Dataset Information

¹⁸F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

ABSTRACT:

Purpose

Human post mortem studies have described the topographical patterns of tau pathology in progressive supranuclear palsy (PSP). Recent advances in tau PET tracers are expected to herald the next era of PSP investigation for early detection of tau pathology in living brains. This study aimed to investigate whether ¹⁸F-Florzolotau PET imaging may capture the distribution patterns and regional vulnerability of tau pathology in PSP, and to devise a novel image-based staging system.

Methods

The study cohort consisted of 148 consecutive patients with PSP who had undergone ¹⁸F-Florzolotau PET imaging. The PSP rating scale (PSPrs) was used to measure disease severity. Similarities and differences of tau deposition among different clinical phenotypes were examined at the regional and voxel levels. An ¹⁸F-Florzolotau pathological staging system was devised according to the scheme originally developed for post mortem data. In light of conditional probabilities for the sequence of events, an ¹⁸F-Florzolotau modified staging system by integrating clusters at the regional level was further developed. The ability of ¹⁸F-Florzolotau staging systems to reflect disease severity in terms of PSPrs score was assessed by analysis of variance.

Results

The distribution patterns of ¹⁸F-Florzolotau accumulation in living brains of PSP showed a remarkable similarity to those reported in post mortem studies, with the binding intensity being markedly higher in Richardson's syndrome. Moreover, ¹⁸F-Florzolotau PET imaging allowed detecting regional vulnerability and tracking tau accumulation in an earlier fashion compared with post mortem immunostaining. The ¹⁸F-Florzolotau staging systems were positively correlated with clinical severity as reflected by PSPrs scores.

Conclusions

¹⁸F-Florzolotau PET imaging can effectively capture the distribution patterns and regional vulnerability of tau pathology in PSP. The ¹⁸F-Florzolotau modified staging system holds promise for early tracking of tau deposition in living brains.

SUBMITTER: Liu FT

PROVIDER: S-EPMC10027831 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

<sup>18</sup>F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

Liu Feng-Tao FT Lu Jia-Ying JY Li Xin-Yi XY Liang Xiao-Niu XN Jiao Fang-Yang FY Ge Jing-Jie JJ Wu Ping P Li Gen G Shen Bo B Wu Bin B Sun Yi-Min YM Zhu Yu-Hua YH Luo Jian-Feng JF Yen Tzu-Chen TC Wu Jian-Jun JJ Zuo Chuan-Tao CT Wang Jian J

European journal of nuclear medicine and molecular imaging 20230111 5

<h4>Purpose</h4>Human post mortem studies have described the topographical patterns of tau pathology in progressive supranuclear palsy (PSP). Recent advances in tau PET tracers are expected to herald the next era of PSP investigation for early detection of tau pathology in living brains. This study aimed to investigate whether <sup>18</sup>F-Florzolotau PET imaging may capture the distribution patterns and regional vulnerability of tau pathology in PSP, and to devise a novel image-based staging ...[more]

PMID: 36627498

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Project description:BackgroundProgressive supranuclear palsy (PSP) is a primary 4-repeat tauopathy with diverse clinical phenotypes. Previous post-mortem studies examined tau deposition sequences in PSP, but in vivo scrutiny is lacking.MethodsWe conducted [18F]Florzolotau tau positron emission tomography (PET) scans on 148 patients who were clinically diagnosed with PSP and 20 healthy controls. We employed the Subtype and Stage Inference (SuStaIn) algorithm to identify PSP subtype/stage and related tau patterns, comparing clinical features across subtypes and assessing PSP stage-clinical severity association. We also evaluated functional connectivity differences among subtypes through resting-state functional magnetic resonance imaging.FindingsWe identified two distinct subtypes of PSP: Subtype1 and Subtype2. Subtype1 typically exhibits a sequential progression of the disease, starting from subcortical and gradually moving to cortical regions. Conversely, Subtype2 is characterized by an early, simultaneous onset in both regions. Interestingly, once the disease is initiated, Subtype1 tends to spread more rapidly within each region compared to Subtype2. Individuals categorized as Subtype2 are generally older and exhibit less severe dysfunctions in areas such as cognition, bulbar, limb motor, and general motor functions compared to those with Subtype1. Moreover, they have a more favorable prognosis in terms of limb motor function. We found significant correlations between several clinical variables and the identified PSP SuStaIn stages. Furthermore, Subtype2 displayed a remarkable reduction in functional connectivity compared to Subtype1.InterpretationWe present the evidence of distinct in vivo spatiotemporal tau trajectories in PSP. Our findings can contribute to precision medicine advancements for PSP.FundingThis work was supported by grants from the National Natural Science Foundation of China (number 82272039, 81971641, 82021002, and 92249302); Swiss National Science Foundation (number 188350); the STI2030-Major Project of China (number 2022ZD0211600); the Clinical Research Plan of Shanghai Hospital Development Center of China (number SHDC2020CR1038B); and the National Key R&D Program of China (number 2022YFC2009902, 2022YFC2009900), the China Scholarship Council (number 202006100181); the Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198).

Project description:The development of novel treatments for Progressive Supranuclear Palsy (PSP) is hindered by a knowledge gap of the impact of neurodegenerative neuropathology on brain structure and function. The current standard practice for measuring postmortem tau histology is semi-quantitative assessment, which is prone to inter-rater variability, time-consuming and difficult to scale. We developed and optimized a tau aggregate type-specific quantification pipeline for cortical and subcortical regions, in human brain donors with PSP. We quantified 4 tau objects ('neurofibrillary tangles', 'coiled bodies', 'tufted astrocytes', and 'tau fragments') using a probabilistic random forest machine learning classifier. The tau pipeline achieved high classification performance (F1-score > 0.90), comparable to neuropathologist inter-rater reliability in the held-out test set. Using 240 AT8 slides from 32 postmortem brains, the tau burden was correlated against the PSP pathology staging scheme using Spearman's rank correlation. We assessed whether clinical severity (PSP rating scale, PSPRS) score reflects neuropathological severity inferred from PSP stage and tau burden using Bayesian linear mixed regression. Tufted astrocyte density in cortical regions and coiled body density in subcortical regions showed the highest correlation to PSP stage (r = 0.62 and r = 0.38, respectively). Using traditional manual staging, only PSP patients in stage 6, not earlier stages, had significantly higher clinical severity than stage 2. Cortical tau density and neurofibrillary tangle density in subcortical regions correlated with clinical severity. Overall, our data indicate the potential for highly accurate digital tau aggregate type-specific quantification for neurodegenerative tauopathies; and the importance of studying tau aggregate type-specific burden in different brain regions as opposed to overall tau, to gain insights into the pathogenesis and progression of tauopathies.

Project description:PurposeThe pattern of flortaucipir tau PET uptake is topographically similar to the pattern of magnetic susceptibility in progressive supranuclear palsy (PSP); both with increased signal in subcortical structures such as the basal ganglia and midbrain, suggesting that they may be closely related. However, their relationship remains unknown since no studies have directly compared these two modalities in the same PSP cohort. We hypothesized that some flortaucipir uptake in PSP is associated with magnetic susceptibility, and hence iron deposition. The aim of this study was to evaluate the regional relationship between flortaucipir uptake and magnetic susceptibility and to examine the effects of susceptibility on flortaucipir uptake in PSP.MethodsFifty PSP patients and 67 cognitively normal controls were prospectively recruited and underwent three Tesla MRI and flortaucipir tau PET scans. Quantitative susceptibility maps were reconstructed from multi-echo gradient-echo MRI images. Region of interest (ROI) analysis was performed to obtain flortaucipir and susceptibility values in the subcortical regions. Relationships between flortaucipir and susceptibility signals were evaluated using partial correlation analysis in the subcortical ROIs and voxel-based analysis in the whole brain. The effects of susceptibility on flortaucipir uptake were examined by using the framework of mediation analysis.ResultsBoth flortaucipir and susceptibility were greater in PSP compared to controls in the putamen, pallidum, subthalamic nucleus, red nucleus, and cerebellar dentate (p<0.05). The ROI-based and voxel-based analyses showed that these two signals were positively correlated in these five regions (r = 0.36-0.59, p<0.05). Mediation analysis showed that greater flortaucipir uptake was partially explained by susceptibility in the putamen, pallidum, subthalamic nucleus, and red nucleus, and fully explained in the cerebellar dentate.ConclusionsThese results suggest that some of the flortaucipir uptake in subcortical regions in PSP is related to iron deposition. These findings will contribute to our understanding of the mechanisms underlying flortaucipir tau PET findings in PSP and other neurodegenerative diseases.

Project description:Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may spread in the brain from cell to cell in a 'prion-like' manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including globose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathological progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease.

Dataset Information

¹⁸F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

Purpose

Methods

Results

Conclusions

Publications

<sup>18</sup>F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

18F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

Purpose

Methods

Results

Conclusions

Publications

<sup>18</sup>F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

¹⁸F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.