Background: People with Huntington’s disease (HD) can be affected by motor, cognitive and behavioural symptoms. The length of the illness trajectory can result in patients receiving care at home for extended periods during which the contribution from family caregivers is invaluable. There has been little research into patient or carer perspectives on needs or how these should be met, and how these correspond to professional viewpoints. Objectives: To gain an understanding of living with, caring for and working in the field of HD. Study design: A collective case study approach was used to gather data from the person with HD, their family carer and a nominated healthcare professional to build 15 cases involving 33 individuals and 115 interactions (68 interviews and 47 observations) over three years of study participation. Findings: Living with HD requires continued readjustment to maintain balance between increasing disability, diminishing cognition and living well at home. Patients and carers were challenged to cope with: the diagnosis; an impulse to secrecy and a duty to share knowledge; autonomy and decision making; the transformation of homes to hospitals; and a shift in the burden of care when the patient moved to a residential care home. Examination of services showed how multidisciplinary working, a keyworker approach, disease, person and service specific knowledge alongside continuity of staffing contribute to quality care. Conclusion: This is the first qualitative study of living with HD incorporating multiple perspectives over time. It explored the complexity of living with HD and the ways in which care can be provided in the community. The study identified a number of daily challenges for both family and professional carers when changes in capacity occur slowly over time. Holistic, multidisciplinary and flexible care is shown to be essential for those trying to balance the delicate equilibrium of living with HD. nb. The journal articles and book extracts in appendix A have not been included in the electronic version for copyright reasons.

CGP 12177 is a high affinity β-blocker that antagonises agonist responses mediated through the catecholamine binding site of the human β1-adrenoceptor (β1AR). However, CGP 12177 also exerts agonist activity through a secondary, low affinity “CGP 12177” binding site/conformational state of the β1AR. In this thesis, we aimed to further our understanding of the nature of the secondary “CGP 12177” site by investigating ligand-receptor interactions at this site at the single cell level, using fluorescent derivatives of CGP 12177 (BODIPY-TMR-CGP, BY-CGP) and propranolol (BODIPY630/650-S-PEG8-propranolol, BY-PROP) in confocal microscopy studies. Initial studies demonstrated that both fluorescent β-adrenoceptor ligands displayed similar pharmacology at the human β1AR to their respective parent compounds, and that both ligands allowed visualisation of β1AR expressed in CHO cells. Using BY-CGP in a live cell fluorescence-based automated screening assay revealed two-phase antagonist displacement binding curves. In subsequent kinetic binding studies performed on a confocal perfusion system, we used infinite dilution conditions to determine dissociation rates of BY-CGP in the absence and presence of unlabelled ligands at the single cell level. BY-CGP dissociation rates were enhanced in the presence of unlabelled ligands, thus highlighting an allosteric mechanism of action of CGP 12177 at the human β1AR. Preliminary data using bimolecular fluorescence complementation suggested that these co-operative interactions between the two β1-adrenoceptor binding sites were mediated across a β1-adrenoceptor homodimer interface.

Most large acute stroke trials have shown no treatment effect. Functional outcome is routinely used as the primary outcome in stroke trials. This is usually analysed using a binary analysis, e.g. death or dependency versus independence. This project assessed which statistical approaches are most efficient in analysing functional outcome data from stroke trials. Fifty five data sets from 47 (54,173 patients) completed randomised trials were assessed. Re-analysing this data with a variety of statistical approaches showed that methods which retained the ordinal nature of functional outcome data were statistically more efficient than those which collapsed the data into two or more groups. Ordinal logistic regression, t-test, robust rank test, bootstrapping the difference in mean rank, or the Wilcoxon test are recommended. When assessing sample size, using ordinal logistic regression to analyse data instead of a binary outcome can reduce the sample size needed for a given power by 28%. Ordinal methods may not be appropriate for trials of treatments which not only increase the proportion of patients having a good outcome but also have an increase in hazard, such as thrombolytics. Adjusting the analysis performed for prognostic factors can have an additional effect on sample size. Re-analysing data from 23 stroke trials (25,674 patients), where covariate data was supplied, showed that ordinal logistic regression adjusted for age, sex and baseline stroke severity reduced the sample size needed for a given statistical power by around 37%. Alternatively trialists could increase the statistical power to find an effect for a given sample size, as it is argued that stroke trials have been too small and therefore underpowered. Stroke prevention trials also routinely collect binary data, e.g. stroke/no stroke. Converting this data into ordinal outcomes, e.g. fatal stroke/non-fatal stroke/no stroke and analysing these with a method which takes into account the ordered nature of the data also increases the statistical power to find a treatment effect. This method also provides additional information on the effect of treatment on the severity of events. Using ordinal methods of analysis may improve the design and statistical analysis of both acute and stroke prevention trials. Smaller trials would help stroke developments by reducing time to completion, study complexity, and financial expense.

Paediatric ependymomas remain a clinical management challenge, with a relatively poor prognosis when compared to other childhood tumours of the central nervous system. An improved understanding of underlying ependymoma biology may identify new correlates of outcome and potential therapeutic targets. To address this, AffymetrixTM 500K SNP arrays were used to establish the nature and range of genomic imbalances in 63 paediatric ependymomas (42 primary and 21 recurrent). Over 80 % of tumours were analysed against patient-matched constitutional DNA. In addition, the Illumina® GoldenGate® Cancer Panel I array was used to identify differences in methylation profile across 98 paediatric ependymomas (73 primary and 25 recurrent). While collective assessment revealed the most common anomalies, specific aberrations were characteristic of certain ependymoma subgroups, particularly those relating to tumour location, patient age, disease recurrence and patient prognosis. The genomic imbalance of 15 selected candidate genes (NSL1, DNAJC25, NAV1, CDKN2A, CHI3L1, HOXA5, TXN, BNIPL, and PRUNE) were confirmed by quantitative Polymerase Chain Reaction. Genomic gain involving regions of chromosome 1q were associated with an unfavourable patient outcome, such as the focal locus on 1q21.3 encompassing PRUNE. The genomic gain of PRUNE correlated with an increased encoded protein expression, as assessed by immunohistochemistry (IHC). This adverse prognostic association with 1q was upheld in the subsequent part of this work. Fluorescent in situ hybridisation and IHC were used to evaluate a panel of six putative prognostic markers (1q25 gain, PRUNE, Tenascin-C, Nucleolin, Ki-67 and NAV1 expression) across a paediatric intracranial ependymoma tissue microarray cohort of 107 primary tumours treated within the confines of two aged defined clinical trials (UK CCLG 1992 04 and SIOP 1999 04). Within the younger UK CCLG 1992 04 cohort, copy number gain of chromosome 1q25 and PRUNE overexpression were independently associated with an increased risk of disease progression, while strong PRUNE expression was also an independent marker of worse overall survival. In addition, increased Tenascin-C expression correlated with a reduced overall survival on univariate analysis. For older children in the SIOP 1999 04 cohort, strong PRUNE expression in ependymomas was again identified as an adverse prognostic marker, correlating with increased mortality on univariate assessment.

Background: An estimated 15-30% of individuals referred to epilepsy clinics are diagnosed with non-epileptic attack disorder (NEAD). NEAD is a well-known clinical problem which poses diagnostic and therapeutic challenges to neurological and psychological professionals (Gates & Erdahl, 1993). There are multiple theories on the mechanisms that underlie non-epileptic seizures; however there is limited empirical support for these. The development of implicit cognition has attracted much attention in the last few decades but has yet to be developed in the context of seizure research. This thesis aimed to offer a novel perspective on the psychological mechanisms underlying NEAD by examining implicit and explicit self-esteem and anxiety in people with seizures. It also explored the relationship of these constructs with experiential avoidance and seizure frequency. Methodology: 86 participants were recruited and completed a series of self-report questionnaires. The Rosenberg self-esteem questionnaire was used to measure explicit self-esteem. Spielberger’s State-Trait Anxiety Inventory was used to assess explicit anxiety. The Patient Health Questionnaire-15 was utilised to estimate somatic symptoms. The Multi-dimensional Experiential Avoidance Questionnaire was used to examine differences in avoidance. Finally they were administered two versions of the Implicit Relational Assessment Procedure (IRAPAnxiety; IRAP-Self-esteem) to examine implicit self-esteem and anxiety. Results: Analysis of Variance (ANOVAs) found no significant differences in implicit self-esteem and anxiety between the NEAD, epilepsy or non-clinical control groups. However, the NEAD group reported a significantly lower explicit self-esteem, higher avoidance and more somatic symptoms than their epilepsy counterparts. Although the NEAD and epilepsy groups reported high levels of anxiety, only the 3 NEAD group differed significantly from controls. The NEAD group had significantly larger implicit-explicit discrepancies for both anxiety and self-esteem, with explicit and discrepant scores correlating with self-reported avoidance and seizure frequency. A logistical regression model using explicit self-esteem, experiential avoidance and somatisation correctly classified 84.9% of individuals with seizures. However, the implicit measures did not add anything to the model. Conclusions: There are several interpretations for the implicit-explicit discrepancies observed. One suggestion is the high implicit low explicit profile reflects ‘damaged’ self-esteem, which can be understood more fully in context of events preceding seizure onset as well as the corollaries of diagnosis. Other authors have suggested that this profile reflects an unstable self-image, understood from early parenting and attachment perspectives. Given the correlation with discrepant scores it is possible that avoidance and seizures serve to reduce dissonance between implicit and explicit cognition. These findings support various psychological models of NEAD and offer a rationale for a range of psychological treatments that target avoidant behaviour patterns as well as deliberate evaluations that are within a person’s awareness.

Objective: Telephone-supported self-help Acceptance and Commitment Therapy (ACT) may be a way of providing accessible and effective psychotherapy to people with Multiple Sclerosis (MS). The aim of this trial was to determine the feasibility of a randomised controlled trial (RCT) of telephone-supported ACT bibliotherapy compared to treatment-as-usual (TAU), explore the effectiveness of the intervention and track individual changes. Design: The study was a randomised controlled feasibility trial. The intervention consisted of eight weekly support calls guiding participants through an ACT self-help text. Participants were assessed at baseline and post-intervention using the Generalised Anxiety Disorder measure (GAD) and the Patient Health Questionnaire (PHQ) as primary outcome measures. The EuroQol (EQ-5D-5L) and Multiple Sclerosis Impact Scale (MSIS-29) were secondary measures, and the Acceptance and Action Questionnaire (AAQ-II) was a process measure. A sample of participants were interviewed and analysed using framework analysis to assess RCT feasibility. Results: Twenty seven participants with MS with anxiety and/or depression were recruited from an outpatient MS clinic and an MS charity. The majority of participants found all components of the RCT acceptable. Overall attrition was 33%, and 64% in the intervention group. Linear mixed model analysis and effect size calculation found a significant effect (p=0.004) and large effect size (0.84 (95% confidence intervals 0.02-1.66)) at post-intervention in favour of the intervention on anxiety. Smaller non-significant positive effects were found on other measures. Participants in both groups exhibited clinically significant improvements and deteriorations. Intervention completers had significantly lower baseline scores on the MSIS and the AAQ-II. Conclusions: Telephone-supported ACT bibliotherapy delivered in a RCT format may be a feasible research method for people with MS if significant changes to the method of delivery are made. The intervention has the potential to be effective in reducing anxiety, however there are limitations in sample size. Future research directions and the applicability of ACT in this population are discussed. Finally, personal reflections on methodology and intervention delivery are made.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by a loss of pigmented dopaminergic neurons in the substantia nigra (SN) pars compacta and loss of pigmented noradrenergic neurons in the locus coeruleus (LC). Diagnosing PD can be challenging, especially in the early stages particularly when the typical movement disorder symptoms such as tremor, rigidity, bradykinesia and postural instability are not easily identifiable. Despite well-established PD clinical diagnostic criteria there is a misdiagnosis rate of up to 15% by neurology specialists and 25 % by general practitioners. The only approved diagnostic test to confirm suspected PD in a tremulous patient is dopamine transporter single photon emission tomography (DaTScanTM). This test is costly (£800 – 1500 in the UK) and has limited geographical availability in the UK. It involves exposure to ionising radiation and can only be used to assess the integrity of the dopaminergic system. Therefore there is a strong need for better and more accessible diagnostic tests for PD. The aim of this thesis is to investigate the sensitivity and specificity of three different MRI techniques as potential biomarkers of PD. MRI at 3T field strength was used in this thesis to demonstrate PD pathology in the pigmented brain stem nuclei of SN, LC and the ventral tegmental area (VTA). The objective was to develop new, easily accessible and affordable disease markers to help clinicians to establish the correct diagnosis early. A promising technique, which is based on the assessment of free motion of water-associated protons in tissue, is termed diffusion tensor imaging (DTI). The amount of free motion in all directions of protons in tissues like the brain can be described using mean diffusivity (MD) as a measure. Diffusion in tissues like the brain is often limited (“restricted”) in certain directions. For example diffusion across the myelin sheaths of nerve-fibres in the brain white matter is constrained, whereas along the direction of the nerve fibre protons can diffuse freely. This is termed anisotropic diffusion and can be described using fractional anisotropy as a measure (FA). Microstructural PD pathological processes may alter these measures of diffusivity especially in the area of the early affected brain region of the SN. In a prospective case control study of 30 patients and 22 controls diffusion tensor imaging alterations of the SN were investigated by measuring regional alterations of fractional FA and MD. In addition, a systematic literature review and meta-analysis was performed to determine the evidence for nigral DTI alterations throughout the literature. The case control study did demonstrate a small but significant increase of nigral MD; however the meta-analysis did not confirm this result when synthesizing effect sizes of nine identified relevant studies. No significant PD induced FA alterations were found in the prospective case control study. The meta-analysis of nigral FA changes did likewise not show significant FA decrease after correcting for studies with unusual high FA measures in the control arm population. In summary the meta-analysis and the results of the case control study did not confirm that standard DTI measurements of the SN are reliable biomarkers of PD pathology. In a further case-control study MRI sequences tracking the neuromelanin content of the pigmented brain stem nuclei like the SN, LC and the ventral tegmental area were investigated. PD induced decline of neurons in these nuclei causes depigmentation due to loss of neuromelanin content. In this study (including data from 24 PD patients and 20 controls) I found that only little neuromelanin related signal could be observed in the ventral tegmental area and there was no significant difference between patients with PD and controls. However, there were significant signal alterations of the SN and LC signal when comparing between the two groups. The neuromelanin related signal loss was most pronounced in the posterior SN even in the earlier stages of the disease. The signal loss in the anterior SN was less severe and correlated with the unified PD rating scale (UPDRS) and Hoehn and Yahr score as a measure of disease severity. The neuromelanin related signal reduction was significant but less extensive in the region of the LC when compared to the SN. The signal alterations in the LC did not correlate with the UPDRS or the Hoehn and Yahr score. In the third part of the experimental section of this thesis, a further prospective case-control study of 19 participants (10 patients with PD) and retrospective study of 105 clinical cases (9 patients with PD) was performed. A high resolution SWI/T2* ‘iron sensitive’ sequence was used to assess MRI changes of the nigrosome-1. Nigrosomes are little islands of dopaminergic cells with physiologically low iron content. The healthy hyperintense signal of the linear shaped nigrosome-1 surrounded by the iron containing low signal SN regions has great resemblance to the appearance of a swallow tail. The PD induced pathological signal reduction within nigrosome-1 resulted in a loss of the typical ‘swallow tail appearance’. Visual qualitative assessment of the MRI scans for absence and presence of nigrosome-1 revealed high sensitivity and specificity (80-100% and 86-89% respectively) to allow differentiation of PD from healthy controls and non-PD patients. In summary I found that standard nigral DTI is not reliable as a PD biomarker. Nigrosome and neuromelanin weighted MRI offers great potential for development into a clinically useful biomarker. Comparing the two techniques, nigrosome imaging has some advantages over neuromelanin weighted imaging: the high resolution SWI/T2* sequence is shorter (2-5 min versus 7-14 min neuromelanin MRI. However, further optimization of neuromelanin MRI sequences may be able to shorten the acquisition time. A further advantage of nigrosome MRI is that the images can be visually assessed for pathological alterations without the need for complicated analysis or data processing. A disadvantage of high resolution SWI/T2* is that it is more prone to artefacts. An advantage of neuromelanin weighted MRI is that changes especially in the anterior substantia nigra correlate to measures of disease severity like the UPDRS, although there is some early evidence from pilot studies that nigrosome imaging (at field strengths of 7T) may also be useful to assess disease severity related changes. Which of the two techniques is better suited to monitor longitudinal progressive PD related changes has to be assessed in future studies. In conclusion standard nigral DTI measures have no proven value as a reliable diagnostic marker of PD. High resolution T2*/SWI MRI and neuromelanin weighted MRI of PD induced alteration of pigmented brain stem neurons distinguish PD from non-PD and control subjects with high sensitivity and specificity. Neuromelanin related alterations especially of the anterior SN correlate to disease severity measures like the UPDRS and therefore have potential as disease progression marker. The easy applicability of the ‘swallow tail sign’ to indicate a healthy nigrosome-1 in the SN may well prove a useful marker to help the clinical diagnosis of PD. If future studies confirm a similar diagnostic accuracy as the current clinical gold standard DaTScanTM, nigrosome MRI may replace DaTScanTM in the standard clinical setting.

Background Brain injury following transient or permanent focal cerebral ischaemia matures from a multifaceted succession of pathophysiological events that progress in time and space. The key biochemical events related with these pathologies include excessive cytoskeletal remodeling, modulation of tight junction proteins, induction of oxidative stress and excessive release of pro-inflammatory cytokines. In addition, other neuropathologies such as multiple sclerosis have been shown to account for the development of these events and the consequent disruption of human blood-brain-barrier (BBB) integrity and function. However this study emphases on potentially new avenues of treatment which can protect the integrity of the blood-brain barrier and decrease post ischaemic consequences such as vasogenic oedema. Hypothermia has been hypothesised as a potent neuroprotectant and its putative effects have been assessed in the present research work. Objectives This thesis focuses on the putative role of hypothermia during intra- and post-ischaemic stroke mimicked by oxygen-glucose deprivation and followed by reperfusion. The impact of hypothermia has been studied on various inflammatory pathways such as pro-inflammatory cytokine levels, rate of apoptosis, extent of cytoskeleton remodeling and integrity and function of the BBB. In addition, we have also focused on the neuroinflammatory effects of multiple sclerosis (MS) on the BBB integrity. Method To mimic ischaemic insult, human brain microvascular endothelial cells, human astrocytes and human pericytes were exposed to oxygen-glucose deprivation (OGD) for 4 and 20 hours in the absence or presence of hypothermia (intra-ischaemic episode) and 4 hours of OGD followed by 20 hours of reperfusion in the presence of hypothermia (post-ischaemic episode) and cells left untreated were served as controls. Similarly, to assess BBB properties, all three cells were cultured simultaneously to establish an in vitro model of human BBB before exposing them to the experimental conditions. The integrity and function of triple cultures were measured via transendothelial electrical resistance (TEER) and paracellular flux via permeability markers such as sodium fluorescein (NaF) and Evan’s blue-labelled albumin (EBA). Various inflammatory inhibitors were also used during the insult to assess the distortion of the barrier. Furthermore, the triple cultures were exposed to multiple sclerosis patients’ serum mainly to study the neuroinflammatory effects. Moreover, with help of specific enzyme-linked immunosorbent assay-based kits pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β were measured during intra- and post-ischaemic episodes in the absence or presence of moderate hypothermia. Lastly, to evaluate the status of oxidative stress during acute ischaemic insult, the levels of superoxide anion generation and NADPH oxidase activities were measured. Results This study shows that moderate hypothermia significantly decreases pro-inflammatory cytokine levels when introduced during intra- and post-ischaemic episodes. Additionally, moderate hypothermia also maintains the BBB integrity and function during intra-and post-ischaemic scenarios. As evidenced by significant increase in resistance across the barrier and by concurrent decrease paracellular flux values. In addition, moderate hypothermia manages to reduce the oxidative stress impact during intra- and post-ischaemic episodes as documented by a decrease in NADPH oxidase and superoxide anion levels. Furthermore, the outlined study shows that MS patients’ serum is fortified with various inflammatory components such as pro-inflammatory cytokines, increase rate of apoptosis and resulting in destruction of the BBB architecture. Conclusions In this study, we have found moderate hypothermia to be a robust neuroprotectant in during intra- and post-ischaemic episodes of ischaemic injury mimicked by oxygen-glucose deprivation alone or followed by reperfusion. If adequately and appropriately maintained, moderate hypothermia may be an effective therapeutic option with minimal adverse effects. Furthermore, MS associated BBB destruction shows a new conduit for future research.

People with multiple sclerosis (MS) commonly experience psychological problems including anxiety and depression. Evidence indicates that psychological interventions based on cognitive behavioural principles can help improve mental health. Such interventions are often delivered in groups and a common assumption is that the social interaction afforded by a group format is beneficial. The aim of this thesis is to explore this assumption and, drawing on social identity theory, investigate why and for whom MS psychological adjustment interventions are effective (or not) when delivered in a group. Social identity refers to the part of an individual’s self-concept that is derived from belonging to social groups. In the first study, a survey was conducted to establish an evidence base for the relationship between psychological wellbeing and social identity processes in people with MS (n=203). Continued membership of groups belonged to prior to diagnosis was associated with reduced psychological distress, highlighting the importance of social identity continuity. Increased anticipation of stigma as a result of having MS was associated with increased psychological distress. Identification with an MS group was associated with a small decrease in psychological distress when the effect of the other variables was accounted for. This raised the possibility that positive effects of MS group identification may be suppressed by an underlying negative influence of identifying with a socially devalued group. A realist synthesis was undertaken to gain further insight into how these processes may contribute to intervention success or failure. This identified several benefits of group format, but indicated that these benefits were more readily obtained when MS was not experienced as posing a threat to identity. When the identity threat from MS was high, there were indications that a group format could have negative consequences for psychological wellbeing. The identity-related benefits and drawbacks of individual and group interventions were explored further in a thematic analysis of interviews with 16 people with MS. Participants had taken part in a feasibility randomised controlled trial (RCT) of group versus individual cognitive behavioural therapy (CBT). Several benefits of group delivery were identified, including shared understanding, normalisation of illness and the opportunity to socialise, share information and challenge negative stereotypes. Perceived drawbacks included unhelpful group norms, putting on a mask and confrontation with a feared identity. Identity threat was found to be especially marked in the group delivery format and appeared to reduce intervention engagement. Identity threat varied depending on social identity continuity, incorporation of MS into identity, stigma, time since diagnosis, symptom progression, ageing and illness narrative. A narrative analysis of two of the interview transcripts highlighted the power of narrative perspective to influence how people respond to MS and offered an explanation for the differing responses to the prospect of taking part in group or individual interventions. This thesis makes valuable contribution to the literature in making explicit those aspects of group intervention format that confer benefit. It also draws attention to the identity-related drawbacks of a group format. The finding that identity threat may influence perceptions of, and engagement with, interventions offers an explanation for the mixed results in the literature regarding the efficacy of group interventions. The thesis findings begin to establish a theoretical basis for clinical decisions regarding whether to offer group or individual psychological adjustment interventions. An important implication is the need to frame, design and deliver group interventions in such a way as to reduce identity threat and promote a positive shared identity. Further research is now needed to investigate whether the proposed identity-related mechanisms impact intervention efficacy. In the planned multi-site RCT of group versus individual CBT it would be valuable to incorporate measures of MS group identification and identity threat. This would enable quantitative investigation of the degree to which these variables influence intervention engagement and efficacy.

There is an intimate spatial and functional relationship between cerebral microvasculature and the neuroglial tissues. It is known that both cerebrovascular and neuroglial alterations occur in multiple sclerosis (MS), but the pathophysiological relationships between these alterations, and the functional consequences, are not well characterised in vivo. Evidence from previous literature indicates that there are subtle changes in blood brain barrier (BBB) in normal appearing white matter (NAWM) of MS. However, lesion development due to subtle BBB leakage remains unclear. Additionally, the haemodynamic alteration and microstructural changes in grey matter (GM) is a well-known feature in MS. Nevertheless, the structural and functional relevance of GM perfusion and diffusion necessitate more exploration. The main objective of this study was further interpretation of lesion development in MS, using advanced MRI techniques. Moreover, the study also aimed to provide valuable understandings into the association of different MRI measures with structural changes and clinical performance in MS, using advanced image analysis methods. The study has focused on the following goals: to determine BBB permeability in NAWM of MS and its correlation with microstructural damage, the relationship of subtle BBB leakage to lesion development, the association of grey matter perfusion with structural changes and functional performance and finally, the cortical diffusion alteration and its relevance with functional performance. Therefore, the main hypothesises of this thesis are: firstly, MS patients have impaired BBB permeability in NAWM compared to healthy controls. Secondly, that mean diffusivity (MD) in NAWM will correlate with BBB permeability in MS. Thirdly, that subtle BBB leakage in NAWM may precede lesion progression in MS. Fourthly, that cortical and deep GM perfusion is reduced in MS patients compared to healthy controls. Fifthly, that cortical perfusion correlates inversely with cortical atrophy in MS and finally, pattern of regional cortical MD variability will explain performance in different functional domains in MS. All MS and healthy participants included in this study underwent an MRI scan at 3T. Functional and cognitive assessment was performed on MS. Dynamic contrast enhance-MRI was used to generate perfusion and permeability maps. The microstructural changes were measured using diffusion imaging. The cortical perfusion and diffusion changes were explored by Surface based analysis approach. Increased BBB permeability in NAWM of MS was detected when compared to healthy controls (p<0.05) and it revealed an association with MD in NAWM (r= 0.48, p = 0.01). The findings also revealed subtle BBB breakdown indicated by an increase in the permeability parameter (Ktrans) in prelesion NAWM. GM hypoperfusion was shown in MS when compared to healthy controls (P<0.05). However, surface based analysis revealed no correlation between cortical hypoperfusion with cortical atrophy and microstructural damage in MS. Furthermore, there was no association between GM perfusion and clinical scores. In addition, the cortical diffusion alteration revealed vertex-wise correlation with functional scores in MS (P<0.05). In conclusion, advanced MRI and advanced image analysis in this study has delivered novel insights on lesion development and other pathological changes affecting GM and WM in MS, which might have prognostic and therapeutic importance in MS.