Magnetic resonance imaging of brain iron

Parkinson's disease (PD) is a common neurodegenerative disease, and apart from a few rare genetic causes, its pathogenesis remains largely unclear. Recent scientific interest has been captured by the involvement of iron biochemistry and the disruption of iron homeostasis, particularly within the brain regions specifically affected in PD. The advent of Quantitative Susceptibility Mapping (QSM) has enabled non-invasive quantification of brain iron in vivo by MRI, which has contributed to the understanding of iron-associated pathogenesis and has the potential for the development of iron-based biomarkers in PD. This review elucidates the biochemical underpinnings of brain iron accumulation, details advancements in iron-sensitive MRI technologies, and discusses the role of QSM as a biomarker of iron deposition in PD. Despite considerable progress, several challenges impede its clinical application after a decade of QSM studies. The initiation of multi-site research is warranted for developing robust, interpretable, and disease-specific biomarkers for monitoring PD disease progression.

Inhibitory control can be less reliable in adolescence, however, in the presence of rewards, adolescents’ performance often improves to adult levels. Dopamine is known to play a role in signaling rewards and supporting cognition, but its role in the enhancing effects of reward on adolescent cognition and inhibitory control remains unknown. Here, we assessed the contribution of basal ganglia dopamine-related neurophysiology using longitudinal MR-based assessments of tissue iron in rewarded inhibitory control, using an antisaccade task. In line with prior work, we show that neutral performance improves with age, and incentives enhance performance in adolescents to that of adults. We find that basal ganglia tissue iron is associated with individual differences in the magnitude of this reward boost, which is strongest in those with high levels of tissue iron, predominantly in adolescence. Our results provide novel evidence that basal ganglia neurophysiology supports developmental effects of rewards on cognition, which can inform neurodevelopmental models of the role of dopamine in reward processing during adolescence.

Heme plays a role in major cellular processes such as signal transduction, protein synthesis, and complex assembly and regulation of transcription and translation. As such, it is essential for brain metabolism, oxygen sensing, and neuronal survival. Its synthesis is composed of eight distinct steps; the first and last three steps take place in the mitochondria. Accumulating evidence point at mitochondrial dysfunction and altered heme metabolism in neuropsychiatric disorders. Here, we will review the growing number of experimental data demonstrating deficits in heme, mitochondria, and specifically the first complex (Co-I) of the electron transport chain in three neuropsychiatric disorders—Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SZ). Furthermore, we will provide evidence for an association between mitochondrial Co-I dysfunction and heme metabolism and suggest their potential to become additional therapeutic targets that will improve the efficiency of the current treatments.

Heme plays a role in major cellular processes such as signal transduction, protein synthesis, and complex assembly and regulation of transcription and translation. As such, it is essential for brain metabolism, oxygen sensing, and neuronal survival. Its synthesis is composed of eight distinct steps; the first and last three steps take place in the mitochondria. Accumulating evidence point at mitochondrial dysfunction and altered heme metabolism in neuropsychiatric disorders. Here, we will review the growing number of experimental data demonstrating deficits in heme, mitochondria, and specifically the first complex (Co-I) of the electron transport chain in three neuropsychiatric disorders—Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SZ). Furthermore, we will provide evidence for an association between mitochondrial Co-I dysfunction and heme metabolism and suggest their potential to become additional therapeutic targets that will improve the efficiency of the current treatments.

Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI). Multimodal strategies combining MRI with complementary analytical techniques ex vivo have emerged, which may lead to improved specificity. Interdisciplinary collaborations will be key to advance beyond simple correlative analyses in the biological interpretation of MRI data and to gain deeper insights into key factors leading to iron accumulation and/or redistribution associated with neurodegeneration.

Magnetic resonance (MR) images of the brain are of immense clinical and research utility. At the atomic and subatomic levels, the sources of MR signals are well understood. However, we lack a comprehensive understanding of the macromolecular correlates of MR signal contrast. To address this gap, we used genome-wide measurements to correlate gene expression with MR signal intensity across the cerebral cortex in the Allen Human Brain Atlas (AHBA). We focused on the ratio of T1-weighted and T2-weighted intensities (T1-w/T2-w ratio image), which is considered to be a useful proxy for myelin content. As expected, we found enrichment of positive correlations between myelin-associated genes and the ratio image, supporting its use as a myelin marker. Genome-wide, there was an association with protein mass, with genes coding for heavier proteins expressed in regions with high T1-w/T2-w values. Oligodendrocyte gene markers were strongly correlated with the T1-w/T2-w ratio, but this was not driven by myelin-associated genes. Mitochondrial genes exhibit the strongest relationship, showing higher expression in regions with low T1-w/T2-w ratio. This may be due to the pH gradient in mitochondria as genes up-regulated by pH in the brain were also highly correlated with the ratio. While we corroborate associations with myelin and synaptic plasticity, differences in the T1-w/T2-w ratio across the cortex are more strongly linked to molecule size, oligodendrocyte markers, mitochondria, and pH. We evaluate correlations between AHBA transcriptomic measurements and a group averaged T1-w/T2-w ratio image, showing agreement with in-sample results. Expanding our analysis to the whole brain results in strong positive T1-w/T2-w correlations for immune system, inflammatory disease, and microglia marker genes. Genes with negative correlations were enriched for neuron markers and synaptic plasticity genes. Lastly, our findings are similar when performed on T1-w or inverted T2-w intensities alone. These results provide a molecular characterization of MR contrast that will aid interpretation of future MR studies of the brain.