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  • 1
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S1 ( 2021-12)
    Abstract: Dynamic 60‐minute positron‐emission‐tomography (PET) imaging with the novel tau radiotracer [ 18 F]PI‐2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). We now aimed to investigate if shorter acquisition and static time windows of [ 18 F]PI‐2620 tau‐PET can be used for imaging of patients with PSP. Method We evaluated 37 patients at five different centers with probable or possible PSP Richardson syndrome (PSP‐RS) together with ten HCs. [ 18 F]PI‐2620 PET was performed by a dynamic 60 minute scan. Distribution volume ratios (DVRs, multilinear reference tissue model 2, cerebellar reference) were calculated using full and truncated scan durations (0‐60, 0‐50, 0‐40, 0‐30, and 0‐20 minutes p.i.). Standardized uptake value ratios (SUVrs, cerebellar reference) were obtained from static imaging windows with 20 minutes duration (20‐40, 30‐50, and 40‐60 minutes 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, receiver operating area under the curve (AUC), multi‐region classifier). Finally, we tested if shorter [ 18 F]PI‐2620 PET imaging can also be applied to patients with Alzheimer’s disease (n=11). Result The effect size of 0‐50 and 0‐40 DVR was equivalent to 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 short static acquisition windows (averaged Cohen’s d: 0.99). The globus pallidus internus discriminated patients with PSP and healthy controls 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%. 0‐40 DVR showed similar performance in Alzheimer’s disease when compared to 0‐60 DVR. Conclusion Short dynamic acquisition and static imaging windows can be used for [ 18 F]PI‐2620 PET imaging of PSP. 0‐40 minute dynamic scanning offers the best balance between accuracy and economic scanning and is may also be suitable for [ 18 F]PI‐2620 PET imaging of Alzheimer’s disease.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 2
    In: JAMA Neurology, American Medical Association (AMA), Vol. 77, No. 11 ( 2020-11-01), p. 1408-
    Type of Medium: Online Resource
    ISSN: 2168-6149
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2020
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  • 3
    In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 41, No. 11 ( 2021-11), p. 2957-2972
    Abstract: The novel tau-PET tracer [ 18 F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer’s disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [ 18 F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [ 18 F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [ 18 F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR 30-60 ) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1 SRTM : 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2 SRTM : 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p  〈  0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p  〈  0.0001), lower SUVR 30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p  〈  0.0001) and flatter slopes of the post-perfusion phase (slope 9-60 : 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p  〈  0.0001) when compared to 3/4R-tau cases. [ 18 F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.
    Type of Medium: Online Resource
    ISSN: 0271-678X , 1559-7016
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2039456-1
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  • 4
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 48, No. 12 ( 2021-11), p. 3872-3885
    Abstract: Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [ 18 F]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 [ 18 F]PI-2620 tau-PET imaging of PSP. Methods Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [ 18 F]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). Results 0–50 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%. Conclusion Truncated and static imaging windows can be used for [ 18 F]PI-2620 PET imaging of PSP. 0–40 min dynamic scanning offers the best balance between accuracy and economic scanning.
    Type of Medium: Online Resource
    ISSN: 1619-7070 , 1619-7089
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2098375-X
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  • 5
    In: Movement Disorders, Wiley, Vol. 36, No. 9 ( 2021-09), p. 2104-2115
    Abstract: Corticobasal syndrome is associated with cerebral protein aggregates composed of 4‐repeat (~50% of cases) or mixed 3‐repeat/4‐repeat tau isoforms (~25% of cases) or nontauopathies (~25% of cases). Objectives The aim of this single‐center study was to investigate the diagnostic value of the tau PET‐ligand [ 18 F]PI‐2620 in patients with corticobasal syndrome. Methods Forty‐five patients (71.5 ± 7.6 years) with corticobasal syndrome and 14 age‐matched healthy controls underwent [ 18 F]PI‐2620‐PET. Beta‐amyloid status was determined by cerebral β‐amyloid PET and/or CSF analysis. Subcortical and cortical [ 18 F]PI‐2620 binding was quantitatively and visually compared between β‐amyloid‐positive and ‐negative patients and controls. Regional [ 18 F]PI‐2620 binding was correlated with clinical and demographic data. Results Twenty‐four percent (11 of 45) were β‐amyloid‐positive. Significantly elevated [ 18 F]PI‐2620 distribution volume ratios were observed in both β‐amyloid‐positive and β‐amyloid‐negative patients versus controls in the dorsolateral prefrontal cortex and basal ganglia. Cortical [ 18 F]PI‐2620 PET positivity was distinctly higher in β‐amyloid‐positive compared with β‐amyloid‐negative patients with pronounced involvement of the dorsolateral prefrontal cortex. Semiquantitative analysis of [ 18 F]PI‐2620 PET revealed a sensitivity of 91% for β‐amyloid‐positive and of 65% for β‐amyloid‐negative cases, which is in excellent agreement with prior clinicopathological data. Regardless of β‐amyloid status, hemispheric lateralization of [ 18 F]PI‐2620 signal reflected contralateral predominance of clinical disease severity. Conclusions Our data indicate a value of [ 18 F]PI‐2620 for evaluating corticobasal syndrome, providing quantitatively and regionally distinct signals in β‐amyloid‐positive as well as β‐amyloid‐negative corticobasal syndrome. In corticobasal syndrome, [ 18 F]PI‐2620 may potentially serve for a differential diagnosis and for monitoring disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2041249-6
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  • 6
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 50, No. 2 ( 2023-01), p. 423-434
    Abstract: Early after [ 18 F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [ 18 F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [ 18 F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. Methods Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0–60 min) [ 18 F]PI-2620 PET imaging. Regional perfusion (0.5–2.5 min p.i.) and tau load (20–40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference] . Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p   〈  0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value − 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset ( n  = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). Results Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale ( R  = 0.402; p  = 0.0012) and activities of daily living ( R  =  − 0.431; p  = 0.0005). Conclusion [ 18 F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.
    Type of Medium: Online Resource
    ISSN: 1619-7070 , 1619-7089
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2098375-X
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  • 7
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 47, No. 12 ( 2020-11), p. 2911-2922
    Abstract: Second-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 [ 18 F]PI-2620 as a potential substitute for [ 18 F]fluorodeoxyglucose ([ 18 F]FDG). Methods Twenty-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 [ 18 F]PI-2620 tau-PET (0–60 min p.i.) and static [ 18 F]FDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R 1 ) of [ 18 F]PI-2620-PET were correlated with corresponding quantification of [ 18 F]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 [ 18 F]PI-2620 tau-PET and [ 18 F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. Results Highest agreement with [ 18 F]FDG-PET quantification was reached for [ 18 F]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 & R 1 ) displayed strong agreement in all cortical target regions for global mean (R SUVr 0.76, R R1  = 0.77) and cerebellar normalization (R SUVr 0.68, R R1  = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [ 18 F]FDG-PET. There were no relevant differences between more and less experienced readers. Conclusion Early-phase imaging of [ 18 F]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 [ 18 F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.
    Type of Medium: Online Resource
    ISSN: 1619-7070 , 1619-7089
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 8
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S6 ( 2022-12)
    Abstract: 4‐repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R‐tauopathies are progressive‐supranuclear‐palsy (PSP) and corticobasal‐syndrome (CBS) characterized by tau accumulation in subcortical nuclei as well as cortical neuronal dysfunction, as shown by PET‐assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces diaschisis‐like neuronal dysfunction in functionally connected cortical regions. Method We included 47 patients with clinically diagnosed PSP or CBS who underwent structural MRI and 18 F‐PI‐2620 tau‐PET. PI‐2620 PET was recorded using a dynamic one‐shot, two‐stop acquisition protocol, to determine an early 0.5‐2.5min post‐tracer‐injection perfusion window for assessing cortical neuroinjury in 200 cortical ROIs of the Schaefer atlas, as well as a 20‐40min post‐tracer‐injection window to determine 4R‐tau load in 32 subcortical ROIs of the TIAN atlas. We determined tau epicenters as 10% of subcortical ROIs with highest tau‐PET, and assessed the connectivity of tau epicenters to cortical ROIs using an age‐matched 3T resting‐state fMRI template derived from 69 healthy elderly. Using linear regression, we assessed whether i) higher subcortical tau‐PET was associated with overall reduced cortical perfusion and ii) whether cortical hypoperfusion was observed preferentially in regions closely connected to subcortical tau epicenters. Result As hypothesized, higher subcortical tau‐PET was associated with lower cortical perfusion (R=‐0,37, p‐value: 〈 0,011, Fig.1). Using group‐average tau‐PET and perfusion‐PET, we found that the seed‐based connectivity pattern of subcortical tau epicenters predicted cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicenter showed stronger hypoperfusion (R=‐0,16, p‐value: 〈 0,023, Fig.2A). This association was also observed on the subject level, as indicated by overall negative b‐values of the association between tau epicenter connectivity and cortical perfusion (one‐sample t‐test: t‐value: ‐3,45, p‐value: 〈 0,001, Fig.3). Conclusion In 4R‐tauopathies subcortical tau‐accumulation is associated with remote neuronal dysfunction in functionally connected cortical regions. This suggests that subcortical tau pathology may induce diaschisis‐like cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 9
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S1 ( 2022-12)
    Abstract: 4‐repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R‐tauopathies are progressive‐supranuclear‐palsy (PSP) and corticobasal‐syndrome (CBS) characterized by tau accumulation in subcortical nuclei as well as cortical neuronal dysfunction, as shown by PET‐assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces diaschisis‐like neuronal dysfunction in functionally connected cortical regions. Method We included 47 patients with clinically diagnosed PSP or CBS who underwent structural MRI and 18 F‐PI‐2620 tau‐PET. PI‐2620 PET was recorded using a dynamic one‐shot, two‐stop acquisition protocol, to determine an early 0.5‐2.5min post‐tracer‐injection perfusion window for assessing cortical neuroinjury in 200 cortical ROIs of the Schaefer atlas, as well as a 20‐40min post‐tracer‐injection window to determine 4R‐tau load in 32 subcortical ROIs of the TIAN atlas. We determined tau epicenters as 10% of subcortical ROIs with highest tau‐PET, and assessed the connectivity of tau epicenters to cortical ROIs using an age‐matched 3T resting‐state fMRI template derived from 69 healthy elderly. Using linear regression, we assessed whether i) higher subcortical tau‐PET was associated with overall reduced cortical perfusion and ii) whether cortical hypoperfusion was observed preferentially in regions closely connected to subcortical tau epicenters. Result As hypothesized, higher subcortical tau‐PET was associated with lower cortical perfusion (R=‐0,37, p‐value: 〈 0,011, Fig.1). Using group‐average tau‐PET and perfusion‐PET, we found that the seed‐based connectivity pattern of subcortical tau epicenters predicted cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicenter showed stronger hypoperfusion (R=‐0,16, p‐value: 〈 0,023, Fig.2A). This association was also observed on the subject level, as indicated by overall negative b‐values of the association between tau epicenter connectivity and cortical perfusion (one‐sample t‐test: t‐value: ‐3,45, p‐value: 〈 0,001, Fig.3). Conclusion In 4R‐tauopathies subcortical tau‐accumulation is associated with remote neuronal dysfunction in functionally connected cortical regions. This suggests that subcortical tau pathology may induce diaschisis‐like cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 10
    In: Movement Disorders, Wiley, Vol. 36, No. 4 ( 2021-04), p. 883-894
    Abstract: Neuroinflammation has received growing interest as a therapeutic target in neurodegenerative disorders, including 4‐repeat tauopathies. Objectives The aim of this cross‐sectional study was to investigate 18 kDa translocator protein positron emission tomography (PET) as a biomarker for microglial activation in the 4‐repeat tauopathies corticobasal degeneration and progressive supranuclear palsy. Methods Specific binding of the 18 kDa translocator protein tracer 18 F‐GE‐180 was determined by serial PET during pharmacological depletion of microglia in a 4‐repeat tau mouse model. The 18 kDa translocator protein PET was performed in 30 patients with corticobasal syndrome (68 ± 9 years, 16 women) and 14 patients with progressive supranuclear palsy (69 ± 9 years, 8 women), and 13 control subjects (70 ± 7 years, 7 women). Group comparisons and associations with parameters of disease progression were assessed by region‐based and voxel‐wise analyses. Results Tracer binding was significantly reduced after pharmacological depletion of microglia in 4‐repeat tau mice. Elevated 18 kDa translocator protein labeling was observed in the subcortical brain areas of patients with corticobasal syndrome and progressive supranuclear palsy when compared with controls and was most pronounced in the globus pallidus internus, whereas only patients with corticobasal syndrome showed additionally elevated tracer binding in motor and supplemental motor areas. The 18 kDa translocator protein labeling was not correlated with parameters of disease progression in corticobasal syndrome and progressive supranuclear palsy but allowed sensitive detection in patients with 4‐repeat tauopathies by a multiregion classifier. Conclusions Our data indicate that 18 F‐GE‐180 PET detects microglial activation in the brain of patients with 4‐repeat tauopathy, fitting to predilection sites of the phenotype. The 18 kDa translocator protein PET has a potential for monitoring neuroinflammation in 4‐repeat tauopathies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2041249-6
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