Alzheimer's disease (AD) is associated with decreased brain energy metabolism. Hypometabolism in the posterior cingulate cortex (PCC) occurs before the onset of memory deficits in subjects at genetic risk for AD who are not yet cognitively impaired. There is a specific inhibition in cytochrome oxidase (C.O.) in the PCC, an area involved in spatial navigation. Creating an animal model that exhibits the early pathophysiology of AD is important for developing and testing drugs that could reverse memory problems associated with such deficits. Methylene blue (MB) is a compound that improves C.O. activity and memory retention in rats. This dissertation had three specific aims: 1) to examine if isolated PCC hypometabolism causes spatial memory deficits in rats; 2) to find a dose of MB that improves memory without nonspecific behavioral effects; and 3) to prevent memory deficits from PCC hypometabolism with low dose MB. PCC hypometabolism was produced by focal administration of sodium azide, an inhibitor of C.O. activity. PCC hypometabolism resulted in impaired spatial memory in a hole board food-search task, increased oxidative damage, and neurotoxicity in the PCC. In addition, PCC hypometabolism resulted in reduced inter-regional correlations in brain activity. Our second set of studies examined the dose-response effects of MB. Our findings demonstrated that a low dose of MB: 1) enhanced memory in open field habituation and object recognition tasks; 2) did not affect general locomotor activity, exploration, motivation, or anxiety; and 3) increased brain oxygen consumption 24 hr after in vivo administration. Finally, our last study found that low dose MB prevented the deficits caused by PCC hypometabolism. MB did not prevent PCC inhibition or cell loss caused by sodium azide. Inter-regional correlations of brain metabolic activity suggested that rats treated with MB were using a different, but equally efficient, strategy for memory retrieval. This animal model of C.O. hypometabolism in the PCC can provide information to understand the mechanisms that regulate early pathological degeneration and reveal new therapeutic strategies aimed at reducing or preventing cognitive decline. Studies of low dose MB in humans are needed to examine its effects in AD patients.

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.

Memory dysfunction is common in association with the course of normal aging. Memory dysfunction is also obligatory in age-associated neurological disorders, such as Alzheimer’s disease. However, despite the ubiquitousness of age-related memory decline, several basic questions regarding this entity remain unanswered. The present investigation addressed two such questions: (1) Can individuals suffering from memory dysfunction due to aging and amnesia due to Alzheimer’s disease improve memory performance if contextual support is provided at the time of acquisition of to-be- remembered material or reproduction of to-be-remembered material? (2) Are memory deficits observed in ‘younger’ older adults similar to the deficits observed in ‘older’ elderly subjects, Alzheimer’s disease, and memory dysfunction in younger subjects? The outcome of this investigation suggests an affirmative answer to the first question. Given appropriate support at encoding and retrieval, even densely amnesic patients can improve their memory performance. As to the second question, a more complex pattern emerges. When attentional demands are varied, subjects of varying ages perform qualitatively similar. However, when semantic aspects of the to-be- remembered material are manipulated, age-associated qualitative differences are observed. These qualitative differences show up between older and younger adults, as well as between ‘younger’ and ‘older’ elderly subjects. / <p>Diss. (sammanfattning) Umeå : Univ., 1992, härtill 6 uppsatser</p> / digitalisering@umu

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] The aim of the present series of studies was to identify barriers to working memory for multifeature visuospatial stimuli in normal aging. Memory for multifeature stimuli requires retention of multiple visuospatial features, as well as the relationships between features within stimuli, known as memory binding. In Experiment 1, younger people (17-25 years) and older people (66-95 years) completed a modification of Wheeler and Treisman’s (2002) visual change detection task, to determine the effects of normal aging on memory binding, and memory for multiple features ... Results indicated that older people did not have a memory binding decrement compared to younger people. Further, younger people performed more accurately when cued to attend to a specific feature, while older people’s performance did not improve with cueing ... Experiment 2 employed the binding condition and the ‘either’ condition, with stimuli presented either sequentially or simultaneously. Results were consistent with Experiment 1, with no age-related binding decrement, regardless of the method of stimulus presentation. In Experiment 1, older people demonstrated a shape memory decrement compared to younger people. Experiments 3A and 3B were performed to determine whether this result did represent a memory decrement per se, or whether it was a consequence of a shape perception decrement ... Compared to younger people, older people demonstrated a similar performance decrement across shape perception and memory tasks, indicating that their performance was mediated by an underlying perceptual decrement. Experiment 4 was conducted to determine if older people had difficulty selectively attending to a feature across multifeature stimuli, as suggested by their failure to benefit from cueing in Experiment 1 ... Older people had a greater performance decrement when the irrelevant feature was incompatible with the correct response, compared to younger people, consistent with a selective attention decrement. Experiment 5B adapted the design of Experiment 4 to both a perception task and a working memory task, while Experiment 5A identified appropriate stimulus features to use in Experiment 5B ... Overall, older people do not have particular difficulty remembering multiple visuospatial features, or binding these features within working memory. Rather, older people’s performance was marked by difficulty selectively attending to a specified feature across multifeature stimuli.

Thesis (Ph. D.)--State University of New York at Binghamton, Department of Psychology, Behavioral Neuroscience, 2008. / Includes bibliographical references.

Thesis (M.A.)--State University of New York at Binghamton, Department of Psychology, 2005. / Includes bibliographical references.

Thesis (Ph. D.)--University of New South Wales, 2006. / "May 2006." Title taken from title screen (viewed October 25, 2007). Includes bibliographical references (p. 188-206) and appendices.

Recentemente, estudos indicam que, juntamente com os sintomas motores clássicos, possam ocorrer déficits de função executiva, cognição e linguagem na Doença de Parkinson (DP). Este estudo objetivou avaliar a recepção de sentenças e relacionar seus suportes de atenção e memória, em pacientes não-demenciados com DP. Participaram do estudo 80 sujeitos, sendo 40 do grupo controle e 40 com diagnóstico de DP, subdivididos em 2 grupos de acordo com a gravidade da doença. Foram aplicados os seguintes testes: Token Test, Extensão de dígitos, Fluência Verbal, Mini Exame do Estado Mental e Escala de Depressão Geriátrica. O presente estudo indica a existência de déficit de compreensão sintática na DP, principalmente nos estágios mais avançados da doença. As sentenças em que ocorrem tais déficits são analisadas e as bases de atenção e memória necessárias à compreensão de sentenças são discutidas. / Recently, studies have indicated that it can occur executive function, cognition and language deficits associated with the classic motor symptoms of Parkinson´s Disease (PD). The aim of this study is to verify sentence comprehension and relate it to attention and memory basis in non-dementia patients with PD. We studied 80 subjects in total, 40 of control group and 40 with a diagnosis of PD, subdivided into 2 groups according to the severity of the disease. The following tests were applied: Token Test, Digit Span, Verbal Fluency, Mini-Mental State Examination and the Geriatric Depression Scale. This study indicates that there is a deficit in sentence comprehension in PD, mainly in more advanced stages of the disease. The sentences which such deficits occur are analyzed and attention and memory basis that are necessary for sentence comprehension are discussed