Previous studies have shown that dietary supplementation of curcumin or omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid can reduce behavioural deficits and β-amyloid (Aβ) pathology in several models of Alzheimer’s disease (AD), including Tg2576 mice. However, no study to date had examined the effect of omega-3 PUFA and curcumin co-supplementation on behaviour or β-amyloid pathology in mouse models of AD. Further to this, no study to date had examined the effect of longitudinal omega-3 PUFA or curcumin supplementation provided from an early age before significant pathological development in the Tg2576 model. This was deemed important since human studies have suggested that lifelong dietary choices before disease development are an important factor in disease risk. Finally, although a plethora of studies has examined the effect of omega-3 PUFA supplementation, none has accurately examined its effect against an appropriate control diet. For example, some control diets contained differential levels of fatty acids such as excess total fat and omega-6 PUFAs. Such differences in the control diet may have contributed to the observed beneficial effects of dietary omega-3 PUFA supplementation, particularly since these dietary factors can exacerbate pathological processes related to AD. Using this experimental design, chapter 3 found longitudinal dietary supplementation of omega-3 PUFA docosahexaenoic acid (DHA) from an early age in Tg2576 mice provided some protection from cognitive decline that was limited to later but not early stages of pathology. In contrast to previous reports however, Aβ pathology was unaltered by DHA supplementation. Providing DHA supplementation from an even earlier age, chapter 4 showed that DHA reduced behavioural deficits at an early age (prior to Aβ pathology), although interestingly, these effects were less robust at the later age. Chapter 5 examined longitudinal supplementation of curcumin, fish oil containing omega-3 PUFAs (DHA and eicosapentaenoic acid, EPA) and their co-supplementation from an early age in Tg2576 mice. The results consistently revealed no beneficial effects of dietary supplementation on behaviour or Aβ pathological measures. The findings from this thesis indicate that dietary supplementation of DHA relative to a suitable control diet can provide only limited protection against behavioural deficits in Tg2576 mice. In contrast, fish oil supplementation containing omega-3 PUFAs DHA and EPA provided no protection, indicating that DHA monotherapy may be a more advisable treatment. The null effects of curcumin supplementation at earlier stages relative to previous studies suggest that curcumin may only be effective during advanced stages of pathology, although further investigation is needed. Finally, the null effects of curcumin and fish oil/omega-3 PUFA co-supplementation suggest that this is not an optimal intervention strategy in reducing Aβ-induced changes.

Objective: There is emerging evidence that exercise may modify disease progression and improve function in a number of neurodegenerative diseases, but this has not been systematically studied in Huntington.s disease (HD). The purpose of this study was to evaluate feasibility, acceptability and benefits of an exercise programme in people with HD. Methods: Using a randomised controlled trial design, 25 participants with manifest HD were allocated to either intervention (home-based exercise; n=13) or control (usual care;n=12) groups. Participants were assessed at baseline and eight weeks later. Eleven participants from the exercise and 10 from the control group completed the intervention study. The primary outcome was gait variability (stride time coefficient of variation (CV)). Secondary outcomes included other measures of gait, disease-specific motor scale and measures of balance, muscle strength, mobility and community walking, functional performance in ADL and quality of life. These measures were included to reflect a range of physical impairments and activity limitations seen in people with HD. Analysis of covariance was used to compare follow-up scores across groups after adjustment for differences at baseline. Effect sizes were calculated for outcome measures based on differences in change scores between groups. Process interviews were conducted at the end of the study to determine acceptability of the intervention to participants. Cross sectional investigation of outcome measures was undertaken initially to investigate discriminant and concurrent validity as well as test re-test reliability and minimal detectable change (MDC95) along the broad spectrum of the disease. Baseline data from 25 participants with manifest HD (who went on to participate in the intervention), in addition to data from 17 individuals with pre-manifest HD and 25 healthy controls were analysed. This data was of use in interpreting the results from the interventional study. In particular, the MDC95 data helped in determining of whether any statistical significant changes due to the intervention are clinically meaningful. Results: Measures of gait variability, some measures of balance, community walking and measures of functional performance in ADL were able to distinguish between people with manifest HD and pre-manifest HD as well as between people with pre-manifest HD and healthy controls suggesting good discriminant validity. All these outcomes had also good concurrent validity with a disease specific motor score. The test re-tests reliability scores for the majority of the outcomes were high and the MDC95 scores were low, suggesting that the individual variability on these outcomes were low. Adherence rates to the exercise programme were high (78.8% of participants reported completion of at least 78% of the prescribed sessions). Participants in the intervention group demonstrated significant improvement in stride time CV (95% CI (-11.5, -0.6))based on complete case analysis. Significant differences between groups were also observed in the disease-specific motor scale and in measures of balance, mobility,community walking and functional performance in ADL, but not muscle strength and health-related quality of life. Effect sizes were large (>0.8) for the majority of the outcomes. The magnitude of the change as a result of the exercise intervention exceeded the calculated MDC95 values for some of the outcomes, which suggest that most of the observed changes are clinically meaningful. Qualitative feedback from the participants who completed the exercise programme suggested high levels of acceptability with positive impact on general health and mobility. Participants identified barriers and facilitators that affected performing the exercises at home and described management strategies that helped adherence to the exercise programme. Conclusions: This study was the first systematic trial to demonstrate that a short-term structured exercise programme is acceptable and can be safely delivered in a home environment; achieve good adherence; and positively affect body function and activity in people with HD. The sensitivity of the outcomes as determined in the cross-sectional study, to mobility deficits the in pre-manifest HD group is important. These outcomes has the potential to be used in future studies of exercise interventions in the premanifest stage which aim to target such deficits early in the disease life cycle, before they begin to impact on a person.s ability to participate in the community. Overall the data presented from this study provides a platform for further investigations to extend these findings about the role of exercise and physical activity in people with HD. Larger and more detailed studies are needed to replicate findings from this study in othercontexts and variations in dose.

People with Parkinson's disease report high levels of non-motor symptoms, including anxiety and depression, that are difficult to treat pharmacologically. Mindfulness-based interventions have been shown to be effective in other long-term conditions. This pilot study explored how a mindfulness-based intervention may have had an effect and for whom, with a view to informing future studies. Volunteers were randomised to a remote delivery, eight-week mindfulness cognitive behavioural group therapy intervention (n=40) or wait-list (n=38), and measures for psychological outcomes and putative mediators were taken at baseline, 4 weeks, 8 weeks and 20-week follow-up. The study showed that all the outcome measures changed in a positive health direction in the intervention group. The intervention had a small effect on decentering (d=.36) and acceptance (d=.27) by mid-point, before depression at 8 weeks (d=-.28) and anxiety at follow-up (d=-.29), indicating an indirect effect between trial arm and levels of distress. Mediation and moderation analysis were conducted using PROCESS, time-lagging the mediators to the outcome variables, but no combined or individual indirect effects had confidence intervals entirely above or below zero, thus mediation cannot be confirmed. When the end of intervention mediators were analysed with the follow-up levels of anxiety and depression, there is evidence of inconsistent mediation, or possible suppression effects. Moderation analysis revealed that the effect on anxiety levels was moderated by gender, with women benefitting more from the mindfulness intervention. Moderated mediation analysis also indicated that the effect of the trial arm on levels of acceptance was conditional by age and time since diagnosis, and the effect of trial arm on levels of mindfulness skills by age, meaning that younger, newly-diagnosed patients were more able to increase mindfulness skills and acceptance.

Developmental prosopagnosia (DP) is a condition associated with severe difficulties recognising familiar faces, which occurs in individuals with normal intelligence, typical low-level vision, and in the absence of manifest brain injuries. The neuro-cognitive origins of DP are still debated. Cognitive accounts have attributed face recognition deficits to reduced holistic processing of faces (i.e., whereby individual features of faces are integrated into a unified perceptual whole), and mnemonic difficulties, whereby prosopagnosics may be able to form accurate percepts, but are unable to maintain those percepts over time. At the neurological level, differences have been reported in the structural and functional connectivity of occipito-temporal regions which include face selective areas. Chapter 2 of this thesis investigated facial emotion recognition in DP and revealed widespread difficulties recognising facial emotion in individuals with apperceptive profiles of DP (i.e., DPs exhibiting difficulties forming view-invariant structural descriptions of faces at early stages of encoding). Chapter 3 explored body recognition in DP and found evidence of impaired body and object recognition in DP individuals. Moreover, the lack of relationship between observers' object and body recognition performances suggested that body and object recognition impairments in DP may co-occur independently. Chapter 4 investigated the susceptibility to the composite face illusion in two independent samples of individuals with DP and failed to show evidence of diminished composite face effects in both samples. Finally, Chapter 5 considered the contribution of perceptual encoding and short term face memory in DP using a delayed match-to-sample task and found that recognition impairments in prosopagnosics were insensitive to changes in retention interval and viewing angle, supporting an apperceptive characterisation of DP. The implications of these findings for the characterisation of DP and for understanding its underlying cognitive mechanisms, are discussed in Chapter 6.

Recognition memory is one of the most basic types of memory. One type of recognition memory is visual familiarity, which is the sense that a visual stimulus has been encountered before. This type of memory is affected in different mental illnesses, like schizophrenia and autism. The perirhinal cortex, which is a part of the medial temporal lobe has long been believed to be crucial for recognition. This work had 2 main lines of research. The first part, described in chapters Chapter 3 and Chapter 4 , set out to investigate whether activity at either the population level or at the single-unit level in the mouse perirhinal cortex was correlated with visual familiarity. In these chapters, the recordings were made also in the visual cortex and the hippocampus to put the perirhinal response in the context of the activity both upstream and downstream from it, respectively. Visual stimuli evoked responses in the perirhinal cortex, no familiarity-related modulation could be detected at both levels of analysis. That was true even when the visual cortex demonstrated familiarity-related differences in response. The second part of the work, described in chapters Chapter 5 and Chapter 6 examined the mice with haplo-insufficiency of the CYFIP1 gene as a possible new model for mental illness. First, the animal’s validity as a model of mentalillness was tested using auditory-evoked potential, one of the most ubiquitous phenomena that appears with mental illness in people and animal models. Then, recognition memory and the neuronal activity in the perirhinal and the visual cortex was tested, to see if they demonstrate other symptoms relating to schizophrenia. In the second line of work, the CYFIP1 mice demonstrated an auditory-evoked potential profile more like that observed in fragile-X syndrome, rather than schizophrenia and did not present any changes in both recognition memory or the electrical activity in the visual and the perirhinal cortex. This work showed that the perirhinal cortex does not show any familiarity-related activity unlike the current assumption in the literature. It also showed that the CYFIP1 mice might be a possible model for autism and Fragile-X syndrome.

No description available.

The mammalian hippocampus is vitally involved in the formation of both episodic memory and semantic memory, and in learning and recognition. These functions are actively involved during spatial navigation through an environment. The rodent hippocampus in particular has been greatly studied, providing a wealth of experimental data; however collation of this data into universally accepted theories of hippocampal function is far from complete. The present study concentrates on events occurring in the rodent hippocampus during such navigation. There is particular emphasis on the hippocampal theta rhythm which is manifested during navigation; on the existence and characteristics of place fields and associated place cells; and on the phenomenon of phase precession. The study has been limited to the CA1 region. Testable assertions are made about these phenomena. These assertions have been incorporated into models which are described in the later chapters of the thesis. The model has been further extended to demonstrate features of serotonergic activity in the CA1 region.

Scottish people have a reputation for being high consumers of alcohol. Certainly this is the case today and was also the case throughout the nineteenth century - the most obvious comparison to be made, a comparison often made both then and now, is with supposedly more moderate English drinking habits. Less well known is the reversal of this perspective during the inter-war years (1918–1939), when Scotland was held in many quarters to be more sober than England. This turnaround was brought about by changes in popular culture alongside specific alcohol control legislation that had a greater impact in Scotland. This thesis is not an exploration per se of why alcohol consumption rose in nineteenth-century Scotland, fell in the first half of the twentieth century and rose again to damaging levels at the end of the twentieth century. This high level of consumption persists in 2017 and the Scottish government is still acting to reduce alcohol-related harm by a variety of measures. Rather this thesis seeks to explore the response of the Scottish medical profession to the changing conditions in relation to alcohol over a seventy-year period from 1855 to 1925. (Chapter 3 and Chapter 4 set the scene). The starting point of 1855 for the period examined in this thesis is taken from the 1855–57 Inquiry by the Scottish Lunacy Commission, which led to the Lunacy Act (Scotland) of 1857. This report demonstrates that Scottish psychiatry was already having to deal with the mental consequences of alcohol and describes oinomania, an early term for alcohol dependence. The report introduces the idea that alcohol can itself cause insanity – an estimated 20% or more of the cases in asylums were caused by intemperance around that time and this figure was deemed to rise as the century wore on. This seems like a curious and excessive causal attribution from today’s perspective. In this thesis I trace how the idea of a persistent form of alcoholic insanity evolved in the Scottish context (Chapters 4 and 6), and I outline changing terminology and ideas around the mental consequences of alcohol (Chapters 5, 6, 7 and 8). These ideas were expounded by physicians and alienists/psychiatrists in the public arena of parliamentary inquiries in the second half of the nineteenth century (Chapter 4) as well as in the specialised literature of the time (Chapters 5, 6, 7 and 8), including the medical reports within the Annual Reports of asylums. Original to this thesis in relation to primary sources is an in-depth analysis of the alcohol cases received by the Delirium Ward at the Royal Infirmary of Edinburgh between 1856 and 1867, in the May to July period of each of these years (Chapter 5). These 178 recorded cases (57% of all admissions with threatening or actual delirium) illustrate that alcohol problems in the form of incipient or established delirium tremens were a common reason for admission to hospital at this early date and that such cases were of particular interest to physicians. It is striking that beyond the acute episode of what was erroneously thought to be an intoxication-induced illness there is no apparent attempt to help the person with their underlying intemperance (Chapter 5). The idea that later emerged of an underlying condition of inebriety, differentiated from insanity, was to have practical consequences in that it led to the setting up and running of Inebriate Reformatories in Scotland, as elsewhere in the British Isles, in the first quarter of the twentieth century (Chapters 7 and 8). I trace this story in detail through to the closure of the Inebriate Reformatories in 1925,whilst examining this in a Scottish context. Other scholars have looked at the era of the Inebriate Reformatories in Scotland from the perspectives of sociology, of history and of feminist theory. I review the previous literature in Chapter 2, and provide a historiography spanning the last hundred years. I also bring a fresh medical perspective to the topic in Chapter 7, which uses records not available to some of the previous scholars, and produce a very detailed analysis of the female cases sent to the Glasgow Reformatory (Girgenti House). This is presented in Chapter 8. The time period cut-off of 1925 for the end of the thesis is made for pragmatic reasons, as the trends in the conception of alcoholism and alcohol use disorders, and in treatment provision, since 1925 would merit separate full consideration. I do, however, sketch out these trends for this later period in a Postscript (Chapter 9) in order to give a context for drawing out some historic lessons from 1855–1925 in my Conclusion and Discussion (Chapter 10) about the “alcohol question” in the Scotland of today. The period I cover therefore includes an historic high in alcohol consumption in the late nineteenth century and an historic low in the 1920s. I aim to show how practice and theory interconnected during these years in the work of medical men such as Thomas Laycock, David Yellowlees, Sir Thomas Clouston, William Tennent Gairdner, James Craufurd Dunlop, John Cunningham and Sir David Henderson. I also describe some of the connections between these key medical figures within the Scottish system in Chapter 4. The post-1920 period also illustrates a sea change from a time where psychiatrists were arguing for the separation of the “inebriate” from the “lunatic” in terms of service provision to one where the “alcoholic” is seen as deserving of new forms of psychiatric help. This shift in practice, around the end of the period of my study, is seen in the context of a changing emphasis from a more biological view of the problem to a more psychodynamic, or dynamic, view as seen in the work of Henderson and others. The fact that this shift in theory and practice coincides with a decline in the alcohol problem is discussed in the light of Skog’s idea that our concerns around alcohol vary in relation to where we are in relation to “waves of consumption” (Chapter 10). My overall aim in this thesis, then, is to set out how from 1855 to 1925 medicine in Scotland responded to the idea that habituated use of alcohol might represent a disease in its own right. The idea of such a “disease of the will” remains both legally and philosophically controversial to this day. This is perhaps why our diagnostic systems continue to change in this area without final resolution. An associated aim of the thesis is to look at three aspects of the “drinking disease”, in Scotland, namely delirium tremens, alcoholic insanity and inebriety, where practice can be examined from case records and related to theory as represented in a range of publications. I also prove, and highlight the fact, that institutionalised medicine cannot escape engagement with the problem of alcohol. From the beginning, Scottish doctors in both infirmaries and asylums were presented with the consequences of heavy drinking in a sizeable proportion of patients. As with recent epidemiological analyses, alcohol consumption levels in the general population during the nineteenth and early twentieth century are shown to correlate highly with the incidence and prevalence of such disease consequences from the Scottish national and local statistics available. Then, as now, doctors were inevitably drawn into the issue of how best to respond to the underlying habit of drinking both at an individual and societal level. I draw lessons from my study of the past for our continuing struggle in this regard.

No description available.

Parkinson's disease (PD) is misdiagnosed throughout its disease course for conditions such as essential tremor, drug-induced parkinsonism, vascular pseudo-parkinsonism, Alzheimer's disease and other degenerative parkinsonian diseases. This thesis aims to verify the accuracy of dopaminergic imaging in early and uncertain parkinsonian/tremor disorders through 3 studies. The first is a prospective United Kingdom multicentre assessment of [1231] FP-CIT SPECT use in 190 patients in pre-defined diagnostic categories and with particular focus on clinical features to assess the influence of imaging in routine practice. The second is a 2 year follow-up study of 150 consecutive patients with normal SPECT, with specific attention to clinical progression and antiparkinson medication use, and includes focus on a subgroup who fulfilled PD criteria where successful antiparkinson medication withdrawal was achieved. The third is a multicentre prospective European study of the accuracy of [1231] FP-CIT SPECT in 99 patients that included serial clinical and imaging assessments. Notably, when initial diagnosis/scan mismatch cases occurred, and with awareness of the scan result, the clinician invariably changed the diagnosis in line with the scan result which confirms the considerable influence of imaging on the practising clinician. Parkinson's disease is clinically overdiagnosed early in its disease course, whereas imaging is more specific, in the vast majority of cases with normal dopaminergic imaging, there was no evidence of clinical or imaging progression which would be in keeping with degenerative parkinsonism.