Dataset Information

Increased basal ganglia binding of ¹⁸ F-AV-1451 in patients with progressive supranuclear palsy.

ABSTRACT:

Background

Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP.

Methods

Regional tau accumulation was studied using ¹⁸ F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study.

Results

¹⁸ F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared with controls (globus pallidus 1.75 vs 1.50; putamen 1.51 vs 1.35). Retention in the basal ganglia was correlated with age in both groups (r?=?.43-.78, P?18 F-AV-1451 retention was observed in the cerebral cortex or white matter of either PSP patients or controls, and autoradiography did not reveal any specific binding of AV-1451 to PSP tau aggregates.

Conclusion

We found higher ¹⁸ F-AV-1451 retention in the basal ganglia of PSP patients when compared with healthy elderly controls, but also increases with age in both controls and patients. As a result of the overlap in retention between diagnostic groups and the age-dependent increase present also in controls, ¹⁸ F-AV-1451 PET might not reliably distinguish individual patients with PSP from controls. However, further studies are needed to evaluate whether ¹⁸ F-AV-1451 PET might be useful as a progression marker in clinical PSP trials. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Smith R

PROVIDER: S-EPMC6204612 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Increased basal ganglia binding of <sup>18</sup> F-AV-1451 in patients with progressive supranuclear palsy.

Smith Ruben R Schain Martin M Nilsson Christer C Strandberg Olof O Olsson Tomas T Hägerström Douglas D Jögi Jonas J Borroni Edilio E Schöll Michael M Honer Michael M Hansson Oskar O

Movement disorders : official journal of the Movement Disorder Society 20161006 1

<h4>Background</h4>Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work-up of PSP.<h4>Methods</h4>Regional tau accumulation was studied using <sup>18</sup> F-AV-1451 PET in 11 patients with PSP and 11 age-matched healthy controls in the Swedish BioFinder study.<h4>Results</h4><sup>18</sup> F-AV-1451 standard uptake volume ratios were significantly higher in the basal ganglia in PSP patients when compared ...[more]

PMID: 27709757

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Project description:The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer's disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake in the putamen, pallidum, thalamus, midbrain, and in the dentate nucleus of the cerebellum (t's > 2.7, P's < 0.02). The support vector machine assigned patients' diagnoses with 94% accuracy. The post-mortem autoradiographic data showed that 18F-AV-1451 strongly bound to Alzheimer-related tau pathology, but less specifically in progressive supranuclear palsy. 18F-AV-1451 binding to the basal ganglia was strong in all groups in vivo. Postmortem histochemical staining showed absence of neuromelanin-containing cells in the basal ganglia, indicating that off-target binding to neuromelanin is an insufficient explanation of 18F-AV-1451 positron emission tomography data in vivo, at least in the basal ganglia. Overall, we confirm the potential of 18F-AV-1451 as a heuristic biomarker, but caution is indicated in the neuropathological interpretation of its binding. Off-target binding may contribute to disease profiles of 18F-AV-1451 positron emission tomography, especially in primary tauopathies such as progressive supranuclear palsy. We suggest that 18F-AV-1451 positron emission tomography is a useful biomarker to assess tau pathology in Alzheimer's disease and to distinguish it from other tauopathies with distinct clinical and pathological characteristics such as progressive supranuclear palsy.

Project description:Primary progressive apraxia of speech (PPAOS) is a term used to describe a neurodegenerative condition in which apraxia of speech (AOS; a planning and/or programming deficit) occurs in the absence of aphasia (a language deficit). PPAOS is strongly associated with 4-repeat tau pathology. Elevated flortaucipir ([18F]AV-1451; FTP) uptake has been observed cross-sectionally in patients with PPAOS and those with aphasia. Here, we evaluated longitudinal changes in previously-identified regions of uptake and their relationship with clinical presentation. Thirteen patients who were diagnosed with PPAOS (5 female) at presentation underwent FTP PET imaging at two visits (mean 1 year interval). Median age was 72, with a median of 4 years disease duration at initial testing. Beta-amyloid status was assessed with Pittsburgh Compound B (PiB), where a global PiB ratio>1.48 was deemed amyloid positive (n = 4). FTP uptake was assessed as cortical to cerebellar crus ratios (SUVr) in cortical regions of interest. A single hierarchical linear model (HLM) compared PPAOS patients to 52 cognitively unimpaired controls of similar age and sex. Annualized SUVr change was the outcome, predicted by region, clinical status, and age. Person-specific effects accounted for intra-patient correlations and contralateral regions were included as repeated measures. Changes in clinical measures were assessed using Wilcoxon signed-rank tests; statistically significant changes in the Montreal Cognitive Assessment, MDS-UPDRS, motor section, and PSP Rating Scale were noted between visits. Changes in FTP SUVr were greater for patients than controls. The strongest changes in PPAOS patients were in the precentral gyrus, pallidum, and mid and superior frontal gyri, per the HLM. Qualitatively, larger changes were seen in patients who had developed aphasia by the time of their baseline scan (n = 5). While the biological mechanisms of FTP signal in non-AD tauopathies are unknown, this study demonstrates the utility of FTP in tracking disease progression in 4R tauopathies.

Project description:BackgroundThe tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.MethodsWe performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.ResultsOn qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

Dataset Information

Increased basal ganglia binding of ¹⁸ F-AV-1451 in patients with progressive supranuclear palsy.

Background

Methods

Results

Conclusion

Publications

Increased basal ganglia binding of <sup>18</sup> F-AV-1451 in patients with progressive supranuclear palsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Increased basal ganglia binding of 18 F-AV-1451 in patients with progressive supranuclear palsy.

Background

Methods

Results

Conclusion

Publications

Increased basal ganglia binding of <sup>18</sup> F-AV-1451 in patients with progressive supranuclear palsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Increased basal ganglia binding of ¹⁸ F-AV-1451 in patients with progressive supranuclear palsy.