Elevated brain iron is associated with higher R2 and more WMH in older adults
Poster No:
1158
Submission Type:
Abstract Submission
Authors:
Md Tahmid Yasar1, Ashley Bush2, Scott Ayton2, Puja Agarwal3, Sonal Agrawal3, David Bennett3, Julie Schneider3, Konstantinos Arfanakis1,3
Institutions:
1Illinois Institute of Technology, Chicago, IL, 2The University of Melbourne, Parkville, Victoria, 3Rush University Medical Center, Chicago, IL
First Author:
Co-Author(s):
Konstantinos Arfanakis
Illinois Institute of Technology|Rush University Medical Center
Chicago, IL|Chicago, IL
Illinois Institute of Technology|Rush University Medical Center
Chicago, IL|Chicago, IL
Introduction:
Iron is an essential micronutrient for brain health. Iron accumulates in the brain throughout lifetime and the variation in iron levels among individuals increases beyond the age of sixty [1]. Elevated iron is a source of free radicals that cause oxidative stress which has been linked to neurodegenerative and cerebrovascular pathologies as well as cognitive impairment among older adults [2]. Iron has a higher magnetic susceptibility than brain tissue and therefore magnetic resonance imaging (MRI) is sensitive to iron levels. To date, the association of iron measurements with various MRI characteristics has not been systematically investigated in older adults [3-5]. Therefore, the aim of this study was to quantify brain iron levels in a large number of community-based older adults and investigate the association of iron levels with transverse relaxation rate, R2, and white matter hyperintensities (WMH), independent of the effects of other metals and age-related neuropathologies [6-8].
Methods:
Cerebral hemispheres from 437 community-based older adults participating in the Rush Memory and Aging Project [9] (Table 1) were involved in this work. All hemispheres were imaged ex-vivo at room temperature, at approximately 30 days postmortem using 3T clinical MRI scanners[6]. R2 maps were generated from multi-echo spin-echo data and then registered to an ex-vivo brain hemisphere template using ANTS[7]. WMH were segmented based on T2-weighted images[8]. WMH volume was normalized by the total hemisphere volume and then log-transformed to account for skewness. Following ex-vivo MRI, all hemispheres underwent detailed neuropathologic assessment. The assessed pathologies included Aβ plaques, neurofibrillary tangles, limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), hippocampal sclerosis (HS), Lewy bodies, cerebral amyloid angiopathy (CAA), gross infarcts, microscopic infarcts, atherosclerosis, and arteriolosclerosis (Table 1).
Inductively coupled plasma mass spectrometry was used on all participants to measure iron levels in four brain regions: mid-frontal, anterior cingulate, inferior temporal cortices, and cerebellum [10]. The log-transformed iron concentrations in the four regions were averaged to generate a global score. Other metals that were assessed included: boron, titanium, manganese, copper, zinc, selenium, rubidium, molybdenum, and mercury (Table 1).
Linear regression models were used to test the voxel-wise association of R2 with iron levels, as well as the association of the total and lobar WMH burden with iron levels. All models were controlled for all other metals and neuropathologies listed above, demographics (age at death, sex, years of education), the presence of the APOE ε4 allele, postmortem interval to fixation and to imaging, and scanner. Statistical analysis was performed using PALM (FMRIB, Oxford, UK) with tail-accelerated 5,000 permutations. Statistical significance was set at p<0.05 after family wise error rate correction.
Inductively coupled plasma mass spectrometry was used on all participants to measure iron levels in four brain regions: mid-frontal, anterior cingulate, inferior temporal cortices, and cerebellum [10]. The log-transformed iron concentrations in the four regions were averaged to generate a global score. Other metals that were assessed included: boron, titanium, manganese, copper, zinc, selenium, rubidium, molybdenum, and mercury (Table 1).
Linear regression models were used to test the voxel-wise association of R2 with iron levels, as well as the association of the total and lobar WMH burden with iron levels. All models were controlled for all other metals and neuropathologies listed above, demographics (age at death, sex, years of education), the presence of the APOE ε4 allele, postmortem interval to fixation and to imaging, and scanner. Statistical analysis was performed using PALM (FMRIB, Oxford, UK) with tail-accelerated 5,000 permutations. Statistical significance was set at p<0.05 after family wise error rate correction.
·Table 1. Demographic, neuropathologic, and trace metal characteristics of the participants
Results:
The voxel-wise analysis revealed a spatial pattern of higher R2 values for higher iron levels, particularly in gray matter (Fig. 1a). The pattern included basal ganglia structures such as the globus pallidus and putamen, as well as cortical regions such as the precentral, postcentral and cuneus cortex (Fig. 1a). Higher lobar and total WMH burden were also associated with higher iron levels (Fig. 1b). No negative associations were observed.
·Figure 1. (a) Sagittal slices showing regions where R2 is associated with iron levels (p<0.05), (b)Total and lobar WMH levels at different iron levels.
Conclusions:
This investigation combined ex-vivo MRI, neuropathology and mass spectrometry in a large number of community-based older adults and showed that higher iron levels are associated with higher R2 in gray matter and higher WMH burden. These associations were independent of the effects of other metal, neuropathologies, demographic and genomic risk factors, suggesting the presence of additional mechanisms of iron accumulation.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 2
Lifespan Development:
Aging 1
Keywords:
Aging
MRI
Other - Iron, White Matter Hyperintensities
1|2Indicates the priority used for review
Provide references using author date format
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