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Previous studies have shown that persons with Parkinson’s disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-thalamo-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however, unsuccessfully. Finally, there were no differences between pwPD and controls in task modulation of the cortico-striato-thalamo-cerebellar network. However, a restricted nigral-striatal model showed that negative modulation of SN to putamen connection was larger in pwPD compared to controls during random trials, while no differ

Previous studies have shown that persons with Parkinson’s disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-thalamo-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however, unsuccessfully. Finally, there were no differences between pwPD and controls in task modulation of the cortico-striato-thalamo-cerebellar network. However, a restricted nigral-striatal model showed that negative modulation of SN to putamen connection was larger in pwPD compared to controls during random trials, while no differ

Purpose Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [F-18]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 [F-18]PI-2620 tau-PET imaging of PSP. Methods Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [F-18]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 [F-18]PI-2620 PET imaging of PSP. 0-40 min dynamic scanning offers the best balance between accuracy and economic scanning.

The novel tau-PET tracer [F-18]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 [F-18]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. [F-18]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [F-18]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 (SUVR30-60) 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 SUVR30-60 (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. [F-18]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.

Purpose Dynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [F-18]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 [F-18]PI-2620 tau-PET imaging of PSP. Methods Thirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [F-18]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 [F-18]PI-2620 PET imaging of PSP. 0-40 min dynamic scanning offers the best balance between accuracy and economic scanning.

The novel tau-PET tracer [F-18]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 [F-18]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. [F-18]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [F-18]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 (SUVR30-60) 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 SUVR30-60 (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. [F-18]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.

Purpose Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several beta-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 [F-18]PI-2620 as a potential substitute for [F-18]fluorodeoxyglucose ([F-18]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 [F-18]PI-2620 tau-PET (0-60 min p.i.) and static [F-18]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 [F-18]PI-2620-PET were correlated with corresponding quantification of [F-18]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 [F-18]PI-2620 tau-PET and [F-18]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 [F-18]FDG-PET quantification was reached for [F-18]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 i

Importance Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective To investigate the potential of the novel tau radiotracer F-18-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants In this cross-sectional study, participants underwent dynamic F-18-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, F-18-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [

Purpose Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several beta-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 [F-18]PI-2620 as a potential substitute for [F-18]fluorodeoxyglucose ([F-18]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 [F-18]PI-2620 tau-PET (0-60 min p.i.) and static [F-18]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 [F-18]PI-2620-PET were correlated with corresponding quantification of [F-18]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 [F-18]PI-2620 tau-PET and [F-18]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 [F-18]FDG-PET quantification was reached for [F-18]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 i

Importance Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective To investigate the potential of the novel tau radiotracer F-18-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants In this cross-sectional study, participants underwent dynamic F-18-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, F-18-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [

Background: The efferent dorsal motor nucleus of the vagal nuclei complex may degenerate early in the course of Parkinson’s disease (PD), while efferent nucleus ambiguous, the principal source of parasympathetic vagal neurons innervating the heart, and afferent somatosensory nuclei remain intact.

Background: The efferent dorsal motor nucleus of the vagal nuclei complex may degenerate early in the course of Parkinson’s disease (PD), while efferent nucleus ambiguous, the principal source of parasympathetic vagal neurons innervating the heart, and afferent somatosensory nuclei remain intact.

Purpose Early after [F-18]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [F-18]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 [F-18]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) [F-18] 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 4R