Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

Background Mitochondrial membrane protein‐associated neurodegeneration is an autosomal‐recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia. Objectives The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1H MR spectroscopy in clinically manifesting membrane protein‐associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers. Methods We present data of 4 clinically affected membrane protein‐associated neurodegeneration patients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age‐matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole‐body system, consisting of whole‐brain gradient‐echo scans and short echo time, single‐volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state‐of‐the‐art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN. Results and Conclusion In membrane protein‐associated neurodegeneration patients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non‐manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein‐associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein‐associated neurodegeneration patients

Hemorrhagic stroke—Pathomechanisms of injury and therapeutic options

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151916/1/cns13225_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151916/2/cns13225.pd

Development of non-invasive analytical techniques for the detection of iron in the human brain

In a range of neurodegenerative diseases including Alzheimer’s Disease and Parkinson’s Disease, iron is found in increased concentrations in various regions of the human brain. Quantitative analysis of iron in the brain is a difficult task – while post-mortem study using highly sensitive analytical techniques such as Inductively Coupled Plasma Mass Spectrometry (ICP-MS) is somewhat straightforward, accurately quantifying brain iron in living patients, necessitating the use of clinical imaging, presents a range of unique challenges. In this thesis, one of the current standard techniques of non-invasive brain iron quantification, Transverse Relaxometry (T2 Relaxometry) using a clinical 3T MRI scanner, is compared with a challenger technique, Dual Energy Computed Tomography. DECT is cheaper and faster than Magnetic Resonance Imaging (MRI) (a standard T2 Relaxometry experiment can take 30-40 minutes, while a DECT scan takes under 20 seconds), and can be used on patients that have some ferromagnetic or electronic implants while MRI cannot. In addition, T2 relaxometry is used to attempt to provide a case for iron concentration quantification as a novel method of diagnosing Chemo Brain, a term that describes a set of symptoms experienced by some patients that have undergone chemotherapy. 9.4T Magnetic Resonance Microscopy was used to investigate the relationship between iron concentrations in aqueous phantoms and the relaxation parameters, to support translational work with 3T clinical MRI. The results of studies into the use of DECT for brain iron quantification show, for the first time, that the technique can be used for sensitive analysis of neurologically relevant iron concentrations in aqueous phantoms, but that there is still work needed to establish whether this is also true in the human brain. The results of the novel human cadaver study described in Chapter 5 indicate that there is no correlation with DECT-acquired CT Number data and iron concentration in cadaveric human brain tissue, but that the discussed limitations of the available cadaver samples (including post-mortem tissue decay and putrefactive gas accumulation) may confound the results from DECT imaging studies

Single cell molecular alterations reveal target cells and pathways of concussive brain injury.

The complex neuropathology of traumatic brain injury (TBI) is difficult to dissect, given the convoluted cytoarchitecture of affected brain regions such as the hippocampus. Hippocampal dysfunction during TBI results in cognitive decline that may escalate to other neurological disorders, the molecular basis of which is hidden in the genomic programs of individual cells. Using the unbiased single cell sequencing method Drop-seq, we report that concussive TBI affects previously undefined cell populations, in addition to classical hippocampal cell types. TBI also impacts cell type-specific genes and pathways and alters gene co-expression across cell types, suggesting hidden pathogenic mechanisms and therapeutic target pathways. Modulating the thyroid hormone pathway as informed by the T4 transporter transthyretin Ttr mitigates TBI-associated genomic and behavioral abnormalities. Thus, single cell genomics provides unique information about how TBI impacts diverse hippocampal cell types, adding new insights into the pathogenic pathways amenable to therapeutics in TBI and related disorders

A new discrete dipole kernel for quantitative susceptibility mapping

PURPOSE: Most approaches for quantitative susceptibility mapping (QSM) are based on a forward model approximation that employs a continuous Fourier transform operator to solve a differential equation system. Such formulation, however, is prone to high-frequency aliasing. The aim of this study was to reduce such errors using an alternative dipole kernel formulation based on the discrete Fourier transform and discrete operators. METHODS: The impact of such an approach on forward model calculation and susceptibility inversion was evaluated in contrast to the continuous formulation both with synthetic phantoms and in vivo MRI data. RESULTS: The discrete kernel demonstrated systematically better fits to analytic field solutions, and showed less over-oscillations and aliasing artifacts while preserving low- and medium-frequency responses relative to those obtained with the continuous kernel. In the context of QSM estimation, the use of the proposed discrete kernel resulted in error reduction and increased sharpness. CONCLUSION: This proof-of-concept study demonstrated that discretizing the dipole kernel is advantageous for QSM. The impact on small or narrow structures such as the venous vasculature might by particularly relevant to high-resolution QSM applications with ultra-high field MRI - a topic for future investigations. The proposed dipole kernel has a straightforward implementation to existing QSM routines

MRI estimates of brain iron concentration in normal aging: Comparison of field-dependent (FDRI) and phase (SWI) methods

Different brain structures accumulate iron at different rates throughout the adult life span. Typically, striatal and brain stem structures are higher in iron concentrations in older than younger adults, whereas cortical white matter and thalamus have lower concentrations in the elderly than young adults. Brain iron can be measured in vivo with MRI by estimating the relaxivity increase across magnetic field strengths, which yields the Field-Dependent Relaxation Rate Increase (FDRI) metric. The influence of local iron deposition on susceptibility, manifests as MR phase effects, forms the basis for another approach for iron measurement, Susceptibility-Weighted Imaging (SWI), for which imaging at only one field strength is sufficient. Here, we compared the ability of these two methods to detect and quantify brain iron in 11 young (5 men, 6 women; 21 to 29 years) and 12 elderly (6 men, 6 women; 64 to 86 years) healthy adults. FDRI was acquired at 1.5 T and 3.0 T, and SWI was acquired at 1.5 T. The results showed that both methods detected high globus pallidus iron concentration regardless of age and significantly greater iron in putamen with advancing age. The SWI measures were more sensitive when the phase signal intensities themselves were used to define regions of interest, whereas FDRI measures were robust to the method of region of interest selection. Further, FDRI measures were more highly correlated than SWI iron estimates with published postmortem values and were more sensitive than SWI to iron concentration differences across basal ganglia structures. Whereas FDRI requires more imaging time than SWI, two field strengths, and across-study image registration for iron concentration calculation, FDRI appears more specific to age-dependent accumulation of non-heme brain iron than SWI, which is affected by heme iron and non-iron source effects on phase.National Institutes of Health (U.S.) (Grant AG017919)National Institutes of Health (U.S.) (Grant AA005965)National Institutes of Health (U.S.) (Grant AA017168