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Of the three forms of human Apolipoprotein E (ApoE2, ApoE3 and ApoE4), the ?4 allele coding for ApoE4 is associated with a higher risk of developing Alzheimer's disease (AD) and an earlier age of onset, whereas ?2 may be protective. The mechanisms underlying such influences are still unclear. This thesis has investigated the influence of ApoE polymorphism on structural synaptic parameters in the middle molecular layer (MML) of the dentate gyrus of wild type (WT), ApoE knockout (KO) and human ApoE (hApoE) transgenic mice, from 6 to 24 months of age using unbiased stereological methods at the EM level. In hApoE4 mice, there was a 34% decrease in the synapse per neuron ratio (Syn/nrn) accompanied by a 22% increase in the mean apposition zone area (mAZA) during aging. This pattern resembles closely the synaptic changes occurring early in AD, which have been correlated to the first symptoms of memory loss in humans. In contrast. there was no such synaptic loss in hApoE2, ApoE KO and WT mice. At old age, hApoE4 mice had the lowest syn/nrn but their mAZA was comparable to that of other groups. These data appear to be consistent with the view that possession of ?4 is deleterious to cognitive functions in the elderly and AD patients. Notably, aged ApoE KO mice did not show any sign of synaptic degeneration, suggesting the involvement of other proteins to compensate for the lack of ApoE. At 18 months old, hApoE2 mice have a greater hippocampal volume and display the highest syn/nrn and glutamate immunogold labelling in presynaptic boutons and dendrites of the MML, compared to hApoE3 and hApoE4 mice. In AD patients, such effects of the ?2 allele may act as a synaptic 'reservoir' and delay the onset of AD symptoms. Thus these lines of hApoE transgenic mice could provide a good basis for the future production of multiple transgenic mice in which to model AD pathogenesis.

Chronically elevated brain glucocorticoid (GC) levels impair cognition. Age-related cognitive deficits or "sickness" behaviour is often associated with neuroinflammation. In rodents, raised GC levels prior to lipopolysaccharide (LPS) administration potentiate neuroinflammation although GC suppresses neuroinflammation if administered after LPS. 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) reductase activity can increase intracellular GC levels, including in the brain, without alteration in circulating levels. Deficiency/pharmacological inhibition of 11β-HSD1 is protective against age related cognitive impairment in both rodent and humans. However, the underlying mechanism remains unclear. 11β-HSD1 reductase activity is coupled to hexose-6-phosphate dehydrogenase activity, itself dependent on cellular energy status. Processes affected by deficiency/inhibition of 11β- HSD1 (e.g. acute inflammation, angiogenesis) are associated with increased glycolysis. Additionally, compared to C57BL/6J controls, adipose tissue of 11β-HSD1 deficient mice shows increased expression of glycolytic and oxidative metabolism genes in a rodent model of obesity, characterised by low-grade chronic inflammation. I hypothesised that 11β-HSD1 has a role in regulation of cellular energetics basally and following inflammation. 11β-HSD1 expression in the brain will be up-regulated during systemic inflammation. Following inflammation, 11β-HSD1 deficiency will attenuate the pro-inflammatory response and subsequently alter energy substrate uptake and/or utilisation in the key areas of brain (i.e. hypothalamus and the hippocampus) that sense and respond to inflammation and energy balance. To test my hypothesis, global 11β-HSD1 KO mice, primary macrophages in vitro and murine models of inflammations were utilised. 11β-HSD1 mRNA and protein expression were confirmed in the hypothalamus and the hippocampus of C57BL/6J mice. In the absence of inflammation, expression of inflammatory markers is low or negligible in the brains of Hsd11b1-/- mice similar to C57BL/6J controls. However, compared to C57BL/6J, Hsd11b1-/- mice show altered mRNA levels of metabolic transporters and enzymes in the hypothalamus and the hippocampus. Overall, the mRNA profiling suggests reduced dependence on glucose in the brains of Hsd11b1-/- mice, either through increased lactate availability (in the whole brain and hippocampus) or through increased glycolysis and mitochondrial number/function (in the hypothalamus). Primary macrophages were utilised to investigate the role of 11β-HSD1 in cellular energetics in vitro. In these cell based assays, glycolysis was found to be the predominant glucose metabolising pathway in C57BL/6J primary macrophages, consistent with the literature. Preliminary data suggested reduced glycolytic activity in Hsd11b1-/- compared to C57BL/6J primary macrophages. However, initial attempts to utilise these cell based assays on primary microglia were unsuccessful. Moreover, Hsd11b1 mRNAs in the brain (down-regulation with inflammation, discussed later) was found to be differentially regulated in comparison to Hsd11b1 mRNA levels in the macrophages (up-regulation with inflammation) hence further investigation was not pursued. To identify a model of peripheral inflammation where 11β-HSD1 is regulated in the brain in vivo, Staph. aureus induced acute lung inflammation and the K/BxN serum transfer induced model of arthritis were utilised. Increased expression of inflammatory markers in the brain was associated with reduced Hsd11b1 mRNA levels in the hippocampus of control mice in these models. Comparison of Hsd11b1-/- and C57BL/6J mice showed increased levels of mRNAs encoding metabolic transporters in the hypothalamus and the hippocampus of Hsd11b1-/- mice following inflammation in the K/BxN serum transfer model of arthritis suggesting increased energy substrate availability. Additionally, increased levels of mRNA encoding metabolic enzymes suggested increased glycolytic capacity and mitochondrial oxidative phosphorylation activity in the hippocampus but not the hypothalamus of Hsd11b1- /-, compared to C57BL/6J mice, following K/BxN serum induced arthritis. Overall, these data suggest that the reduction in expression of 11β-HSD1 could be a potential mechanism to increase energy substrate availability, glycolytic capacity and mitochondrial activity in the hippocampus to provide metabolic support for neuronal metabolism and function following peripheral inflammation. The role of 11β-HSD1 in the pro-inflammatory response and cellular energetics in the hippocampus was further investigated in a well characterised sterile peritonitis model of systemic inflammation in which a low to moderate dose of LPS was used. Mice were administered LPS or vehicle (0.9% saline) by a single i.p. injection and culled 3h, 6h or 9h post injection. Inflammation resulted in significant reduction in burrowing activity both in Hsd11b1-/- and C57BL/6J mice suggesting sickness behaviour.. The number of circulating immune cells, as a measure of peripheral inflammation, did not differ between genotypes. Similarly, plasma corticosterone levels were elevated following inflammation but no genotype difference was observed. However, levels of plasma 11-dehydrocorticosterone, the inert substrate for 11β- HSD1, were significantly elevated in the Hsd11b1-/-, compared to C57BL/6J mice, following inflammation. Levels of mRNA encoding inflammatory markers were lower in the hippocampus of Hsd11b1-/-, compared to C57BL/6J mice, following inflammation. Also, Hsd11b1 mRNA levels were reduced in the hippocampus of C57BL/6J mice following inflammation, consistent with the finding above. Principal component analysis on levels of mRNA encoding metabolite transporters and enzymes revealed a distinct metabolic response in the hippocampus of Hsd11b1-/-, compared to C57BL/6J mice, 6h post LPS. At the same time point in the hippocampus, levels of mRNAs encoding metabolite transporters and enzymes suggested an attenuated switch to aerobic glycolysis with maintenance of mitochondrial function/activity. Quantification of hippocampal energy metabolites using targeted metabolomics in the Hsd11b1-/- compared to C57BL/6J mice 6h post LPS showed correspondence with the mRNA results. Overall, these results suggest that reduced expression of 11β-HSD1 could be a potential mechanism to reduce the pro-inflammatory response and provide better metabolic support for neuronal function and metabolism in the hippocampus, following systemic inflammation. In summary, the current work provides evidence for neuroprotection with 11β-HSD1 deficiency, following systemic inflammation. The suggestive neuroprotection is at least in part mediated via an attenuated pro-inflammatory responses and increased energy substrate uptake and/or utilisation providing better metabolic support for neuronal function following inflammation. It argues for the development of tissue specific small molecule inhibitors of 11β-HSD1 that can cross the blood brain barrier as therapeutic agents against the adverse cognitive effects of systemic inflammation and/or inflammaging.

>Magister Scientiae - MSc / Parkinson’s disease (PD) is a neurodegenerative disorder that occurs due to a loss of dopaminergic neurons in the substantia nigra. It is one of the most common neurodegenerative disorders, ranking second only to Alzheimer’s disease. Research on the genetic causes of PD over the past two decades has led to the discovery of several PD-associated genes. Currently, researchers have identified 23 genes that are linked to rare monogenic forms of PD with Mendelian inheritance. In sub-Saharan Africa (SSA), PD has received little attention due to factors such as underfunded healthcare infrastructure, the absence of epidemiological data, and a scarcity of neurologists. In the relatively few published studies, it has been shown that the known PD mutations play a minor role in disease etiology in SSA populations. In the current study, we follow up on previous work done in an MMed study investigating a South African family with several family members (mother and three sons) suffering from PD. / 2023

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The goals of the present research were two fold: first to examine an acute head injury sample to test memory functions, second to study what parts of the memory process are most affected during post traumatic amnesia with special emphasis on retrieval of structured material in delayed recall. Subsidiary interests include studying recovery and the relationship between memory functioning and severity of injury. After head injury a common complaint is a transitory period of amnesia for recent events (PTA). PTA is often thought of as one stage in the recovery of consciousness and is believed to be an index of neurological severity. A model was proposed to account for amnesia. Two separate memory mechanisms prior to permanent storage were hypothesized, one for short term and the other for long term storage. Inputs are coded on the basis of recurrent patterns of common features. Retrieval occurs by means of the coded representation. Amnesia is viewed as a malfunctioning of the coding mechanism. Amnesia is thus held to be an inability to fully utilize coding of stimulus material as an aid in recall. Following this theory, it was predicted that the perceptive and cognitive functions were operating in amnesia and that immediate recall was also unimpaired. The major prediction was that retrieval of structured stimulus material by delayed recall would be impaired compared to normals, while retrieval of unrelated stimulus material would be unimpaired. Retrieval by recognition would only be mildly impaired because less information is required for recognition than for recall. Hence, the memory event can be reconstructed in recognition on the basis of partial coding. It was further predicted that, with recovery, there would be improvement of memory functioning and that there would be a relationship between severity of injury and memory functioning. A Memory Scale was constructed which included four subtests designed to test the above theory. Each subtest included both related and unrelated stimulus material. An additional test (a Picture Similarities Test) was employed to measure conceptualization. Forty seven acute head injury patients were tested as soon after injury as possible and matched with forty four control subjects (patients with acute trauma, but no head injury) on the basis of age, education, occupation and performance on the Ammons Picture Vocabulary Test. Head injury patients with approximately normal intelligence (Ammons I.Q. 80 or above) followed the predictions with these exceptions: Immediate recall and recognition of related stimulus material showed a trend toward impairment, though immediate recall and recognition of unrelated stimulus material did not. The findings with the patients with normal intelligence suggest, that while cognitive and perceptual abilities are not affected by trauma, utilization of organization as an aid in recall of related stimulus material is not as effective in the experimental· as in the control group. Head injury patients with low I.Q.'s (79 or below on the Ammons) demonstrated impairment of perception and immediate recall as well as the predicted impairment of delayed recall. These patients appeared to exhibit a generalized cognitive disturbance. No definite trends toward recovery were observed on any of the memory tests. There was also no relationship between severity of injury and performance on the Memory Scale. However, there was a significant correlation between performance on the Ammons and Picture Similarities tests and neurological severity. Patients with the lowest scores on these tests were most impaired neurologically. Intelligence thus appears to be more closely associated with severity of injury than is memory functioning per se. / 2031-01-01

No / In recent years there has been a resurgence of interest in the use of arts, humanities and media-based approaches to teaching students in medicine, health, and social care-related disciplines. Here, it is widely assumed that 'the arts' are an undifferentiated force for good which will humanise curricula dominated by medical and scientific perspectives. Such approaches tend, however, to be implemented in something of a theoretical vacuum with little consideration of critical perspectives derived from cultural studies. 'Cinemeducation' is a term recently coined for the use of mainstream films which touch on particular medical conditions or 'disorders' in the education of medical students (Alexander et al, eds 2005). What is overlooked by advocates of this approach is that such films often perpetuate stereotypical views of the nature and causes of physical and emotional ill-being, and collude in their medicalisation. Scriptwriters and directors may also give in to the temptation to sensationalise or misrepresent conditions because this makes for box office success. Finally, there are subtleties related to denotation and connotation in film which mean that little can straightforwardly be assumed about educational outcomes. This presentation will draw on a study of both independent and mainstream films related to memory loss and cognitive impairment in the context of my own teaching in dementia studies, and will include clips from source material. Drawing on Ricoeur's concept of the hermeneutics of suspicion I seek to introduce a note of caution to the current 'arts and health' agenda.

Dans ce travail de recherche en psychologie clinique et psychopathologie, nous interrogeons la dimension de l'oubli dans la démence chez des personnes âgées. Plus spécifiquement, nous questionnons les mécanismes qui sous-tendent l'oubli, ses effets chez le patient et dans la relation ; ainsi que les techniques thérapeutiques spécifiques à mettre en place. L'utilisation du dispositif de psychodrame de groupe nous permet de mettre à jour des possibilités de traitement de l'oubli démentiel. Le fonctionnement groupal facilite une relance des fonctions psychiques de maintenance, de contenance et de pare-excitations des sujets déments. Les passages par le corps, l'affect et la motricité permettent de réaccéder à des traces corporelles, non verbales et de relancer un travail de représentation. La démarche de réminiscence se constitue dans le groupe, dans l'articulation des psychés en présence ; en ce sens nous parlons de construction intersubjective du souvenir. Dans notre pensée l'oubli démentiel apparaît comme une tentative adaptative du sujet face à la désorganisation démentielle. Nous distinguons deux formes d'oublis : une forme sidérative qui attaque la trace mnésique et provoque une déconstruction momentanée de l'inscription. Une forme progressive qui désinvestit les liens associatifs entre les différentes traces mnésiques, et coupe pour un temps l'inscription du réseau de sens. / This study in clinical psychology and psychopathology explores the extent of memory loss amongst the elderly. More specifically, it examines the mechanisms underlying memory loss and the effects of this mental condition on both the patient and the patient's relationships. Another aspect of our research is to develop new therapeutic techniques using group psychodrama which gives us greater insight on the possibilities of treatments for memory loss dementia patients. The psychic functions are facilitated by group therapy which boosts the abilities of memory by volume, capacity and participation in dementia subjects. By looking at the body, the affects and motor skill, permit us to see the physical traits, the non-verbal traits and continue working to better their performance. In the psyche of the group we can see that this approach establishes a joint ability to recollect in the present; we are speaking about the intersubjectivity of collective memory. As we see it, memory loss dementia appears as an adaptive attempt by the subject confronted with disorganizational dementia. We can distinguish two forms of memory loss; one in which the end result attacks the traces of memory and provokes an unraveling of the ability to remember and a progressive form which reduces the associative links between the different forms of remembrance and cuts for a time the ability of memory to link to other senses.