Synopsis

Using QSM and R2* mapping we found higher iron levels in specific basal ganglia structures in a cohort of 100 patients with AD when compared to 100 age-matched controls. Iron load in the basal ganglia was negatively correlated with brain volume measures.

Introduction

Based on histological findings showing iron-induced free radical damage and oxidative stress^1,2 recent in vivo studies have demonstrated that higher iron concentrations in Alzheimer's Disease (AD) are linked to memory and cognitive decline^3–5. While tau promotes the export of iron by facilitating the movement of APP to the surface⁶, senile plaques are agglomerations of amyloid-beta proteins which have been found highly affine to paramagnetic iron AD brains⁷.

In this work we utilize quantitative susceptibility mapping (QSM), a novel MRI technique as well as R2* relaxation rate mapping to assess iron deposition in the basal ganglia (BG) in patients with AD^8,9.

Methods

We included 100 patients with probable and possible AD according to the NINCDS-ADRDA criteria (mean age=71.24±8.06 years; male/female=43/57). For comparison we selected 100 healthy controls matched for age (±1 year; male/female=37/63) (HC) from an ongoing study in community dwelling subjects¹⁰.

Patients and controls underwent extensive clinical testing as well as a consistent quantitative MRI protocol at 3 Tesla (Siemens TimTrio). MRI included a structural T1-weighted MPRAGE sequence with 1mm isotropic resolution, FLAIR imaging for lesion detection and a 3D multi-echo gradient echo sequence (TR/TE1/FA=35ms/4.92ms/20° with 6 equally spaced echoes, 0.9x0.9x2mm³ resolution, 64 slices). R2* relaxation data was obtained by Sinc-corrected modeling of the magnitude decay¹¹ and QSM images calculated by using a TGV-based dipole inversion algorithm and normalized to CSF¹².

Anatomical structures were automatically segmented using FSL FIRST¹³ to obtain regional median R2* and QSM values for the Caudate, Putamen, Pallidum, Hippocampus, and Thalamus. Normalized brain volume metrics were analyzed by using SIENAX from FSL¹³. For correlation analyses and statistical tests with clinical and volumetric variables we utilized the global basal ganglia value BG = mean (Caudate, Putamen, Pallidum).

Results

R2* and QSM were increased in the putamen of patients with AD, and R2* was also higher in the caudate nucleus of AD patients. Global BG values for QSM and R2* where higher in AD compared to controls (Table 1).

We found positive correlation of BG R2* and BG QSM with ventricular cerebrospinal fluid volume in both AD and controls. Only in AD patients, QSM and R2* were inversely related to total brain volume and volume of gray matter, white matter, and neocortex (Table 2).

Discussion and Conclusion

We found higher iron levels in structures of the basal ganglia in a cohort of 100 patients with AD when compared to 100 age-matched controls. Although QSM and R2* are both highly sensitive to brain iron they exhibit a counteracting behavior regarding myelin and axonal damage and may thus provide complementary information about underlying pathological tissue changes.

Increased iron deposition was linked to bigger ventricular volume in both groups. Nonetheless, only AD patients but not controls showed additionally negative correlations between BG iron load and brain volume metrics, indicating a more widespread pattern of disease compared to healthy aging, at least to a certain extent.

These findings support the view that iron deposition in the basal ganglia is at least partly involved in neurodegenerative processes. Future studies in this cohort will determine the clinical significance and combined QSM and R2* assessment will test which of the two measures, if any, relates more closely to the clinical status of patients.

Acknowledgements

References

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