Advances in noninvasive myelin imaging

Myelin is important for the normal development and healthy function of the nervous system. Recent developments in MRI acquisition and tissue modeling aim to provide a better characterization and more specific markers for myelin. This allows for specific monitoring of myelination longitudinally and noninvasively in the healthy brain as well as assessment of treatment and intervention efficacy. Here, we offer a nontechnical review of MRI techniques developed to specifically monitor myelin such as magnetization transfer (MT) and myelin water imaging (MWI). We further summarize recent studies that employ these methods to measure myelin in relation to development and aging, learning and experience, and neuropathology and psychiatric disorders

Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

BackgroundAlthough the contrast-enhancing (CE) lesion on T1-weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T2-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden.MethodsFifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy.ResultsThe Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data.ConclusionsThe similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM

Quantitative MRI correlates of hippocampal and neocortical pathology in intractable temporal lobe epilepsy

Intractable or drug-resistant epilepsy occurs in over 30% of epilepsy patients, with many of these patients undergoing surgical excision of the affected brain region to achieve seizure control. Advances in MRI have the potential to improve surgical treatment of epilepsy through improved identification and delineation of lesions. However, validation is currently needed to investigate histopathological correlates of these new imaging techniques. The purpose of this work is to investigate histopathological correlates of quantitative relaxometry and DTI from hippocampal and neocortical specimens of intractable TLE patients. To achieve this goal I developed and evaluated a pipeline for histology to in-vivo MRI image registration, which finds dense spatial correspondence between both modalities. This protocol was divided in two steps whereby sparsely sectioned histology from temporal lobe specimens was first registered to the intermediate ex-vivo MRI which is then registered to the in-vivo MRI, completing a pipeline for histology to in-vivo MRI registration. When correlating relaxometry and DTI with neuronal density and morphology in the temporal lobe neocortex, I found T1 to be a predictor of neuronal density in the neocortical GM and demonstrated that employing multi-parametric MRI (combining T1 and FA together) provided a significantly better fit than each parameter alone in predicting density of neurons. This work was the first to relate in-vivo T1 and FA values to the proportion of neurons in GM. When investigating these quantitative multimodal parameters with histological features within the hippocampal subfields, I demonstrated that MD correlates with neuronal density and size, and can act as a marker for neuron integrity within the hippocampus. More importantly, this work was the first to highlight the potential of subfield relaxometry and diffusion parameters (mainly T2 and MD) as well as volumetry in predicting the extent of cell loss per subfield pre-operatively, with a precision so far unachievable. These results suggest that high-resolution quantitative MRI sequences could impact clinical practice for pre-operative evaluation and prediction of surgical outcomes of intractable epilepsy

Characterization of Normal Development and Injury in the Premature Baboon Brain

Nearly 13% of infants born in the United States each year are preterm - that is, born before 37 weeks gestation. Although improvements in clinical care have contributed to survival rates that now exceed 85%, premature infants are at high risk for motor, sensory, cognitive and behavioral disabilities. In order to develop therapeutic interventions to prevent these adverse neurodevelopmental outcomes, we must first understand the nature of cerebral injury associated with premature birth and the mechanisms by which it leads to altered brain development. A baboon: Papio papio) model of preterm birth was used to evaluate cerebral development from 90 days of gestation: dg) to term: ∼ 185 dg). Conventional magnetic resonance imaging: MRI) and diffusion tensor imaging: DTI) was obtained on fixed brains. In addition, histopathology was obtained. Analysis of this model led to the following conclusions.: 1) MRI/DTI findings during brain maturation closely paralleled those from live premature infants, indicating that the preterm baboon is a good model of human development.: 2) Both qualitative MRI scoring and quantitative analysis of DTI parameters correlated with pathologic abnormalities in cerebral white matter. In particular, reduced oligodendrocyte number was associated with increased radial diffusivity and decreased diffusion anisotropy, while astrocytosis corresponded to increased apparent diffusion coefficient.: 3) The birth weight of control animals correlated strongly with cerebral development as measured with MRI/DTI, with lower weight corresponding to less mature brain. Since birth weight may be an indicator of the quality of the intrauterine environment, it may better predict cerebral growth and maturation than gestational age.: 4) Clinical therapies differentially affect cerebral development and provide opportunities for neuroprotection. Positive pressure and high frequency ventilation were associated with more cerebral injury: as measured using both histology and MRI/DTI) than nasal continuous positive airway pressure.: 5) High-dose erythropoietin, a novel neuroprotective agent, had no adverse effects on cerebral development and may increase the potential for cerebral repair by inducing proliferation of cells in the subventricular zone

Apparent thinning of human visual cortex during childhood is associated with myelination

Human cortex appears to thin during childhood development. However, the underlying microstructural mechanisms are unknown. Using functional magnetic resonance imaging (fMRI), quantitative MRI (qMRI), and diffusion MRI (dMRI) in children and adults, we tested what quantitative changes occur to gray and white matter in ventral temporal cortex (VTC) from childhood to adulthood, and how these changes relate to cortical thinning. T1 relaxation time from qMRI and mean diffusivity (MD) from dMRI provide independent and complementary measurements of microstructural properties of gray and white matter tissue. In face- and character-selective regions in lateral VTC, T1 and MD decreased from age 5 to adulthood in mid and deep cortex, as well as in their adjacent white matter. T1 reduction also occurred longitudinally in children’s brain regions. T1 and MD decreases 1) were consistent with tissue growth related to myelination, which we verified with adult histological myelin stains, and 2) were correlated with apparent cortical thinning. In contrast, in place-selective cortex in medial VTC, we found no development of T1 or MD after age 5, and thickness was related to cortical morphology. These findings suggest that lateral VTC likely becomes more myelinated from childhood to adulthood, affecting the contrast of MR images and, in turn, the apparent gray–white boundary. These findings are important because they suggest that VTC does not thin during childhood but instead gets more myelinated. Our data have broad ramifications for understanding both typical and atypical brain development using advanced in vivo quantitative measurements and clinical conditions implicating myelin

An examination of the temporal and spatial evolution of a small permanent focal ischemic lesion

The research reported here was designed to validate our hypothesis that noninvasive imaging could delineate the evolution of a small ischemic infarct. Furthermore, the alterations observed by MR were correlated to histological and inflammatory markers. Finally, intervention with a calcium buffering agent was hypothesized to prevent many of these changes. The first part of this study investigated the development of a small focal cortical lesion produced as a result of a cortical devascularization injury. Diffusion-weighted images (DWI) were collected before injury and at 12, 24, 48 hours and 3, 5, 7 and 14 days after injury and apparent diffusion coefficient (ADC) maps were calculated from the DW images to quantify lesion development. As a second measure of injury, tissue morphology was analyzed using cresyl violet histochemistry. Results indicated a significant reduction in ADC values within the lesion cortex that first appeared at 12 hours after injury and then recovered to control levels by 14 days. ADC changes were also observed in the contralateral cortex. This type of injury also resulted in the progressive but relatively slow formation of a pannecrotic infarct. Both astrocyte and microglia activation occurred early and were present in both hemispheres, however inflammatory cell infiltration was delayed until 48 hours after the injury. Many of these inflammatory cells were tumor necrosis factor a (TNF-a) and interferon y (IFN-y) immunoreactive. Overall, the quantitative and histological measures of this lesion were consistent with those observed in ischemic injury. Moreover, we found DWI to be a sensitive measure of damage associated with a cortical devascularization injury. The second part of this study used 2-aminophenol-N, N, O-triacetic acid acetoxymethyl ester (APTRA-AM) to determine the effectiveness of a calcium buffer in providing neuroprotection after a cortical devascularization injury. Animals were given two intravenous injections of either saline, DMSO, or APTRA-AM at 1 and 12 hours after injury. Animals were then imaged using a multiple b-value DWI sequence prior to injury and then at 12, 24,48 hours, 3 and 7 days after injury. After 7 days the animals were sacrificed and correlative histological and immunocytochemical studies were done. Our results indicate that saline injection after injury resulted in a decrease in the ADC of the lesion cortex within the first 12 hours of injury, which then slowly returned to prescan levels. In contrast, the injection of either DMSO or APTRA-AM after injury resulted in no significant changes in the ADC within the lesion area. Histologically, both saline and DMSO injected animals had pan-necrotic infarcts with concomitant glial activation and inflammatory cell infiltration. APTRA-AM treated animals showed an 86% reduction in lesion area and no evidence of inflammatory cell infiltration. The results presented here clearly demonstrate the effectiveness of APTRA-AM in preventing neuronal cell death and the accompanying inflammatory response when administered post-injury, suggesting that this molecule may be an excellent candidate for future clinical neuroprotection studies

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology

Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial

Objective To evaluate whether placental transfusion influences brain myelination at 4 months of age. Study design A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, \u3e5 minutes) or immediate clamping (ICC, \u3c20 \u3eseconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. Results In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P \u3c .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P \u3c .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. Conclusion At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development

Development and application of quantitative image analysis for preclinical MRI research

The aim of this thesis is to develop quantitative analysis methods to validate MRI and improve the detection of tumour infiltration. The major components include a description of the development the quantitative methods to better validate imaging biomarkers and detect of infiltration of tumour cells into normal tissue, which were then applied to a mouse model of glioblastoma invasion. To do this, a new histology model, called Stacked In-plane Histology (SIH), was developed to allow a quantitative analysis of MRI. Validating imaging biomarkers for glioblastoma infiltration Cancer can be defined as a disease in which a group of abnormal cells grow uncontrollably, often with fatal outcomes. According to (Cancer research UK, 2019), there are more than 363,000 new cancer cases in the UK every year, an increase from the 990 cases reported daily in 2014-2016, with only half of all patients recovering. Glioblastoma (GB) is the most frequent and malignant form of primary brain tumours with a very poor prognosis. Even with the development of modern diagnostic strategies and new therapies, the five-year survival rate is just 5%, with the median survival time only 14 months. Unfortunately, glioblastoma can affect patients at any age, including young children, but has a peak occurrence between the ages of 65 and 75 years. The standard treatment for GB consists of surgical resection, followed by radiotherapy and chemotherapy. However, the infiltration of GB cells into healthy adjacent brain tissue is a major obstacle for successful treatment, making complete removal of a tumour by surgery a difficult task, with the potential for tumour recurrence. Magnetic Resonance Imaging (MRI) is a non-invasive, multipurpose imaging tool used for the diagnosis and monitoring of cancerous tumours. It can provide morphological, physiological, and metabolic information about the tumour. Currently, MRI is the standard diagnostic tool for GB before the pathological examination of tissue from surgical resection or biopsy specimens. The standard MRI sequences used for diagnosis of GB include T2-Weighted (T2W), T1-Weighted (T1W), Fluid-Attenuated Inversion Recovery (FLAIR), and Contrast Enhance T1 gadolinium (CE-T1) scans. These conventional scans are used to localize the tumour, in addition to associated oedema and necrosis. Although these scans can identify the bulk of the tumour, it is known that they do not detect regions infiltrated by GB cells. The MRI signal depends upon many physical parameters including water content, local structure, tumbling rates, diffusion, and hypoxia (Dominietto, 2014). There has been considerable interest in identifying whether such biologically indirect image contrasts can be used as non-invasive imaging biomarkers, either for normal biological functions, pathogenic processes or pharmacological responses to therapeutic interventions (Atkinson et al., 2001). In fact, when new MRI methods are proposed as imaging biomarkers of particular diseases, it is crucial that they are validated against histopathology. In humans, such validation is limited to a biopsy, which is the gold standard of diagnosis for most types of cancer. Some types of biopsies can take an image-guided approach using MRI, Computed Tomography (CT) or Ultrasound (US). However, a biopsy may miss the most malignant region of the tumour and is difficult to repeat. Biomarker validation can be performed in preclinical disease models, where the animal can be terminated immediately after imaging for histological analysis. Here, in principle, co-registration of the biomarker images with the histopathology would allow for direct validation. However, in practice, most preclinical validation studies have been limited to using simple visual comparisons to assess the correlation between the imaging biomarker and underlying histopathology. First objective (Chapter 5): Histopathology is the gold standard for assessing non-invasive imaging biomarkers, with most validation approaches involving a qualitative visual inspection. To allow a more quantitative analysis, previous studies have attempted to co-register MRI with histology. However, these studies have focused on developing better algorithms to deal with the distortions common in histology sections. By contrast, we have taken an approach to improve the quality of the histological processing and analysis, for example, by taking into account the imaging slice orientation and thickness. Multiple histology sections were cut in the MR imaging plane to produce a Stacked In-plane Histology (SIH) map. This approach, which is applied to the next two objectives, creates a histopathology map which can be used as the gold standard to quantitatively validate imaging biomarkers. Second objective (Chapter 6): Glioblastoma is the most malignant form of primary brain tumour and recurrence following treatment is common. Non-invasive MR imaging is an important component of brain tumour diagnosis and treatment planning. Unfortunately, clinic MRI (T1W, T2W, CE-T1, and FLAIR) fails to detect regions of glioblastoma cell infiltration beyond the solid tumour region identified by contrast enhanced T1 scans. However, advanced MRI techniques such as Arterial Spin Labelling (ASL) could provide us with extra information (perfusion) which may allow better detection of infiltration. In order to assess whether local perfusion perturbation could provide a useful biomarker for glioblastoma cell infiltration, we quantitatively analysed the correlation between perfusion MRI (ASL) and stacked in-plane histology. This work used a mouse model of glioblastoma that mimics the infiltrative behaviour found in human patients. The results demonstrate the ability of perfusion imaging to probe regions of low tumour cell infiltration, while confirming the sensitivity limitations of clinic imaging modalities. Third objective (Chapter 7): It is widely hypothesised that Multiparametric MRI (mpMRI), can extract more information than is obtained from the constituent individual MR images, by reconstructing a single map that contains complementary information. Using the MRI and histology dataset from objective 2, we used a multi-regression algorithm to reconstruct a single map which was highly correlated (r>0.6) with histology. The results are promising, showing that mpMRI can better predict the whole tumour region, including the region of tumour cell infiltration