M. Tech. / Memory loss refers to the loss of ability to learn new information and the inability to retrieve information previously learnt (Karlawish & Clark, 2003). It is estimated that more than 40% of individuals over the age of 60 are affected by memory loss (Jackson, 2004). There are no recommended treatment options available for mild forms of memory loss (D‟Esposito & Weksler, 2000). The aim of the study was to determine the effects of the anthroposophical medicine, Scleron® in the treatment of memory loss associated with ageing, assessed by digit span; verbal and visual recall and recognition and a memory questionnaire. The trial was a double-blind placebo controlled study using matched pairs. Participants selected to take part in the study were between the ages of 60 and 75 and presented with subjective symptoms of memory loss. Participants were excluded from the study if they scored less than 24 out of 30 on the Mini-Mental State Exam; were previously diagnosed with memory or cognitive disorders; had a previous history of stroke, epilepsy, head injury, psychiatric disease and drug or alcohol dependence. Participants were divided into two groups in matched pairs according to age, education level, occupation and Mini-Mental State Exam scores. At the start of the study, participants completed a memory test and memory questionnaire. Participants in the experimental group received Scleron®, while participants in the placebo group received unmedicated tablets. Participants were required to take 2 tablets in the morning for a period of six weeks. The memory test and memory questionnaire was once again completed by participants at the end of the study. Thirty six participants completed the study. The results of the study were analysed and frequencies and descriptives were calculated for the sample group. The Wilcoxon test was used to compare the data within groups, while the Mann-Whitney test was used to compare the results between the two groups. iv After analysis of the results of the study, it was concluded that Scleron® did not appear to improve the symptoms of memory loss when using tests of digit span, verbal and visual recall or verbal and visual recognition. Furthermore, it did not appear to improve subjective symptoms of memory loss assessed by the use of a memory questionnaire.

This study investigated the development of acquisition and long term retention processes in Learning Disabled (LD) and Non-Learning Disabled children aged 7-12. One hundred six subjects were randomly assigned to memorize either a list of unrelated words (with free recall), or a list of taxonomically related words (with recall cued by category). Each subject had a 16 word list presented in visual and auditory modes. The repeated recall paradigm alternated study and test trials, with a buffer activity between trials. The acquisition phase ended when the subject reached 100% criterion. After an interval of two weeks, each subject was given 5 additional recall tests. Acquisition results indicated significant main effects for age, group (LD, Non-LD) and list type (unrelated, categorized) on measures of trial-of-last-error and total-errors. Overall, the groups which acquired the lists most quickly were the older and Non-LD subjects, with the categorized list. There was a List x Group interaction on the trial-of-last-error. With the categorized list, only age was significant, and conversely, with the unrelated list, only group was significant. On the retention measures, there were main effects for list and group, with a List x Group interaction. The only significant age effect was with total-words on the categorized list. Over the five trials (repeated measures), there was a significant effect for trials. A consistent hypermnesia effect (increase in net recall) was predominant. Further model-based analyses (Brainerd, Kingma, Howe, & Reyna, 1988) revealed storage failure, rather than retrieval failure to be the major action in children's forgetting. Learning Disabled children had significantly more storage failure than the Non-LD children. Both groups had more storage failure on the unrelated lists. There was retrieval relearning with all groups. Results are discussed within the framework of the disintegration/redintegration theory, which pertains to the gradual weakening and redintegration of bonds that unite features to form a trace.

No description available.

As the aging population continues to grow worldwide, age-related complications are becoming more apparent within the aging population. One of the first age-related complications to become apparent is age-associated memory impairment and it can make the elderly more dependent on caregivers early on. The N-methyl-D-aspartate (NMDA) receptor is important to learning and memory and appears to be especially vulnerable to the process of aging. The density of NMDA receptors declines with age more than any other ionotropic glutamate receptor. Both the density of NMDA receptors and the mRNA and protein expression of its subunits decline with age. In particular, the GluN2B subunit of the NMDA receptor shows the greatest age-related declines in expression across multiple brain regions, including the frontal lobe (including the prefrontal and frontal cortices), caudate nucleus and hippocampus. These declines are strongly correlated to age-related declines in spatial memory. Specifically, age-related decreases in the protein expression of the GluN2B subunit within crude synaptosomes of the frontal cortex of C57BL/6 mice show a relationship to the declines in performance in a long-term spatial memory task across age groups. However, within the population of aged mice, there was a subpopulation of aged mice in which higher expression of the GluN2B subunit within the synaptic membrane of the hippocampus was associated with poorer performance in the same task. Moreover, transgenic mice designed to express higher levels of the GluN2B subunit from birth also possess superior memory, including spatial memory, across adulthood to middle-age. Taken together, these data led to the hypothesis that increasing the expression of the GluN2B subunit within the aged brain could potentially alleviate age-related declines in memory. However, increasing its expression regionally was first examined since higher expression of the GluN2B subunit within the hippocampus has been associated with poorer memory in aged animals. Since age-related decreases in the protein expression of the GluN2B subunit within the frontal cortex show a relationship to impaired memory function, the first study was designed to determine if increasing GluN2B subunit expression in the frontal lobe would improve memory in aged mice. Mice received bilateral injections of either an adenoviral vector, containing cDNA specific for the GluN2B subunit and enhanced Green Fluorescent Protein (eGFP) (GluN2B vector); an adenoviral vector containing only the cDNA for eGFP (control vector); or vehicle into their frontal lobe. Spatial memory, cognitive flexibility and associative memory were assessed using the Morris water maze. Aged mice, with increased GluN2B subunit expression in the frontal lobe, exhibited improved long-term spatial memory, comparable to young mice, in the second day of training. Moreover, a higher concentration of the specific GluN2B antagonist, Ro 25-6981, was required to impair long-term spatial memory in aged mice with enhanced GluN2B subunit expression, as compared to aged controls. The requirement for greater antagonism in aged mice to block memory performance suggests that the number of GluN2B-containing receptors in their frontal lobe was enhanced and contributed to the improved memory. This study provides suggestive evidence that therapies that enhance GluN2B subunit expression within the aged brain could have the potential to ameliorate age-related memory loss. Since higher expression of the GluN2B subunit within the hippocampus of aged mice is associated with poorer memory, the second study was designed to determine if increasing GluN2B subunit expression in the hippocampus would improve or further impair memory in aged mice. This would help to determine if a therapy aimed at enhancing the GluN2B subunit expression or function of GluN2B-containing receptors throughout the aged brain could help ameliorate age-associated memory loss. Mice were injected bilaterally with either the GluN2B vector, a control vector or vehicle into the hippocampus. Spatial memory, cognitive flexibility and associative memory were assessed using the Morris water maze. Aged mice, with increased GluN2B subunit expression in the hippocampus, exhibited improved long-term spatial memory, comparable to young mice, early in training. However, there was a trend for impaired memory later in the long-term spatial memory trials. Still, these data suggest that enhancing GluN2B subunit expression in the aged hippocampus could be more beneficial to memory than harmful. In addition, the results of this study suggest that enhancing GluN2B subunit expression in different brain regions may improve memory at different phases of learning. Therefore, therapies that enhance GluN2B subunit expression throughout the aged brain could help ameliorate age-related memory loss. The first two studies demonstrated that enhancing the expression of the GluN2B subunit within either the frontal lobe or hippocampus of the aged brain has the potential to reduce age-related memory declines. However, the increase was not global nor specific to the synapse. Therefore, a third study was developed with the intent of garnering a more global increase in GluN2B subunit expression that was localized to the synapse. Cyclin dependent kinase 5 (Cdk5) enhances endocytosis of the GluN2B subunit-containing NMDA receptors from the synapse. Previous research has shown that inhibiting Cdk5 increases the number of GluN2B subunits at the synapse and within the whole cell and improves memory in young mice. This study was designed to determine if using antisense phosphorodiamidate morpholino oligomers (Morpholinos) to decrease the expression of Cdk5 protein within the brain would improve memory in aged mice. Morpholinos were conjugated to a cell penetrating peptide, which enhances cellular uptake, and delivered bilaterally to the lateral ventricles of both young and aged mice via acute stereotaxic injection. Treatments consisted of equivalent volumes and concentrations of either vehicle, control Morpholino or a Morpholino targeting the mRNA of Cdk5 (Cdk5 Morpholino). Memory was evaluated in the Morris water maze and using a novel object recognition task. Aged mice treated with the Cdk5 Morpholino exhibited improved early acquisition and spatial bias in the long-term spatial memory trials, as well as improved performance overall, compared to control Morpholino-treated aged animals. However, aged mice treated with the Cdk5 Morpholino performed similarly to vehicle-treated aged animals. The presence of the peptide-conjugated Morpholinos within the brain may have worsened performance in the Morris water maze task since control Morpholino-treated animals performed significantly worse than vehicle-treated animals. In concurrence, there was significantly greater gliosis in peptide-conjugated Morpholino-treated animals over vehicle-treated brains, suggesting it was neurotoxic. In contrast, young mice treated with the Cdk5 Morpholino showed impaired early acquisition and spatial bias but a trend for improved later learning in the long-term spatial memory task compared to control Morpholino-treated animals. Treatment with the Cdk5 Morpholino had no significant effect on cognitive flexibility, associative memory or novel object recognition for young or aged animals. Immunohistochemistry revealed increased GluN2B subunit expression within cells with characteristics of neurons and astroglia in regions of the frontal lobe, caudate nucleus and hippocampus of aged mice who received the Cdk5 Morpholino compared to control treatments. However, the increased GluN2B subunit expression appeared to be greater within the hippocampus. These results suggest that inhibiting the translation of Cdk5 using Morpholinos increased GluN2B subunit expression in both young and aged mice and may have contributed to the improved long-term spatial memory observed in aged mice, despite the Morpholino being administered at a presumably toxic concentration. An additional group of mice was used to determine a non-neurotoxic dosage of the peptide conjugated Morpholino. However, future studies are needed to determine the efficacy of the Cdk5 Morpholino at this dosage. Taken together, the studies presented here suggest that increasing expression of the GluN2B subunit within the aged brain does improve age-associated memory declines. In addition, cell penetrating peptide- conjugated Morpholinos show promise as tools for genetic manipulation within the brain and Cdk5 could prove to be a novel target for enhancing GluN2B subunit expression within the aged brain. Though future studies are needed, the studies presented here do suggest that therapies that enhance GluN2B subunit expression within the aged brain have the potential to help ameliorate memory loss. However, since enhanced GluN2B subunit expression itself can increase the potential for excitotoxicity, an optimal dose of such a therapeutic would need to be determined. / Graduation date: 2013

Thesis (Ph. D.)--University of California, San Diego, and San Diego State University, 2004. / Vita. Includes bibliographical references (leaves 86-93).

Thesis (Ph. D.)--York University, 2000. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 64-76). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pNQ56232.

It has been argued that patients with frontal lobe lesions are impaired in temporal context memory and, more generally, in retrieving the source of one's knowledge or ideas. Furthermore, it has been speculated that a failure to retrieve source information may result in an increased susceptibility to distortions of episodic memories in patients with frontal lobe lesions. The precise role of the frontal cortex, however, in source or episodic retrieval is not clear. Does this region of cortex play a primary role or a secondary, executive role in the processing of such memories? Studies of patients with temporal lobe lesions have also shown impairments in episodic memory, including difficulties in the retrieval of source information. An important issue, therefore, is whether these two brain regions make different contributions to the processing of source information and to the retrieval of episodic memories. / In the present experiments, patients with unilateral excisions restricted to frontal cortex or to the anterior temporal lobe were compared on various tasks examining source memory performance and the accurate retrieval of episodic information. The results of these studies failed to support the general contention that patients with frontal cortex excisions have source (or temporal context) memory impairments. Instead, differences between these patients and normal control subjects appeared to be contingent on whether strategic organizational or control processes were necessary for efficient processing of episodic information. The memory of patients with left temporal lobe excisions, on the other hand, was significantly impaired for both content and source information in most tasks. Furthermore, these subjects showed high rates of inaccuracies and distortions of memory. The false memories of this patient group were attributed to a combination of their poor memory for the specific items of the task and their over-reliance on semantic "gist" or on inferential knowledge about the events. Patients with right temporal lobe excisions were generally less severely impaired on the verbal memory tasks compared with those with left-sided lesions, but were impaired in their memory for the contextual aspects of an event.

This thesis investigated the nature of the deficit in story recall associated with temporal-lobe damage in the left hemisphere dominant for speech. The first three experiments examined whether excision of this region (1) slows the rate at which verbal material is processed, (2) reduces working-memory capacity, or (3) interferes with the integration of information across sentences. Left temporal lobectomy does not impair these aspects of the initial processing of stories, since on none of the above variables was the performance of left temporal-lobe groups deficient relative to that of normal control subjects, or patients with unilateral frontal- or right temporal-lobe removals. The fourth experiment examined the effect of left temporal lobectomy on how quickly a passage was forgotten after it had been learned to criterion. Although patients with such an excision took more trials to learn a story than did normal control subjects, only those patients with extensive left hippocampal removal were impaired when recalling this story 20 minutes later. These results highlight the role of the left hippocampus in the long-term maintenance of story information.

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.