Age-related changes in global motion coherence: conflicting haemodynamic and perceptual responses

Our aim was to use both behavioural and neuroimaging data to identify indicators of perceptual decline in motion processing. We employed a global motion coherence task and functional Near Infrared Spectroscopy (fNIRS). Healthy adults (n = 72, 18-85) were recruited into the following groups: young (n = 28, mean age = 28), middle-aged (n = 22, mean age = 50), and older adults (n = 23, mean age = 70). Participants were assessed on their motion coherence thresholds at 3 different speeds using a psychophysical design. As expected, we report age group differences in motion processing as demonstrated by higher motion coherence thresholds in older adults. Crucially, we add correlational data showing that global motion perception declines linearly as a function of age. The associated fNIRS recordings provide a clear physiological correlate of global motion perception. The crux of this study lies in the robust linear correlation between age and haemodynamic response for both measures of oxygenation. We hypothesise that there is an increase in neural recruitment, necessitating an increase in metabolic need and blood flow, which presents as a higher oxygenated haemoglobin response. We report age-related changes in motion perception with poorer behavioural performance (high motion coherence thresholds) associated with an increased haemodynamic response

In vivo MRI mapping of brain iron deposition across the adult lifespan

Disruption of iron homeostasis as a consequence of aging is thought to cause iron levels to increase, potentially promoting oxidative cellular damage. Therefore, understanding how this process evolves through the lifespan could offer insights into both the aging process and the development of aging-related neurodegenerative brain diseases. This work aimed to map, in vivo for the first time with an unbiased whole-brain approach, age-related iron changes using quantitative susceptibility mapping (QSM)—a new postprocessed MRI contrast mechanism. To this end, a full QSM standardization routine was devised and a cohort of N = 116 healthy adults (20–79 years of age) was studied. The whole-brain and ROI analyses confirmed that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their exact anatomical location. Whereas only patchy signs of iron scavenging were observed in white matter, strong, bilateral, and confluent QSM–age associations were identified in several deep-brain nuclei—chiefly the striatum and midbrain—and across motor, premotor, posterior insular, superior prefrontal, and cerebellar cortices. The validity of QSM as a suitable in vivo imaging technique with which to monitor iron dysregulation in the human brain was demonstrated by confirming age-related increases in several subcortical nuclei that are known to accumulate iron with age. The study indicated that, in addition to these structures, there is a predilection for iron accumulation in the frontal lobes, which when combined with the subcortical findings, suggests that iron accumulation with age predominantly affects brain regions concerned with motor/output functions

Iron and Alzheimer’s Disease: From Pathogenesis to Therapeutic Implications

As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, and ultimately leads to cell death. There is an imbalance in iron homeostasis in Alzheimer’s disease (AD). Excessive iron contributes to the deposition of β-amyloid and the formation of neurofibrillary tangles, which in turn, promotes the development of AD. Therefore, iron-targeted therapeutic strategies have become a new direction. Iron chelators, such as desferoxamine, deferiprone, deferasirox, and clioquinol, have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Given the limitations and side effects of the long-term application of traditional iron chelators, alpha-lipoic acid and lactoferrin, as self-synthesized naturally small molecules, have shown very intriguing biological activities in blocking Aβ-aggregation, tauopathy and neuronal damage. Despite a lack of evidence for any clinical benefits, the conjecture that therapeutic chelation, with a special focus on iron ions, is a valuable approach for treating AD remains widespread

Determinants of age-related brain iron accumulation and links to neurocognitive functions

Iron is crucial for development and normal functioning of the brain. With increasing age, it accumulates in the cells and can cause irreparable damage, affecting both the structure and function of the brain. Despite these findings, the factors which influence iron accumulates and the longitudinal effects of iron are still poorly understood. This doctoral thesis aimed to explore what influences brain iron accumulation in normal aging, and how this accumulation impacts molecular, and functional properties of the brain, and working-memory. Study I investigated if iron accumulation in striatum and DLPFC affected working memory change in normal aging, and if this accumulation and relationship to performance varied based on availability of dopamine, specified by COMT genotype status. We found that iron accumulated in both striatum and DLPFC. Greater iron accumulation in DLPFC was related to more deleterious change in working-memory performance. In addition, iron accumulation was amplified in older adults with presumably lowest levels of dopamine. These individuals were also driving the link between changes in iron and working-memory performance. Study II investigated if iron was linked to dopamine receptor availability and whether this association affected working memory. The study revealed that more iron was related to lower receptor availability in DLPFC and that this, coupled together with older age, contributed to reduced brain activity during a working-memory task. Additionally, the reduction in brain activity was in turn related to poorer task performance. Study III assessed (1) if brain iron content and accumulation were related to longitudinal changes in in brain activity during working-memory performance in normal aging, (2) potential association with glutamate, and (3) whether glutamate mitigated iron-brain activity relationship. In this study, we found that younger adults with initial elevated iron down-regulated more brain activity over a 3-year period, while performing the task. The results also showed a potential age-dependent relationship between iron and glutamate, such that younger adults with elevated iron content had more glutamate in DLPFC. Study IV explored biological and lifestyle factors that might influence iron accumulation in normal aging. Here, blood iron markers, physical activity, diet, and cardiovascular health significantly influenced brain iron content and accumulation. Furthermore, the associations between these factors and brain iron were influenced by age, highlighting the complexity of these relationships. Collectively, our studies show that age-related brain iron accumulation can be influenced by a number of factors, both modifiable and non-modifiable, such as lifestyle choices and genetic predisposition respectively. The potential to attenuate the accumulation of brain iron is essential, as we have also shown that iron can have deleterious effects on brain function and cognition older age. Finally, the links between iron and the dopaminergic system could partially explain age-related alterations, such as diminished receptor availability. Understanding the role of neurotransmitters on attenuating iron accumulation can pave the way for tailoring interventions in neurodegenerative disorders

Investigating the Roles of Vacuoles in Iron Trafficking in Saccharomyces cerevisiae

Transition metals play essential roles in biological systems, but Fe can also be toxic to cells. In order to maintain this balance between necessity and toxicity mechanisms are employed for regulating and storing intracellular Fe. In Saccharomyces cerevisiae, vacuoles are responsible for sequestering, storing, and supplying Fe to the cytosol. Many of the proteins and regulatory pathways involved in Fe trafficking and storage in S. cerevisiae have been identified, but the forms of Fe which are involved in these processes have not been fully characterized. In these studies, biophysical and bioanalytical techniques were used to study intracellular Fe distributions in S. cerevisiae cells and organelles. Ultimately, Fe-containing species were biophysically characterized and absolute Fe concentrations in cells and organelles were quantified. The motivation for these studies stemmed from previous studies which revealed that the majority of the whole-cell Fe is a non-heme, high-spin (NHHS) form of Fe^(3+). This Fe is not localized to the mitochondria. The purpose of these studies was to determine if the vacuoles contained this NHHS Fe^(3+). A large-scale isolation procedure was developed to obtain purified vacuoles from S. cerevisiae and to investigate the Fe in these organelles. Mössbauer and EPR analysis revealed that the primary form of Fe in vacuoles is a mononuclear, NHHS Fe^(3+) species. A second form of Fe was also observed as superparamagnetic ferric phosphate nanoparticles (NP). By investigating model compounds of Fe and polyphosphate we determined that a shift in vacuolar pH induces the conversion between NHHS Fe^(3+) and NP. These results showed that there are at least two forms of Fe in vacuoles, and that the ratio of these two forms is dependent upon the pH of these organelles. Biophysical analyses of whole cells also revealed the presence of low concentrations of a non-heme, high-spin Fe^(2+) species. The goal of these next projects was to determine if this NHHS Fe^(2+) species was localized to the cytosol. Genetic strains lacking or over-expressing the vacuolar Fe import protein Ccc1p were studied by Mössbauer spectroscopy (∆CCC1 and CCC1-up, respectively). ∆CCC1 cells showed low vacuolar Fe (NHHS Fe3+ and NP), and increased NHHS Fe^(2+). We hypothesize that this NHHS Fe^(2+) is cytosolic Fe. We also propose that this NHHS Fe^(2+) is involved in the regulating intracellular Fe levels. CCC1-up cells accumulated more Fe than wild-type (WT) cells, and showed elevated levels of vacuolar Fe (NHHS Fe^(3+) and NP). These cells also accumulated high levels of NHHS Fe^(2+). The CCC1-up cells exhibited an adenine deficient phenotype, where the cells developed a red color during growth. With excess adenine the levels of NHHS Fe^(2+) declined, which indicated that this Fe accumulation was related to adenine deficiency. We conclude that adenine deficiency leads to the accumulation of a sequestered (possibly vacuolar) form of NHHS Fe^(2+). Overall, we have identified two separate pools of NHHS Fe^(2+) in ∆CCC1 and CCC1-up cells. In ∆CCC1 cells the NHHS Fe^(2+) pool is localized to the cytosol and is sensed by the cell. In CCC1-up cells the NHHS Fe^(2+) is sequestered from the Fe regulatory mechanism- possibly in the vacuoles. These data have helped us better understand the roles of vacuoles in Fe trafficking and the dynamics of vacuolar Fe trafficking

Biophysical Probes of Iron Metabolism in Yeast Cells, Mitochondria, and Mouse Brains

Iron is essential in nearly all organisms. It is a cofactor in many proteins and enzymes. This transition metal can also be toxic because it participates in reactions which produce reactive oxygen species. To avoid these toxic effects while still being used for essential processes, the cell must regulate tightly iron import, metabolism, trafficking, and homeostasis. These processes were studied using biophysical methods centered on Mossbauer spectroscopy supplemented by electron paramagnetic resonance, electronic absorption spectroscopy, and inductively coupled plasma mass spectrometry. This integrated biophysical approach was applied to yeast cells, isolated yeast mitochondria, and mouse brains. We determined the concentration of Fe, and the proportion of that Fe present as iron-sulfur clusters, heme centers, mononuclear nonheme centers, and as Fe3+ oxyhydroxide (phosphate) nanoparticles for each system. In yeast, the dependence of metabolic mode of growth and iron in the growth medium on this distribution was studied. Approximately three-quarters of the iron in fermenting cells was located in vacuoles, where it was present as high-spin mononuclear Fe3+ species with rhombic symmetry. The remaining quarter was present in the mitochondria. In fermenting mitochondria 4 distinct species of iron were observed, including [Fe4S4]2+ clusters and low-spin Fe2+ hemes arising from respiratory complexes, non-heme high spin (NHHS) Fe2+ species, high spin nonheme Fe3+ species, and nanoparticles. These distributions (in both the cells and mitochondria) change when the cells are grown on iron deficient medium but remained relatively unaltered as iron in the growth medium was increased. Respiring cells had less Fe associated with vacuoles, and more Fe present as HS Fe2+. Respiring mitochondria contain more [Fe4S4]2+ clusters and low-spin Fe2+ hemes, more S = 1/2 [Fe2S2]1+ clusters, and less NHHS Fe2+, HS Fe3+ species and Fe3+ nanoparticles. These changes were rationalized by assuming that the NHHS Fe2+ and Fe3+ species, and the nanoparticles were in equilibrium within the matrix of the mitochondria, and that the Fe2+ species served as feedstock for the synthesis of iron-sulfur clusters and heme centers. The iron in the mouse brain consisted mostly of [Fe4S4]2+ clusters and Fe2+ hemes from mitochondria respiratory complexes, and of ferritin, an Fe storage protein complex. NHHS Fe2+ and Fe3+ species were also observed. The ratio of stored Fe to mitochondrial Fe was sensitive to age. The brains of prenatal animals were dominated by ferritin. Following birth up to the first 4 weeks of life, there was an increase in mitochondrial Fe and a decline of ferritin Fe. Beyond 4 weeks up to 58 weeks, levels of ferritin increased and mitochondrial Fe remained constant. The brains of mice fed an Fe-deficient diet were also studied; most of the Fe in these brains was present as mitochondrial Fe, with little stored as ferritin. A model was developed to explain these changes