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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    In: European Journal of Nuclear Medicine and Molecular Imaging, Springer Science and Business Media LLC, Vol. 44, No. 13 ( 2017-12), p. 2239-2248
    Type of Medium: Online Resource
    ISSN: 1619-7070 , 1619-7089
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2098375-X
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  • 5
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 12 ( 2021-7-2)
    Abstract: Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [ 18 F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP). Methods: We applied [ 18 F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities. Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMR frozen vs. CWMR FFPE : 2.5-fold, p & lt; 0.001), whereas the opposite was observed in PSP tissue (CWMR frozen vs. CWMR FFPE : 0.8-fold, p = 0.004). In FFPE samples, [ 18 F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP ( R = 0.641, p & lt; 0.001) and AD tissue ( R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD ( R = 0.417, p = 0.014) but not in PSP tissue ( R = −0.115, p = n.s.). Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [ 18 F]PI-2620. The [ 18 F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients.
    Type of Medium: Online Resource
    ISSN: 1664-2295
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2564214-5
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  • 6
    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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  • 7
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Cortico‐basal degeneration (CBD) and progressive supranuclear palsy (PSP) are 4R‐tauopathies characterized by progressive tau pathology spread that typically starts in the subcortex. Pre‐clinical studies suggest that tau spreads across connected neurons in an activity‐dependent manner, indicating that the brains’ connectome may mediate tau spreading. Supporting this, we found in Alzheimer’s disease that PET‐assessed cortical tau spreads across functionally connected regions. Here, we assessed whether connectivity mediates cortical/subcortical tau spreading also in 4R‐tauopathies, by combining resting‐state fMRI connectivity with i) 2 nd generation in vivo tau‐PET (PI2620) in CBS and PSP and ii) post‐mortem tau assessments in PSP. Method We assessed PI2620 tau‐PET in 24 CBS‐patients, 28 PSP‐patients and 15 healthy controls. Voxel‐wise tau‐PET differences were determined between patients vs. controls and mean tau‐PET SUVRs were assessed for 232 cortical/subcortical‐ROIs (Fig. 1A). Semi‐quantitative post‐mortem AT8‐stained neuronal tau was assessed in two additional, non‐overlapping PSP samples (Munich: n=96; & UPENN: n=97). Neuropathological ROIs were reconstructed in MRI‐standard‐space (Figs. 1B & C). Functional connectivity was assessed between tau‐PET‐ROIs and neuropathological‐ROIs using out‐of‐sample resting‐state fMRI from 69 elderly amyloid‐ and tau‐negative controls. Using linear regression, we assessed the association between ROI‐to‐ROI connectivity and covariance in tau‐PET or post‐mortem tau levels in spatially corresponding ROI pairs. For tau‐PET, we further tested at the subject level, whether functional connectivity of tau epicenters (i.e. ROIs with highest tau‐PET in a given subject) predicted tau deposition in connected regions, using linear mixed models controlling for age, gender and random intercept. Result PSP and CBS patients showed elevated tau‐PET compared to controls (Fig. 2). Higher functional connectivity was associated with higher covariance in tau‐PET in PSP and CBS (b=0.402‐0.715, Fig. 3A‐D, all p 〈 0.001). For post‐mortem data, higher ROI‐to‐ROI functional connectivity was also associated higher covariance in tau in both PSP samples (b=0.468 & 0.765, p 〈 0.001, Fig. 3E & F). Using tau‐PET we found further that connectivity patterns of subject‐level subcortical tau epicenters was associated with subject‐level tau‐PET uptake in connected regions (Fig. 4B‐E, all p 〈 0.001). Conclusion Highly functionally connected brain regions share similar tau levels in 4R‐tauopathies as indicated by tau‐PET and post‐mortem assessments, suggesting that brain connectivity is associated with inter‐regional tau spreading in 4R‐tauopathies.
    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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  • 8
    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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  • 9
    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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  • 10
    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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