Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-6968, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 03/2011; 36(7):1375-84. DOI: 10.1038/npp.2011.22
Source: PubMed


Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON- status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

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    • "The mechanisms explaining how accumulation of iron in the basal ganglia contributes to alterations in processing force related information is not clear. It is suggested that when iron exceeds the metabolic requirements of cellular system it causes axonal injury, apoptosis (Zhang et al. 2009) and demyelination (Bartzokis et al. 2011) that, in turn, contribute to progression of neurodegenerative diseases (Zecca et al. 2004). "
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    ABSTRACT: Increased brain iron content has been linked to neural degeneration and to age-related decline of cognitive and motor functions. The basal ganglia (BG), which contain significant amount of iron, play an important role in establishing and modulating force requirements in hand grasp to meet specific task demands. However, it is unclear if increased BG iron content contributes to age differences in hand grasp performance. To investigate the relationship between BG iron content and hand grasp force matching in older (65.0 ± 8.9 years) healthy women, participants generated a 20 % maximum voluntary exertion reference force that was matched with the opposite hand in the Contralateral Remembered (CR) and Contralateral Concurrent (CC) conditions and with the same hand in the Ipsilateral Remembered (IR) condition. T2* relaxation times calculated from MRI scans served to estimate iron content in the caudate nucleus (Cd), globus pallidus (GP), and putamen (Pt). Greater iron content in all BG was associated with relatively greater number of errors committed when matching force with the opposite hand in the CR and CC conditions than with the same hand in the IR condition. Younger women with greater estimated iron content committed more errors than their older counterparts with lesser estimated iron content in Cd and Pt. Greater iron content in the BG may contribute to sensorimotor declines in healthy women, and relative iron content quantified by MRI may be a promising biomarker of such.
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    • "A recent study suggested that there are increased markers of iron deposition (including SF levels ) and oxidative stress in patients with cognitive dysfunction (Umur et al., 2011). Furthermore, the authors suggested that it seems likely that these markers had a negative effect on the MMSE score (Smith et al., 2010; Bartzokis et al., 2011; Umur et al., 2011; Penke et al., 2012). Ethical clearance was obtained from the Health Sciences Ethical committee from the University of Pretoria and informed consent was obtained from family members who act as guardians of the patients. "
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    ABSTRACT: Introduction: Unliganded iron both contributes to the pathology of Alzheimer's disease (AD) and also changes the morphology of erythrocytes (RBCs). We tested the hypothesis that these two facts might be linked, i.e., that the RBCs of AD individuals have a variant morphology, that might have diagnostic or prognostic value. Methods: We included a literature survey of AD and its relationships to the vascular system, followed by a laboratory study. Four different microscopy techniques were used and results statistically compared to analyze trends between high and normal serum ferritin (SF) AD individuals. Results: Light and scanning electron microscopies showed little difference between the morphologies of RBCs taken from healthy individuals and from normal SF AD individuals. By contrast, there were substantial changes in the morphology of RBCs taken from high SF AD individuals. These differences were also observed using confocal microscopy and as a significantly greater membrane stiffness (measured using force-distance curves). Conclusion: We argue that high ferritin levels may contribute to an accelerated pathology in AD. Our findings reinforce the importance of (unliganded) iron in AD, and suggest the possibility both of an early diagnosis and some means of treating or slowing down the progress of this disease.
    Full-text · Article · Dec 2013 · Frontiers in Aging Neuroscience
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    • "Although there is no proof of a causal relationship, the fact that elevated levels have been observed in preclinical disease (Smith et al., 2010) has generated the hypothesis that an accelerated trajectory of brain iron accumulation, and the associated oxidative damage, may occur during the transition from healthy ageing to dementia. Bartzokis et al. (2011) measured hippocampal iron in healthy older people (aged 55–76 y) of mixed racial origin and found that in men, but not women, there was a significant decrease in memory function with increase hippocampal ferritin iron (p = 0.003), and independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron (p = 0.005) in individuals without the H63D and TfC2 gene variants. The authors suggest a combination of genetic and MTI biomarkers may be useful for identifying high risk groups for primary prevention clinical trials. "
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