No description available.

Transient epileptic amnesia (TEA) is a form of epilepsy of which the principle manifestation is recurrent, transient episodes of isolated memory loss. Although the phenomenon has been recognised for over a century, it is scantily documented in the medical literature and is often misdiagnosed by clinicians. Recent work has highlighted a number of apparently consistent clinical features among the published cases. However, to date there has been no large, systematic study of the condition. The aim of the work reported in this thesis was to investigate a substantial number of prospectively recruited patients with TEA, and thus be able to provide a detailed and authoritative description of its clinical, neuropsychological and radiological characteristics. Fifty patients with TEA were recruited from around the United Kingdom using established diagnostic criteria, together with a group of matched healthy control subjects. Participants underwent a clinical interview, comprehensive neuropsychological testing and structural magnetic resonance imaging of the brain. The study demonstrated the following features. TEA typically begins in later life. The amnesic episodes are frequent, brief and often occur upon waking. They are characterised by a mixed anterograde and retrograde amnesia, the anterograde component of which is often incomplete. Attacks are commonly associated with olfactory hallucinations. They respond well to anticonvulsant medication. Nevertheless, many patients complain of persistent difficulties with memory. Despite generally performing well on standard tests of anterograde memory, many patients show i) accelerated forgetting of new information over a three-week delay and ii) temporally extensive deficits in autobiographical memory. TEA is associated with subtle medial temporal lobe atrophy on magnetic resonance imaging. This atrophy correlates with performance on standard memory tests, but not with long-term forgetting rates or autobiographical memory deficits. It is proposed that TEA is a distinctive syndrome of epilepsy, typically misdiagnosed at presentation, caused by medial temporal seizure activity and associated with accelerated long-term forgetting and autobiographical memory loss. These unusual forms of memory impairment have been documented in other forms of epilepsy. They pose challenges to current models of memory. The syndrome of TEA is therefore both clinically and theoretically important.

The relationship between cerebrovascular disease (CVD) risk factors and cognitive impairment or dementia has been widely studied with significant variability in findings between groups. We hypothesized that chronic small vessel injury in the form of arteriolar sclerosis, measured quantitatively using MRI to measure total white matter hyperintensity (WMH) volumes, would identify specific association of CVD risk factors and patterns of cognitive decline, associated with mild cognitive impairment of the cerebrovascular type, that represent the core features of vascular cognitive impairment in our cohort. A Cross-sectional analysis of clinical and quantitative MRI data on 114 subjects with normal cognitive function (n=52) and mild cognitive impairment (MCI; n=62) was performed. Quantitative total WMH volumes were examined in relation to potentially causative CVD risk factors and resultant test scores across cognitive domains using linear regression models adjusted for age, gender, and education. Among CVD risk factors analyzed, age (p< 0.001), education (p= 0.003), hypertension (p= 0.012), and hyperlipidemia (p= 0.008) demonstrated the strongest associations with WMH volumes. Conversely, diabetes, smoking, history of heart attacks, atrial fibrillation, and history of stroke that have shown associations with CVD pathology on imaging in other studies were not statistically associated with increased WMH in this cohort. WMH volumes were associated with decrease performance on the Trial Making Test type A & B and long delayed free recall on the California Verbal Learning Test. Our findings suggest similarities and yet differences in comparison to other studies. Hypertension and hyperlipidemia appear to represent common shared risks across geographically disparate groups. Our findings, like others, suggest CVD pathology impact processing speed and executive function and provide further evidence for CVD effects on short-term memory in those at risk for cognitive decline and the future development of dementia in our cohort.

No description available.

Stroke is the third leading cause of death in the developed world and is the leading neurological cause of disability with a massive impact on personal life and society. Large artery atherosclerosis is one of the main causes of ischaemic stroke. However, in several aspects of this condition there is still a significant amount of uncertainty about its prevalence, appropriate investigation and possible treatment. Reliable data on epidemiology are therefore necessary to provide clinicians and researchers with crucial information to guide diagnostic and therapeutic management as well as further research. With this thesis I aimed to provide useful information about the prevalence of large artery disease in certain groups of patients, and to contribute to investigation- and managementstrategies using data from a large population based study, the Oxford Vascular Study (OXVASC). OXVASC is a prospective, population-based incidence study of vascular disease in Oxfordshire, UK, which started in 2002 and is ongoing. The study population comprises all 91,106 individuals registered with nine general practices and uses multiple methods of case ascertainment to identify all patients with vascular events. Firstly, I have shown that the prevalence of ≥50% vertebral or basilar artery stenosis in posterior circulation TIA or minor stroke is more than twice as high as the prevalence of ≥50% carotid stenosis in patients with carotid territory events, and is associated with a very high early risk of stroke of 22% and TIA of 46%. Furthermore, severe vertebral and/or basilar artery stenosis is associated with multiple TIAs at first presentation. Secondly, I have shown that early risk of stroke was higher after posterior circulation TIA, with a 1-year risk of 16%, than after carotid territory TIA, with a 1-year risk of 9%. In addition, I was able to show for the first time, that the ABCD2 score was predictive of early stroke not only in patients with carotid circulation TIA but also in patients with vertebrobasilar TIA. Thirdly, in a pilot feasibility study about arterial spin labelling magnetic resonance imaging in patients with large artery disease in the vertebrobasilar circulation I have shown that patients with severe large artery disease have significantly impaired occipital brain perfusion. My results suggest that this new technique might be a useful tool to identify suitable patients for interventional treatment of vertebrobasilar large artery disease. Fourthly, I was able to show that the risk of ipsilateral stroke and TIA in patients with an asymptomatic carotid stenosis is very low with contemporary best medical treatment alone, suggesting that routine carotid endarterectomy for asymptomatic carotid stenosis might not longer be feasible. Finally, I have clarified that lower rates of intervention for moderate to severe symptomatic carotid stenosis in women than in men can be explained by sex-differences in the populationbased incidence of carotid large artery disease and not due to under-investigation or reluctance amongst women to undergo investigation or treatment.

Prior evidence has shown a reduction of neglect on line bisection tasks as a function of altered hemispace presentation and left cueing. The present study was conducted to examine the effect of these factors in reducing symptoms of neglect on measures of general cognitive functioning. To examine proposed changes, revised versions of the Raven's Coloured Progressive Matrices and the Memory-for-Designs (MFD) Test were constructed by placing the target stimuli in the right hemifield. Two experimental presentations, a right hemispace condition and a right hemispace plus left cue prompt condition, were compared to the standard presentation format. The primary hypotheses predicted that RBD neglect patients would reveal enhanced performance on the criterion measures as a result of these manipulations. Significant correlations were predicted between the neglect measures and between the two scoring systems for the MFD. The sample was comprised of 54 hospitalized patients, assigned to either a RBD neglect group (N = 18), a RBD nonneglect group (N = 18) , or an orthopedic control group (N = 18) . Both RBD groups were administered the Mini Inventory of Right Brain Injury, to document the presence and severity of right brain injury. Presence of neglect was assessed via the Schenkenberg Line Bisection Task and the Bells Test for Visual Neglect. Subjects were examined under all three conditions by administering one third of the items for each condition. Neglect subjects demonstrated significantly poorer performance on both criterion measures than the two comparison groups. However, no significant improvement in performance was revealed with right hemispace presentation of stimuli or left cue prompts combined with the right hemispace version. Ancillary predictions concerning correlations for the neglect measures and MFD scoring systems were confirmed. Results are interpreted in terms of increased attentional demands and task complexity. These results suggest that, despite the frequent clinical use of these manipulations in the cognitive assessment of this population, support for the efficacy of these procedures is lacking.

Epilepsy is one of the most common neurological disorders, affecting more than 2% of children and 1% of adults in the U.S. Emerging research has demonstrated that calcium, as a major second messenger system, underlies many of these injury-induced plasticity changes associated with the development of epilepsy. Recent evidence has suggested that long term elevations in neuronal resting calcium levels play a role in initiating and maintaining epileptogenesis (the development of epilepsy). Collaborations between our lab and others have produced microarray data that suggests that a major calcium-binding protein, calbindin D-28k, mRNA levels are decreased in epileptic rats even up to one year following pilocarpine treatment. The goal of this research effort was to determine if epileptogenesis alters basal calcium levels by producing a long-term change in the expression of the major calcium binding protein in neurons, calbindin D-28k. Immunohistochemistry (MC) and western blot experiments have been conducted to test the hypothesis that epileptogenesis produces a long lasting decrease in the expression of calbindin in the hippocampus in the rat pilocarpine model of acquired epilepsy. IHC experiments indicated that changes in calbindin expression occur gradually over a 2-4 week interval after the initial injury. Significant decreases in calbindin immunoreactivity are seen in the hippocampus of epileptic animals, at one month, four months, and six months post-pilocarpine treatment. However, these changes were not seen as early as 4 days post-status epilepticus. Western blots quantitated differences between epileptic animals and naive controls. Long lasting decreases in calbindin may play an important role in the altered calcium homeostatic mechanisms observed in epileptic neurons. These findings will help to elucidate one of many changes that occurs in epilepsy.

<strong>Background</strong>. Pathological processes in Parkinson’s disease (PD) start long before the first symptoms appear and by the time the disease is clinically established the results of neurodegeneration may be irreversible. Efforts to prevent or stem disease progression need to start in early disease and good characterization and new markers of early PD are urgently needed. <strong>Objectives</strong>. This thesis aims to characterize early disease stages in three projects. Firstly, clinical features of PD within 3 years of diagnosis will be explored in an incident cohort of patients and controls, using a range of tools to cover the whole breadth of clinical presentation of PD. Secondly, functional imaging studies in PD published so far will be examined through a meta-analysis to identify the most robust functional imaging markers. Thirdly, a functional MRI resting-state study in early PD will be performed to identify reproducible differences between patients and matched control subjects. <strong>Results</strong>. The cohort analysis found that age was a strong predictor of disease severity, independent of disease duration, while gender was seen to affect disease severity depending on the body region. A meta-analysis of all published functional imaging studies across all disease stages showed abnormal activations in the Basal Ganglia but also in a wide range of motor and non-motor brain areas. Dopamine supplementation normalized activations in the Basal Ganglia and some other areas, while other circuits remained resistant to medication suggesting non-dopaminergic abnormality. In the resting-state study, the Basal Ganglia Network showed greatly reduced connectivity in early PD compared to controls, which normalized on administration of dopaminergic medication. Reduced BGN connectivity was also validated on a separate group of PD subjects achieving very good separation of patients from controls. <strong>Conclusions</strong>. The effect of gender and age on early presentation of PD has potential significance for early diagnosis and choice of outcome measures for clinical trials. Within the realm of imaging, traditional task-based fMRI studies fail to show a clear and reproducible pattern of activations making this method unfeasible for early diagnostic testing. In contrast, resting-state fMRI connectivity in the Basal Ganglia Network appears to be a promising and reliable method even in the early stages of PD. Clinical profiling and resting imaging changes offer avenues for developing future biomarkers in early PD.

Introduction: Preterm birth is increasing worldwide and is a major cause of neonatal death. Survivors are at increased risk of neurodisability, cognitive, social and psychiatric disorders in later life. Alterations to the white matter can be assessed using diffusion tensor imaging (DTI) MRI and are associated with poor neurodevelopmental outcome. The pathogenesis of white matter injury is multifactorial and several clinical risk and resilience factors have been identified. DNA methylation (DNAm) is an epigenetic process which links stressful early life experience to later life disease and is associated with normal brain development, neuronal processes and neurological disease. Several studies have shown DNAm is altered by the perinatal environment, however its role in preterm white mater injury is yet to be investigated. Aims: 1. To examine the relationship between preterm birth and white matter integrity 2. To investigate the effect of neuroprotective treatments and deleterious clinical states on white matter integrity in preterm infants 3. To assess the best DTI method of quantifying white matter integrity in a neonatal population 4. To investigate the effect of preterm birth on DNA methylation and 5. To determine the clinical and imaging factors that contribute to the variance in DNA Methylation caused by preterm birth Methods: DTI data was acquired from preterm infants (< 32 weeks' gestation or < 1500 grams at birth) at term equivalent age (TEA) and term controls (> 37 weeks' gestation at birth). Region-of-interests (ROI) and tract-averaged methods of DTI analysis were performed to obtain measurements of fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum, posterior limb of internal capsule and centrum semiovale. Clinical data was collected for all infants and the effect of prematurity, neuroprotective agents and clinical risk factors on white matter integrity were analysed. 8 major white matter tracts were segmented using probabilistic neighbourhood tractography (PNT), a tract-averaged technique which also allowed the calculation of tract shape. The two DTI techniques were compared to evaluate agreement between results. DNA was collected from preterm infants and term controls at TEA, and a genome-wide analysis of DNAm was performed. DTI parameters from probabilistic neighborhood tractography (PNT) methodology and clinical risk and resilience factors were used to inform a principal components analysis to investigate the contribution of white matter integrity and clinical variables to variance in DNAm. Results: FA and MD were significantly affected by preterm birth on ROI analysis. In addition, DTI parameters were affected by clinical factors that included antenatal magnesium sulphate, histological chorioamnionitis and bronchopulmonary dysplasia. Evaluation of DTI methodology revealed good accuracy in repeated ROI measurements but limited agreement with tract-averaged values. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants, compared with controls. 10 of these genes have a documented association with neural function or neurological disease. Differences detected in the array were validated with pyrosequencing which captured additional differentially methylated CpGs. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 principal components (PC); corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Conclusions: Preterm birth is associated with alterations in white matter integrity which is modifiable by clinical risk factors and neuroprotective agents. ROI analysis may not provide sufficient representation of white matter tracts in their entirety. Prematurity is related to alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for future work and contributed to the understanding of the pathogenesis of preterm brain injury.

Background: Previous studies that have examined functional status in relation to vascular events have focused on the short term after events and have measured functional status a limited number of times. The trajectories of functional status before and after vascular events are not well characterized, and the factors influencing these trajectories are not well known. Methods: A comprehensive, structured, narrative review was performed on the topic of trajectories of disability and cognition surrounding vascular events. Then using 2 large population-based epidemiologic cohorts, the Northern Manhattan Study (NOMAS) and the Cardiovascular Health Study (CHS), trajectories of functional status were examined. In Analysis A, in NOMAS, the effect of inflammatory biomarkers (interleukin-6 [IL6], tumor necrosis factor receptor-1 [TNFR1], C-reactive protein [CRP], and lipoprotein-associated phospholipase-A2 [LpPLA2]) on the intercept and slope of functional status was determined over a median of 13 years, measured with yearly assessments by the Barthel index. In Analysis B, in NOMAS, a similar modeling strategy was used to examine whether subclinical ischemic disease on brain MRIs, measured by subclinical brain infarct (SBI) and white matter hyperintensity volume (WMHV), was associated with functional trajectories. In Analysis C, in CHS, participants had yearly assessments of disability with a combined activities of daily living (ADL) and instrumental ADL scale. The slope of change in disability was compared before and after vascular events (stroke and myocardial infarction [MI]). Results: In Analysis A, CRP (-0.41 BI points per 1 SD increase, 95% CI -0.82 to 0.002) and LpPLA2 (-0.40, 95% CI -0.75 to -0.04) were associated with baseline BI but not change over time. TNFR1 was associated with baseline BI (-0.93, 95% CI -1.59 to -0.26) and change over time (-0.36 BI points per year, 95% CI -0.69 to -0.03). In Analysis B, functional change was -0.85 BI points per year (95%CI -1.01 to -0.69); among those with SBI there were -0.88 additional points annually (-1.44 to -0.32). In WMHV models, annual functional change was -1.04 points (-1.2 to -0.88), with -0.74 additional points annually per SD WMHV increase (-0.99 to -0.49). In Analysis C, stroke (0.88, 95% CI 0.57-1.20, p<0.0001) was associated with a greater acute increase in disability than MI (0.20, 0.06-0.35, p=0.006). The annual increase in disability before stroke (0.06 points per year, 0.002-0.12, p=0.04) more than tripled after stroke (0.15 additional points per year, 0.004-0.30, p=0.04). The annual increase in disability before MI (0.04 points per year, 0.004-0.08, p=0.03) did not change significantly after MI (0.02 additional points per year, -0.07-0.11, p=0.7). Conclusions: In these large population-based studies with repeated measures of functional status and disability over long-term follow-up, several trajectories were found. In Analysis A, TNFR1 predicted worse overall functional status as well as accelerated decline over time. In Analysis B, both SBI and WMHV were associated with accelerated decline. In Analysis C, there was a steeper decline in function after stroke but not MI. These findings help to elucidate the course and potential etiologies of long-term functional decline related to vascular events, and they suggest directions for future research in this area.