Anatomic & metabolic brain markers of the m.3243A>G mutation: A multi-parametric 7T MRI study

One of the most common mitochondrial DNA (mtDNA) mutations, the A to G transition at base pair 3243, has been linked to changes in the brain, in addition to commonly observed hearing problems, diabetes and myopathy. However, a detailed quantitative description of m.3243A>G patients' brains has not been provided so far. In this study, ultra-high field MRI at 7T and volume- and surface-based data analyses approaches were used to highlight morphology (i.e. atrophy)-, microstructure (i.e. myelin and iron concentration)- and metabolism (i.e. cerebral blood flow)-related differences between patients (N = 22) and healthy controls (N = 15). The use of quantitative MRI at 7T allowed us to detect subtle changes of biophysical processes in the brain with high accuracy and sensitivity, in addition to typically assessed lesions and atrophy. Furthermore, the effect of m.3243A>G mutation load in blood and urine epithelial cells on these MRI measures was assessed within the patient population and revealed that blood levels were most indicative of the brain's state and disease severity, based on MRI as well as on neuropsychological data. Morphometry MRI data showed a wide-spread reduction of cortical, subcortical and cerebellar gray matter volume, in addition to significantly enlarged ventricles. Moreover, surface-based analyses revealed brain area-specific changes in cortical thickness (e.g. of the auditory cortex), and in T1, T2* and cerebral blood flow as a function of mutation load, which can be linked to typically m.3243A>G-related clinical symptoms (e.g. hearing impairment). In addition, several regions linked to attentional control (e.g. middle frontal gyrus), the sensorimotor network (e.g. banks of central sulcus) and the default mode network (e.g. precuneus) were characterized by alterations in cortical thickness, T1, T2* and/or cerebral blood flow, which has not been described in previous MRI studies. Finally, several hypotheses, based either on vascular, metabolic or astroglial implications of the m.3243A>G mutation, are discussed that potentially explain the underlying pathobiology. To conclude, this is the first 7T and also the largest MRI study on this patient population that provides macroscopic brain correlates of the m.3243A>G mutation indicating potential MRI biomarkers of mitochondrial diseases and might guide future (longitudinal) studies to extensively track neuropathological and clinical changes

Decreased Default Mode Network connectivity correlates with age-associated structural and cognitive changes

Ageing entails cognitive and motor decline as well as brain changes such as loss of gray (GM) and white matter (WM) integrity, neurovascular and functional connectivity alterations. Regarding connectivity, reduced resting-state fMRI connectivity between anterior and posterior nodes of the Default Mode Network (DMN) relates to cognitive function and has been postulated to be a hallmark of ageing. However, the relationship between age-related connectivity changes and other neuroimaging-based measures in ageing is fragmentarily investigated. In a sample of 116 healthy elders we aimed to study the relationship between antero-posterior DMN connectivity and measures of WM integrity, GM integrity and cerebral blood flow (CBF), assessed with an arterial spin labeling sequence. First, we replicated previous findings demonstrating DMN connectivity decreases in ageing and an association between antero-posterior DMN connectivity and memory scores. The results showed that the functional connectivity between posterior midline structures and the medial prefrontal cortex was related to measures of WM and GM integrity but not to CBF. Gray and WM correlates of anterio-posterior DMN connectivity included, but were not limited to, DMN areas and cingulum bundle. These results resembled patterns of age-related vulnerability which was studied by comparing the correlates of antero-posterior DMN with age-effect maps. These age-effect maps were obtained after performing an independent analysis with a second sample including both young and old subjects. We argue that antero-posterior connectivity might be a sensitive measure of brain ageing over the brain. By using a comprehensive approach, the results provide valuable knowledge that may shed further light on DMN connectivity dysfunctions in ageing

Grey Matter Perfusion in Clinically Isolated Syndrome and Relapsing-Remitting Multiple Sclerosis

Die vorliegende Studie vergleicht Merkmale der mittels Kernspin-Tomografie bestimmten zerebralen Perfusion in verschiedenen Regionen der Grauen Substanz von Patienten mit klinisch isoliertem Syndrom und Patienten mit schubförmig-remittierender Multipler Sklerose. Als Marker der klinischen Schwere der Erkrankung wurden das normalisierte Hirnvolumen und der erreichte Wert auf der Expanded Disability Status Scale verwendet. In einem simplen Gruppenvergleich findet sich ein keiner der betrachteten Regionen ein Unterschied im Hinblick auf die lokale Perfusion. Die Ergebnisse einer simultanen Korrelationsanalyse suggerieren jedoch, dass es durchaus Unterschiede in der lokalen Perfusion der Grauen Substanz gibt. Die Ergebnisse dieser Studie legen daher nahe, dass einfache Gruppenvergleiche nur schlecht geeignet sind, um Variationen der regionalen Perfusion zu erfassen. Zusammengefassend legt die vorliegende Studie nahe, dass der den hämodynamischen Veränderungen bei Patienten mit klinisch isoliertem Syndrom und schubförmig-remittierender Multipler Sklerose zu Grunde liegende Mechanismus eher diffus als fokal ist und darüber hinaus einer gewissen (zeitlichen) Entwicklung unterliegt.This study compares magnetic resonance imaging-derived cerebral grey matter perfusion characteristics in patients diagnosed with clinically isolated syndrome and patients diagnosed with relapsing-remitting multiple sclerosis. Normalized brain volume and the Expanded Disability Status Scale were used as markers of disease severity. There is no difference between both subject subgroups with respect to perfusion parameters in any of the analysed grey matter regions in a simple group comparison. However, the results from the simultaneous correlation analysis indicate that there is a difference in local perfusion between the two groups of patients. This study therefore suggests that simply group comparisons are not a suitable tool to analyse regional perfusion metrics. In summary, the results of this study suggest that the underlying mechanism responsible for hemodynamic changes in clinically isolated syndrome and relapsing-remitting multiple sclerosis is diffuse rather than focal and is subject to some sort of (temporal) evolution. 2017-10-1

Mapping the Impact and Plasticity of Cortical-Cardiovascular Interactions in Vascular Disease Using Structural and Functional MRI

There is growing interest in the role of vascular disease in accelerating age-related decline in cerebrovascular structural and functional integrity. Since an increased number of older adults are surviving chronic diseases, of which cardiovascular disease (CVD) is prevalent, there is an urgent need to understand relationships between cardiovascular dysfunction and brain health. It is unclear if CVD puts the brains of older adults, already experiencing natural brain aging, at greater risk for degeneration. In this thesis, the role of CVD in accelerating brain aging is explored. Because physical activity is known to provide neuroprotective benefits to brains of older adults, the role of physical activity in mediating disease effects were also explored. Using novel neuroimaging techniques, measures of gray matter volume and cerebrovascular hemodynamics were compared between groups of coronary artery disease patients and age-matched controls, to describe regional effects of CVD on the brain. In a sub-set of patients, imaging measures were repeated after completion of a 6-month exercise training, part of a cardiac rehabilitation program, to examine exercise effects. Differences in cerebrovascular hemodynamics were measured as changes in resting cerebral blood flow (CBF) and changes in cerebrovascular reactivity (CVR) to hypercapnia (6% CO2) using a non-invasive perfusion magnetic resonance imaging technique, arterial spin labelling (ASL). We found decreased brain volume, CBF and CVR in several regions of the brains of coronary artery disease patients compared to age-matched healthy controls. The reductions in CBF and CVR were independent of underlying brain atrophy, suggesting that changes in cerebrovascular function could precede changes in brain structure. In addition, increase in brain volume and CBF were observed in some regions of the brain after exercise training, indicating that cardiac rehabilitation programs may have neurorehabiliation effects as well. Since, CBF measured with ASL is not the [gold] standard measure of functional brain activity, we examined the regional correlation of ASL-CBF to glucose consumption rates (CMRglc) measured with positron emission tomography (PET), a widely acceptable marker of brain functional activity. Simultaneous measurements of ASL-CBF and PET-CMRglc were performed in a separate study in a group of older adults with no neurological impairment. Across brain regions, ASL-CBF correlated well with PET-CMRglc, but variations in regional coupling were found and demonstrate the role of certain brain regions in maintaining higher level of functional organization compared to other regions. In general, the results of the thesis demonstrate the impact of CVD on brain health, and the neurorehabiliation capacity of cardiac rehabilitation. The work presented also highlights the ability of novel non-invasive neuroimaging techniques in detecting and monitoring subtle but robust changes in the aging human brain

Role of the advanced MRI sequences in predicting the outcome of preterm neonates

AIM The aim of the project is to evaluate the role of advanced MRI sequences (susceptibility weight imaging (SWI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion) in detecting early changes that affect preterm neonatal brain, especially in those patients without lesions at conventional MRI or with small brain injuries (i.e. low grade germinal matrix-intraventricular hemorrhage (GMHIVH)), and to correlate these subtle brain abnormalities with neurodevelopmental outcome at 24 months. METHODS Since November 2015 until June 2017, 287 preterm neonates and 108 term neonates underwent a 3T or 1.5T MRI study at term corrected age (40\ub11 weeks). SWI, DTI and ASL sequences were performed in all neonates. SWI sequences were evaluated using both a qualitative (SWI venography) and quantitative (Quantitative Susceptibility Map analysis (SWI-QSM)) approach. DTI data were analyzed using a Tract-Based Spatial Statistics analysis (TBSS). ASL studies were processed to estimate Cerebral Blood Flow (CBF) maps. Perinatal clinical data were collected for all neonates. Neurodevelopmental data were evaluated at 24 months in 175 neonates using 0-2 Griffiths Developmental Scales. RESULTS The analysis performed on SWI-venography revealed differences in subependymal veins morphology between preterm and term neonates with normal brain MRI, with a higher variability from the typical anatomical pattern in preterm neonates. The same analysis performed in preterm neonates with GMH-IVH revealed that the anatomical features of subependymal veins may play a potential role as predisposing factor for GMH-IVH. Moreover, the SWI-QSM analysis revealed a greater paramagnetic susceptibility in several periventricular white matter (WM) regions in preterm neonates with GMH-IVH than in healthy controls. This finding is likely related to the accumulation of hemosiderin/ferritin following the diffusion of large amounts of intraventricular blood products into the WM, and it is also supposed to trigger the cascade of lipid peroxidation and free radical formation that promote oxidative and inflammatory injury of the WM in neonatal brain after GMH-IVH. The TBSS analysis confirmed that microstructural WM injury can occur in preterm neonates with low grade GMH-IVH even in the absence of overt signal changes on conventional MRI, with different patterns of WM involvement depending on gestational age. Moreover, the distribution of these WM microstructural alterations after GMH-IVH correlates with specific neurodevelopmental impairments at 24 months of age. Finally, the analysis of brain perfusion at term-corrected age revealed lower CBF in preterms with sub-optimal neuromotor development, reinforcing the hypothesis that impaired autoregulation of CBF may contribute to the development of brain damage in preterm neonates. CONCLUSION Advanced MRI sequences can assist the standard perinatal brain imaging in the early diagnosis of preterm neonatal brain lesions and can provide new insights for predicting the neurodevelopmental trajectory. However, detailed and serial imaging of carefully chosen cohorts of neonates coupled with longer clinical follow-up are essential to ensure the clinical significance of these novel findings

Regional cerebral blood flow during wakeful rest in older subjects with mild to severe obstructive sleep apnea

Objectives: To evaluate changes in regional cerebral blood flow (rCBF) during wakeful rest in older subjects with mild to severe obstructive sleep apnea (OSA) and healthy controls, and to identify markers of OSA severity that predict altered rCBF. Design: High-resolution 99mTc-HMPAO SPECT images during wakeful rest. Setting: Research sleep laboratory affiliated with a University hospital. Participants: Fifty untreated OSA patients aged between 55 and 85 years divided into mild, moderate and severe OSA and 20 age-matched healthy controls. Interventions: N/A Measurements: Using statistical parametrical mapping, rCBF was compared between groups and correlated with clinical, respiratory and sleep variables. Results: Whereas no rCBF change was observed in mild and moderate groups, participants with severe OSA had reduced rCBF compared to controls in the left parietal lobules, precentral gyrus, bilateral postcentral gyri, and right precuneus. Reduced rCBF in these regions and in areas of the bilateral frontal and left temporal cortex was associated with more hypopneas, snoring, hypoxemia, and sleepiness. Higher apnea, micro-arousal, and body mass indexes were correlated to increased rCBF in the basal ganglia, insula, and limbic system. Conclusions: While older individuals with severe OSA had hypoperfusions in the sensorimotor and parietal areas, respiratory variables and subjective sleepiness were correlated with extended regions of hypoperfusion in the lateral cortex. Interestingly, OSA severity, sleep fragmentation and obesity correlated with increased perfusion in subcortical and medial cortical regions. Anomalies with such a distribution could result in cognitive deficits and reflect impaired vascular regulation, altered neuronal integrity, and/or undergoing neurodegenerative processes

Neuroimaging Biomarkers in Paediatric Sickle Cell Disease

Sickle Cell Disease (SCD) is a collection of genetic haemoglobinopathies, the most common and severe being homozygous sickle cell anaemia. In the UK, it has been estimated that 1 in 2000 children are born with SCD. The disease is characterised by chronic anaemia, recurrent pain crises and vascular occlusion. Neurologically, there is a high incidence of stroke in childhood, as well as cognitive dysfunction. Newborn screening programmes and preventative treatments have allowed a much longer lifespan; however recently, neurological research has shifted to characterising subtler aspects of brain development and functioning that may be critically important to the individual’s quality of life. This thesis overviews the neurological and neurocognitive complications of SCD, and how magnetic resonance imaging (MRI) can provide biomarkers for severity of disease. During the PhD, retrospective and prospective cognitive and MRI data were collected and analysed. Diagnostic clinical MRI sequences and advanced MRI sequences were applied, as well as a neuropsychological test battery aimed at intelligence and executive function. First, this thesis reviews the intelligence literature in SCD and includes previously unreported data, finding patients, regardless of abnormality seen on conventional MRI, have lowered full-scale intelligence quotient than controls. Then, to determine imaging biomarkers, volumetric differences and diffusion characteristics were identified. Patients were found to have decreased volumes of subcortical structures compared to controls, in groups corresponding to disease severity. Results from a three-year longitudinal clinical trial suggest evidence of atrophy in paediatric patients, with no apparent protective effect of treatment. Diffusion tensor imaging revealed reduced white matter integrity across the brain, correlating with recognised markers of disease severity (i.e. oxygen saturation and haemoglobin from a full blood count). Overall, the four experiments bridge a gap in the cognitive and neuroimaging literature of the extent of neurological injury in children with SCD

Cortical Iron Disrupts Functional Connectivity Networks Supporting Working Memory Performance in Older Adults

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control for contributions of brain volume. Task performance was positively correlated with strength of task-based functional connectivity (tFC) between brain regions of the frontoparietal working memory network. However, higher cortical iron concentration was associated with lower tFC within this frontoparietal network and with poorer working memory performance after controlling for both cerebral blood flow and brain volume. Our results suggest that high cortical iron concentration disrupts communication within frontoparietal networks supporting working memory and is associated with reduced working memory performance in older adults

Integrated Structural And Functional Biomarkers For Neurodegeneration

Alzheimer\u27s Disease consists of a complex cascade of pathological processes, leading to the death of cortical neurons and development of dementia. Because it is impossible to regenerate neurons that have already died, a thorough understanding of the earlier stages of the disease, before significant neuronal death has occurred, is critical for developing disease-modifying therapies. The various components of Alzheimer\u27s Disease pathophysiology necessitate a variety of measurement techniques. Image-based measurements known as biomarkers can be used to assess cortical thinning and cerebral blood flow, but non-imaging characteristics such as performance on cognitive tests and age are also important determinants of risk of Alzheimer\u27s Disease. Incorporating the various imaging and non-imaging sources of information into a scientifically interpretable and statistically sound model is challenging. In this thesis, I present a method to include imaging data in standard regression analyses in a data-driven and anatomically interpretable manner. I also introduce a technique for disentangling the effect of cortical structure from blood flow, enabling a clearer picture of the signal carried by cerebral blood flow beyond the confounding effects of anatomical structure. In addition to these technical developments in multi-modal image analysis, I show the results of two clinically-oriented studies focusing on the relative importance of various biomarkers for predicting presence of Alzheimer\u27s Disease pathology in the earliest stages of disease. In the first, I present evidence that white matter hyperintensities, a marker of small vessel disease, are more highly associated with Alzheimer\u27s Disease pathology than current mainstream imaging biomarkers in elderly control patients. In the second, I show that once Alzheimer\u27s Disease has progressed to the point of noticeable cognitive decline, cognitive tests are as predictive of presence of Alzheimer\u27s pathology as standard imaging biomarkers. Taken together, these studies demonstrate that the relative importance of biomarkers and imaging modalities changes over the course of disease progression, and sophisticated data-driven methods for combining a variety of modalities is likely to lead to greater biological insight into the disease process than a single modality