Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neurofibrillary tangles, senile plaques and loss of synapses. Many studies support the notion that oxidative stress plays an important role in AD pathogenesis. Previous studies from our laboratory employed redox proteomics to identify oxidatively modified proteins in the AD inferior parietal lobule (IPL). The proteins were consistent with AD pathology and have been central to further investigations of the disease. The present study was focused on the identification of specific targets of protein S-glutathionylation in AD, early AD (EAD), and mild cognative impairment (MCI) using a redox proteomics approach. In AD IPL we identified deoxyhemoglobin, α-crystallin B, glyceraldehyde phosphate dehydrogenase (GAPDH), and α-enolase as significantly S-glutathionylated relative to these brain proteins in control IPL. Both, GAPDH and α-enolase were also shown to have reduced activity in the AD IPL. With further investigation gammaenolase, dimethylarginine dimethylaminohyrdolase (DDAH), Cathepsin D, and 14-3-3 gamma were identified as significantly S-glutathionylated in the EAD IPL. Alpha enolase was also identified as significantly S-glutathionylated in MCI IPL. These results provide a correlation in proteins S-glutathionylated in the progression of AD even in the reversible conditions of amnestic MCI. Amyloid beta-peptide (1-42) [Aβ(1-42)], one of the main component of senile plaque, can induce in vitro and in vivo oxidative damage to neuronal cells through its ability to produce free-radicals. The aim of this study was to investigate the protective effect of the xanthate, D609, on Aβ(1-42)-induced protein oxidation using a redox proteomics approach. D609 was recently found to be a free radical scavenger and antioxidant. In the present study, rat primary neuronal cells were pretreated with 50 μM of D609 followed by incubation with 10 μM Aβ(1-42) for 24 hours. In the cells treated with Aβ(1-42) alone four proteins that were significantly oxidized were identified: Glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase, malate dehydrogenase, and 14-3-3 zeta. Pretreatment of neuronal cultures with D609 prior to Aβ (1-42) protects all the identified oxidized proteins in the present study against Abeta(1- 42)-mediated protein oxidation. Therefore, D609 may ameliorate the Aβ(1-42)-induced oxidative modification.

The role cholesterol plays in the brain has long been underappreciated even though the brain contains a disproportionately high percentage of body cholesterol. Recent studies have found a link between the dysregulation of lipid metabolism and the risk of acquiring Alzheimer’s disease (AD) as well as a predisposition to cognitive decline. The goal of these studies was to elucidate the possible role lipid metabolism plays in pathological and normal brain aging by pharmacologically manipulating lipid metabolism and determining effects on key hippocampal biomarkers of AD and age-related cognitive decline. One series of experiments used an agonist (TO901317) to the liver X receptor (LXR) in two transgenic AD mouse models. Chronic LXR activation reduced AD associated pathology and improved cognitive performance in AD mouse models. However, long-term potentiation (LTP) was not enhanced and peripheral side effects were observed. In another series of experiments the effects of chronically inhibiting cholesterol synthesis on cognitive aging in rats was determined. Animals were treated with either of two commonly prescribed statins, simvastatin or atorvastatin. Simvastatin, the more lipophilic statin, increased LTP and reduced the duration of the afterhyperpolarization (AHP). In addition, simvastatin upregulated key genes of the cholesterol synthesis pathway in the hippocampus as revealed by microarray analyses, but was associated with impaired performance in the Morris Water Maze, a hippocampal dependent task. Atorvastatin, a less lipophilic statin, reduced the AHP, but did not affect LTP or cognitive performance. Atorvastatin modulated a very different set of genes and reduced brain cholesterol more than simvastatin. These results suggest that manipulation of cholesterol metabolism selectively modulates key aspects of AD and brain aging.

Introduction: Dementia is an age-associated neurodegenerative disorder characterized by a progressive loss of neuro-cognitive function and the emergence of a wide variety of behavioral symptoms. Alzheimer's disease (AD) is the most common types of dementia. Sleep disturbances in patients with Alzheimer's disease is common and previous studies from North America, Europe and Japan reported light therapy could improve the sleep circadian rhythm ( rest-activity) disturbances in AD. However, there was no previous Chinese study on light exposure and sleep quality nor the circadian rhythm in Chinese Alzheimer's disease patients. Objective : The objective of the present study was to investigate the association of light exposure intensity with the quality of sleep and behavioural symptoms in Chinese Alzheimer’s disease (AD) patients Method: This was a cross-sectional observational study. 203 Chinese elderly patients with Alzheimer's disease were recruited from the Memory Clinic in Queen Mary Hospital, the University of Hong Kong, from July 2014 to December 2014. Socio-demographic data and comorbid diseases information were collected from all subjects. Their sleep qualities, quantities and conditions of light exposure were recorded with a sleep logbook and light meter. Their cognitive function, disturbing behaviour, depressive mood and quality of life scales were assessed by a semi-structured questionnaire. Light exposure intensity measured by Light meter (Model SDL 400). Measure for cognitive function were the Abbreviated Mental Test (AMT), Behavioral symptoms measured by the Neuropsychiatric Inventory (NPI) and mood by Geriatric Depression Scale. (GDS-15) The association of outdoor or indoor light exposure with sleep quality and quantities were analyzed by descriptive, bivariate and multivariate analyses. Main outcome measures: The main outcome measure was the sleep quality and quantities of patient, measured by Pittsburgh Sleep Quality Index. (PSQI) Results: 203 subjects (60 males and 143 females) were recruited. 70.4 % of the studied subjects were females. Male to female ratio is 1:2.38. Mean age of them was 81.6 years. The mean (SD) scores of the recruited were: AMT = 4.5 (2.9); PSQI = 6.9 (3.4); NPI =14.4 (17.2); GDS-15= 4.3 (2.8); QOL-AD (patients) = 30.7 (4.9); QOL-AD (caregivers) = 29.5 (4.7) respectively. In bivariate analysis, the Global PSQI score was significantly associated with the morning and afternoon outdoor light exposure. (r = -0.634 and -0.466, respectively) For the total light exposure and mean light exposure, both of them showed strong significant negative correlation with Global PSQI score. (r = -0.769 and -0.769 respectively). Mean (SD) light exposure per day for morning and afternoon outdoor setting were 2372.9 lux (2564.7) and 1090.8 lux (1894.6) respectively. Mean(SD) light exposure per day was 1196.7 lux (866.1) Gender identity showed significant correlation with Global PSQI score (r = 0.034). Global PSQI score was significantly associated with the NPI total score (r = 0.261, p<0.001), the GDS-15 score (r = 0.336, p<0.001), the QOL-AD for patients (r = -0.257, p<0.001), and the QOL-AD for caregivers. (-0.313, p<0.001) In multivariate analyses, using general linear models, the Global PSQI score was highly independent associated with the total light exposure (p=0.000), and significantly associated with the NPI score and Gender (p = 0.011 and 0.021), after adjusting for potential confounders in bivariate analysis. (i.e. gender, activity of daily living status, hypertension and Chronic obstructive airway disease). Confounding factors were NPI and gender. Conclusion: In the present study, We found the intensity of natural light exposure was related to good sleep quality in older Chinese Alzheimer’s disease patients with age 65 years and above in Hong Kong as well as lesser episode of behavioural symptoms. Hence, daily outdoor light exposure is highly recommended for persons with Alzheimer’s disease. / published_or_final_version / Medicine / Master / Master of Medical Sciences

This thesis describes a program of research that investigated the sensitivity of healthy young adults, healthy older adults and individuals with Alzheimer’s disease (AD) to happiness, sadness and fear emotion specified in facial expressions. In particular, the research investigated the sensitivity of these individuals to the distinctions between spontaneous expressions of emotional experience (genuine expressions) and deliberate, simulated expressions of emotional experience (posed expressions). The specific focus was to examine whether aging and/or AD effects sensitivity to the target emotions. Emotion-categorization and priming tasks were completed by all participants. The tasks employed an original set of cologically valid facial displays generated specifically for the present research. The categorization task (Experiments 1a, 2a, 3a, 4a) required participants to judge whether targets were, or were not showing and feeling each target emotion. The results showed that all 3 groups identified a genuine expression as both showing and feeling the target emotion whilst a posed expression was identified more frequently as showing than feeling the emotion. Signal detection analysis demonstrated that all 3 groups were sensitive to the expression of emotion, reliably differentiating expressions of experienced emotion (genuine expression) from expressions unrelated to emotional experience (posed and neutral expressions). In addition, both healthy young and older adults could reliably differentiate between posed and genuine expressions of happiness and sadness, whereas, individuals with AD could not. Sensitivity to emotion specified in facial expressions was found to be emotion specific and to be independent of both the level of general cognitive functioning and of specific cognitive functions. The priming task (Experiments 1b, 2b, 3b,4b) employed the facial expressions as primes in a word valence task in order to investigate spontaneous attention to facial expression. Healthy young adults only showed an emotion-congruency priming effect for genuine expressions. Healthy older adults and individuals with AD showed no priming effects. Results are discussed in terms of the understanding of the recognition of emotional states in others and the impact of aging and AD on the recognition of emotional states. Consideration is given to how these findings might influence the care and management of individuals with AD.

Several tasks examined implicit and explicit memory in matched samples of Alzheimer's (AD) and Parkinson's disease (PD) patients, and healthy elderly subjects. Lexical priming, pursuit-rotor tracking, and a fragmented pictures test, followed by explicit memory tests, were given. AD patients were impaired on all explicit tests and on lexical priming, but were intact on pursuit-rotor tracking and the procedural learning (PL) component of the fragmented pictures test. PD patients were significantly better than AD patients on all explicit memory tests, but were selectively impaired on the PL component of the fragmented pictures test. Finally, a mirror reading test was given to the PD patients and matched control subjects, with no significant differences in performance between the two groups demonstrated. Results are discussed in terms of hypothetical cognitive processes and brain circuits underlying different explicit and implicit memory domains.

No description available.

Alzheimer’s disease (AD) is a neurodegenerative disorder with no existing cure. Since cognitive control influences saccade behaviour, saccades provide a valuable tool when studying cognitive changes in healthy and pathological aging. This thesis aims to evaluate differences in predictive capacity and working memory between cognitively normal older adults (NC) and mild AD patients using customized saccade paradigms and a battery of neuropsychological tests. In the predictive paradigm, we hypothesize that AD participants would display a decreased level of prediction, predictive capacity and learning capacity. In the memory-guided paradigm, we hypothesize that AD participants would have a decreased ability to maintain fixation and capacity to retain information and reproduce it correctly. Overall, we found that in the predictive paradigm, NC displayed a greater degree of prediction than AD participants. However, both groups had an optimal level of prediction at intermediate inter-stimulus intervals (ISI) (750 and 1000 ms). As ISI increased, both groups, although more so in AD, elicited a greater proportion of SRTs below -200 ms and -400 ms. This may suggest that as ISI increased, participants switched from a predictive to an anticipatory/guessing strategy. At an ISI of 500 ms, NC’s learning capacity was greater than AD participants. Cognitive scores of neuropsychological tests did not correlate with learning capacity in NC. However, learning capacity in AD participants was positively correlated with working memory capacity and attentional control. The memory-guided paradigm revealed AD participants completed less viable trials, less correct trials, and had more combined directional and timing errors than NC. Cognitive correlations showed that NC’s working memory capacity positively correlated with the frequency of correct trials, whilst negatively correlating with saccade errors. Since AD participants completed 10% of viable trials correctly, the task may have been too difficult for AD participants to comprehend, rendering correlations invalid. These findings suggest that although the predictive paradigm does not solely assess for prediction, it may provide a measure to cognitively differentiate NC from AD patients, and detect AD severity. Since the memory-guided paradigm may be too difficult for AD participants, it may provide a better indicator of cognitive changes associated with healthy aging. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2013-05-21 18:54:19.492

Senile plaques (Aβ) and neurofibrillary tangles (tau) are pathological hallmarks of Alzheimer’s disease (AD). If and how the formation of these deposits are mechanistically linked remains mainly unknown. In recent years, the focus has shifted from insoluble protein deposits to soluble aggregates of Aβ and tau. Protofibrils are large soluble Aβ oligomers which were linked to AD by the discovery of the Arctic AβPP mutation. Treatment of young tg-ArcSwe mice with an Aβ protofibril-selective antibody, mAb158, cleared protofibrils, prevented amyloid plaque deposition and protected cultured cells from protofibril-mediated toxicity. This suggests that Aβ protofibrils are necessary for the formation of Aβ deposits. Functional assessment of tg-ArcSwe mice in IntelliCage demonstrated hippocampal-dependent behavioral deficits such as memory/learning impairments, hyperactivity and perseverance behavior. Learning impairments did not correlate to Aβ-measures but to calbindin, which might be a good marker for Aβ-mediated neuronal dysfunction. Splicing of exon 10 in the tau gene differs between human and mouse brain. Exon 10 is part of the microtubule-binding domains which helps to maintain microtubule stability and axonal transport, functions vital to neuronal viability. Axonal transport dysfunction has been proposed as a common pathway of Aβ and tau pathogenesis in AD. Generation of a novel tau mouse model with absence of exon 10 led to age-dependent sensorimotor impairments which may relate to dysfunctions in cerebellum. No tau pathology was evident suggesting that a trigger of tau fibrillization e.g. a human Aβ or tau aggregate is needed. Generation of AβPPxE10 bitransgenic mice with no exon 10 showed lower Aβ plaque burden. Possibly changes in microtubule function lead to altered intracellular AβPP transport and Aβ production. Initiation of tau pathology in AβPPxE10 mice might require a certain type of Aβ-aggregates which is not produced or exist at too low concentration in transgenic mouse brain. In summary, the Aβ protofibril-selective antibody was found to be a promising treatment for AD. The IntelliCage system was proven to be useful for functional evaluation of AβPP mice. Exon 10 in tau was shown to affect sensorimotor functions and Aβ pathology in bitransgenic mice by mechanisms that deserve further investigation.

Memory binding is a cognitive process that enables complex objects to be stored or retrieved coherently during perception, learning, or action. Binding functions are aimed at reducing the misattribution of the features of objects in crowded and changing sensory contexts, ensuring accurate representation in visual working memory. Binding is a relatively new concept in working memory research. However, as an integrative function it provides a rich context in which to investigate the mechanisms underlying memory deterioration. In this PhD project, a range of experimental temporary binding paradigms were used to investigate whether some of the memory impairments observed in patients with Alzheimer’s Disease could be accounted for by deficits in this memory function. A set of neuropsychological tasks were used to investigate binding operations across memory domains (i.e., verbal and nonverbal), sensory modalities (i.e., visual and auditory), types of information (e.g., objects and colours), and retrieval processes (i.e., recognition and recall) in healthy individuals, Alzheimer’s Disease patients and other clinical populations. The results suggest that the efficiency of short-term memory to store bound complex events depends on the nature of the information presented (e.g., type of information bound into objects) (Chapter 2). Short-term memory seems to be equipped with relatively separate mechanisms to store integrated objects and individual features (Chapter 4). It was also observed that the binding properties of short-term memory apply to healthy young and older people, and are functions which are preserved in the elderly (Chapter 3). In two additional experimental chapters (5 and 6) the preserved binding abilities of older people were compared with temporary binding in Alzheimer’s Disease. The latter group showed a very large impairment in binding that was distinct from their impairments in memory for individual features. These findings suggest that memory binding tasks could reliably separate the cognitive changes in normal ageing from those linked with Alzheimer’ Disease. Moreover, the results of Chapter 7 suggested that memory binding tasks may detect memory changes in people that will develop Alzheimer’ Disease (i.e., asymptomatic carriers of the gene defect E280A of the Preseniline-1 gene) almost 10 years before the average age of onset. These results are relevant to our understanding of short-term memory and to the memory models currently available. Finally, it is suggested that the constructs of memory binding may increase the sensitivity of current assessment procedures for people at risk of developing Alzheimer’s Disease.

Background: Despite substantial research and development investment in Alzheimer's disease (AD), effective therapeutics remain elusive. Significant emerging evidence has linked cholesterol, beta-amyloid and AD, and several studies have shown a reduced risk for AD and dementia in populations treated with statins. However, while some clinical trials evaluating statins in general AD populations have been conducted, these resulted in no significant therapeutic benefit. By focusing on subgroups of the AD population, it may be possible to detect endotypes responsive to statin therapy. Methods: Here we investigate the possible protective and therapeutic effect of statins in AD through the analysis of datasets of integrated clinical trials, and prospective observational studies. Results: Re-analysis of AD patient-level data from failed clinical trials suggested by trend that use of simvastatin may slow the progression of cognitive decline, and to a greater extent in ApoE4 homozygotes. Evaluation of continual long-term use of various statins, in participants from multiple studies at baseline, revealed better cognitive performance in statin users. These findings were supported in an additional, observational cohort where the incidence of AD was significantly lower in statin users, and ApoE4/ApoE4-genotyped AD patients treated with statins showed better cognitive function over the course of 10-year follow-up. Conclusions: These results indicate that the use of statins may benefit all AD patients with potentially greater therapeutic efficacy in those homozygous for ApoE4.