Tau PET Ligand Research Articles

Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline.

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (β=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β=0.006, p < 0.01) and global tau SUVR (β=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.

Detection of individual brain tau deposition in Alzheimer's disease based on latent feature-enhanced generative adversarial network

ObjectiveThe conventional methods for interpreting tau PET imaging in Alzheimer's disease (AD), including visual assessment and semi-quantitative analysis of fixed hallmark regions, are insensitive to detect individual small lesions because of the spatiotemporal neuropathology's heterogeneity. In this study, we proposed a latent feature-enhanced generative adversarial network model for the automatic extraction of individual brain tau deposition regions. MethodsThe latent feature-enhanced generative adversarial network we propose can learn the distribution characteristics of tau PET images of cognitively normal individuals and output the abnormal distribution regions of patients. This model was trained and validated using 1131 tau PET images from multiple centres (with distinct races, i.e., Caucasian and Mongoloid) with different tau PET ligands. The overall quality of synthetic imaging was evaluated using structural similarity (SSIM), peak signal to noise ratio (PSNR), and mean square error (MSE). The model was compared to the fixed templates method for diagnosing and predicting AD. ResultsThe reconstructed images archived good quality, with SSIM = 0.967 ± 0.008, PSNR = 31.377 ± 3.633, and MSE = 0.0011 ± 0.0007 in the independent test set. The model showed higher classification accuracy (AUC = 0.843, 95 % CI = 0.796−0.890) and stronger correlation with clinical scales (r = 0.508, P < 0.0001). The model also achieved superior predictive performance in the survival analysis of cognitive decline, with a higher hazard ratio: 3.662, P < 0.001. InterpretationThe LFGAN4Tau model presents a promising new approach for more accurate detection of individualized tau deposition. Its robustness across tracers and races makes it a potentially reliable diagnostic tool for AD in practice.

Cortical and substantia nigra 18F‐PI‐2620 tau PET signal in Lewy body disease

AbstractBackgroundTau PET imaging is a potential tool for measuring comorbid tau pathology in patients with Lewy body disease. Furthermore, tau PET ligands are known to bind to neuromelanin within substantia nigra (SN), with reduced binding in Parkinson’s disease relative to healthy individuals. We sought to characterize 18F‐PI‐2620, a next generation PET tracer, in patients from across the Lewy body disease spectrum.MethodA total of 126 participants from the Stanford Alzheimer’s Disease Center (ADRC) and the Stanford Aging and Memory Study (SAMS) were recruited for PET scanning with 18F‐PI‐2620. We compared 18F‐PI‐2620 uptake within medial temporal (entorhinal cortex, amygdala) and occipital (precuneus, lingual gyrus) regions as well as SN across patients with Parkinson’s disease (PD, n = 26), dementia with Lewy bodies (DLB, n = 6), and Alzheimer’s disease spectrum (AD, n = 21), in addition to cognitively normal older adults (healthy controls, HC, n = 73). Mean bilateral signal was extracted from cortical regions of interest in native space 18F‐PI‐2620 SUVRs (inferior cerebellar gray reference). Amyloid status was determined either by 18F‐florbetaben PET or CSF. To quantify SN, SUVRs were normalized to template space and an anatomical mask was used to extract mean signal. MDS‐UPDRS‐III motor exam scores, collected in an off‐medication state for all patients, were used as a measure of motor impairment.ResultEntorhinal and amygdala SUVR were significantly elevated in the AD group relative to all other groups, and in amyloid‐positive relative to amyloid‐negative HC (Fig 1). Tau burden in all regions was low across PD and DLB groups and did not differ based on amyloid status. SN SUVR was significantly lower in the PD group compared to the HC and AD group (Fig 2A). In patients with Lewy body disease (PD &amp; DLB), MDS‐UPDRS‐III scores were negatively associated with SN SUVR (Fig 2B).ConclusionThese findings suggest that cortical tau is low in Lewy body disease. Neuromelanin‐related 18F‐PI‐2620 signal within SN carries information about disease severity. Cortical tau and SN binding represent two unique signals in the same tau PET image that may be informative in the context of Lewy body disease.

Cortical and substantia nigra 18F‐PI‐2620 tau PET signal in Lewy body disease

AbstractBackgroundTau PET imaging is a potential tool for measuring comorbid tau pathology in patients with Lewy body disease. Furthermore, tau PET ligands are known to bind to neuromelanin within substantia nigra (SN), with reduced binding in Parkinson’s disease relative to healthy individuals. We sought to characterize 18F‐PI‐2620, a next generation PET tracer, in patients from across the Lewy body disease spectrum.MethodA total of 126 participants from the Stanford Alzheimer’s Disease Center (ADRC) and the Stanford Aging and Memory Study (SAMS) were recruited for PET scanning with 18F‐PI‐2620. We compared 18F‐PI‐2620 uptake within medial temporal (entorhinal cortex, amygdala) and occipital (precuneus, lingual gyrus) regions as well as SN across patients with Parkinson’s disease (PD, n = 26), dementia with Lewy bodies (DLB, n = 6), and Alzheimer’s disease spectrum (AD, n = 21), in addition to cognitively normal older adults (healthy controls, HC, n = 73). Mean bilateral signal was extracted from cortical regions of interest in native space 18F‐PI‐2620 SUVRs (inferior cerebellar gray reference). Amyloid status was determined either by 18F‐florbetaben PET or CSF. To quantify SN, SUVRs were normalized to template space and an anatomical mask was used to extract mean signal. MDS‐UPDRS‐III motor exam scores, collected in an off‐medication state for all patients, were used as a measure of motor impairment.ResultEntorhinal and amygdala SUVR were significantly elevated in the AD group relative to all other groups, and in amyloid‐positive relative to amyloid‐negative HC (Fig 1). Tau burden in all regions was low across PD and DLB groups and did not differ based on amyloid status. SN SUVR was significantly lower in the PD group compared to the HC and AD group (Fig 2A). In patients with Lewy body disease (PD &amp; DLB), MDS‐UPDRS‐III scores were negatively associated with SN SUVR (Fig 2B).ConclusionsThese findings suggest that cortical tau is low in Lewy body disease. Neuromelanin‐related 18F‐PI‐2620 signal within SN carries information about disease severity. Cortical tau and SN binding represent two unique signals in the same tau PET image that may be informative in the context of Lewy body disease.

Radiopharmaceutical selection for tau PET imaging

AbstractBackgroundThe accumulation of pathologically misfolded tau is a feature that is shared by a group of neurodegenerative disorders that are collectively referred to as tauopathies. AD is the most prevalent of these tauopathies. Neurofibrillary tangles are characterized by the presence of hyperphosphorylated protein (tau), and senile plaques are characterized by the presence of amyloid peptide aggregates. PET imaging is fully quantitative and enables accurate spatial assessment. However, as a result of non‐specific binding and the limited spatial resolution of PET scanners, this technique requires not only the presence of tau inclusions in a brain region but also sufficient density and spatial extent of those inclusions in order to generate a sufficient signal‐to‐noise ratio. With the development of tau‐specific ligands for use with PET, it is now possible to investigate the role that tau pathology plays in the development and progression of these disorders. The purpose of this study is to analyze, compare, and rank the currently available tau PET tracers for imaging in research and routine clinical settings.MethodWe proposed using the fuzzy Preference Ranking Organization Method for Enrichment of Evaluations (PROMETHEE), a multicriteria decision‐making (MCDM) tool. First‐generation tau PET tracers ([18F]AV1451, [11C]PBB3, [18F]THK5117, [18F]THK5351, [18F]THK5317, and [18F]THK5105) and second‐generation compounds ([18F]MK‐6240, [18F]JNJ‐067, [18F] PI‐2620, [18F]RO‐948 (previously referred to as [18F]RO69558948), [18F]PM‐PBB3, [18F]GTP1, [18F]JNJ‐64349311 ([18F]JNJ311), [11C]RO‐6931643, and [11C]RO‐6924963) were selected to investigate in this study. The evaluation is based on relative parameters, such as specificity, target binding accuracy, neocortical uptake, radiation exposure, brain penetration, free fraction in plasma, defluorination, and adverse reactions, and the importance that is placed on each of these parameters is weighted differently.ResultThe results from this study show that [18F]RO‐948 is the most favorable tau PET ligand, while[18F]THK5105 is the least favorable one based on the considered weighted criteria in this study.ConclusionFuzzy PROMETHEE can be used as a decision‐aid system to select the proper radiopharmaceuticals for tau PET imaging. This study can be extended to include more tracers and criteria and might help researchers and concerned readers to select the optimal tau PET tracer.

Comparative assessment of regional tau distribution by Tau-PET and Post-mortem neuropathology in a representative set of Alzheimer's & frontotemporal lobar degeneration patients.

Flortaucipir (FTP) PET is a key imaging technique to evaluate tau burden indirectly. However, it appears to have greater utility for 3R+4R tau found in Alzheimer's disease (AD), compared to other non-AD tauopathies. The purpose of this study is to determine how flortaucipir uptake links to neuropathologically determined tau burden in AD and non-AD tauopathies. We identified nine individuals who had undergone antemortem tau-PET and postmortem neuropathological analyses. The cohort included three patients with low, moderate, and high AD neuropathologic changes (ADNC), five patients with a non-AD tauopathy (one Pick's disease, three progressive supranuclear palsies, and one globular glial tauopathy), and one control without ADNC. We compared regional flortaucipir PET uptake with tau burden using an anti-AT8 antibody. There was a very good correlation between flortaucipir uptake and tau burden in those with ADNC although, in one ADNC patient, flortaucipir uptake and tau burden did not match due to the presence of argyrophilic grains disease. Non-AD patients showed lower flortaucipir uptake globally compared to ADNC patients. In the non-AD patients, some regional associations between flortaucipir uptake and histopathological tau burden were observed. Flortaucipir uptake is strongly linked to underlying tau burden in patients with ADNC but there are instances where they do not match. On-the-other hand, flortaucipir has a limited capacity to represent histopathological tau burden in non-AD patients although there are instances where regional uptake correlates with regional tau burden. There is a definite need for the development of future generations of tau-PET ligands that can detect non-AD tau.

18F‐MK‐6240 Tau PET as a Biomarker for Chronic Traumatic Encephalopathy: Case Series of 10 Symptomatic Former National Football League Players

AbstractBackgroundThe pathognomonic lesion of chronic traumatic encephalopathy (CTE) is the perivascular deposition of neuronal phosphorylated tau (p‐tau). Patchy p‐tau deposits initially accumulate in frontotemporal cortices. Medial temporal lobes (MTL) become involved in late stage. Validated in vivo biomarkers for CTE p‐tau do not exist. 18F‐MK‐6240 is a second‐generation tau PET ligand with improved imaging properties compared with first‐generation ligands, but its utility in CTE is unknown. We report initial results from an ongoing proof‐of‐concept study investigating MK‐6240 in people at risk for CTE.MethodTen older adult male symptomatic former National Football League (NFL) players completed tau (MK‐6240) and amyloid (florbetapir) PET imaging and neuropsychological testing. MK‐6240 data were acquired from 36 cognitively unimpaired males without traumatic brain injury history (but unknown contact sport history) from the Wisconsin Registry for Alzheimer’s Prevention (mean age=66.3, SD=6.3; mean MMSE=29.6, SD=0.5). Using cerebellar gray matter reference, 70‐90 min MK‐6240 SUVR images were created. W‐score (age‐adjusted z‐scores) maps were generated using the control data and thresholded at w&gt;1.65 to visualize high binding voxels. Images and scatter plots of uptake in NFL players and controls were qualitatively assessed due to the small sample size.ResultsSample characteristics are in Table 1 (age range:51‐72, 5/10 Black). All NFL players had a negative florbetapir PET. 9/10 were cognitively impaired, particularly in memory and executive functions (Table 2). One former NFL player (case 4) had MTL MK‐6240 uptake greater than all controls, along with focal low intensity uptake in the superior frontal cortex (Figure 1). Two NFL players (cases 6 and 9) had mildly elevated MTL MK‐6240 uptake, particularly in entorhinal cortex and parahippocampus, though similar binding was seen in some controls (Figure 2). There was minimal MTL uptake in the remaining NFL players. Cortical uptake was complicated by contamination from off‐target meningeal binding.ConclusionsExisting data suggests current radioligands (e.g., flortaucipir) developed for Alzheimer’s disease might have restricted utility to late stage CTE. This might be true for MK‐6240 and off‐target meningeal binding complicates detection of cortical p‐tau. Data collection is ongoing and the larger data set will inform on MK‐6240 as a biomarker for CTE.

The relationship between cortical grey to white matter signal contrast (GWC) and tau pathology in atypical AD

AbstractBackgroundGrey to white matter signal intensity ratio (GWC) has been studied as a novel metric of integrity and as a marker of neurodegeneration in Alzheimer’s disease (AD). Regions with reduced GWC co‐localize with regions of cortical atrophy in AD (Salat et al. 2011; Salat et al. 2009). Cortical atrophy in AD robustly colocalizes with tau pathology measured using tau PET ligands (Putcha et al. 2019). For this study, we hypothesized that GWC co‐localizes with tau pathology and shows greater sensitivity to tau pathology than cortical atrophy across the atypical phenotypic spectrum of AD.MethodWe studied 29 amyloid‐positive atypical AD patients, including 16 patients with posterior cortical atrophy (PCA), 10 with logopenic variant primary progressive aphasia (lvPPA), and 3 with an amnestic dysexecutive presentation. Whole‐cortex maps of GWC and cortical atrophy were generated for each individual using FreeSurfer. Tau PET (18F‐Flortaucipir) signal was projected for each individual to the cortical surface using PETsurfer. Eta squared (η2) was computed to determine the spatial overlap of each measure of neurodegeneration (GWC, cortical atrophy) with tau PET signal for each subject and then averaged across the whole group.ResultBoth GWC and cortical atrophy revealed a pattern of neurodegeneration consistent with AD, including in medial parietal, lateral parietal, and posterior lateral temporal cortices. Lower GWC was also observed in several regions beyond the areas of cortical atrophy in patients including in bilateral dorsolateral and dorsomedial prefrontal cortices. Supporting our hypothesis, there was greater spatial overlap between the GWC and tau PET maps (η2 = 0.30) compared to cortical atrophy and tau PET maps (η2 = 0.24; t=4.49, p=0.0001).ConclusionWhile both measures of neurodegeneration (GWC, cortical atrophy) showed a high degree of spatial overlap with tau PET signal across our sample of atypical AD participants, we conclude that GWC, a novel MRI‐derived biomarker of neurodegeneration in AD, correlates more strongly with AD‐related tau neuropathology than traditional cortical atrophy measures. This suggests that GWC could be a sensitive biomarker of AD‐related tissue changes that may represent neuronal injury or neurodegeneration. Further work is needed to establish how GWC tracks with tau pathology over time.

Improved comparability between measurements of mean cortical amyloid plaque burden derived from different PET tracers using multiple regions‐of‐interest and machine learning

AbstractBackgroundThe conversion of standard uptake value ratios (SUVRs) to Centiloid units using previously described methods has partially but not completely improved the ability to compare measurements of mean cortical amyloid plaque burden, classify positive versus negative amyloid PET scans, assess changes over time, and evaluate amyloid‐modifying treatment effects using different radiotracers. Here, we demonstrate improved harmonization between PiB and florbetapir (FBP) PET measurements of mean cortical SUVRs (mcSUVRs) using multiple regions‐of‐interest (ROIs) and machine learning algorithms.MethodsPiB and FBP PET image pairs from 91 subjects in the Open Access Series of Imaging Studies (https://www.oasis‐brains.org/) were used as the training set to optimize the algorithms to generate each subject’s pseudo‐PiB mcSUVR measurements from his or her FBP multi‐ROI SUVRs . PiB and FBP image pairs from 46 subjects in the Avid‐related Centiloid Project (www.gaain.org/centiloid‐project) were then used as the test set to compare Pearson’s correlation coefficients (r) between the pseudo and actual PiB mcSUVR measurements using our approach to that used in the Centiloid method. SUVRs with cerebellar reference were extracted from multi‐ROIs using FreeSurfer with partial volume correction. Pseudo mcSUVRs were generated using ensemble regression, partial least square regression (PLSR) and artificial neural network (ANN) separately, and their correlations with the actual PiB mcSUVR were compared to the PiB‐FBP correlation on Centiloid in both training and test sets.ResultsIn the training set, the Centiloid based PiB‐FBP correlation was r=0.904. An ANN with 7/6 neurons in the 1st/2nd hidden layers improved it to 0.987 (p≤8.3e‐12) and PLSR to 0.973 (p≤3.8e‐5). In the independent test set, ANN improved r to 0.981 from 0.927 (p≤6.6e‐4) and PLSR to 0.964 (p=0.011). Ensemble regression did not improve r.ConclusionThe ANN and PLSR algorithms mapping multi‐ROI FBP SUVRs to PiB mcSUVR appear to increase the comparability between measurements of mean cortical amyloid plaque burden using different PET tracers. Additional studies are needed to demonstrate the generalizability to other amyloid PET tracers, clarify its comparability in distinguishing between positive and negative amyloid PET scans, demonstrate its value in longitudinal studies and clinical trials, and extend our approaches to different tau PET ligands.

Cortical [18 F]PI-2620 Binding Differentiates Corticobasal Syndrome Subtypes.

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). 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. 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. 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. 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.

MAPT rs242557 variant is associated with hippocampus tau uptake on 18F‐AV‐1451 PET in non‐demented elders

AbstractBackgroundThe microtubule‐associated protein tau gene rs242557 variant is associated with multiple tauopathies and dementia. This study investigated whether it was correlated with brain tau‐PET uptake in non‐demented elders.MethodNinety non‐demented elders were identified from the Alzheimer's Disease Neuroimaging Initiative cohort. We compared standardized uptake value ratios of tau‐PET tracer 18F‐AV‐1451 between rs242557 variant carriers and non‐carriers in 25 regions of interest.ResultThe minor allele A was associated with increased hippocampus 18F‐AV‐1451 uptake in non‐demented elders (left: β = 0.111, Bonferroni corrected p = 0.035; right: β = 0.103, Bonferroni corrected p = 0.031). Aβ‐positive participants (left: β = 0.206, Bonferroni corrected p = 0.029; right: β = 0.198, Bonferroni corrected p = 0.035) and APOE ε4 non‐carriers (left: β = 0.140, Bonferroni corrected p = 0.006; right: β = 0.134, Bonferroni corrected p = 0.004) exhibited approximately the same findings in hippocampus.ConclusionConsidering no obvious associations in other regions, we confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau deposition in non‐demented elders. With higher magnitude signals in the hippocampus that is more likely to be uniquely affected in AD, the tau PET ligand 18F‐AV‐1451 seemed to possess a specific binding property for AD‐like tau pathology.

Neuroimaging of Alzheimer's disease: focus on amyloid and tau PET.

Although the diagnosis of dementia is still largely a clinical one, based on history and disease course, neuroimaging has dramatically increased our ability to accurately diagnose it. Neuroimaging modalities now play a wider role in dementia beyond their traditional role of excluding neurosurgical lesions and are recommended in most clinical guidelines for dementia. In addition, new neuroimaging methods facilitate the diagnosis of most neurodegenerative conditions after symptom onset and show diagnostic promise even in the very early or presymptomatic phases of some diseases. In the case of Alzheimer's disease (AD), extracellular amyloid-β (Aβ) aggregates and intracellular tau neurofibrillary tangles are the two neuropathological hallmarks of the disease. Recent molecular imaging techniques using amyloid and tau PET ligands have led to preclinical diagnosis and improved differential diagnosis as well as narrowed subject selection and treatment monitoring in clinical trials aimed at delaying or preventing the symptomatic phase of AD. This review discusses the recent progress in amyloid and tau PET imaging and the key findings achieved by the use of this molecular imaging modality related to the respective roles of Aβ and tau in AD, as well as its specific limitations.

Corticobasal degeneration: advances in clinicopathology and biomarkers.

Corticobasal degeneration (CBD) is a rapidly progressive neurodegenerative tauopathy diagnosed postmortem by pathological examination. The clinical presentation of corticobasal syndrome (CBS) is an apraxic, dystonic, and rigid limb with asymmetrical cortical signs and myoclonus. However, less than half of the patients with CBS receive a CBD diagnosis. As tau-lowering therapies have entered clinical trials, improved antemortem diagnosis of CBD is needed. Here, clinicopathological, neuroimaging, and biofluid data in CBS and/or CBD patients are briefly summarized and some knowledge gaps identified. Developments of MRI-based and nuclear medicine imaging modalities have increased pathophysiological insights of CBS and may improve diagnostic accuracy. In particular, several tau-PET ligands have been evaluated in CBS patients. Cerebrospinal fluid and plasma levels of neurofilament light chain can distinguish CBS from Parkinson's disease but not from other atypical forms of Parkinsonism. Structural and functional imaging approaches provide some aid in the diagnosis of CBD but have low-content validity. None of the currently available tau-PET ligands is suitable for detecting straight filament 4repeat tau disease in clinical routine. Biofluid markers reflecting the distinct tau and/or astrocyte disease of CBD are needed. Examining biosamples along with clinical parameters from longitudinally followed patients with autopsy-confirmed CBD diagnosis shall hopefully delineate improved biomarkers.

HEAD-TO-HEAD IN VIVO COMPARISON OF TAU POSITRON EMISSION TOMOGRAPHY LIGANDS 18F-FLORTAUCIPIR AND 18F-RO948

18F-Flortaucipir (FTP) is the most widely used PET ligand for the in vivo assessment of tau pathology. It binds to paired-helical filament tau and has been shown to be useful in the diagnosis of AD. However, off-target binding e.g. in the choroid plexus and the basal ganglia hamper accurate quantification of FTP in these and adjacent regions. Recently, several other tau PET ligands have been developed. Here, we compare 18F-FTP with the novel tau ligand 18F-RO948 head-to-head in vivo. Within this study, 33 individuals have undergone 18F-FTP PET at 80–100 min and 18F-RO948 at 70- 90 min post ligand injection. Four subjects have undergone dynamic scanning 0–100 min. Subject diagnoses were: 18 AD (Aβpositive), three MCI (Aβpositive), four Progressive Supranuclear Palsy patients, three with semantic variant Primary Progressive Aphasia, one Dementia with Lewy Bodies and four neurologically healthy controls (mean age 71.6 ± 8.2 y). The average time between PET scans was 21 ± 41 days. Standardized uptake value ratios (SUVR) were created using an inferior cerebellar reference region. The neocortical retention of the two radioligands was highly similar when assessed using SUVR-values. A small, but significant, increase in retention was found in the entorhinal cortex (Braak stage I-II) using 18F-RO948 (Figure 1). On visual inspection, 18F-RO948 uptake was substantially lower in the basal ganglia, the thalamus, and the choroid plexus, but not in the substantia nigra compared to 18F-FTP uptake (Figure 2). Statistical comparison confirmed significantly lower 18F-RO948 uptake in the choroid plexus and the basal ganglia (Figure 3). However, some cases exhibited strong 18F-RO948 signal in the skull or the meninges, which was not observed for 18F-FTP, and at a group level the skull/meningeal binding was significantly higher in the 18F-RO948 scans.

18F-PI2620 TAU-PET IN PROGRESSIVE SUPRANUCLEAR PALSY: A MULTI-CENTER EVALUATION

Progressive supranuclear palsy (PSP) is a 4-repeat (4R) tauopathy and region-specific tau deposits establish the neuropathological diagnosis of “definite PSP” post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers to validate the specific presence of the target before therapy initiation. The novel second generation tau-PET ligand 18F-PI2620 proved absent off-target binding to monoamine oxidases and high affinity to 3/4R tau in Alzheimer's disease (AD). The aim of this multicenter-evaluation was to investigate 18F-PI2620 in patients with suspected 4R tau pathology in clinically diagnosed PSP. Eighteen patients (70±6y, n=9 female) with probable or possible PSP Richardson syndrome according to MDS-PSP criteria underwent 18F-PI2620 PET at four different centers together with ten healthy controls and ten disease controls (Multi-system atrophy, Parkinson's disease, and AD). Standardized uptake value ratios (SUVr, 30-60min) of predefined subcortical brain regions were generated using cerebellar scaling. SUVr data were compared between PSP, HC, and disease controls. Statistical parametric mapping (SPM, V12) was performed between PSP and HC. SUVr and SPM data were corrected for different centers. An in vitro pilot autoradiography using 18F-PI2620 incubation of brain slices was performed. Elevated 18F-PI2620 SUVr was observed in PSP patients (PSP rating scale: 40±17; range 13-71) in the globus pallidus (1.34±0.16; p=0.001; d=1.72) and the substantia nigra (1.33±0.13; p=0.002; d=1.52) when compared to HC (1.12±0.09/1.15±0.08). Disease controls showed a similar signal in the globus pallidus (1.12±0.08; p=n.s.) and a moderate elevation in the substantia nigra (1.25±0.10; p=n.s.) when compared to HC. SPM revealed elevated 18F-PI2620 uptake in the globus pallidus, in the substantia nigra, and frontal and parietal cortices (all p<0.001, uncorrected) as compared to HC. Subjects with low disease severity (PSP rating scale ≤30; n=4) already had a significantly elevated 18F-PI2620 uptake in the globus pallidus when compared to HC (1.38±0.13; p=0.001; d=2.32). Preliminary in vitro autoradiography showed distinguishable 18F-PI2620 binding in the globus pallidus of a PSP patient which was however lower when compared to cortical binding in AD.

MAPT rs242557 variant is associated with hippocampus tau uptake on 18F-AV-1451 PET in non-demented elders.

The microtubule-associated protein tau gene (MAPT) rs242557 variant is associated with multiple tauopathies and dementia. This study investigated whether it was correlated with brain tau-PET uptake in non-demented elders. Ninety non-demented elders were identified from the Alzheimer's Disease Neuroimaging Initiative cohort. We compared standardized uptake value ratios (SUVRs) of tau-PET tracer 18F-AV-1451 between rs242557 variant carriers and non-carriers in 25 regions of interest (ROIs). The minor allele A was associated with increased hippocampus 18F-AV-1451 uptake in non-demented elders (left: β = 0.111, Bonferroni corrected p = 0.035; right: β = 0.103, Bonferroni corrected p = 0.031). Aβ-positive participants (left: β = 0.206, Bonferroni corrected p = 0.029; right: β = 0.198, Bonferroni corrected p = 0.035) and APOE ε4 non-carriers (left: β = 0.140, Bonferroni corrected p = 0.006; right: β = 0.134, Bonferroni corrected p = 0.004) exhibited approximately the same findings in hippocampus. Considering no obvious associations in other regions, we confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau deposition in non-demented elders. With higher magnitude signals in the hippocampus that is more likely to be uniquely affected in AD, the tau PET ligand 18F-AV-1451 seemed to possess a specific binding property for AD-like tau pathology.

MRI Outperforms [18F]AV‐1451 PET as a Longitudinal Biomarker in Progressive Supranuclear Palsy

Elevated uptake of the [18 F]AV-1451 tau-PET ligand has been observed cross-sectionally in subjects with progressive supranuclear palsy (PSP). However, it is unknown how the ligand performs longitudinally in PSP. We aimed to determine how regional measures of change on [18 F]AV-1451 PET perform as longitudinal biomarkers of PSP compared with the more established biomarker of rate of midbrain atrophy. Sixteen subjects with PSP underwent 2 serial [18 F]AV-1451 tau-PET scans and 3-Tesla MRI over 12 months and were age- and sex-matched to 39 healthy controls with longitudinal [18 F]AV-1451 PET. Median [18 F]AV-1451 uptake was calculated for each scan for regions of interest across the brain and divided by uptake in cerebellar crus to create standard uptake value ratios. Midbrain volume on MRI was also calculated for each scan. Sample sizes required to power placebo-controlled treatment trials were calculated. Rate of midbrain atrophy was significantly increased in PSP compared with controls. [18 F]AV-1451 regional change measures were significantly increased in PSP compared with controls in the pallidum, precentral cortex, dentate nucleus of the cerebellum, and midbrain. Change over time in the PSP Rating Scale correlated with change in midbrain volume but did not correlate with change in the [18 F]AV-1451 measures. Smallest sample-size estimates were obtained with rate of midbrain atrophy, followed by the PSP Rating Scale, with both outperforming [18 F]AV-1451 measures. [18 F]AV-1451 tau-PET measures increase over time in subjects with PSP, but longitudinal [18 F]AV-1451 measures may not perform as well as rate of midbrain atrophy as biomarkers for PSP clinical trials. © 2018 International Parkinson and Movement Disorder Society.

Tau Imaging in Parkinsonism: What Have We Learned So Far?

Positron emission tomography ligands are now available that bind to tau proteins in the brain, providing the exciting opportunity to assess the presence and distribution of tau in vivo in living patients. This manuscript performed a systematic review of studies that have performed tau PET imaging in patients with parkinsonian disorders. Pubmed was searched up to November 2017, and the review included case reports and patient-control studies. Most tau-PET studies have utilized the [18F]AV-1451 ligand, with a few using the [11C]PBB3 and [18F]THK-5351 ligands. Elevated cortical tau-PET uptake has been observed in Parkinson's disease dementia and dementia with Lewy bodies, presumed to be related to Alzheimer's disease-related pathology. Mild patterns of tau-PET uptake have been observed in subcortical structures in progressive supranuclear palsy and subcortical structures and motor cortex in corticobasal syndrome, although discrepancy with autoradiographic studies that show lack of binding to 4-repeat tau and "off-target" binding observed in subcortical structures limits interpretation of these findings. Findings in frontotemporal dementia with tau mutations are variable, but elevated signal is most pronounced in mutations with deposition of both 3 and 4-repeat tau. Elevated tau-PET uptake has also been observed in multiple system atrophy, a synucleinopathy. The value of the current generation of tau-PET ligands varies across Parkinsonian syndromes depending upon underlying variability in tau pathology and "off-target" binding. More work is needed to understand the biological basis of binding and more specific tau PET ligands are needed to study parkinsonian disorders.

18F‐AV‐1451 and CSF T‐tau and P‐tau as biomarkers in Alzheimer's disease

To elucidate the relationship between cerebrospinal fluid (CSF) total‐tau (T‐tau) and phosphorylated tau (P‐tau) with the tau PET ligand 18F‐AV‐1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T‐tau and P‐tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F‐AV‐1451, and mainly in demented AD patients. 18F‐AV‐1451, but not CSF T‐tau or P‐tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F‐AV‐1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F‐AV‐1451 retention was always increased at this disease stage. We conclude that CSF T‐tau and P‐tau mainly behave as biomarkers of “disease state”, since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F‐AV‐1451 is a biomarker of “disease stage”, since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.

Fluorescence and autoradiographic evaluation of tau PET ligand PBB3 to α-synuclein pathology.

The tau PET ligand 2-((1E,3E)-4-(6-([11 C]methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([11 C]PBB3) binds to a wide range of tau pathology; however, binding property of PBB3 to non-tau inclusions remains unknown. To clarify whether [11 C]PBB3 binds to α-synuclein pathology, reactivity of PBB3 was assessed by in vitro fluorescence and autoradiographic labeling of brain sections from α-synucleinopathies patients. Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of α-synuclein severity based on the quantitative analysis of α-synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for α-synuclein and phospho-tau, Prussian blue staining, and in vitro autoradiography with [11 C]PBB3 were performed for these selected samples. PBB3 fluorescence labeled various α-synuclein lesions including Lewy bodies, Lewy neurites, spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [11 C]PBB3 at 10 nM demonstrated no significant binding in Lewy body disease cases. In contrast, significant autoradiographic binding of [11 C]PBB3 to the striatopallidal fibers was found in 2 MSA cases, which had high densities of glial cytoplasmic inclusions without tau or iron deposits in this region. Given that the maximum concentration of [11 C]PBB3 in human PET scans is approximately 10 nM, the present data imply that α-synuclein pathology in Lewy body disease is undetectable by [11 C]PBB3-PET, whereas those in a subset of MSA cases with high densities of glial cytoplasmic inclusions could be captured by this radioligand. © 2017 International Parkinson and Movement Disorder Society.