Introduction

Quantitative susceptibility mapping (QSM) has been widely used to study abnormal iron deposition in neurodegenerative diseases¹. Several studies have suggested that iron is involved in tau aggregation in tauopathies such as Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP)^{2, 3}. Previous studies have investigated the relationship between QSM and tau PET in AD and found positive correlations in cortical and subcortical regions⁴. However, it remains unknown whether the relationship between these two modalities exists in other tauopathies such as PSP. Since the patterns of QSM and tau PET uptake are topographically similar in PSP; both are increased in the subcortical regions such as the basal ganglia and midbrain^{1, 5}, we hypothesized that they would be strongly associated in these subcortical regions. The aim of this study is to investigate the relationships between these two modalities in PSP.

Methods

Subjects
Fifty PSP patients (26 females) were prospectively recruited and diagnosed according to the Movement Disorder Society (MDS)-PSP diagnostic criteria⁶. Of the 50 patients, 19 were diagnosed with PSP Richardson syndrome (PSP-RS), 22 with subcortical clinical variants of PSP (including parkinsonism, gait freezing and postural instability variants) and nine with cortical variants of PSP (including frontal, corticobasal and speech-language variants).

MRI and PET processing
All patients underwent 3 Tesla MRI and tau PET scans using standardized protocols. The Siemens MRI scan included a five-echo gradient echo (GrE) and magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequences⁷. QSM images were reconstructed from the GrE images by using MATLAB and STI suites⁸. Brain atlases for regional analysis were nonlinearly registered from the template space to each subject space by using Advanced Normalization Tools. A 20-minute PET acquisition was performed 80 minutes after the injection of approximately 370 MBq flortaucipir. Gray-matter cerebellar crus was used as the reference region to calculate standardized uptake value ratio (SUVR) images. Both QSM and SUVR images were spatially normalized and smoothed after rigid registration to MPRAGE images for the voxel-based analysis.

Regional and voxel-based correlation analysis
For regional analysis, mean susceptibility and SUVR were calculated in seven subcortical regions, including caudate, putamen, pallidum, subthalamic nucleus, substantia nigra, red nucleus, and cerebellar dentate, using brain atlases as previously reported⁹. Spearman's partial correlation coefficients between susceptibility and SUVR were calculated with age and sex as covariates in these seven regions. Voxel-based correlation analysis was performed by using VoxelStats software¹⁰. This software fits a linear regression in each voxel to assess the association between two modalities. Age and sex were again included as covariates in the linear model (SUVR ~ QSM + age + sex). Surviving regions were presented using the p<0.001 threshold and random field theory based multiple comparison correction¹⁰.

Results

In the regional analysis, magnetic susceptibility and flortaucipir SUVR were positively correlated in most subcortical regions, including putamen (r=0.37), pallidum (r=0.36), subthalamic nucleus (r=0.43), red nucleus (r=0.59), and cerebellar dentate (r=0.42) (FDR corrected p<0.05) (Figure 1), while no significant correlation was observed in caudate (r=0.23) and substantia nigra (r=0.19). The results of the voxel-based analysis were consistent with those of the regional analysis (Figure 2). A positive correlation between two signals was observed in the caudate, putamen, pallidum, thalamus, subthalamic nucleus, and red nucleus. In addition, a significant positive correlation was observed in the bilateral frontal white matter and the right fusiform gyrus.

Discussion

We found a positive correlation between magnetic susceptibility and flortaucipir SUVR in most subcortical regions. These results suggest that some flortaucipir PET uptake is related to iron, given that estimated susceptibility is strongly correlated with iron concentration in the subcortical regions¹¹. The positive correlations may be due to several reasons, including off-target binding of iron or iron-related proteins¹² or the coexistence of iron and tau², although this study cannot address the cause of the correlation. Voxel-based correlation analysis supported the regional analysis and additionally found a positive correlation in the bilateral frontal white matter. These frontal regions are consistent with the regions where a previous diffusion tensor study found white matter degeneration in PSP¹³. This positive correlation in the frontal white matter may be indicative of the relationship between tau uptake and white matter degeneration, given that myelin loss is likely to be associated with increased susceptibility. No correlation was found in the substantia nigra in either analysis, which may be confounded by other off-target substances such as neuromelanin¹⁴.

Conclusion

Flortaucipir tau PET and QSM signals were positively correlated in subcortical regions in PSP, suggesting the possibility that some flortaucipir uptake is associated with iron.

Acknowledgements

We would like to acknowledge AVID Radiopharmaceuticals for provision of AV-1451 precursor, chemistry production advice and oversight, and FDA regulatory cross-filing permission and documentation needed for this work. This study is supported by NIH grants R01-NS89757, R01-DC12519, R01-DC14942 and RF1-NS112153.

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