Large-scale transient peri-ictal perfusion magnetic resonance imaging abnormalities detected by quantitative image analysis.

Epileptic seizures require a rapid and safe diagnosis to minimize the time from onset to adequate treatment. Some epileptic seizures can be diagnosed clinically with the respective expertise. For more subtle seizures, imaging is mandatory to rule out treatable structural lesions and potentially life-threatening conditions. MRI perfusion abnormalities associated with epileptic seizures have been reported in CT and MRI studies. However, the interpretation of transient peri-ictal MRI abnormalities is routinely based on qualitative visual analysis and therefore reader dependent. In this retrospective study, we investigated the diagnostic yield of visual analysis of perfusion MRI during ictal and postictal states based on comparative expert ratings in 51 patients. We further propose an automated semi-quantitative method for perfusion analysis to determine perfusion abnormalities observed during ictal and postictal MRI using dynamic susceptibility contrast MRI, which we validated on a subcohort of 27 patients. The semi-quantitative method provides a parcellation of 3D T1-weighted images into 32 standardized cortical regions of interests and subcortical grey matter structures based on a recently proposed method, direct cortical thickness estimation using deep learning-based anatomy segmentation and cortex parcellation for brain anatomy segmentation. Standard perfusion maps from a Food and Drug Administration-approved image analysis tool (Olea Sphere 3.0) were co-registered and investigated for region-wise differences between ictal and postictal states. These results were compared against the visual analysis of two readers experienced in functional image analysis in epilepsy. In the ictal group, cortical hyperperfusion was present in 17/18 patients (94% sensitivity), whereas in the postictal cohort, cortical hypoperfusion was present only in 9/33 (27%) patients while 24/33 (73%) showed normal perfusion. The (semi-)quantitative dynamic susceptibility contrast MRI perfusion analysis indicated increased thalamic perfusion in the ictal cohort and hypoperfusion in the postictal cohort. Visual ratings between expert readers performed well on the patient level, but visual rating agreement was low for analysis of subregions of the brain. The asymmetry of the automated image analysis correlated significantly with the visual consensus ratings of both readers. We conclude that expert analysis of dynamic susceptibility contrast MRI effectively discriminates ictal versus postictal perfusion patterns. Automated perfusion evaluation revealed favourable interpretability and correlated well with the classification of the visual ratings. It may therefore be employed for high-throughput, large-scale perfusion analysis in extended cohorts, especially for research questions with limited expert rater capacity

Intelligent Imaging of Perfusion Using Arterial Spin Labelling

Arterial spin labelling (ASL) is a powerful magnetic resonance imaging technique, which can be used to noninvasively measure perfusion in the brain and other organs of the body. Promising research results show how ASL might be used in stroke, tumours, dementia and paediatric medicine, in addition to many other areas. However, significant obstacles remain to prevent widespread use: ASL images have an inherently low signal to noise ratio, and are susceptible to corrupting artifacts from motion and other sources. The objective of the work in this thesis is to move towards an "intelligent imaging" paradigm: one in which the image acquisition, reconstruction and processing are mutually coupled, and tailored to the individual patient. This thesis explores how ASL images may be improved at several stages of the imaging pipeline. We review the relevant ASL literature, exploring details of ASL acquisitions, parameter inference and artifact post-processing. We subsequently present original work: we use the framework of Bayesian experimental design to generate optimised ASL acquisitions, we present original methods to improve parameter inference through anatomically-driven modelling of spatial correlation, and we describe a novel deep learning approach for simultaneous denoising and artifact filtering. Using a mixture of theoretical derivation, simulation results and imaging experiments, the work in this thesis presents several new approaches for ASL, and hopefully will shape future research and future ASL usage

Role of Cerebrovascular Abnormality in Neurodegenerative Disease and Subcortical Ischemic Disease: CT Perfusion and PET Imaging

Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimer’s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and β-amyloid (Aβ, a pathological hallmark of AD) toxicity, and in patients with small subcortical ischemic lesions. Chapter 2 investigates the early hemodynamic disturbances within the first month after transient CI insult in the presence of Aβ toxicity in the comorbid rat model. CT perfusion revealed significantly lower cerebral blood flow (CBF) and blood volume (CBV) at acute phase due to the transient ischemia, and increased CBF and CBV in the ipsilateral striatum of CI+Aβ and CI groups at the first week post ischemia. These results suggest that CI is the primary driving factor of cerebrovascular abnormalities at early stage, and prolonged hyperperfusion and hypervolemia may imply reperfusion-related injury and downstream inflammation. Chapter 3 further addresses these questions with CT Perfusion-PET imaging. Chapter 3 describes the temporal profiles of blood-brain barrier (BBB) disruption and neuroinflammation over 3 months after CI with and without concurrent Aβ toxicity in the comorbid rat model. CT perfusion showed significantly higher BBB permeability surface product (BBB-PS) in the ipsilateral striatum of CI+Aβ group at day 7, month 2 and 3, as compared to CI and sham group. PET imaging revealed the highest level of neuroinflammation as reflected by the significantly increased 18F-FEPPA uptake due to microglial activation in the striatal lesion of CI+Aβ group at day 7 and 14. The temporal features of these cererbrovascular and cellular changes may serve as early imaging biomarkers for development of cognitive impairment in high-risk patients post ischemic insult. Chapter 4 investigates the temporal changes in BBB-PS and cerebral perfusion using CT perfusion over the first 3 months after small lacunar/subcortical stroke in patients. This longitudinal investigation suggests the chronic BBB leakage detected by CT perfusion may contribute to cognitive impairment and associated pathology in lacunar/subcortical stroke. Overall, the imaging results presented in this thesis have demonstrated that BBB-PS, CBF, CBV and activated microglia can be used as imaging biomarkers for delineating the early pathogenic pattern and underlying contribution of cerebral ischemia to the disease development in the animal comorbid model and subcortical stroke patients

ADVANCEMENTS IN QUANTITATIVE PERFUSION MAGNETIC RESONANCE IMAGING (MRI) OF DEMENTIA

Alzheimer's disease (AD) affects a considerable, and increasing, part of the population. Early diagnosis of AD is very important to permit effective therapy, and minimize AD's social and economic burden. The goal of our research is to evaluate the changes of cerebral perfusion (i.e., blood flow) in the early stages of AD and the effects from hypertension.We studied volunteers with Mild Cognitive Impairment (MCI) and early AD from the Pittsburgh cohort of the Cardiovascular Health Study (CHS) Cognitive Study during a four-year follow-up. Previously, studies used referral patients who typically have more advanced AD. No perfusion data concerning the early and transitional disease stages are currently available from population studies (i.e., subjects who have been monitored longitudinally in time). There are no common techniques for perfusion quantification and image analysis so that inconsistencies are observed between/within studies, modalities, and researchers. Several advancements were achieved in preparation for the cohort study. First, we improved the accuracy and speed of brain perfusion quantification. Second, we improved the accuracy of image registration to a reference brain using quantitative validation of a registration method and performance comparison with a popular registration method. Third, we improved the method of statistical analysis for evaluating the changes of perfusion between groups. Fourth, we evaluated the changes of cerebral perfusion between cognitive groups (controls, MCIs, ADs), and hypertension and normo-tensive subgroups.Individual perfusion maps were improved by measuring and incorporating individual arrival time, saturation effects, and individual inversion efficiency. A fully deformable registration technique was shown to be more accurate than standard techniques like statistical parametric mapping to detect local perfusion changes. All of the published literature for perfusion up-to-date reported decreased perfusion in AD, but we found hyperperfusion in some regions. The regional findings imply that a hemodynamic process, at the capillary level, accompanied the neurodegenerative process. Hypertensive normal cognitive controls demonstrated hypoperfusion in regions usually involved in AD pathology. However, the effect of hypertension was attenuated after the onset of the pathological cognitive process

Inefficient Involvement of Insula in Sensorineural Hearing Loss

The insular cortex plays an important role in multimodal sensory processing, audio-visual integration and emotion; however, little is known about how the insula is affected by auditory deprivation due to sensorineural hearing loss (SNHL). To address this issue, we used structural and functional magnetic resonance imaging to determine if the neural activity within the insula and its interregional functional connectivity (FC) was disrupted by SNHL and if these alterations were correlated clinical measures of emotion and cognition. Thirty-five SNHL subjects and 54 Controls enrolled in our study underwent auditory evaluation, neuropsychological assessments, functional and structure MRI, respectively. Twenty five patients and 20 Controls underwent arterial spin labeling scanning. FC of six insula subdivisions were assessed and the FC results were compared to the neuropsychological tests. Interregional connections were also compared among insula-associated networks, including salience network (SN), default mode network (DMN), and central executive network (CEN). Compared to Controls, SNHL subjects demonstrated hyperperfusion in the insula and significantly decreased FC between some insula subdivisions and other brain regions, including thalamus, putamen, precentral gyrus, postcentral gyrus, mid-cingulate cortex, dorsolateral prefrontal cortex, rolandic operculum. Anxiety, depression and cognitive impairments were correlated with FC values. Abnormal interactions among SN, DMN, and CEN were observed in SNHL group. Our result provides support for the “inefficient high-order control” theory of the insula in which the auditory deprivation caused by SNHL contributes to impaired sensory integration and central deficits in emotional and cognitive processing

A comparison of neuroimaging abnormalities in multiple sclerosis, major depression and chronic fatigue syndrome (Myalgic Encephalomyelitis): is there a common cause?

There is copious evidence of abnormalities in resting-state functional network connectivity states, grey and white matter pathology and impaired cerebral perfusion in patients afforded a diagnosis of multiple sclerosis, major depression or chronic fatigue syndrome (CFS) (myalgic encephalomyelitis). Systemic inflammation may well be a major element explaining such findings. Inter-patient and inter-illness variations in neuroimaging findings may arise at least in part from regional genetic, epigenetic and environmental variations in the functions of microglia and astrocytes. Regional differences in neuronal resistance to oxidative and inflammatory insults and in the performance of antioxidant defences in the central nervous system may also play a role. Importantly, replicated experimental findings suggest that the use of high-resolution SPECT imaging may have the capacity to differentiate patients afforded a diagnosis of CFS from those with a diagnosis of depression. Further research involving this form of neuroimaging appears warranted in an attempt to overcome the problem of aetiologically heterogeneous cohorts which probably explain conflicting findings produced by investigative teams active in this field. However, the ionising radiation and relative lack of sensitivity involved probably preclude its use as a routine diagnostic tool

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

Cerebral Circulation

Diagnostics and diseases related to the cerebrovascular system are constantly evolving and updating. 3D augmented reality or quantification of cerebral perfusion are becoming important diagnostic tools in daily practice and the role of the cerebral venous system is being constantly revised considering new theories such as that of “the glymphatic system.” This book provides updates on models, diagnosis, and treatment of diseases of the cerebrovascular system

Relationship between lifestyle factors and neurodegeneration in midlife as expressed on arterial spin labelling and structural magnetic resonance imaging

Introduction: Studies have demonstrated a relationship between neurodegeneration and lifestyle factors. Neurodegeneration in midlife (40 – 59 years old) can be assessed using neuroimaging. The aim of the thesis was to evaluate the relationship between lifestyle factors and neurodegeneration in midlife as expressed on arterial spin labelling and structural magnetic resonance imaging. Methods: A systematic review of the relationship between lifestyle and neurodegeneration in midlife as expressed on functional magnetic resonance imaging (fMRI) was undertaken. Additionally, the impact of lifestyle on the arterial spin labelling (ASL) and structural magnetic resonance imaging (sMRI) expression of neurodegeneration in a midlife cohort was analytically assessed. Results: Seven lifestyle factors associated with neurodegeneration in midlife as expressed on fMRI were identified by the systematic review. Using data from the PREVENT Dementia cohort, linear regression analysis demonstrated multiple associations between lifestyle and neurodegeneration in midlife as expressed on ASL and sMRI. Discussion: The findings from this thesis can guide future analysis of PREVENT Dementia cohort data. Furthermore, the findings from this thesis could be shared with the public through the NHS Health Check in England and the Keep Well Programme in Scotland, to help promote lifestyle interventions to optimise brain health in midlife