published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

This thesis focused on the spatiotemporal patterning of classical excitatory and inhibitory synaptic contacts accounting for the majority of cerebral cortical connections, in relation to ageing and cognitive status. These investigations tested the hypothesis that higher CNS functions depend on the balance between excitatory and inhibitory synaptic connections. Glutamatergic and GABAergic presynaptic bouton densities were determined in aged animals segregated according to their cognitive status into aged and cognitively unimpaired (AU) and aged and cognitively impaired (AI), using the Morris water maze. These two groups were compared in terms of behaviour and the pattern of excitatory and inhibitory synapses. It was evident that an excitatory and inhibitory presynaptic decline is associated with age-related cognitive impairments; whereby both glutamatergic and GABAergic boutons gradually diminish from young to AU to AI. Nevertheless, the balance between excitatory and inhibitory presynaptic inputs was maintained. To determine whether postsynaptic sites differed with respect to ageing and cognitive impairments, excitatory and inhibitory postsynaptic scaffold proteins were investigated in the same cohort of segregated aged animals. There was an imbalance in density ratio between immunoreactive sites of excitatory versus inhibitory postsynaptic scaffold proteins in AI animals. This resulted from a marked decrease in the density of excitatory postsynaptic sites. To further investigate ultrastructural aspects of excitatory synapses I carried out electron microscopical studies of cerebral cortex to measure the abundance of NR2 receptor subunits of the NMDA receptor- a receptor site directly associated with excitatory postsynaptic scaffold proteins. This study revealed that NR2 immunoreactive sites were largely preserved during age-related cognitive decline with an uneven profile distribution. Finally, protein expression of specific receptor subunits and key proteins representative of excitatory and inhibitory postsynaptic sites was investigated by semi-quantitative Western blot analyses in selected cortical areas. It was clear that many of these postsynaptic proteins are affected by age and cognitive status. The most striking change was a marked up-regulation in neuroligin-1 in AI animals, which may affect the delicate balance between excitatory versus inhibitory synaptic inputs. Another notable finding was the down-regulated expression of GluR2 receptor subunits in AI animals, which should have implications for neuronal Ca2+ regulation. In conclusion, we have demonstrated the greater vulnerability of excitatory postsynaptic sites in aged and cognitively impaired animals.

While most people with schizophrenia face the functional consequences of a lifelong disorder, very few studies have investigated the specific domain of daily living activities performance. The purpose of this thesis was to examine the relationships between daily activity performance, cognitive deficits, and community functioning in people with schizophrenia. More specifically, the objectives were: 1) to describe functional limitations during daily task performance, 2) to explore the existence of subgroups of participants with similar functional limitations profiles, 3) to explore the relationships between daily task performance and cognitive functions as well as 4) with community functioning. This thesis tested the hypothesis that limitations in task performance negatively influence community functioning. / A sample of 82 individuals with schizophrenia and 28 healthy controls participated in this study and were assessed during a meal preparation task with the Perceive, Recall, Plan and Perform (PRPP) System of Task Analysis and on cognitive tests of visuospatial memory, spatial working memory, visuomotor coordination, planning and selective attention. Community functioning was assessed with the Independent living Skills Survey and the Multnomah Community Ability Scale. Limitations in the Perceive, Recall and Plan quadrants of the PRPP System, were found in participants with schizophrenia when compared to a control group (n = 28), as well as in the complete sample (n = 82). Participants in the high-efficiency subgroup ( n =36) were more independent in daily living and performed better on the visuospatial associative learning task than the low-efficiency subgroup (n = 46). At the specific level of individual profiles, participants were distributed along a continuum of low- to high-functioning on the PRPP System factors and on functional, cognitive, and clinical characteristics. / The associative learning task was most associated with task performance, along with working memory and planning. Finally, less efficient planning skills were associated with a lower level of community functioning, confirming the hypothesis. These results emphasize the relationship of associative visual memory to daily task performance, as well as that of efficiency in daily activities for residential status. Integrating these findings into the rehabilitation process will contribute to better meeting the needs of people with schizophrenia.

Integral (holistic) and separable (analytic) processing were studied in ADD-H and normal children using restricted classification tasks composed of separable dimensions and triad/tetrad combinations. In Studies One and Three classifications of ADD-H children and controls were compared on size/brightness and length/density combinations. In Study Two classifications of four age groups of normal subjects (mean ages 5-3, 7-9, 11-1 years and adults) were compared on size-brightness combinations. ADD-H children demonstrated significantly fewer separable responses than normal controls only on the tetrads. Normal subjects showed a developmental trend towards differential separable responding to size as compared to brightness. ADD-H children appear to show a lag of about two years on this developmental trend. Results suggest that ADD-H children resort more readily than normals to integral responding under increased processing load. Results are discussed in terms of the cognitive deficits of ADD-H children and current theories of perceptual differentiation.

Despite the overwhelming evidence for atrophy of the NGF-dependant Basal Forebrain Cholinergic neurons during aging, there is no persuasive evidence towards a decrease in NGF and/or NGF mRNA content in the brain of aged animals. Previous experiments from our laboratory have shown that NGF is released as a precursor protein and cleaved into the mature form in the extracellular space under the influence of a complex protease cascade. These recent findings have lead us to propose that any alterations in levels and/or activity of this maturation/degradation cascade might affect NGF's biological activity and perhaps lead to cognitive impairments in a subset of aged rats. To investigate this possibility, we measured protein and mRNA levels of the protease cascade players (NGF, pro-NGF, tPA, plasminogen, plasmin, MMP-9, neuroserpin). We found significantly decreased levels of both pro-NGF protein and NGF mRNA, but no difference in the remaining elements of the protease cascade, when comparing aged impaired (Al) to the aged unimpaired (AU) animals. Our second objective was to investigate whether animals trained in the Morris Water Maze would preserve their cognitive status in two additional behavioral paradigms, the Novel Object Location (NOL, spatial memory) and Novel Object Recognition (NOR, nonspatial memory) tasks. We found that both AU and AI animals in the MWM were impaired in the NOL when compared to the young controls, with the AI animals performing significantly worse than the AU in this particular task. In the NOR tasks, AI animals performed significantly worse compared to both young and AU animals. In conclusion, further experiments are required to better understand the implication of the complex protease cascade involved in NGF's maturation and degradation as well as its effect on memory of aged animals. In addition, because the segregation of animals (aged impaired/unimpaired) is a crucial step in aging research, we now have additional behavioral paradigms (NOL/NOR) that confirm the cognitive status of these animals.

The purpose of the study was to validate the use of the Geriatric Functional Rating Scale (GFRS) in assessing cognitively impaired individuals 65 years of age and older to determine the need for institutionalization. The population of interest consisted of individuals 65 years of age and older exhibiting cognitive impairment and residing in Delaware County, Indiana. A nonrandomized two-group experimental design was utilized for the study. Eighty subjects were selected from two subpopulations consisting of 40 institutionalized and 40 noninstitutionalized elderly.Two geriatric assessment tools were used for the study, the Mental Status Questionnaire (MSQ) and the Geriatric Functional Rating Scale (GFRS). The hypothesis for the study stated that the mean GFRS score of the noninstitutionalized subjects, the control group, would be significantly greater than the mean score of the institutionalized subjects, the experimental group.The MSQ scores as well as the means and standard deviations for the seven subscales of the GFRS were reported for the two groups. A one-tailed t-test was used to test the hypothesis. A decision with regard to the hypothesis was made at the .05 level.Findings of the study included the following:1. The subjects ranged in age from 65 to 92 years, were 90 percent female, and predominantly Protestant, 88 percent.2. The MSQ scores for the combined groups ranged from minimal cognitive impairment, 71 percent, to severe cognitive impairment, four percent.3. The total mean score on the GFRS for the institutionalized group was 6.8 indicating a need for institutionalization.4. The total score on the GFRS of the noninstitutionalized was over 10 times higher at 70.7.5. The noninstitutionalized group scored significantly higher in the GFRS (p<.00) than the institutionalized counterparts.In conclusion, the research supports the use of the Geriatric Functional Rating Scale in assessing the need for institutionalization in cognitively impaired individuals, 65 years of age and older in Delaware County, Indiana. / Department of Educational Administration and Supervision

A growing body of research suggests that substantial variability exists among cognitive abilities within individuals. This within-person variability, across cognitive domains is termed dispersion. The present study examined 304 non-demented, older adults to investigate the relationship between aging and the dispersion of cognitive functions in both a quantitative (overall levels of dispersion) and qualitative manner (patterns of dispersion). Quantitatively, higher levels of dispersion were observed in older-old adults and those identified as having suffered cognitive decline, suggesting that dispersion level may serve as a marker of cognitive integrity. Qualitatively, three distinct dispersion profiles were identified through clustering methods and found to be related to demographic, health and performance characteristics of the individuals displaying the particular profile patterns, suggesting that the patterns of dispersion may be a meaningful indicator of individual differences.

Doctor of Philosophy(PhD) / In recent years there has been a substantial increase in research examining the role of subjective memory complaints (SMC) in cognitive function and Alzheimer’s disease. These studies have related SMC to many different cognitive outcomes, such as retaining normal cognitive function, a fluctuating cognitive performance and the development of Alzheimer’s disease. Most of these studies have focused on older populations and have employed a limited assessment of cognitive function. This limits the available evidence regarding the clinical utility of SMC. The literature on the role of SMC in younger subjects is scarce. It is not known whether memory complaints are useful in predicting future cases of Alzheimer’s disease in younger community-based subjects. Aims: The main aim of the present study was to determine whether SMC predict the development of cognitive impairment in a younger cohort of subjects, many of whom were under the age of 70 years (73%), based on their risk profile and neuropsychological assessment. A further aim was to ascertain whether the DRS or 7MS are sensitive screening tools for MCI and examine whether the presence of SMC affects the 3-year cognitive outcome of subjects. To address these aims, this study consisted of two parts: a cross-sectional design and a longitudinal follow-up component. Methods: This study was carried out with 86 community-dwelling subjects recruited via advertisement within the catchment area of Central Sydney Area Health Service. The mean age of the subjects was 63.1 years (SD=8.4). Subjective memory complaints were assessed using a single question. Cognitive function was assessed using a comprehensive battery of tests, selected on the basis of their sensitivity to identifying cognitive impairment typically associated with Alzheimer’s disease. After the initial analysis between those with SMC and without SMC, subjects were further classified according to their performance on an episodic memory task (i.e., delayed verbal recall, Rey, 1964) as having normal memory function, SMC or aMCI. Results: Part 1 - Subjective memory complaints (SMC) were reported by 63% of the sample. The initial analysis between subjects with SMC (n=54) and without SMC (n=32) suggested an initial relationship between SMC and cognitive functioning. Subjects with SMC had impaired global cognitive functioning on two brief screening tests (7MS and DRS), working memory, verbal recall and visuomotor speed. However, subsequent screening with the delayed verbal recall test showed that 12 of the 54 subjects with SMC demonstrated significant cognitive impairment, scoring 2 SD below the control group mean. After these subjects were removed to form the aMCI group, the cognitive differences between subjects with SMC and without SMC were no longer apparent. Subjects with aMCI showed evidence of multiple cognitive deficits (below 1 SD of control group mean) with a high percentage of subjects demonstrating impairment on tests of verbal learning, verbal recall, verbal ability and visuomotor speed. Further analysis showed a significant association between age and subjects identified as having SMC (r=-.581, p<.001) and aMCI (r=.692, p<.001). From the age of 60 onwards, both the SMC and aMCI groups demonstrated a more rapid cognitive decline with increasing age in several cognitive domains. Part 2 - After a mean interval of 3.2 years, 43 subjects were followed up. Subjects with aMCI showed evidence of greater decline on both screening tests (7MS; DRS), whilst the SMC group had significantly higher scores. This trend was also apparent with other neuropsychological testing. The analysis of change over time in cognitive function showed that the majority of subjects (both SMC aMCI) either remained stable or improved their cognitive performance. It is likely that the small sample size and short follow-up interval of the present study contributed to the present observation of no change in cognitive function over time. Discussion: The present findings suggest that subjective memory complaints are a poor predictor of cognitive function. In isolation, SMC are unlikely to be useful for identifying cases with significant cognitive impairment. This is particularly relevant for subjects under the age of 70 years. However, for subjects over the age of 70 years, SMC are likely to identify significant cases with neuropsychological assessment (such as animal fluency and delayed recall). Conclusion: The present study showed that SMC are a poor predictor of cognitive function in subjects under the age of 70 years. This study provided evidence that selected and relatively quick to administer formal neuropsychological tests of cognitive function (in particular tests of animal fluency and delayed recall) are better able to identify those at risk of developing cognitive impairment associated with Alzheimer’s disease, at an earlier age. This would thus allow exposure to earlier treatment options, such as donepezil, aricept, vitamin E, and memantine”.

Doctor of Philosophy(PhD) / In recent years there has been a substantial increase in research examining the role of subjective memory complaints (SMC) in cognitive function and Alzheimer’s disease. These studies have related SMC to many different cognitive outcomes, such as retaining normal cognitive function, a fluctuating cognitive performance and the development of Alzheimer’s disease. Most of these studies have focused on older populations and have employed a limited assessment of cognitive function. This limits the available evidence regarding the clinical utility of SMC. The literature on the role of SMC in younger subjects is scarce. It is not known whether memory complaints are useful in predicting future cases of Alzheimer’s disease in younger community-based subjects. Aims: The main aim of the present study was to determine whether SMC predict the development of cognitive impairment in a younger cohort of subjects, many of whom were under the age of 70 years (73%), based on their risk profile and neuropsychological assessment. A further aim was to ascertain whether the DRS or 7MS are sensitive screening tools for MCI and examine whether the presence of SMC affects the 3-year cognitive outcome of subjects. To address these aims, this study consisted of two parts: a cross-sectional design and a longitudinal follow-up component. Methods: This study was carried out with 86 community-dwelling subjects recruited via advertisement within the catchment area of Central Sydney Area Health Service. The mean age of the subjects was 63.1 years (SD=8.4). Subjective memory complaints were assessed using a single question. Cognitive function was assessed using a comprehensive battery of tests, selected on the basis of their sensitivity to identifying cognitive impairment typically associated with Alzheimer’s disease. After the initial analysis between those with SMC and without SMC, subjects were further classified according to their performance on an episodic memory task (i.e., delayed verbal recall, Rey, 1964) as having normal memory function, SMC or aMCI. Results: Part 1 - Subjective memory complaints (SMC) were reported by 63% of the sample. The initial analysis between subjects with SMC (n=54) and without SMC (n=32) suggested an initial relationship between SMC and cognitive functioning. Subjects with SMC had impaired global cognitive functioning on two brief screening tests (7MS and DRS), working memory, verbal recall and visuomotor speed. However, subsequent screening with the delayed verbal recall test showed that 12 of the 54 subjects with SMC demonstrated significant cognitive impairment, scoring 2 SD below the control group mean. After these subjects were removed to form the aMCI group, the cognitive differences between subjects with SMC and without SMC were no longer apparent. Subjects with aMCI showed evidence of multiple cognitive deficits (below 1 SD of control group mean) with a high percentage of subjects demonstrating impairment on tests of verbal learning, verbal recall, verbal ability and visuomotor speed. Further analysis showed a significant association between age and subjects identified as having SMC (r=-.581, p<.001) and aMCI (r=.692, p<.001). From the age of 60 onwards, both the SMC and aMCI groups demonstrated a more rapid cognitive decline with increasing age in several cognitive domains. Part 2 - After a mean interval of 3.2 years, 43 subjects were followed up. Subjects with aMCI showed evidence of greater decline on both screening tests (7MS; DRS), whilst the SMC group had significantly higher scores. This trend was also apparent with other neuropsychological testing. The analysis of change over time in cognitive function showed that the majority of subjects (both SMC aMCI) either remained stable or improved their cognitive performance. It is likely that the small sample size and short follow-up interval of the present study contributed to the present observation of no change in cognitive function over time. Discussion: The present findings suggest that subjective memory complaints are a poor predictor of cognitive function. In isolation, SMC are unlikely to be useful for identifying cases with significant cognitive impairment. This is particularly relevant for subjects under the age of 70 years. However, for subjects over the age of 70 years, SMC are likely to identify significant cases with neuropsychological assessment (such as animal fluency and delayed recall). Conclusion: The present study showed that SMC are a poor predictor of cognitive function in subjects under the age of 70 years. This study provided evidence that selected and relatively quick to administer formal neuropsychological tests of cognitive function (in particular tests of animal fluency and delayed recall) are better able to identify those at risk of developing cognitive impairment associated with Alzheimer’s disease, at an earlier age. This would thus allow exposure to earlier treatment options, such as donepezil, aricept, vitamin E, and memantine”.

[Truncated abstract.] Alzheimer’s disease (AD) is the most common form of dementia world-wide accounting for more than two thirds of all dementia cases. AD is characterised by the presence of extracellular amyloid plaques, neurofibrillary tangles and congophillic amyloid angiopathy in the brain tissue of affected individuals. Of these neuropathological features the extracellular amyloid plaques are the most characteristic containing a peptide termed amyloid- beta (Aβ); the major protein component of these structures. In addition a number of genetic risk factors for AD have been identified. Of these the ε4 allele of the apolipoprotein E (APOE) gene found on chromosome 19 is considered to be the main genetic risk factor attributing to about 40-60% of all AD cases in most populations. Although there is strong evidence that genetic risk factors play an important role in AD they do not actually trigger the disease process. Deficits in memory and learning are the most common clinical signs of AD in the initial stages of the disease. Neuropsychological tests such as the CAMCOG and California Verbal Learning Test (CVLT) are important diagnostic tools used for the assessment of cognition. The CAMCOG is an accurate and efficient measure of global cognitive ability, while the CVLT is more specific to areas of cognition influenced in the early stages of the disease such as verbal memory. Substantial evidence indicates that changes in sex hormones following menopause in women are important factors in AD. Specifically, the reduced levels of oestrogen in post-menopausal women have been linked to cognitive decline and an increased risk of dementia. In addition the elevated level of the gonadotropins, a characteristic of the post-menopausal period, have been implicated with the disease. Numerous nonhormonal factors such as age and education may also be associated with the development and progression of cognitive decline.