MRI estimates of brain iron concentration in normal aging: Comparison of field-dependent (FDRI) and phase (SWI) methods

Abstract

Different brain structures accumulate iron at different rates throughout the adult life span. Typically, striatal and brain stem structures are higher in iron concentrations in older than younger adults, whereas cortical white matter and thalamus have lower concentrations in the elderly than young adults. Brain iron can be measured in vivo with MRI by estimating the relaxivity increase across magnetic field strengths, which yields the Field-Dependent Relaxation Rate Increase (FDRI) metric. The influence of local iron deposition on susceptibility, manifests as MR phase effects, forms the basis for another approach for iron measurement, Susceptibility-Weighted Imaging (SWI), for which imaging at only one field strength is sufficient. Here, we compared the ability of these two methods to detect and quantify brain iron in 11 young (5 men, 6 women; 21 to 29 years) and 12 elderly (6 men, 6 women; 64 to 86 years) healthy adults. FDRI was acquired at 1.5 T and 3.0 T, and SWI was acquired at 1.5 T. The results showed that both methods detected high globus pallidus iron concentration regardless of age and significantly greater iron in putamen with advancing age. The SWI measures were more sensitive when the phase signal intensities themselves were used to define regions of interest, whereas FDRI measures were robust to the method of region of interest selection. Further, FDRI measures were more highly correlated than SWI iron estimates with published postmortem values and were more sensitive than SWI to iron concentration differences across basal ganglia structures. Whereas FDRI requires more imaging time than SWI, two field strengths, and across-study image registration for iron concentration calculation, FDRI appears more specific to age-dependent accumulation of non-heme brain iron than SWI, which is affected by heme iron and non-iron source effects on phase.

Introduction

Convergent postmortem (Hallgren and Sourander, 1958) and in vivo data indicate that deep gray matter brain structures accumulate ferritin at different rates throughout adult aging (Bartzokis et al., 1994Bartzokis et al., 2007b, Bizzi et al., 1990). The structures affected support motor functioning, and increasing iron deposition may contribute to age-related motor slowing. Abnormal iron accumulation has been reported in neurological conditions involving the striatum, including Parkinson's disease, multiple sclerosis, substantia nigra degeneration, multisystems atrophy, Huntington's disease, and Hallervorden–Spatz syndrome (reviewed in Bartzokis et al., 2007aBartzokis et al., 2007b, Brass et al., 2006, Haacke et al., 2005Haacke et al., 2009, Mittal et al., 2009), and suggests that iron burden contributes to age- and disease-related functional decline (Bartzokis et al., 2008, Sullivan et al., 2009).

Iron can be measured in vivo with MR imaging because of iron's effect on signal intensity, causing signal darkening on T2⁎ and T2-weighted images that is greater with increasing magnetic field strength. By estimating the transverse relaxivity increase across field strengths, the MR Field-Dependent Relaxation Rate (R2) Increase (FDRI) can be calculated (Bartzokis et al., 1993Bartzokis et al., 2007b, Pfefferbaum et al., 2009). For example, acquisition of spin-echo data with a constant TR and multiple echoes at 1.5 T and 3.0 T allows the computation of R2 at each field strength, with the difference between R2s divided by the field strength difference producing FDRI in units of s⁻¹/Tesla.

In addition to affecting relaxivity, local iron influences MR gradient-echo image phase, which forms the basis for another method for iron quantification, Susceptibility-Weighted Imaging (SWI) (Haacke et al., 2004, 2005). The paramagnetic properties of tissue ferritin cause local field inhomogeneity that can be detected by examining the phase of the spins computed from the relationship of the real and imaginary components of quadrature-detected signal in a gradient-echo sequence. The phase of the spins at a given field strength and echo time are influenced by iron concentration in each voxel. The ferromagnetic property of the iron causes the protons to accrue more negative phase in iron-rich tissue in addition to off-resonance phase accrued linearly with field strength and echo time. For a right-handed system, reconstructed MR phase images typically yield positive phase values for white matter (less iron), whereas deep gray matter structures tend to have negative phase (more iron). In addition to iron content, the phase of the spins in a voxel can also be influenced by other sources, including main-field inhomogeneities due to air–tissue interfaces, flowing or moving spins, and the ratio of oxy- and dexoyhemoglobin. At optimal acquisition parameters, the more iron in a voxel, the lower will be the measured phase (Haacke et al., 2004). An advantage of this approach is that it does not require scanning at two field strengths (Haacke et al., 2005, 2007).

We compared the FDRI and SWI approaches to the measurement of brain iron in regions known to vary widely in their iron content—high in striatum and brain stem nuclei and low in white matter—and affected differentially by age. To establish convergent validity of the results, we correlated the regional iron values obtained with each acquisition method with published postmortem values on regional brain iron (Hallgren and Sourander, 1958).