Associations of quantitative susceptibility mapping with Alzheimer's disease clinical and imaging markers

Abstract

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.

Keywords: Alzheimer's disease; Beta amyloid PET; Quantitative susceptibility mapping; Tau PET.

Fig. 1.

Median susceptibility by region using the ADIR28 atlas. The unnormalized QSM data are shown. For each region, each participant is represented by a dot, blue for left and orange for right. The ROIs are listed from high to low median value. The basal ganglia and inferior gray nuclei show positive susceptibility with a broad range among participants compared to the cortical ROIs, which show signal centered about zero with a relatively narrow range.

Fig. 2.

Normal densities reflecting the estimated SDs from the variance components analysis for susceptibility, amyloid PET SUVR, tau PET SUVR, and cortical gray matter volume. Analysis was performed using the unnormalized susceptibility measures and PET and volume measures were log-transformed. Results are shown separately for cortical (top row) and deep and inferior gray nuclei (bottom row). The x-axis differs among plots and is representative of spread or variation in values. The y-axis represents amplitude with values based on the SD of each measure such that the area under the curve is equal to 1.

Fig. 3.

Estimated mean (95% confidence interval) difference in susceptibility for an increase in age of 10 years, diagnosis of amnestic dementia (aDem) or mild cognitive impairment (MCI) relative to cognitively unimpaired (CU), and a decrease in Short Test of Mental Status (STMS) score of 5 points. Linear regression models were fit separately for each region and variable of interest. All models except age were adjusted for age and sex. All age models were fit among MCSA participants only. Cortical regions and deep and inferior gray nuclei are shown separately due to differences in effect sizes. Those regions whose 95% confidence interval does not cross zero are statistically significant.

Fig. 4.

Estimated mean (95% confidence interval) difference in susceptibility for a 20% increase in amyloid PET SUVR, 20% increase in tau PET SVUR, and a 20% decrease in gray matter volume. Linear regression models were fit separately for each region and variable of interest. All models were adjusted for age and sex, and volume models were adjusted for TIV. Cortical regions and deep and inferior gray nuclei are shown separately due to differences in effect sizes. Those regions whose 95% confidence interval does not cross zero are statistically significant.

Fig. 5.

Images from representative participants. QSM, tau PET, and amyloid PET for (A) a 35-year-old participant and (B) an 83-year-old participant, both cognitively unimpaired. In the older participant, there was elevated susceptibility and tau PET SUVR in the pallidum and putamen. Though not quantified, the extent of elevated susceptibility and tau PET SUVR do not appear to exactly overlap on visual inspection, which may imply more than one process contributes to these signal changes on QSM and PET. Amyloid PET SUVR was low throughout for both of the participants.