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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
151

A psychophysiological investigation into fluctuating levels of consciousness in neurodegenerative dementia

Walker, Matthew Paul January 1999 (has links)
No description available.
152

Neurobiological changes in bipolar affective disorder

El-Badri, Selim Mohamed January 1998 (has links)
No description available.
153

On the involvement of the rat nucleus accumbens in instrumental performance

De Borchgrave, Rupert January 1995 (has links)
No description available.
154

A comparison of neuropsychological test performance on the Ravello Profile between bulimia nervosa and anorexia nervosa

MacDonald, Kirsty January 2011 (has links)
Background The Ravello Profile is a battery of standardised neuropsychological measures of areas of functioning that evidence indicates are impaired in Anorexia Nervosa (AN), namely visuo-spatial functioning, central coherence and executive functioning. The neuropsychological profile of individuals with Bulimia Nervosa (BN) is less well established. The current study aimed to examine differences in cognitive performance between people with BN, AN and non-eating disordered controls on the Ravello Profile. Methods The AN group (N=60) comprised participants from an existing database (Frampton et al. 2009). The BN group (N=22) largely comprised participants from NHS adult out-patient services. The non-eating disordered control group (N=20) comprised of colleagues and acquaintances of the researcher. Differences between AN, BN and control samples on visuo-spatial functioning, central coherence, executive functioning and error rates were examined. Results The AN group performed significantly worse than the BN group on a measure of central coherence and on some measures of executive function, but the BN group did not perform worse than the control group. There was no significant difference between the groups on three measures of visuo-spatial functioning. However, the AN group was significantly slower than both the BN and control group to copy the figure. The results showed some evidence of increased error rates in BN relative to AN, which may reflect greater impulsivity in BN. Conclusions The results indicate separate patterns of neuropsychological performance between AN, BN and controls, with AN demonstrating poorer performance on measures of executive function and central coherence, whilst BN participants showed higher rates of errors. The BN group were also generally faster to complete some tasks, indicative of a preference for speed over accuracy or impulsivity. Those working with individuals with AN or BN should take into consideration possible effects of their respective cognitive limitations and adapt interventions accordingly.
155

Neural basis of energy balance and growth in photoperiodic mammals

Reilly, Laura January 2009 (has links)
The Siberian hamster and Fischer 344 (F344) rat exhibit strong natural alterations in body weight that are programmed by the ambient photoperiod and allow preparation for the approaching season, whereby they have a lower body weight in winter-like photoperiods (8 h light per day). The mechanisms that permit this dynamic regulation of body weight may identify novel targets for anti-obesity drugs. Siberian hamster studies involved analysis of photoperiod-driven gene expression changes in the hypothalamic paraventricular nucleus using tissue obtained by laser capture microdissection.  Juvenile F344 rats were susceptible to diet-induced obesity and defended a photoperiod-sensitive rate of lean mass deposition.  In addition, mRNA levels of various genes were found to be photoperiodically regulated in the mediobasal hypothalamus (MBH) including traditional energy balance genes and growth-related genes (e.g. neuropeptide Y and growth hormone releasing hormone). Furthermore, a time course study using Affymetrix arrays was used to analyse the changes in gene expression following 3 d, 14 d and 28 d of exposure to long or short photoperiod in the MBH.  Dramatic changes in gene expression in the thyroid hormone system were found at all time points and confirmed by <i>in situ</i> hybridisation.  The changes found correlated with recent findings in the quail and sheep documenting thyrotropin release from the pituitary regulating thyroid hormone levels in the MBH.  These studies also identified strong photoperiodic regulation of two novel systems related to the thyroid hormone axis; the retinoid and Wnt signalling pathways. Thus, these studies establish the F344 rat as an interesting seasonal animal model and further understanding of the underlying mechanisms of photoperiodism.
156

Exploring block and permeation of N-methyl-D-Aspartate (NMDA) receptor channels for treatment of neurodegenerative disorders

Abu, Izuddin Fahmy January 2016 (has links)
N-methyl-D-aspartate receptors (NMDAR) are ionotropic glutamate receptors which can be blocked by Mg2+ in a voltage-dependent manner and are highly permeable to Ca2+, hence they represent a medically relevant target for neurodegenerative disorders caused by excitotoxicity. The two main objectives of this study were, (i) to determine the impact of Q/R/N, +1 and -8 sites modification in the M2 pore region of GluN2A NMDAR subunit on Mg2+ block and other open channel blockers; and (ii) to evaluate novel multi-target-directed ligands (MTDL) for Alzheimer’s disease therapy. The Xenopus laevis oocyte expression system was employed where NMDAR subunit cRNAs were injected into the oocytes and responses to NMDA/glycine and channel blockers were recorded using two-electrode voltage clamp (TEVC) electrophysiology. Pore region mutations to investigate the impact of Q/R/N and adjacent sites were characterized using Mg2+, memantine, MK-801, philanthotoxin analogues and an MTDL compound, CR18. NN at the Q/R/N and +1 sites in GluN2A subunits were mutated to GR and RR, while W at the -8 position (in relation to the Q/R/N site), was mutated to N. Wild type and mutated GluN2A were co-expressed with GluN1-1a in Xenopus oocytes and antagonistic responses by channel blockers were recorded with TEVC. At -75 mV, the RR mutation significantly increased IC50s of Mg2+, memantine and MK-801 by 27-, 42- and 325-fold respectively, compared to wild-type. As for the GR mutation, IC50s were also significantly increased for memantine and MK-801 by 5- and 132-fold respectively, compared to wild type. W to N mutation at the -8 position did not significantly affect blocking potencies for all channel blockers. Blocking potency for PhTX-343 was not significantly altered by any mutations. This study provided evidence that the presence of G and R at the Q/R/N and +1 sites are likely responsible for the changes in blocking sensitivity and play important roles in ion permeability. The fact that PhTX-343 remained potent despite the mutations suggest that this compound might have a different mode of action or different binding site other than the M2 region and should be further characterized. In the MTDL study, twenty one novel compounds were tested on GluN1-1a/GluN2A NMDAR subunits. Thirteen were memantine-derivatives (MAB) incorporated with antioxidant moieties, three were spermine-derived polyamines also incorporated with antioxidants, and five were combinatorial forms of donepezil and carvedilol. The antagonistic properties of the compounds were tested electrophysiologically at -60 mV and compared with Mg2+ and memantine. The MAB series were found to be weak NMDAR channel blockers suggesting the loss of memantine functionality due to attachment of the antioxidant structure to its amine group. Subsequently, modification of the linker point to memantine moieties to free its amine group eventually resulted in weaker NMDAR channel blockers with IC50s of more than 100 µM. The spermine-derived polyamines (CR compounds) were potent NMDAR blockers with IC50s (0.69 to 2.35 µM) comparable to memantine (2.28 µM) and significantly lower than Mg2+ (10.1 µM) and also exhibited voltage-dependence block. Our mutation study revealed that CR18, the most potent MTDL compound was less sensitive in NMDAR containing GR or RR mutation in GluN2A subunits. This is a favourable property of an NMDAR blocker for potential Alzheimer’s disease treatment since GluN3 subunits containing GR or RR at the Q/R/N and +1 sites are less permeable to Ca2+ influx and has been shown to exert neuroprotective effects.
157

Cognitive Control in Schizophrenia

Eich, Teal January 2014 (has links)
Schizophrenia is the ninth leading cause of disability worldwide (e.g., Lopez et al., 2006), and is a devastating psychiatric illness. Although diagnosis is made based upon the occurrence of positive and negative symptoms (First, Spitzer, Gibbon & Williams, 1995), it is the cognitive symptoms that are most strongly associated with functional outcome (Green, 1996 ). Cognitive control, including the ability to appropriately update relevant information and resist interference from irrelevant information, is critical for flexible and adaptive goal-directed behavior, and is among the most frequently noted of the cognitive symptoms in schizoprenia (Barch, 2005; Barch & Smith, 2008). Despite this, deficits in cognitive control are unaffected by medications used to treat the clinical symptoms of the disorder (Greene et al, 2008). Understanding both the behavioral and the neural mechanisms that comprise this deficit is thus of paramount importance. Although deficits in cognitive control in schizoprenia have been extensively studied, a number of questions still remain. Here, I ask two main questions: First, is cognitive control impaired globally, or are only certain aspects of cognitive control impaired in schizophrenia? I found that that there are (at least) two different selection mechanisms, and that people with schizophrenia are impaired in only one of these: dysregulation in left posterior ventrolateral prefrontal cortex correlates with impaired behavioral performance on a working memory task, suggesting that deficits in inhibiting irrelevant information from working memory is the crux of the deficit. Second, I asked whether the nature of the information affects cognitive control. I found that people with schizophrenia are able to deploy cognitive control processes more effectively than healthy controls in cases in which salient, emotional information competes with active cognitive goals, suggesting specific underlying deficits in emotional processing.
158

Investigating genetic variation in Alzheimer's disease

Patel, Tulsi January 2018 (has links)
Alzheimer's disease (AD) is the most common form of dementia, now the leading cause of death in the UK, which affects more than 35 million people worldwide. Genome-wide association studies identified 20 genetic loci associated with disease susceptibility, however these only exerted small effects on risk. Next-generation sequencing is now being employed to identify more of the missing heritability. This project utilised whole-exome sequencing to explore genetic variation using the Brains for Dementia Research (BDR) resource, a well-characterised cohort of neuropathologically confirmed samples. Exome-wide and candidate gene approaches were employed to assess coding variants for association with AD, using single-variant and burden tests. Coding variants in other neurodegenerative disease genes were also analysed as potential susceptibility factors for AD. Furthermore, polygenic risk scores (PRS) were generated to explore the ability to classify case and control individuals based on their genetic profiles. A synonymous variant in PILRA (rs2405442) was nominally associated with 3-fold increased risk of AD, also contributing strongly to PILRA burden. It was previously linked to AD through risk gene ZCWPW1; however, it has not been directly associated until now. Additional variants in GWAS gene ABCA7 (rs3764645, rs3752234, rs3752237, rs4147915) and rare variants in CLU were also implicated, further supporting their roles in AD susceptibility. A variant in PD gene LRRK2 (rs35303786) inferred protection against AD, implicating potential pleiotropy across the two diseases. PRS could distinguish AD cases from controls with 85.3% accuracy and also identified controls with high PRS but no cognitive impairments. This could be useful for identifying individuals at risk of developing AD in the future. We have uncovered tentative associations both in established and newly identified loci; highlighting several interesting candidates for further investigation. Although there remains a large amount of missing heritability, we hope that as the BDR resource grows, we will achieve increased power to detect significant associations with AD.
159

Development and analysis of CTG repeat expansion cell lines to understand molecular events in myotonic dystrophy type 1

Malik, Naveed Altaf January 2018 (has links)
Myotonic dystrophy type 1 (DM1) is a dominant human neuromuscular disorder caused by a CTG repeat expansion at the 3' end of the DMPK gene. Pathogenesis of DM1 is linked to a toxic gain of function due to mutant RNA and is manifested by nuclear retention of expanded CUG repeats and aberrant splicing. The development of an inducible model for DM1 with uninterrupted CTG repeats could help us to better understand early pathogenic changes in DM1 due to CUG repeat expansion. In the first part of this thesis, I report an inducible C2C12 mouse myoblast cell line in which the pTetOne inducible system was used to express 174 CTG repeats. This resulted in the production of RNA foci in 26% of cells. Efforts to make larger un-interrupted CTG repeats were unsuccessful due to their instability in the E.coli plasmid. In the second part of the thesis, I used the CRISPR/Cas9-induced genome-editing technique to knock-in an inducible promoter into the endogenous DMPK gene in a DM1 fibroblast cell line. For this, I employed two different CRISPR/Cas9 based strategies which exploit homology-directed repair (HDR) and non-homologous end joining (NHEJ). Our results suggest that CRISPR/Cas9 induced knock-in is enabled by non-homologous end joining more efficiently as compared to homology-directed repair. In the last part of the thesis, TruSeq RNA Sequencing was used to quantify the number of mutant DMPK transcripts and other molecular markers of DM1 pathogenesis that could be a valuable tool for the evaluation of the efficacy of therapeutic compounds. The sequencing results reveal the significant low abundance of mutant DMPK transcripts in the cytoplasmic fraction of DM1 lines and confirm the previously reported nuclear retention of mutant DMPK transcripts. We identify six potential genes which are dysregulated in DM1 fibroblasts and the absolute quantification of mutant DMPK transcripts along with these six reported dysregulated genes can be suitable biomarkers for disease severity and therapeutic response in DM1 fibroblasts. Additionally, these assays could be further refined to provide valuable tools to assess therapeutic compounds.
160

Neuropsychological predictors of conversion from amnestic Mild Cognitive Impairment (aMCI) to dementia : a 4-year clinic-based longitudinal study

Lonie, Jane Alexandra January 2010 (has links)
Background: Elderly people who demonstrate memory impairment that falls short of dementia, are referred to as having amnestic Mild Cognitive Impairment (aMCI). AMCI patients have an elevated risk of developing dementia, although not all will do so. Clinical criteria for Alzheimer's Disease (AD) and aMCI do not specify how impairment of a cognitive nature should be defined. The process of differentially diagnosing these conditions can be improved, if knowledge of neuropsychological measures that best discriminate between neurodegenerative and non-neurodegenerative cognitive impairment is used to implement diagnostic criteria for aMCI and AD. Aims: We sought to 1) determine the frequency of aMCI referrals to our specialist memory clinic, 2) characterise the detailed neuropsychology of a group of patients with aMCI, 3) determine the utility in differential diagnosis and test-retest reliability of these neuropsychological measures, and 4) establish a subset of neuropsychological measures that were of prognostic utility in aMCI. Methods: The case notes of 187 consecutive referrals received by our Royal Edinburgh Hospital memory assessment service across an 18-month period were reviewed retrospectively and numbers of patients fulfilling aMCI criteria were recorded. The baseline neuropsychological performances of 46 patients with aMCI, 20 patients with very early stage AD, 20 elderly patients with depressive symptoms and 24 healthy elderly participants were compared in order to determine their usefulness in differential diagnosis. AMCI participants were followed-up across an average of 4 years. Baseline neuropsychological performances of the aMCI dementia converters and aMCI non-converters were compared. Logistic regression analysis was applied to ascertain the predictive accuracy of a combination of these. Results: One quarter of referrals received by our memory assessment service met criteria for aMCI, most of whom displayed additional neuropsychological impairments of a non-memory nature, all the while performing above the highest cut off points on even the most comprehensive dementia screening measures. A number of neuropsychological measures were highly sensitive and specific to early AD however, similar combinations of both high sensitivity and specificity to aMCI were not achieved. Forty one percent of patients presenting to our service who fulfilled criteria for aMCI, received a clinical diagnosis of dementia across an average 4-year period. Performances on a comprehensive cognitive screening measure and a measure of delayed word recognition accuracy at baseline, classified 74% of aMCI patients comprising our clinic sample in accordance with their prognostic fate. Conclusion: A significant proportion of patients presenting to specialist memory clinics display episodic and semantic memory or executive impairment that falls short of dementia and that is not detectable using traditional bedside screening measures. The vast majority of such patients (i.e. 72%) experience persisting or progressive cognitive impairment, and a significant proportion (41%) go on to receive a clinical diagnosis of dementia. The baseline neuropsychological performance of aMCI patients who do and do not develop dementia differs, and contributes over and above clinical information to the prediction of long-term diagnostic outcome. The high frequency with which aMCI is encountered in clinical practice, coupled with the minority of aMCI patients who experience resolution of their cognitive impairment, and the sensitivity and prognostic utility of several neuropsychological tasks, has implications for the clinical management of patients with aMCI.

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