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Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2 nd generation 18 F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples ( n  = 97 and n  = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies. Tau pathology drives neuronal dysfunction in 4- repeat tauopathies. Here, the authors combine tau-PET, resting-state fMRI and histopathology data, to show that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

PurposeSecond-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG).MethodsTwenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson’s disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0–60 min p.i.) and static [18F]FDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers.ResultsHighest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5–2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers.ConclusionEarly-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

PurposeDynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [18F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [18F]PI-2620 tau-PET imaging of PSP.MethodsThirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [18F]PI-2620 PET was performed by a dynamic 60-min scan. Distribution volume ratios (DVRs) were calculated using full and truncated scan durations (0–60, 0–50, 0–40, 0–30, and 0–20 min p.i.). Standardized uptake value ratios (SUVrs) were obtained 20–40, 30–50, and 40–60 min p.i.. All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP-RS from HCs in predefined subcortical and cortical target regions (effect size, area under the curve (AUC), multi-region classifier).Results0–50 and 0–40 DVR showed equivalent effect sizes as 0–60 DVR (averaged Cohen’s d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0–30 or 0–20 DVR. The 20–40 SUVr indicated the best performance of all static acquisition windows (averaged Cohen’s d: 0.99). The globus pallidus internus discriminated patients with PSP-RS and HCs at a similarly high level for 0–60 DVR (AUC: 0.96), 0–40 DVR (AUC: 0.96), and 20–40 SUVr (AUC: 0.94). The multi-region classifier sensitivity of these time windows was consistently 86%.ConclusionTruncated and static imaging windows can be used for [18F]PI-2620 PET imaging of PSP. 0–40 min dynamic scanning offers the best balance between accuracy and economic scanning.

Background/Objectives: Positron emission tomography (PET) imaging with radiolabeled amino acids is increasingly used in glioma patients for biopsy planning, tumor delineation, prognostication, and therapy response assessment. This study investigated whether baseline amino acid PET imaging could identify regions at risk of future tumor recurrence. Methods: Retrospective case series of 14 patients with high-grade glioma. Contrast-enhanced magnetic resonance imaging (MRI) data of tumor recurrence and baseline imaging (PET-MRI) were co-registered. Volumes of interest (VOIs) of the high-grade glioma were derived from contrast-enhanced MRI at baseline and follow-up and from amino acid PET at baseline. The Dice similarity coefficient (DSC) was used to assess the overlap between VOIs. Furthermore, dynamic and static PET parameters were compared between the VOIs derived from contrast-enhanced MRI at follow-up and from the region of increased amino acid transport at baseline. Results: Regions of tumor recurrence in high-grade glioma patients overlap significantly more with baseline regions of increased amino acid transport on PET compared to regions of contrast enhancement on baseline MRI (p < 0.001). However, the static and dynamic PET statistics did not differentiate between regions that would later develop tumor recurrence and other areas of increased amino acid transport at baseline. Conclusions: These findings reaffirm the ability of amino acid PET to visualize the infiltrative components of gliomas not detected by contrast-enhanced MRI. Also, this study supports the role of amino acid PET in visualizing glioma infiltration beyond the MRI-visible tumor, but also indicates that accurately predicting the specific regions of recurrence based on baseline PET remains limited.

Purpose In recent years, several [ 18 F]-labeled amyloid-PET tracers have been developed and have obtained clinical approval. Despite their widespread scientific use, studies in routine clinical settings are limited. We therefore investigated the impact of [ 18 F]-florbetaben (FBB)-PET on the diagnostic management of patients with suspected dementia that was still unclarified after [ 18 F]-fluordeoxyglucose (FDG)-PET. Methods All subjects were referred in-house with a suspected dementia syndrome due to neurodegenerative disease. After undergoing an FDG-PET exam, the cases were discussed by the interdisciplinary dementia board, where the most likely diagnosis as well as potential differential diagnoses were documented. Because of persistent diagnostic uncertainty, the patients received an additional FBB-PET exam. Results were interpreted visually and classified as amyloid-positive or amyloid-negative, and we then compared the individual clinical diagnoses before and after additional FBB-PET. Results A total of 107 patients (mean age 69.4 ± 9.7y) were included in the study. The FBB-PET was rated as amyloid-positive in 65/107. In 83% of the formerly unclear cases, a final diagnosis was reached through FBB-PET, and the most likely prior diagnosis was changed in 28% of cases. The highest impact was observed for distinguishing Alzheimer’s dementia (AD) from fronto-temporal dementia (FTLD), where FBB-PET altered the most likely diagnosis in 41% of cases. Conclusions FBB-PET has a high additive value in establishing a final diagnosis in suspected dementia cases when prior investigations such as FDG-PET are inconclusive. The differentiation between AD and FTLD was particularly facilitated by amyloid-PET, predicting a considerable impact on patient management, especially in the light of upcoming disease-modifying therapies.

Background Both enantiomers of [ 18 F]flubatine are new radioligands for neuroimaging of α 4 β 2 nicotinic acetylcholine receptors with positron emission tomography (PET) exhibiting promising pharmacokinetics which makes them attractive for different clinical questions. In a previous preclinical study, the main advantage of (+)-[ 18 F]flubatine compared to (−)-[ 18 F]flubatine was its higher binding affinity suggesting that (+)-[ 18 F]flubatine might be able to detect also slight reductions of α 4 β 2 nAChRs and could be more sensitive than (−)-[ 18 F]flubatine in early stages of Alzheimer’s disease. To support the clinical translation, we investigated a fully image-based internal dosimetry approach for (+)-[ 18 F]flubatine, comparing mouse data collected on a preclinical PET/MRI system to piglet and first-in-human data acquired on a clinical PET/CT system. Time-activity curves (TACs) were obtained from the three species, the animal data extrapolated to human scale, exponentially fitted and the organ doses (OD), and effective dose (ED) calculated with OLINDA. Results The excreting organs (urinary bladder, kidneys, and liver) receive the highest organ doses in all species. Hence, a renal/hepatobiliary excretion pathway can be assumed. In addition, the ED conversion factors of 12.1 μSv/MBq (mice), 14.3 μSv/MBq (piglets), and 23.0 μSv/MBq (humans) were calculated which are well within the order of magnitude as known from other 18 F-labeled radiotracers. Conclusions Although both enantiomers of [ 18 F]flubatine exhibit different binding kinetics in the brain due to the respective affinities, the effective dose revealed no enantiomer-specific differences among the investigated species. The preclinical dosimetry and biodistribution of (+)-[ 18 F]flubatine was shown and the feasibility of a dose assessment based on image data acquired on a small animal PET/MR and a clinical PET/CT was demonstrated. Additionally, the first-in-human study confirmed the tolerability of the radiation risk of (+)-[ 18 F]flubatine imaging which is well within the range as caused by other 18 F-labeled tracers. However, as shown in previous studies, the ED in humans is underestimated by up to 50 % using preclinical imaging for internal dosimetry. This fact needs to be considered when applying for first-in-human studies based on preclinical biokinetic data scaled to human anatomy.

Single-session, multiparametric [¹⁸F]FET PET/MRI is used to detect tumor recurrence in high-grade glioma, but its prognostic value for overall survival remains uncertain. This study evaluated whether biological tumor volume, tumor-to-background ratio (TBRmax), cerebral blood volume (rCBVmax), and choline/NAA ratio (Cho/NAA) could predict survival in recurrent high-grade glioma.BACKGROUND AND PURPOSESingle-session, multiparametric [¹⁸F]FET PET/MRI is used to detect tumor recurrence in high-grade glioma, but its prognostic value for overall survival remains uncertain. This study evaluated whether biological tumor volume, tumor-to-background ratio (TBRmax), cerebral blood volume (rCBVmax), and choline/NAA ratio (Cho/NAA) could predict survival in recurrent high-grade glioma.Twenty-six patients with histopathologically confirmed tumor progression underwent simultaneous [¹⁸F]FET PET/MRI. PET-derived biological tumor volume and TBRmax, MRI-derived rCBVmax, and Cho/NAA ratio were analyzed. A Cox proportional hazards model assessed associations with overall survival, adjusting for the number of lesions and treatment strategy.MATERIALS AND METHODSTwenty-six patients with histopathologically confirmed tumor progression underwent simultaneous [¹⁸F]FET PET/MRI. PET-derived biological tumor volume and TBRmax, MRI-derived rCBVmax, and Cho/NAA ratio were analyzed. A Cox proportional hazards model assessed associations with overall survival, adjusting for the number of lesions and treatment strategy.Biological tumor volume (hazard ratio = 2.22, 95%-CI: 1.035-4.762, p = 0.041) and the number of lesions (hazard ratio = 1.03, 95%-CI 1.00-1.06, p = 0.036) were significantly associated with survival. TBRmax (p = 0.089), rCBVmax (p = 0.088), and Cho/NAA ratio (p = 0.734) were not predictive. Treatment strategy after tumor recurrence diagnosis did not significantly impact overall-survival (HR = 0.208, p = 0.649). PET/MRI interaction terms did not enhance survival prediction.RESULTSBiological tumor volume (hazard ratio = 2.22, 95%-CI: 1.035-4.762, p = 0.041) and the number of lesions (hazard ratio = 1.03, 95%-CI 1.00-1.06, p = 0.036) were significantly associated with survival. TBRmax (p = 0.089), rCBVmax (p = 0.088), and Cho/NAA ratio (p = 0.734) were not predictive. Treatment strategy after tumor recurrence diagnosis did not significantly impact overall-survival (HR = 0.208, p = 0.649). PET/MRI interaction terms did not enhance survival prediction.Biological tumor volume is a significant prognostic imaging biomarker in recurrent high-grade glioma, emphasizing tumor burden over metabolic activity or perfusion of individual lesions. Volume-based PET metrics may offer better survival prediction than traditional PET or MRI parameters. Prospective multicenter studies are needed to validate these findings and explore automated segmentation and machine learning approaches for improved prognostication.CONCLUSIONBiological tumor volume is a significant prognostic imaging biomarker in recurrent high-grade glioma, emphasizing tumor burden over metabolic activity or perfusion of individual lesions. Volume-based PET metrics may offer better survival prediction than traditional PET or MRI parameters. Prospective multicenter studies are needed to validate these findings and explore automated segmentation and machine learning approaches for improved prognostication.

Heterogeneity in clinical phenotypes has led to the description of different phenotypes of Alzheimer's disease (AD). Besides the most frequent amnestic variant of AD (aAD), patients presenting with language deficits are diagnosed with logopenic variant primary progressive aphasia (lvPPA), whereas patients presenting with visual deficits are classified as posterior cortical atrophy (PCA).PURPOSEHeterogeneity in clinical phenotypes has led to the description of different phenotypes of Alzheimer's disease (AD). Besides the most frequent amnestic variant of AD (aAD), patients presenting with language deficits are diagnosed with logopenic variant primary progressive aphasia (lvPPA), whereas patients presenting with visual deficits are classified as posterior cortical atrophy (PCA).This study set out to investigate the value of a multi-parametric [18F]PI-2620 tau PET/MRI protocol to distinguish aAD, lvPPA and PCA to support clinical diagnosis in 32 patients. Phenotype-specific information about tau accumulation, relative perfusion, grey matter density, functional network alterations and white matter microstructural alterations was collected.METHODSThis study set out to investigate the value of a multi-parametric [18F]PI-2620 tau PET/MRI protocol to distinguish aAD, lvPPA and PCA to support clinical diagnosis in 32 patients. Phenotype-specific information about tau accumulation, relative perfusion, grey matter density, functional network alterations and white matter microstructural alterations was collected.The aAD patients showed significantly higher tau accumulation, relative hypoperfusion and grey matter density loss in the temporal lobes compared to PCA and lvPPA patients. PCA patients, on the other hand, showed significantly higher tau accumulation in the occipital lobe as compared to aAD patients. Relative hypoperfusion in the occipital lobe and loss of functional connectivity of the posterior cingulate cortex to supplementary visual cortical regions helped to distinguish PCA from lvPPA. Tau accumulation in the cerebellum and microstructural changes in the cingulum were found to help differentiate lvPPA from aAD.RESULTSThe aAD patients showed significantly higher tau accumulation, relative hypoperfusion and grey matter density loss in the temporal lobes compared to PCA and lvPPA patients. PCA patients, on the other hand, showed significantly higher tau accumulation in the occipital lobe as compared to aAD patients. Relative hypoperfusion in the occipital lobe and loss of functional connectivity of the posterior cingulate cortex to supplementary visual cortical regions helped to distinguish PCA from lvPPA. Tau accumulation in the cerebellum and microstructural changes in the cingulum were found to help differentiate lvPPA from aAD.This study highlights structural and functional differences between patients with different AD phenotypes. Differences in regional tau PET signals suggest that refinements in the Braak staging system are needed for the non-aAD cases. These patterns of tau accumulation align with the cascading network failure hypothesis, though more research is needed to warrant the here presented results in larger patient cohorts.CONCLUSIONThis study highlights structural and functional differences between patients with different AD phenotypes. Differences in regional tau PET signals suggest that refinements in the Braak staging system are needed for the non-aAD cases. These patterns of tau accumulation align with the cascading network failure hypothesis, though more research is needed to warrant the here presented results in larger patient cohorts.

Purpose Heterogeneity in clinical phenotypes has led to the description of different phenotypes of Alzheimer’s disease (AD). Besides the most frequent amnestic variant of AD (aAD), patients presenting with language deficits are diagnosed with logopenic variant primary progressive aphasia (lvPPA), whereas patients presenting with visual deficits are classified as posterior cortical atrophy (PCA). Methods This study set out to investigate the value of a multi-parametric [ 18 F]PI-2620 tau PET/MRI protocol to distinguish aAD, lvPPA and PCA to support clinical diagnosis in 32 patients. Phenotype-specific information about tau accumulation, relative perfusion, grey matter density, functional network alterations and white matter microstructural alterations was collected. Results The aAD patients showed significantly higher tau accumulation, relative hypoperfusion and grey matter density loss in the temporal lobes compared to PCA and lvPPA patients. PCA patients, on the other hand, showed significantly higher tau accumulation in the occipital lobe as compared to aAD patients. Relative hypoperfusion in the occipital lobe and loss of functional connectivity of the posterior cingulate cortex to supplementary visual cortical regions helped to distinguish PCA from lvPPA. Tau accumulation in the cerebellum and microstructural changes in the cingulum were found to help differentiate lvPPA from aAD. Conclusion This study highlights structural and functional differences between patients with different AD phenotypes. Differences in regional tau PET signals suggest that refinements in the Braak staging system are needed for the non-aAD cases. These patterns of tau accumulation align with the cascading network failure hypothesis, though more research is needed to warrant the here presented results in larger patient cohorts.

Purpose We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [ 18 F]PI-2620 tau-positron-emission-tomography (PET) imaging with [ 123 I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. Methods Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [ 18 F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. Results In patients with 4R-tauopathies, [ 18 F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (β =  − 0.464, p  = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [ 18 F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (β = 0.078, p  = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [ 18 F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (β =  − 0.522, p  = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. Conclusion Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.