Iron plays a central role in brain development and brain aging. Transmission of neuronal signals, optimization and maintenance of brain structure demand substantial energy and require iron as co-factor for energy supply, myelination and neurotransmitter synthesis. However, iron turns toxic and harmful when present in certain chemical forms and at high concentrations. Increased iron accumulation in age leads to faster brain decline, diminished cognitive abilities and increased risk of neurodegenerative diseases. Understanding these mechanisms and following iron trajectories both on the cellular and the whole brain level is key to an in-depth understanding of brain development, plasticity and aging. Magnetic Resonance Imaging (MRI) is the method of choice for in vivo studies of the iron distribution in the human brain. Relaxation rates and susceptibility measurements provide a wealth of information on both the quantity and distribution of iron. It can potentially access iron dispersion down to the cellular level and provide unique information on the iron chemistry. I propose an innovative approach that combines multimodal quantitative MRI at 3T and 7T with biophysical modeling informed by quantitative iron histology. Thereby, brain tissue composition and cellular iron distribution can be linked to quantitative MRI measures. Two applications are selected to demonstrate how knowledge on MR contrast mechanisms can be employed to create sensitive and specific biomarkers of cellular iron distribution. The first example is a study in superficial white matter, where iron is accumulated in oligodendrocytes and potentially in the short association fibres. It is shown that iron in superficial white matter is not homogeneously distributed across the brain, but accumulated in iron deposits in U-fibre-rich frontal, temporal and parietal association areas. This observation is assigned to higher fibre density or late myelination. In the second study, dopaminergic neurons in substantia nigra are mapped. This information is a first step towards a specific in vivo biomarker for the density of dopaminergic neurons and may therefore provide a future diagnostic for Parkinson’s disease. [mehr]

Quantitative MRI offers the potential to characterize human brain microstructure. Mapping of several MR parameters can be efficiently done using the multi-parameter mapping (MPM) protocol, which allows for quantification of PD, R2*, R1 and MT contrasts, reflecting respectively water content, iron concentration, myelin and macromolecular content. Even small improvements in the reliability of parameter maps are relevant in the context of quantifying myelination changes (for example in disease), which are typically in the order of a couple of percent. Therefore, we investigated correction of physiological artifacts caused by breathing and head motion, which are especially prominent at 7T and in long high resolution acquisitions, and applied the corrections in an elderly cohort including Alzheimer patients. Additionally, we modified the MPM protocol to measure an inhomogenous MT (ihMT) metric that has been shown to have higher specificity to myelin than simple MT contrast, and optimized the measurement protocol at our 3T scanners. [mehr]

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The loss of dopaminergic neurons in the substantia nigra leads to the primary motor symptoms of Parkinson’s disease but starts more than ten years before diagnosis. Dopaminergic neurons contain iron in the pigment neuromelanin. Thus, iron-sensitive MRI promises to map these neurons and their loss. However, the exact mechanisms of MRI contrast in the substantia nigra are not well understood, hindering the development of robust biomarkers. We propose and validate a biophysical model of iron-induced transverse MRI relaxation in the substantia nigra, combining quantitative 3D iron histology with ultra-high-field and -resolution post mortem MRI. We quantify a missing but central parameter of this model, the susceptibility of neuromelanin-bound iron, using quantitative susceptibility mapping at cellular resolution. We demonstrate that iron in dopaminergic neurons, although being only a tiny fraction of all tissue iron, contributes predominantly to iron-induced effective transverse relaxation rate R2* and propose biomarkers of this iron pool. We leverage our understanding of iron-induced transverse relaxation to revisit the interpretation of a potent diagnostic marker of Parkinson’s, the swallow tail sign. Our results provide directions for developing biomarkers for early detection of dopaminergic neuron depletion in Parkinson’s disease. [mehr]