AV-1451 Binding Research Articles

Differential Synaptic Loss in β-Amyloid Positive Versus β-Amyloid Negative Corticobasal Syndrome.

The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to β-amyloid status. Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had β-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the β-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Increased retention of tau PET ligand [18F]-AV1451 in Alzheimer\u2019s Disease Psychosis

Psychosis in Alzheimer’s disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [18F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer’s disease neuroimaging initiative (ADNI) who had [18F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [18F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [18F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [18F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline.

Lack of association between bridging integrator 1 (BIN1) rs744373 polymorphism and tau-PET load in cognitively intact older adults.

IntroductionThe bridging integrator 1(BIN1) rs744373 risk polymorphism has been linked to increased [18F]AV1451 signal in non‐demented older adults (ie., mild cognitive impairment [MCI] plus cognitively normal [CN] individuals). However, the association of BIN1 with in vivo tau, amyloid beta (Aβ) burden, and cognitive impairment in the asymptomatic stage of Alzheimer's disease (AD) remains unknown.MethodsThe BIN1 effect on [18F]AV1451 binding was evaluated in 59 cognitively normal (CN) participants (39% apolipoprotein E [APOE ε4]) from the Flemish Prevent AD Cohort KU Leuven (F‐PACK), as well as in 66 Alzheimer's Disease Neuroimaging Initiative (ADNI) CN participants, using voxelwise and regional statistics. For comparison, 52 MCI patients from ADNI were also studied.ResultsForty‐four percent of F‐PACK participants were BIN1 rs744373 risk‐allele carriers, 21% showed high amyloid burden, and 8% had elevated [18F]AV1451 binding. In ADNI, 53% and 50% of CNs and MCIs, respectively, carried the BIN1 rs744373 risk‐allele. Amyloid positivity was present in 23% of CNs and 51% of MCIs, whereas 2% of CNs and 35% of MCIs showed elevated [18F]AV1451 binding. There was no significant effect of BIN1 on voxelwise or regional [18F]AV1451 in F‐PACK or ADNI CNs, or in the pooled CN sample. No significant association between BIN1 and [18F]AV1451 was obtained in ADNI MCI patients. However, in the MCI group, numerically higher [18F]AV1451 binding was observed in the BIN1 risk‐allele group compared to the BIN1 normal group in regions corresponding to more progressed tau pathology.DiscussionWe could not confirm the association between BIN1 rs744373 risk‐allele and elevated [18F]AV1451 signal in CN older adults or MCI. Numerically higher [18F]AV1451 binding was observed, however, in the MCI BIN1 risk‐allele group, indicating that the previously reported positive effect may be confounded by group. Therefore, when studying how the BIN1 risk polymorphism influences AD pathogenesis, a distinction should be made between asymptomatic, MCI, and dementia stages of AD.

18F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

While [18F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of ‘off-target’ [18F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [18F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson’s disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n = 14). Associations with motor symptoms, cognition and disease duration were evaluated using linear regression models. The dementia with Lewy bodies group had significantly reduced substantia nigra [18F]-AV-1451 binding compared to controls after adjusting for age (P < 0.05). However, there were no significant differences in substantia nigra [18F]-AV-1451 binding between Parkinson’s disease and controls. Substantia nigra [18F]-AV-1451 binding was not associated with age, disease duration, Movement Disorders Society—Unified Parkinson’s Disease Rating Scale and cognitive scores in dementia with Lewy bodies and Parkinson’s disease groups. Despite the reduction of substantia nigra [18F]-AV-1451 binding in dementia with Lewy bodies, these findings suggest that substantia nigra [18F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson’s disease. Further investigations in longitudinal cohorts are warranted.

Cryptic Sites in Tau Fibrils Explain the Preferential Binding of the AV-1451 PET Tracer toward Alzheimer's Tauopathy.

Tauopathies are a subclass of neurodegenerative diseases characterized by an accumulation of microtubule binding tau fibrils in brain regions. Diseases such as Alzheimer’s (AD), chronic traumatic encephalopathy (CTE), Pick’s disease (PiD), and corticobasal degeneration (CBD) belong to this subclass. Development of tracers which can visualize and discriminate between different tauopathies is of clinical importance in the diagnosis of various tauopathies. Currently, several tau tracers are available for in vivo imaging using a positron emission tomography (PET) technique. Among these tracers, PBB3 is reported to bind to various types of tau fibrils with comparable binding affinities. In contrast, tau tracer AV-1451 is reported to bind to specific types of tau fibrils (in particular to AD-associated and CTE) with higher binding affinity and only show nonspecific or weaker binding toward tau fibrils dominant with 3R isoforms (associated with PiD). The tau fibrils associated with different tauopathies can adopt different microstructures with different binding site microenvironments. By using detailed studies of the binding profiles of tau tracers for different types of tau fibrils, it may be possible to design tracers with high selectivity toward a specific tauopathy. The microstructures for the tau fibrils from patients with AD, PiD, and CTE have recently been demonstrated by cryogenic electron microscopy (cryo-EM) measurements allowing structure-based in silico simulations. In the present study, we have performed a multiscale computational study involving molecular docking, molecular dynamics, free energy calculations, and QM fragmentation calculations to understand the binding profiles of tau tracer AV-1451 and its potential use for diagnosis of AD, CTE, and PiD tauopathies. Our computational study reveals that different affinity binding sites exist for AV-1451 in the tau fibrils associated with different tauopathies. The binding affinity of this tracer toward different tau fibrils goes in this order: PiD > AD > CTE. The interaction energies for different tau fibril–tracer complexes using the QM fragmentation scheme also showed the same trend. However, by carrying out molecular dynamics simulations for the AD-derived tau fibrils in organic solvents, we found additional high affinity binding sites for AV-1451. The AV-1451 binding profile in these cryptic sites correctly explains the preferential binding of this tracer toward the AD fibrils when compared with the PiD fibrils. This study clearly demonstrates having a cryo-EM structure is still not sufficient for the structure-based tracer discovery for certain targets, as they may have “potential but hidden” high affinity binding sites, and we need additional strategies to identify them.

Imaging tau burden in dementia with Lewy bodies using [18F]-AV1451 positron emission tomography

Alzheimer's disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [18F]-AV1451 positron emission tomography in people with DLB (n = 10), AD (n = 27), and healthy controls (n = 14). A subset of patients with Lewy body diseases (n = 4) also underwent [11C]-PK11195 positron emission tomography to estimate microglial activation. [18F]-AV1451 BPND was lower in DLB than AD across widespread regions. The medial temporal lobe [18F]-AV1451 BPND distinguished people with DLB from AD (AUC = 0.87), and negatively correlated with Addenbrooke's Cognitive Examination-Revised and Mini-Mental State Examination. There was a high degree of colocalization between [18F]-AV1451 and [11C]-PK11195 binding (p < 0.001). Our findings of minimal tau burden in DLB confirm previous studies. Nevertheless, the associations of [18F]-AV1451 binding with cognitive impairment suggest that tau may interact synergistically with other pathologic processes to aggravate disease severity in DLB.

Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy.

We examined the relationship between tau pathology and neuroinflammation using [11 C]PK11195 and [18 F]AV-1451 PET in 17 patients with progressive supranuclear palsy (PSP) Richardson's syndrome. We tested the hypothesis that neuroinflammation and tau protein aggregation colocalize macroscopically, and correlate with clinical severity. Nondisplaceable binding potential (BPND ) for each ligand was quantified in 83 regions of interest (ROIs). The [11 C]PK11195 and [18 F]AV-1451 BPND values were correlated across all regions. The spatial distributions of [11 C]PK11195 and [18 F]AV-1451 binding were determined by principal component analyses (PCAs), and the loading of each spatial component compared against the patients' clinical severity (using the PSP rating scale). Regional [11 C]PK11195 and [18 F]AV-1451 binding were positively correlated (R = 0.577, p < 0.0001). The PCA identified 4 components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [11 C]PK11195 and [18 F]AV-1451 components' loadings were found in both subcortical (R = 0.769, p < 0.0001) and cortical regions (R = 0.836, p < 0.0001). There were positive correlations between clinical severity and both subcortical tau pathology (R = 0.667, p = 0.003) and neuroinflammation (R = 0.788, p < 0.001). We show that tau pathology and neuroinflammation colocalize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine causal associations between these molecular pathologies, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP. ANN NEUROL 2020;88:1194-1204.

Improving Choroid Plexus Segmentation in the Healthy and Diseased Brain: Relevance for Tau-PET Imaging in Dementia.

Recent studies have revealed the possible role of choroid plexus (ChP) in Alzheimer's disease (AD). T1-weighted MRI is the modality of choice for the segmentation of ChP in humans. Manual segmentation is considered the gold-standard technique, but given its time-consuming nature, large-scale neuroimaging studies of ChP would be impossible. In this study, we introduce a lightweight segmentation algorithm based on the Gaussian Mixture Model (GMM). We compared its performance against manual segmentation as well as automated segmentation by Freesurfer in three separate datasets: 1) patients with structural MRIs enhanced with contrast (n = 19), 2) young healthy subjects (n = 20), and 3) patients with AD (n = 20). GMM outperformed Freesurfer and showed high similarity with manual segmentation. To further assess the algorithm's performance in large scale studies, we performed GMM segmentations in young healthy subjects from the Human Connectome Project (n = 1,067), as well as healthy controls, mild cognitive impairment (MCI), and AD patients from the Alzheimer's Disease Neuroimaging Initiative (n = 509). In both datasets, GMM segmented ChP more accurately than Freesurfer. To show the clinical importance of accurate ChP segmentation, total AV1451 (tau) PET binding to ChP was measured in 108 MCI and 32 AD patients. GMM was able to reveal the higher AV1451 binding to ChP in AD compared with MCI. Our results provide evidence for the utility of the GMM in accurately segmenting ChP and show its clinical relevance in AD. Future structural and functional studies of ChP will benefit from GMM's accurate segmentation.

Binding of [18F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients

PurposeIn vivo tau-PET tracer retention in the anterior temporal lobe of patients with semantic variant primary progressive aphasia (SV PPA) has consistently been reported. This is unexpected as the majority of these patients have frontotemporal lobar degeneration TDP (FTLD-TDP).MethodsWe conducted an in vitro [18F]AV1451 autoradiography binding study in five cases with a clinical diagnosis of SV PPA constituting the range of pathologies (i.e., three FTLD-TDP, one Alzheimer’s disease (AD), and one Pick’s disease (PiD)). Binding was compared with two controls without neurodegeneration, two typical AD, one corticobasal syndrome with underlying AD, and one frontotemporal dementia behavioral variant with FTLD-TDP. The effect of blocking with the authentic reference material and with the MAO-B inhibitor deprenyl was assessed. Immunohistochemistry was performed on adjacent cryosections.ResultsAbsence of specific [18F]AV1451 binding was observed for all three SV PPA FTLD-TDP cases. The absence of binding in controls as well as the successful blocking with authentic AV1451 in cases with tauopathy demonstrated specificity of the [18F]AV1451 signal for tau. The specific [18F]AV1451 binding was highest in AD, followed by PiD. This binding colocalized with the respective tau lesions and could not be blocked by deprenyl. Similar pilot findings were obtained with [18F]THK5351.ConclusionIn vitro autoradiography showed no [18F]AV1451 binding in SV PPA due to FTLD-TDP, while specific binding was present in SV PPA due to AD and PiD. The discrepancy between in vitro and in vivo findings remains to be explained. The discordance is not related to [18F]AV1451 idiosyncrasies as [18F]THK5351 findings were similar.

18F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series

IntroductionChronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.ObjectiveTo study the binding properties of [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.MethodsWe performed [18F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.ResultsDespite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [18F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.ConclusionAV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.

Multi-Modal Signatures of Tau Pathology, Neuronal Fiber Integrity, and Functional Connectivity in Traumatic Brain Injury.

[18F]AV-1451 (aka 18F-Flortaucipir, [18F]T807) was developed for positron-emission tomography (PET) imaging of paired helical filaments of hyperphosphorylated tau, which are of interest in a range of neuropathologies, including traumatic brain injury (TBI). Magnetic resonance imaging (MRI) techniques like diffusion tensor imaging (DTI) and resting state functional connectivity assess structural and functional characteristics of the brain, complementing the molecular information that can be obtained by PET. The goal herein was to explore the utility of such multi-modal imaging in a case series based on a population of TBI subjects. This study probes the interrelationship between tau deposition, white matter integrity, and gray matter functional connectivity across the spectrum of TBI. Nineteen subjects (11 controls, five former contact sports athletes, one automotive accident, and two with military-related injury) underwent [18F]AV-1451 PET and magnetic resonance scanning procedures. [18F]AV-1451 distribution volume ratio (DVR) was estimated using the Logan method and the cerebellum as a reference region. Diffusion tractography images and fractional anisotropy (FA) images were generated using diffusion toolkit and FSL. Resting-state functional MRI (fMRI) analysis was based on a graph theory metric, namely weighted degree centrality. TBI subjects showed greater heterogeneity in [18F]AV-1451 DVR when compared with control subjects. In a subset of TBI subjects, areas with high [18F]AV-1451 binding corresponded with increased FA and diminished white matter tract density in DTI. Functional MRI results exhibited an increase in functional connectivity, particularly among local connections, in the areas where tau aggregates were more prevalent. In a case series of a diverse group of TBI subjects, brain regions with elevated tau burden exhibited increased functional connectivity as well as decreased white matter integrity. These findings portray molecular, microstructural, and functional corollaries of TBI that spatially coincide and can be measured in the living human brain using noninvasive neuroimaging techniques.

STUDIES TO EVALUATE THE PUTATIVE BINDING OF THE TAU POSITRON EMISSION TOMOGRAPHY TRACER 18F-AV-1451 TO MONOAMINE OXIDASE-B (MAO-B)

Although MAO-B inhibitors selegiline (deprenyl) and rasagiline have been reported not to block 18F-AV-1451 binding in clinical studies, other researchers have reported 3H-AV-1451 binding to MAO-B with nanomolar affinity in in vitro binding studies. In light of these contrasting data, we conducted an extensive set of experiments to investigate potential MAO-B liability for 18F-AV-1451. Equilibrium dissociation constants (Kd) for compound binding to recombinant MAO-B were determined by filtration binding. Nonspecific binding was defined as the binding of the ligand to control microsomes lacking MAO-B. Bound ligand was measured by Liquid Chromatography - Mass Spectrometry (LC-MS) for cold compounds and by gamma counter for F18-ligands. IC50s for each compound were determined in an LC-MS Safinamide:MAO-B competition binding assay. 18F-AV-1451 autoradiography blocking studies were performed on normal tissue with MAO-A/B inhibitors using mild washing conditions. No direct binding of AV-1451 to recombinant MAO-B was detected by radioligand binding or by LC-MS for 1 nM to 15 μM AV-1451. Using the same conditions, the binding of a control MAO-B ligand safinamide was determined to be 57 nM Kd. Evidence of potential AV-1451 interaction with recombinant MAO-B was observed by the weak inhibition by AV-1451 of the binding of safinamide to MAO-B (1.3 μM IC50). By autoradiography, 18F-AV-1451 binding is observed only on tau rich AD tissue and not on normal control tissue when stringent wash conditions are used (i.e. 30% and 70% EtOH) . However, when mild aqueous wash conditions are used, some off-target binding is observed on both AD and normal tissue. Weak blocking of off target 18F-AV-1451 binding on normal tissue was observed for MAO-B inhibitors deprenyl and safinamide (IC50 > 10 μM). There is limited evidence of AV-1451 binding to MAO-B that would impact in vivo 18F-AV-1451 PET imaging as demonstrated by the lack of direct in vitro binding of AV-1451 to recombinant MAO-B, the weak inhibition by AV-1451 of safinamide: MAO-B binding, and the reported lack of effect of MAO-B inhibitor treatment on 18F-AV-1451 PET signal in patients treated with selegiline or rasagiline.

Tau positron emission tomography imaging in C9orf72 repeat expansion carriers.

AV-1451 (18 F-AV-1451, flortaucipir)positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation. Nine clinically characterized C9orf72 expansion carriers and 18 age- and gender- matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV-1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV-1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures. C9orf72 expansion carriers had increased AV-1451 binding in the entorhinal cortex compared to controls. Primary age-related tauopathy was observed postmortem in one patient. AV-1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers. C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age-related tauopathy. However, AV-1451 accumulation was not associated with psychometric performance in our cohort.

18F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion.

The PET ligand [18F]AV‐1451 was developed to bind tau pathology in Alzheimer's disease, but increased binding has been shown in both genetic tauopathies and in semantic dementia, a disease strongly associated with TDP‐43 pathology. Here we assessed [18F]AV‐1451 binding in behavioral variant frontotemporal dementia due to a hexanucleotide repeat expansion in C9orf72, characterized by TDP‐43 pathology. We show that the C9orf72 mutation increases binding in frontotemporal cortex, with a distinctive distribution of binding compared with healthy controls.

18F]AV1451 PET IN RELATION TO ATROPHY ACROSS THE ALZHEIMER’S DISEASE SPECTRUM

Neuropathological Braak staging of neurofibrillary tangles has been introduced to capture the spatial spreading of tau. Using [18F]AV1451 PET, it is now possible to visualize these Braak stages in vivo. The aim of this study was to investigate whether and how specific [18F]AV1451 binding in ascending Braak stages relates to regional atrophy patterns across the Alzheimer's disease (AD) spectrum. We included 70 subjects (35 subjective cognitive decline [SCD], 6 mild cognitive impairment [MCI] and 29 AD dementia) who underwent a 130-minute dynamic [18F]AV1451 PET scan and structural MRI (table1). For [18F]AV1451, receptor parametric mapping (RPM) with cerebellar grey matter as reference region was used to calculate binding potential (BPND). Separate regional values for 1) Braak stage I/II (enthorinal), 2) Braak stage III/IV (limbic) and 3) Braak stage V/VI (neocortical) (Schöll et al, 2016) were extracted (figure 1). T1-weighted MR images were used to assess grey matter (GM) volumes. We performed whole-brain voxelwise analyses using the 3 regional Braak [18F]AV1451 BPND as independent variables, and GM volumes as the dependent variable, adjusting for age, sex and total intracranial volume, with a threshold of p<0.001 (uncorrected for multiple comparisons). These analyses were repeated using region-of-interest analyses for both [18F]AV1451 BPND and GM volumes. [18F]AV1451 BPND values per Braak region, according to diagnosis. Abbreviations: BPND= binding potential, SCD = subjective cognitive decline, MCI = Mild Cognitive Impairment, AD = Alzheimer's Disease. In the MCI/AD group, [18F]AV1451 BPND in Braak stage I/II showed limited associations with GM volumes. Greater [18F]AV1451 BPND in Braak stage III/IV, however, was associated with lower GM volumes in temporal, parietal and frontal cortices (figure2). These associations were similar for [18F]AV1451 BPND in Braak stage V/VI, although slightly less widespread (figure2). For SCD, only subtle associations between [18F]AV1451 BPND in Braak III/IV and GM volumes were observed (figure3). Region-of-interest analyses were in line with these findings (table2, figure4). Associations between regional [18F]AV1451 BPND and voxelwise brain GM volumes in MCI/AD. Analyses were adjusted for age, sex and TIV. Displayed are p-values, thresholded at an uncorrected p<0.001. Associations between regional [18F]AV1451 BPND and voxelwise brain GM volumes in SCD. Analyses were adjusted for age, sex and TIV. Displayed are p-values, thresholded at an uncorrected p<0.001. Relationships between [18F]AVIASI BPND and gray matter ROIs. Displayed are relationships between [18F]AV1451 BPND in Braak 1-2 (panel A,D), Braak 3-4 (panel B,E) and Braak 5-6 (panel C,F) and gray matter in medial temporal lobe (panel A-C) and temporoparietal lobe (panel D-F). Data are shown for SCD in blue and MCI/AD in red. Beta coefficients and p-values are displayed in blue boxes for SCD and in red boxs for MCI/AD. Abbreviations: BPND = binding potential GM = gray matter; ROI = region of interest, SCD = subjective cognitive decline, MCI = mild cognitive decline, AD = Alzheimer's disease These data suggest that tau pathology in Braak stages III/IV is most strongly associated with gray matter volume loss in patients with MCI and AD. Higher tau specific binding in Braak stage V/VI is not related to more extensive atrophy. In SCD and in Braak stage I/II in MCI/AD, only subtle associations between tau pathology and gray matter were observed. These findings could possibly be influenced by partial volume effects.

Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson\u2019s case

[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer’s disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson’s disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was present in the basal ganglia of the PD case or any of the other subjects. Off-target binding in postmortem choroid plexus samples was only observed in subjects harboring leptomeningeal melanocytes within the choroidal stroma. Off-target binding to parenchymal hemorrhages was noticed in postmortem material from subjects with cerebral amyloid angiopathy. The imaging-postmortem correlation analysis in this PD case reinforces the notion that [F-18]-AV-1451 has strong affinity for neurofibrillary tau pathology but also exhibits off-target binding to neuromelanin, melanin and blood components. The robust off-target in vivo retention in basal ganglia and choroid plexus, in the absence of tau deposits, meningeal melanocytes or any other identifiable binding substrate by autoradiography in the PD case reported here, also suggests that the PET signal in those regions may be influenced, at least in part, by biological or technical factors that occur in vivo and are not captured by autoradiography.

18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia

IntroductionSemantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which...

18F]AV-1451 binding to neuromelanin in the substantia nigra in PD and PSP.

This study investigated binding of [18F]AV-1451 to neuromelanin in the substantia nigra of patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). [18F]AV-1451 is a positron emission tomography radiotracer designed to bind pathological tau. A post-mortem study using [18F]AV-1451 discovered off-target binding properties to neuromelanin in the substantia nigra. A subsequent clinical study reported a 30% decrease in [18F]AV-1451 binding in the midbrain of PD patients. A total of 12 patients and 10 healthy age-matched controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio (SUVR) from 60 to 90min post-injection was calculated for the substantia nigra, using the cerebellar cortex as the reference region. The substantia nigra was delineated using automated region of interest software. An independent samples ANOVA and LSD post hoc testing were used to test for differences in [18F]AV-1451 SUVR between groups. Substantia nigra SUVR from 60 to 90min was significantly greater in HC compared to both PSP and PD groups. Although the PD group had the lowest SUVR, there was no significant difference in substantia nigra uptake between PD and PSP. [18F]AV-1451 may be the first PET radiotracer capable of imaging neurodegeneration of the substantia nigra in parkinsonisms. Further testing must be done in PD and atypical parkinsonian disorders to support this off-target use of [18F]AV-1451.

AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure

Utilizing [18F]-AV-1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data-driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]-AV-1451 binding. 84 cognitively normal participants who had undergone AV-1451 PET imaging were used in a sparse k-means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest-weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV-1451 uptake. We propose an AV-1451 SUVR cut-off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data-derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by β-amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and β-amyloid PET imaging in a diseased population.

18F]AV1451 POSITRON EMISSION TOMOGRAPHY IN SEMANTIC VARIANT PRIMARY PROGRESSIVE APHASIA

[18F]AV1451 is selective for Tau vs Beta-amyloid and vs alpha-synuclein. Binding in Alzheimer's disease shows strong correlations with phenotypic variants and severity. Studies in non-AD tauopathy are discordant, with significant binding in vivo contrasting with weak binding post mortem. Binding to TDP-43 pathology is poorly characterised. The semantic variant of primary progressive aphasia (svPPA) has a strong clinico-pathological correlation with TDP43 type C pathology at post mortem. We hypothesise that in cases clinically diagnosed with svPPA, [18F]AV1451 non-displaceable binding potential (BPND) is not increased compared with age-matched controls. 7 patients with svPPA and 12 controls underwent dynamic [18F]AV1451 PET. BPND was determined by kinetic modelling with a simplified reference tissue model (superior cerebellum). Partial volume corrected regional analysis of BPNDmaps was performed using PetSurfer following Freesurfer Desikan-Killiany cortical parcellation of 3T T1-MRI. We compared group BPND and tissue volume in each brain region using t-tests and quantifying effects with Cohen's d. We then assessed for distributional differences in BPND using hierarchical cluster analysis. Significant increases in [18F]AV1451 binding were seen in svPPA compared to controls. These were observed across left temporal lobe, in left fusiform gyrus, left insula and right amygdala (p<0.05 Bonferroni corrected). The effect size of the difference between svPPA and control binding was correlated with that of grey matter volume. Nonparametric hierarchical clustering classified svPPA with 86% sensitivity and 100% specificity. There is significantly increased [18F]AV1451 binding in regions where TDP43 pathology is known to be localised in svPPA and where atrophy was demonstrated in our cohort. Given the strong association between svPPA and TDP43 pathology it seems unlikely that all patients had undiagnosed Alzheimer's or Pick's pathology. The anatomical distribution is as expected for the clinical syndrome, undermining the previously proposed ‘off target’ binding sites, such as Iron, Calcium, Neuromelanin and Biondi ring tangles. Regardless of the molecular basis of [18F]AV1451 binding, the regionally selective binding we observe suggests a potential role as biomarker in longitudinal and therapeutic studies of svPPA. Post mortem validation will be useful in furthering our understanding of [18F]AV1451 binding in Frontotemporal lobar degeneration.