal cognition (PD-NC), and 9 age-matched healthy controls (HCs) were enrolled. Clinical assessments and 18 F-florzolotau PET/CT imaging were performed. RESULTS: 18 F-Florzolotau uptake was significantly higher in the cortical regions of patients with PDD compared with both PD-NC and HCs, especially in the temporal lobe. Notably, 18 F-florzolotau uptake in the occipital lobe of patients with PDD showed a significant correlation with cognitive impairment as reflected by Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: 18 F-Florzolotau PET imaging can effectively capture the occurrence of tau pathology in patients with PDD, which was also linked to MMSE scores. © 2022 International Parkinson and Movement Disorder Society.

18 F-Florzolotau Positron Emission Tomography Imaging of Tau Pathology in the Living Brains of Patients with Corticobasal Syndrome.

BACKGROUND: Recent development in tau-sensitive tracers has sparkled significant interest in tracking tauopathies using positron emission tomography (PET) biomarkers. However, the ability of 18 F-florzolotau PET imaging to topographically characterize tau pathology in corticobasal syndrome (CBS) remains unclear. Further, the question as to whether disease-level differences exist with other neurodegenerative tauopathies is still unanswered. OBJECTIVE: To analyze the topographical patterns of tau pathology in the living brains of patients with CBS using 18 F-florzolotau PET imaging and to examine whether differences with other tauopathies exist. METHODS: 18 F-florzolotau PET imaging was performed in 20 consecutive patients with CBS, 20 cognitively healthy controls (HCs), 20 patients with Alzheimer's disease (AD), and 16 patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). Cerebrospinal fluid (CSF) levels of ß-amyloid biomarkers were quantified in all patients with CBS. 18 F-florzolotau uptake was quantitatively assessed using standardized uptake value ratios. RESULTS: Of the 20 patients with CBS, 19 (95%) were negative for CSF biomarkers of amyloid pathology; of them, three had negative 18 F-florzolotau PET findings. Compared with HCs, patients with CBS showed increased 18 F-florzolotau signals in both cortical and subcortical regions. In addition, patients with CBS were characterized by higher tracer retentions in subcortical regions compared with those with AD and showed a trend toward higher signals in cortical areas compared with PSP-RS. An asymmetric pattern of 18 F-florzolotau uptake was associated with an asymmetry of motor severity in patients with CBS. CONCLUSIONS: In vivo 18 F-florzolotau PET imaging holds promise for distinguishing CBS in the spectrum of neurodegenerative tauopathies. © 2023 International Parkinson and Movement Disorder Society.

18 F-Florzolotau Tau Positron Emission Tomography Imaging in Patients with Multiple System Atrophy-Parkinsonian Subtype.

BACKGROUND: Anecdotal evidence suggests that patients diagnosed with the parkinsonian subtype of multiple system atrophy (MSA-P) may show uptake of the second-generation tau positron emission tomography (PET) tracer 18 F-Florzolotau (previously known as 18 F-APN-1607) in the putamen. OBJECTIVES: This study systematically investigated the localization and magnitude of 18 F-Florzolotau uptake in a relatively large cohort of patients with MSA-P. METHODS: 18 F-Florzolotau PET imaging was performed in 31 patients with MSA-P, 24 patients with Parkinson's disease (PD), and 20 age-matched healthy controls. 18 F-Florzolotau signal in the striatum was analyzed by visual inspection and classified as either positive or negative. Regional 18 F-Florzolotau binding was also expressed as standardized uptake value ratio (SUVR) to assess whether it was associated with core symptoms of MSA-P after adjustment for potential confounders. RESULTS: By visual inspection and semiquantitative SUVR comparisons, patients with MSA-P showed elevated 18 F-Florzolotau uptake in the putamen, globus pallidus, and dentate-a finding that was not observed in PD. This increased signal was significantly associated with the core symptoms of MSA-P. In addition, patients with MSA-P with cerebellar ataxia showed an elevated 18 F-Florzolotau uptake in the cerebellar dentate. CONCLUSIONS: 18 F-Florzolotau tau PET imaging findings may reflect the clinical severity of MSA-P and can potentially discriminate between this condition and PD. © 2022 International Parkinson and Movement Disorder Society.

Human biodistribution and radiation dosimetry for the tau tracer [18F]Florzolotau in healthy subjects.

BACKGROUND: Tau pathology plays a crucial role in neurodegeneration diseases including Alzheimer's disease (AD) and non-AD diseases such as progressive supranuclear palsy. Tau positron emission tomography (PET) is an in-vivo and non-invasive medical imaging technique for detecting and visualizing tau deposition within a human brain. In this work, we aim to investigate the biodistribution of the dosimetry in the whole body and various organs for the [18F]Florzolotau tau-PET tracer. A total of 12 healthy controls (HCs) were enrolled at Chang Gung Memorial Hospital. All subjects were injected with approximately 379.03 ± 7.03 MBq of [18F]Florzolotau intravenously, and a whole-body PET/CT scan was performed for each subject. For image processing, the VOI for each organ was delineated manually by using the PMOD 3.7 software. Then, the time-activity curve of each organ was acquired by optimally fitting an exponential uptake and clearance model using the least squares method implemented in OLINDA/EXM 2.1 software. The absorbed dose for each target organ and the effective dose were finally calculated. RESULTS: From the biodistribution results, the elimination of [18F]Florzolotau is observed mainly from the liver to the intestine and partially through the kidneys. The highest organ-absorbed dose occurred in the right colon wall (255.83 µSv/MBq), and then in the small intestine (218.67 µSv/MBq), gallbladder wall (151.42 µSv/MBq), left colon wall (93.31 µSv/MBq), and liver (84.15 µSv/MBq). Based on the ICRP103, the final computed effective dose was 34.9 µSv/MBq with CV of 10.07%. CONCLUSIONS: The biodistribution study of [18F]Florzolotau demonstrated that the excretion of [18F]Florzolotau are mainly through the hepatobiliary and gastrointestinal pathways. Therefore, a routine injection of 370 MBq or 185 MBq of [18F]Florzolotau leads to an estimated effective dose of 12.92 or 6.46 mSv, and as a result, the radiation exposure to the whole-body and each organ remains within acceptable limits and adheres to established constraints. TRIAL REGISTRATION: Retrospectively Registered at Clinicaltrials.gov (NCT03625128) on 12 July, 2018, https://clinicaltrials.gov/study/NCT03625128 .

Visual reading for [18F]Florzolotau ([18F]APN-1607) tau PET imaging in clinical assessment of Alzheimer's disease.

Introduction: Tau-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 methods: A 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. Results: The 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). Conclusion: The 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.

Uncovering distinct progression patterns of tau deposition in progressive supranuclear palsy using [18F]Florzolotau PET imaging and subtype/stage inference algorithm.

BACKGROUND: Progressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy with diverse clinical phenotypes. Previous post-mortem studies examined tau deposition sequences in PSP, but in vivo scrutiny is lacking. METHODS: We conducted [18F]Florzolotau tau positron emission tomography (PET) scans on 148 patients who were clinically diagnosed with PSP and 20 healthy controls. We employed the Subtype and Stage Inference (SuStaIn) algorithm to identify PSP subtype/stage and related tau patterns, comparing clinical features across subtypes and assessing PSP stage-clinical severity association. We also evaluated functional connectivity differences among subtypes through resting-state functional magnetic resonance imaging. FINDINGS: We identified two distinct subtypes of PSP: Subtype1 and Subtype2. Subtype1 typically exhibits a sequential progression of the disease, starting from subcortical and gradually moving to cortical regions. Conversely, Subtype2 is characterized by an early, simultaneous onset in both regions. Interestingly, once the disease is initiated, Subtype1 tends to spread more rapidly within each region compared to Subtype2. Individuals categorized as Subtype2 are generally older and exhibit less severe dysfunctions in areas such as cognition, bulbar, limb motor, and general motor functions compared to those with Subtype1. Moreover, they have a more favorable prognosis in terms of limb motor function. We found significant correlations between several clinical variables and the identified PSP SuStaIn stages. Furthermore, Subtype2 displayed a remarkable reduction in functional connectivity compared to Subtype1. INTERPRETATION: We present the evidence of distinct in vivo spatiotemporal tau trajectories in PSP. Our findings can contribute to precision medicine advancements for PSP. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (number 82272039, 81971641, 82021002, and 92249302); Swiss National Science Foundation (number 188350); the STI2030-Major Project of China (number 2022ZD0211600); the Clinical Research Plan of Shanghai Hospital Development Center of China (number SHDC2020CR1038B); and the National Key R&D Program of China (number 2022YFC2009902, 2022YFC2009900), the China Scholarship Council (number 202006100181); the Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198).