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Brain iron load, as measured by Quantitative Susceptibility Mapping, promotes beta-Amyloid associated functional brain change in elderly subjects but not in Super-Agers1Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland, 2F.M. Kirby center for Functional Brain Imaging, Kennedy Krieger Institute and Johns Hopkins School of Medicine, MD, United States, 3Department of Nuclear Medicine, University of Zurich, Switzerland
Synopsis
To investigate whether brain iron load has an impact on Aβ associated functional brain change, this study investigated a large sample of cognitively healthy adults including 44 Super-Agers (subjects over the age of 85 without cognitive impairments) using simultaneous assessment of Amyloid-PET for Aβ-plaque-density, QSM for estimation of iron load and resting-state-fMRI.
Our findings indicate that the combination of Aβ-plaque-density with other neurodegenerative change (iron), has an impact on brain functionality, reflected by significant changes of resting state functional connectivity. Additionally, Aβ-plaque-density had no significant effect on functional connectivity in Super-Agers.
Introduction
While accumulation of cerebral beta-Amyloid (Aβ) is a neuropathological hallmark of Alzheimer's Disease (AD), its deposition can be measured in cognitively healthy elderly subjects, long before manifestation of clinical symptoms1. Recent studies suggest that the coexistence of Aβ with other neurodegenerative alterations confers increased risk for progression to cognitive impairment due to AD2,3. Neurodegenerative brain change in AD is characterized by cerebral atrophy and several pathological processes implicated in neurodegenerative brain damage have been demonstrated to be reflected by accumulation of iron4–8. Aβ associated functional brain change, as reflected by impaired integrity of the Default Mode Network (DMN), has been demonstrated to precede the clinical manifestation of AD in subjects with high Aβ-plaque-density9. To investigate whether brain iron load has an impact on Aβ associated functional brain change, this study investigated a large sample of cognitively healthy adults including 44 Super-Agers (subjects over the age of 85 without cognitive impairments) using simultaneous assessment of 18F-Flutemetamol-PET for Aβ-plaque-density, QSM for estimation of iron load (indicated by susceptibility) and functional MRI (fMRI) at rest for assessing Functional Connectivity (FC).Methods
80 elderly individuals (Figure 1) were studied using a 3T SIGNA General-Electrics Healthcare combined PET-MR instrument. All participants received medical and psychiatric examination, as well as standardized neuropsychological assessment to assure normal cognitive function in cognitive subdomains. Significant brain pathologies were excluded by visual inspection of MRI-scans (by P.G.U.). A T1-weighted BRAVO image (TI=450ms, voxel size=1x1x1mm3, flip-angle=12°, ASSET factor=2) was acquired for segmentation using a multi-atlas approach10,11. Regions of interest were eroded by 2 pixels before being applied as a mask in further processing. QSM images were reconstructed from a 3D multi-echo GRE sequence (TR/TE/ΔTE=40/6/4ms, voxel size=1x1x1mm3, flip angle=15°, bandwidth=±62.5 kHz, flow compensated, ASSET factor=2) using the echoes with echo time between 15 and 27ms. Sequentially, Laplacian phase unwrapping, V-SHARP for background removal12 and an iLSQR based approach for dipole inversion13 were used to create the QSM image. After removal of the background field, the resulting images of the 4 echoes were averaged14. Deep frontal white matter was selected as a reference region for the final susceptibility quantification. All reported susceptibility values are relative to this reference region. Aβ-plaque-density was estimated by PET acquisition of 18F-Flutametamol15 (85-105 minutes post injection) and reconstructed using time-of-flight reconstruction (voxel size=1.2x1.2x2.78mm3). The PET image was segmented using the parcellation created from the T1-weighted image and all PET-values were referenced to the cerebellar gray matter. As single measures of individual cortical Aβ-plaque-density and iron-load for each subject the average of a number of cortical gray matter ROIs16 was calculated and in the case of Flutemetamol a cutoff value was determined, as reported earlier to distinguish Amyloid positive and negative subjects15. fMRI resting-state scans using a gradient echo EPI sequence (voxel size=3x3x3mm3, TR=2.547s, duration=8:42min) were acquired and then preprocessed using SPM12 and the CONN-toolbox17. Seed-to-voxel analyses of the DMN were performed using seeds in the Medial Prefrontal Cortex (MPFC) and Posterior Cingulate Cortex (PCC). The linear measures of Aβ-plaque-density and iron-load per subject were used as covariates in group-level analysis while correcting for age and gender, statistical threshold was set to p < 0.001 with a cluster threshold p-FDR-corrected < 0.05.Results
Aβ-plaque-density and iron-load as a covariate did not result in significant alterations in either of the groups. However, in the non-Super-Agers the contrast Aβ-plaque-density*Iron-load resulted in a region of 1249 voxels (T1,36=3.10) with significantly increased activations (Figure 2). The same contrast in the Super-Agers group did not result in significant activations.Discussion
Our preliminary findings indicate that the combination of Aβ-plaque-density with other neurodegenerative change (as reflected by iron) has an impact on brain functionality, reflected by significant changes of resting state functional connectivity. While previous studies have found significant impact of Amyloid positive status in cognitively normal elderly of a similar age to our non-Super-Ager population we could not detect such changes in our sample using linear measures. The studied non-Super-Ager sample had few subjects with such high cortical Aβ-plaque-density, indicating the increase in sensitivity added by including measures of cerebral iron-load. Additionally, the fact that Aβ-plaque-density had no significant effect on functional connectivity in Super-Agers, despite a larger number of subjects with high cortical Aβ-plaque-density, may reflect inherent biological factors of resilience against ageing-related brain pathology in this population. This result supports the hypothesis of a synergistic effect of neurodegeneration and Aβ on brain functioning3 in non-Super-Agers. However, further studies and follow-ups are needed to determine the relevance of iron-load on the on possible future cognitive decline of the non-Super-Agers and the protective factors in Super-Agers.Acknowledgements
No acknowledgement found.References
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