Early characterisation of neurodegeneration with high-resolution magnetic resonance elastography

This thesis contributes to recent interest within medical imaging regarding the development and clinical application of magnetic resonance elastography (MRE) to the human brain. MRE is a non-invasive phase-contrast MRI technique for measurement of brain mechanical properties in vivo, shown to reflect the composition and organisation of the complex tissue microstructure. MRE is a promising imaging biomarker for the early characterisation of neurodegeneration due to its exquisite sensitivity to variation among healthy and pathological tissue. Neurodegenerative diseases are debilitating conditions of the human nervous system for which there is currently no cure. Novel biomarkers are required to improve early detection, differential diagnosis and monitoring of disease progression, and could also ultimately improve our understanding of the pathophysiological mechanisms underlying degenerative processes. This thesis begins with a theoretical background of brain MRE and a description of the experimental considerations. A systematic review of the literature is then performed to summarise brain MRE quantitative measurements in healthy participants and to determine the success of MRE to characterise neurological disorders. This review further identified the most promising acquisition and analysis methods within the field. As such, subsequent visits to three brain MRE research centres, within the USA and Germany, enabled the acquisition of exemplar phantom and brain data to assist in discussions to refine an experimental protocol for installation at the Edinburgh Imaging Facility, QMRI (EIF-QMRI). Through collaborations with world-leading brain MRE centres, two high-resolution - yet fundamentally different - MRE pipelines were installed at the EIF-QMRI. Several optimisations were implemented to improve MRE image quality, while the clinical utility of MRE was enhanced by the novel development of a Graphical User Interface (GUI) for the optimised and automatic MRE-toanatomical coregistration and generation of MRE derived output measures. The first experimental study was performed in 6 young and 6 older healthy adults to compare the results from the two MRE pipelines to investigate test-retest agreement of the whole brain and a brain structure of interest: the hippocampal formation. The MRE protocol shown to possess superior reproducibility was subsequently applied in a second experimental study of 12 young and 12 older cognitively healthy adults. Results include finding that the MRE imaging procedure is very well tolerated across the recruited population. Novel findings include significantly softer brains in older adults both across the global cerebrum and in the majority of subcortical grey matter structures including the pallidum, putamen, caudate, and thalamus. Changes in tissue stiffness likely reflect an alteration to the strength in the composition of the tissue network. All MRE effects persist after correcting for brain structure volume suggesting changes in volume alone were not reflective of the detected MRE age differences. Interestingly, no age-related differences to tissue stiffness were found for the amygdala or hippocampus. As for brain viscosity, no group differences were detected for either the brain globally or subcortical structures, suggesting a preservation of the organisation of the tissue network in older age. The third experiment performed in this thesis finds a direct structure-function relationship in older adults between hippocampal viscosity and episodic memory as measured with verbal-paired recall. The source of this association was located to the left hippocampus, thus complementing previous literature suggesting unilateral hippocampal specialisation. Additionally, a more significant relationship was found between left hippocampal viscosity and memory after a new procedure was developed to remove voxels containing cerebrospinal fluid from the MRE analysis. Collectively, these results support the transition of brain MRE into a clinically useful neuroimaging modality that could, in particular, be used in the early characterisation of memory specific disorders such as amnestic Mild Cognitive Impairment and Alzheimer’s disease

Evaluation of cerebral cortex viscoelastic property estimation with nonlinear inversion magnetic resonance elastography

Objective. Magnetic resonance elastography (MRE) of the brain has shown promise as a sensitive neuroimaging biomarker for neurodegenerative disorders; however, the accuracy of performing MRE of the cerebral cortex warrants investigation due to the unique challenges of studying thinner and more complex geometries. Approach. A series of realistic, whole-brain simulation experiments are performed to examine the accuracy of MRE to measure the viscoelasticity (shear stiffness, μ, and damping ratio, ξ) of cortical structures predominantly effected in aging and neurodegeneration. Variations to MRE spatial resolution and the regularization of a nonlinear inversion (NLI) approach are examined. Main results. Higher-resolution MRE displacement data (1.25 mm isotropic resolution) and NLI with a low soft prior regularization weighting provided minimal measurement error compared to other studied protocols. With the optimized protocol, an average error in μ and ξ was 3% and 11%, respectively, when compared with the known ground truth. Mid-line structures, as opposed to those on the cortical surface, generally display greater error. Varying model boundary conditions and reducing the thickness of the cortex by up to 0.67 mm (which is a realistic portrayal of neurodegenerative pathology) results in no loss in reconstruction accuracy. Significance. These experiments establish quantitative guidelines for the accuracy expected of in vivo MRE of the cortex, with the proposed method providing valid MRE measures for future investigations into cortical viscoelasticity and relationships with health, cognition, and behavior

The effects of automatic spelling correction software on understanding and comprehension in compensated dyslexia: improved recall following dictation

Dyslexia is associated with difficulties in language-specific skills such as spelling, writing and reading; the difficulty in acquiring literacy skills is not a result of low intelligence or the absence of learning opportunity, but these issues will persist throughout life and could affect long-term education. Writing is a complex process involving many different functions, integrated by the working memory system; people with dyslexia have a working memory deficit, which means that concentration on writing quality may be detrimental to understanding. We confirm impaired working memory in a sample of university students with (compensated) dyslexia, and using a within-subject design with three test conditions, we show that these participants demonstrated better understanding of a piece of text if they had used automatic spelling correction software during a dictation/transcription task. We hypothesize that the use of the autocorrecting software reduced demand on working memory, by allowing word writing to be more automatic, thus enabling better processing and understanding of the content of the transcriptions and improved recall. Long-term and regular use of autocorrecting assistive software should be beneficial for people with and without dyslexia and may improve confidence, written work, academic achievement and self-esteem, which are all affected in dyslexia

Aging brain mechanics: Progress and promise of magnetic resonance elastography

Neuroimaging techniques that can sensitivity characterize healthy brain aging and detect subtle neuropathologies have enormous potential to assist in the early detection of neurodegenerative conditions such as Alzheimer's disease. Magnetic resonance elastography (MRE) has recently emerged as a reliable, high-resolution, and especially sensitive technique that can noninvasively characterize tissue biomechanical properties (i.e., viscoelasticity) in vivo in the living human brain. Brain tissue viscoelasticity provides a unique biophysical signature of neuroanatomy that are representative of the composition and organization of the complex tissue microstructure. In this article, we detail how progress in brain MRE technology has provided unique insights into healthy brain aging, neurodegeneration, and structure-function relationships. We further discuss additional promising technical innovations that will enhance the specificity and sensitivity for brain MRE to reveal considerably more about brain aging as well as its potentially valuable role as an imaging biomarker of neurodegeneration. MRE sensitivity may be particularly useful for assessing the efficacy of rehabilitation strategies, assisting in differentiating between dementia subtypes, and in understanding the causal mechanisms of disease which may lead to eventual pharmacotherapeutic development

Magnetic resonance elastography (MRE) of the human brain: technique, findings and clinical applications

Neurological disorders are one of the most important public health concerns in developed countries. Established brain imaging techniques such as magnetic resonance imaging (MRI) and x-ray computerised tomography (CT) have been essential in the identification and diagnosis of a wide range of disorders, although usually are insufficient in sensitivity for detecting subtle pathological alterations to the brain prior to the onset of clinical symptoms—at a time when prognosis for treatment is more favourable. The mechanical properties of biological tissue provide information related to the strength and integrity of the cellular microstructure. In recent years, mechanical properties of the brain have been visualised and measured non-invasively with magnetic resonance elastography (MRE), a particularly sensitive medical imaging technique that may increase the potential for early diagnosis. This review begins with an introduction to the various methods used for the acquisition and analysis of MRE data. A systematic literature search is then conducted to identify studies that have specifically utilised MRE to investigate the human brain. Through the conversion of MRE-derived measurements to shear stiffness (kPa) and, where possible, the loss tangent (rad), a summary of results for global brain tissue and grey and white matter across studies is provided for healthy participants, as potential baseline values to be used in future clinical investigations. In addition, the extent to which MRE has revealed significant alterations to the brain in patients with neurological disorders is assessed and discussed in terms of known pathophysiology. The review concludes by predicting the trends for future MRE research and applications in neuroscience

Change in prevalence of post-traumatic stress disorder in the two years following trauma:a meta-analytic study

Background: Understanding the course of post-traumatic stress disorder (PTSD) and the factors that impact this is essential to inform decisions about when and for whom screening and intervention are likely to be beneficial. Objective: To provide meta-analytic evidence of the course of recovery from PTSD in the first year following trauma, and the factors that influence that recovery. Method: We conducted a meta-analysis of observational studies of adult PTSD prevalence which included at least two assessments within the first 12 months following trauma exposure, examining prevalence statistics through to 2 years post-trauma. We examined trauma intentionality (intentional or non-intentional), PTSD assessment method (clinician or self-report), sample sex distribution, and age as moderators of PTSD prevalence over time. Results: We identified 78 eligible studies including 16,484 participants. Pooled prevalence statistics indicated that over a quarter of individuals presented with PTSD at 1 month post-trauma, with this proportion reducing by a third between 1 and 3 months. Beyond 3 months, any prevalence changes were detected over longer intervals and were small in magnitude. Intentional trauma, younger age, and female sex were associated with higher PTSD prevalence at 1 month. In addition, higher proportions of females, intentional trauma exposure, and higher baseline PTSD prevalence were each associated with larger reductions in prevalence over time. Conclusions: Recovery from PTSD following acute trauma exposure primarily occurs in the first 3 months post-trauma. Screening measures and intervention approaches offered at 3 months may better target persistent symptoms than those conducted prior to this point. HIGHLIGHTS: PTSD rates in the immediate aftermath of trauma exposure decline from 27% at 1 month to 18% at 3 months post-trauma, showing significant spontaneous recovery.Problems appear to stabilize after 3 months.Screening/intervention for PTSD at 3 months post-trauma is indicated

Sex-based contributors to and consequences of post-traumatic stress disorder

Purpose of Review Women are twice as likely to develop post-traumatic stress disorder (PTSD) compared to men after a traumatic experience. The purpose of this mini review was to explore recent research on biological contributors to this sex difference. Recent Findings We identified 51 studies published since 2019. Studies found that beyond the influence of sex on the prevalence and symptoms of PTSD, there is evidence for and against sex-based differences in genetic and epigenetic factors (n = 8), brain structure and function (n = 11), neuroendocrine and inflammatory responses (n = 5), and in the role of sleep on emotional memory processing (n = 1). Sex differences were also observed in recovery and during PTSD treatment (n = 16). Finally, there is emerging evidence of sex-differentiated risk for medical and psychiatric comorbidities in PTSD (n = 10). Summary Rapid advances are being made using integrated multidisciplinary approaches to understand why females are at a heightened risk for developing PTSD

Network analysis of canine brain morphometry links tumour risk to oestrogen deficiency and accelerated brain ageing.

Structural 'brain age' is a valuable but complex biomarker for several brain disorders. The dog is an unrivalled comparator for neurological disease modeling, however canine brain morphometric diversity creates computational and statistical challenges. Using a data-driven approach, we explored complex interactions between patient metadata, brain morphometry, and neurological disease. Twenty-four morphometric parameters measured from 286 canine brain magnetic resonance imaging scans were combined with clinical parameters to generate 9,438 data points. Network analysis was used to cluster patients according to their brain morphometry profiles. An 'aged-brain' profile, defined by a small brain width and volume combined with ventriculomegaly, was revealed in the Boxer breed. Key features of this profile were paralleled in neutered female dogs which, relative to un-neutered females, had an 11-fold greater risk of developing brain tumours. Boxer dog and geriatric dog groups were both enriched for brain tumour diagnoses, despite a lack of geriatric Boxers within the cohort. Our findings suggest that advanced brain ageing enhances brain tumour risk in dogs and may be influenced by oestrogen deficiency-a risk factor for dementia and brain tumours in humans. Morphometric features of brain ageing in dogs, like humans, might better predict neurological disease risk than patient chronological age

Acute effects of high-intensity exercise on brain mechanical properties and cognitive function

Previous studies have shown that engagement in even a single session of exercise can improve cognitive performance in the short term. However, the underlying physiological mechanisms contributing to this effect are still being studied. Recently, with improvements to advanced quantitative neuroimaging techniques, brain tissue mechanical properties can be sensitively and noninvasively measured with magnetic resonance elastography (MRE) and regional brain mechanical properties have been shown to reflect individual cognitive performance. Here we assess brain mechanical properties before and immediately after engagement in a high-intensity interval training (HIIT) regimen, as well as one-hour post-exercise. We find that immediately after exercise, subjects in the HIIT group had an average global brain stiffness decrease of 4.2% (p < 0.001), and an average brain damping ratio increase of 3.1% (p = 0.002). In contrast, control participants who did not engage in exercise showed no significant change over time in either stiffness or damping ratio. Changes in brain mechanical properties with exercise appeared to be regionally dependent, with the hippocampus decreasing in stiffness by 10.4%. We also found that one-hour after exercise, brain mechanical properties returned to initial baseline values. The magnitude of changes to brain mechanical properties also correlated with improvements in reaction time on executive control tasks (Eriksen Flanker and Stroop) with exercise. Understanding the neural changes that arise in response to exercise may inform potential mechanisms behind improvements to cognitive performance with acute exercise