Biological tissues were studied with synchrotron infrared (IR) microspectroscopy, a technique that allows the spatially resolved determination and mapping of multiple components in situ at high spatial resolution. The first project involved studying brain tissue from TgCRND8 mice, a transgenic model of Alzheimer’s disease (AD). AD is the main cause of dementia in the ageing population, marked by the deposition of plaques composed of the Aβ peptide. Dense-cored and diffuse plaques were IR mapped and the results correlated with histochemistry and immunostaining. Spectral analysis confirmed that congophilic plaque cores were composed of highly aggregated protein in a β-sheet conformation. The amide I maximum of plaque cores was 1623 cm-1; there was no evidence of the high frequency (1680-1690 cm-1) peak seen in in vitro Aβ fibrils and attributed to anti-parallel β-sheet. A significant elevation in phospholipids was found around dense-cored plaques in TgCRND8 mice ranging in age from 5 to 21 months. This was due to an increase in cellular membranes from dystrophic neurites and glial cells around the core, but could also contribute to Aβ aggregation through the interaction of newly secreted Aβ with phospholipids. In contrast, diffuse plaques were not associated with infrared detectable changes in protein secondary structure or relative concentrations of other tissue components. In addition, focally elevated deposits of creatine, a molecule with a crucial role in energy metabolism, were discovered in AD brain tissue with IR microspectroscopy. The creatine deposits may be a previously undiscovered disease marker. A second project was part of a larger Natural Sciences and Engineering Research Council Collaborative Health Research Project (NSERC-CHRP) to test the hypothesis that treatment with anti-oxidants, L-2-oxo-thiazolidine-4-carboxylate (OTC) and quercetin, following spinal surgery may reduce oxidative stress, inflammation, and scarring. The effect of OTC and quercetin on scar tissue formation was evaluated in rats that had undergone laminectomy. Synchrotron IR microspectroscopy data were collected on scar tissue from OTC, quercetin and saline (control) treated animals, sacrificed at 3 and 21 days post-surgery. Spectral differences could be correlated with the stages of wound healing.

The thesis was designed to gain insight into how Alzheimer’s disease influences selfhood from first-personal accounts of illness. The focus of the study was narrowed further by concentrating on the autobiographies of individuals diagnosed with Early-Onset Alzheimer’s disease (EOAD). The purpose of this thesis was to analyze the autobiographies of individuals with EOAD with the aim of understanding their selfhood. In this thesis I argue that, Alzheimer’s disease may influence a change in self, however, the self is not lost entirely. This thesis draws on the philosophical conception of narrated self as it allows for one perpetually constructed self, whereby a change in self does not necessarily mean the self is lost entirely. Through an interpretive analysis of six autobiographical accounts of Alzheimer’s, this thesis demonstrates that Alzheimer’s disease influences a loss of sense of self but that autobiography enables individuals with Alzheimer’s to (re)construct self.

Little is known about the specific cognitive impairments that may be the cause of the reported increased crash rate in individuals with early dementia. Though, it is widely accepted that attention, visuospatial and perceptual abilities are central in being able to operate a vehicle safely. This study had three objectives. The first was to clarify the neuropsychological profile, with an emphasis on attention, visuospatial and perceptual abilities, of individuals with early dementia with Lewy bodies (DLB), the next was to examine the driving performances of two groups of individuals with early dementia (i.e., early Alzheimer’s disease, AD, and early DLB) and the last was to examine the degree of association between neuropsychological impairments and driving impairments in hopes of predicting poor driving outcomes. Fifty-six participants were recruited from three groups; 20 individuals diagnosed with early AD, 15 individuals diagnosed with early DLB and 21 healthy age-matched controls. All participants were administered the following neuropsychological tests: the Mini-Mental Status Exam (MMSE), the Dementia Rating Scale (DRS-2), the Boston Naming Test (BNT), the Test of Everyday Attention (TEA), the Visual Object and Space Perception Test (VOSP) and the Useful Field of View (UFOV). Additionally, a simulated driving task was completed, with data being collected through primary measures recorded by the simulator as well as an experimenter based driving assessment using a demerit-point test. Results indicated that individuals with early DLB were found to be most impaired in their visuospatial abilities, selective and divided attention abilities, and were found to have significant cognitive fluctuations. Driving performances confirmed that drivers with early dementia were at greater risk for motor vehicle collisions (MVC) and they were found to commit a significant number of driving errors during the driving simulation. Finally, this study was able to demonstrate that in drivers with early AD, attentional impairments were the strongest predictors of driving impairment, whereas in drivers with early DLB, visuospatial impairments were indicative of driving impairment.

This thesis describes the results obtained from the phytochemical analysis of Matricaria chamomilla, and the microbial transformation of oxymatrine (85) and harmine (87), as summarized below. 1. Chemical investigation of the crude methanolic extract of Matricaria chamomilla resulted in the isolation of a new natural product, matriisobenzofuran (72), along with four known compounds: apigenin (73), apigenin-7-O-β-glucopyranoside (74), scopoletin (75), and fraxidin (76). The structures of compounds 72-76 were elucidated with the aid of extensive NMR and mass spectroscopic studies. All of the aforementioned compounds showed moderate to good inhibitory activities against glutathione S-transferase, an enzyme which has been implicated in the resistance of cancer cells to chemotherapeutic agents. These compounds were also evaluated for antioxidant activity and displayed moderate to good free radical scavenging activity. Additionally, compounds 72-76 were screened for anti-leishmanial activity. Compounds 75 and 76 were significantly active in this assay, while the remaining compounds were weakly active. In the antibacterial and antifungal assays, compounds 72-76 were not active. 2. The second part of this thesis deals with the biotransformation studies on oxymatrine (85) and harmine (87). Oxymatrine (85) was metabolized to the deoxy analogue, matrine (84) by Penicillum chrysogeneum (ATCC 9480), Cunninghamella bainieri (ATCC 9244), Cunninghamella blakesleena (ATCC 9245 and 8688A), Curvularia lunata (ATCC 12017), and Fusarium sp. In the time-based analysis of this transformation, the metabolism of oxymatrine (85) could be detected after 48 hours of incubation. Additionally, incubation of harmine (87) with Mucor plumbeus (ATCC 4740) resulted in the isolation of harmine-N-oxide (94). The biotransformed products (84 and 94) were identified using IR, UV, NMR, and mass spectroscopic techniques. Compound 94 was evaluated for its ability to inhibit the enzyme acetylcholinestrase, whose overexpression has been linked to Alzheimer’s disease, and was found to possess weaker activity than harmine (87).

<p>Hypoxia is a profound stressor of the central nervous system implicated in numerous neurodegenerative diseases. While it is increasingly evident that the early effects of hypoxia cause impairment at the level of the axon, the precise mechanisms through which hypoxia compromises axonal structure and function remain unclear. However, links between hypoxia-induced axonopathic disease and the amyloid cascade, as well as the upregulation of amyloid precursor protein (APP) and amyloid beta (A&beta;) by hypoxic stress, give rise to the hypothesis that proteolytic cleavage of APP into A&beta; may be specifically responsible for axonopathy under conditions of hypoxia. </p><p>The goal of this dissertation was thus to understand dependence of hypoxia-induced axonal morphological and functional impairment on APP cleavage and the production of A&beta;. I have developed a model of hypoxia-induced axonopathy in retinal explants. Using this model, I have experimentally addressed the core hypothesis that APP cleavage, and in particular the formation of A&beta;, is necessary and sufficient to mediate morphological and functional axonopathy caused by hypoxia. I have found that there is a dissociation between the mechanisms responsible for hypoxia-induced morphological and functional impairment of the axon in the explanted retina, with the former being dependent on APP-to-A&beta; processing and the latter likely being dependent on cleavage of a non-APP substrate by the enzyme BACE1. These findings shed light on mechanisms of hypoxia-induced axonopathy.</p> / Dissertation

There is research which demonstrates that traumatic head injury (TBI) is associated with increased incidence of dementia as well as with greater cognitive impairment than is expected in normal aging. However, this literature remains equivocal; studies exploring head injury as a risk factor for dementia and Alzheimer’s disease have yielded conflicting results. The present study examines morbidity, mortality, cognitive impairment and psychosocial issues in seniors with a history of head injury of sufficient severity to cause loss of consciousness. These results suggest that over time, a history of TBI is associated with some increased morbidity with age. Associations between TBI and changes in personality that may lead to impaired psychosocial functioning were also suggested by the findings of this study. Specifically, the results indicated traumatic brain injury may be associated with marital breakdown and social isolation. Additional results suggest that people who have sustained a TBI have an increased likelihood of living in a nursing home or chronic-care facility.

Alzheimerio liga (AL) yra viena neurodegeneracinių ligų, pasižyminti progresuojančiu atminties, kalbos, pažintinių funkcijų blogėjimu, kasdienės veiklos pasyvėjimu, elgsenos pokyčiais bei neuropsichiatriniais simptomais. Vienas iš devynių žmonių (11 proc.), vyresnių nei 65 metai serga AL. Vyresnių nei 85 metai asmenų tarpe šios ligos dažnis padidėja iki 32 proc. Didžioji dalis sergančiųjų AL gyvena namuose, slaugomi šeimos narių. Globėjams tenka rūpintis sergančiuoju 24 val. per parą, o tai sukelia fizinį, emocinį ir protinį nuovargį bei lemia gyvenimo kokybės blogėjimą. Darbo tikslas – nustatyti kaip ergoterapeuto konsultacijos veikia sergančiųjų Alzheimerio liga savarankiškumą kasdienėje veikloje bei juos globojančių asmenų gyvenimo kokybę. Uždaviniai: 1. Įvertinti globėjų, slaugančių Alzheimerio liga sergančius asmenis gyvenimo kokybę. 2. Įvertinti ergoterapeuto konsultacijų poveikį globėjų gyvenimo kokybei. 3. Nustatyti sergančiųjų Alzheimerio liga kasdienės veiklos problemas. 4. Įvertinti ergoterapeuto konsultacijų poveikį sergančiųjų Alzheimerio liga savarankiškumui kasdienėje veikloje. Tyrimo metodika. Tyrime dalyvavo 30 globėjų, namuose slaugančių sergančiuosius Alzheimerio liga. Tyrimas atliktas Lietuvos Alzheimerio ligos asociacijos Kauno klube ir Lietuvos Alzheimerio ligos asociacijos Alytaus klube. Tyrimo metu buvo naudojamos trys anketos. Sergančiųjų Alzheimerio liga negalios laipsniui įvertinti buvo naudojama Spartaus negalios vertinimo skalė, globėjų gyvenimo... [toliau žr. visą tekstą] / Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory, language, cognitive, daily activities deterioration, behavioral changes and neuropsychiatric symptoms. One of the nine people (11 percent) over 65 years old suffers from AD. Among the people older than 85 years the disease incidence increases to 32 percent. The majority of patients with AD live at home, cared for by family members. Caregivers have to take care of AD patients 24 hours per day, which leads to physical, emotional and mental fatigue and worsen the quality of life. Aim of the research: assess the impact of occupational therapist consultations in patients with Alzheimer's independence in daily activities and their caregiver’s quality of life. Goals of the research: 1. Evaluate AD patients caregivers quality of life. 2. Assess the effect of occupational therapist consultations on caregiver’s quality of life. 3. Assess AD patient’s problems in activities of daily living. 3. 4. Evaluate the impact of occupational therapist consultations in patients with Alzheimer's disease independence in daily activities. Research methods. The study involved 30 caregivers, caring patients with Alzheimer's disease at home. The study was conducted in Kaunas club of Lithuania Alzheimer's Association and Alytus club of Lithuania Alzheimer's Association. Three questionnaires were used in this study. Disability in patients with Alzheimer's disease was assessed by Rapid Disability Rating Scale... [to full text]

We have recently established that aberrant alkylacylglycerophosphocholine metabolism results in the increased tissue concentration of platelet activating factors (PAFs) in the temporal cortex of Alzheimer Disease (AD) patients and in TgCRND8 mice over-expressing mutant human amyloid precursor protein. PAF lipids activate a G-protein coupled receptor (PAFR) reported to be expressed by microglia and subsets of neurons in rat. It is not known whether this same expression pattern is recapitulated in mice however, as the expression has only been inferred by use of pharmacological PAFR antagonists, many of which impact on both PAFR-dependent and PAFR-independent signalling pathways. PAFR plays a role in long term potentiation (LTP) induction in rats. PAFR has also been implicated in behavioural indices of spatial learning and memory in rats. Contradictory reports using mice provide ambiguity regarding the role of PAFR in LTP induction in mice. To assess whether PAFR is expressed in murine neurons, I localized PAFR mRNA in wild-type C57BL/6 mice using PAFR KO mice as a negative control. I further showed that the loss of PAFR did not impair learning and memory although this assessment must be considered preliminary as the behavioural test employed was not optimized to detect changes in learning and memory of C57BL/6 mice over time adequately.Finally, I showed that the loss of PAFR in TgCRND8 mouse model of AD had no impact upon Aβ plaque number. My observations suggest that PAFR is restricted to microglial-like cells in mouse hippocampus and as such, it may not play a role in learning and memory.

Relationships between the steroid hormones estradiol (E2), testosterone (T), cortisol (CRT) and dehydroepiandrosterone-sulfate (DHEAS), memory and mood were investigated in men, in women estrogen-users and non-users, and in patients with Alzheimer's Disease (AD). In Study 1, 72 year-old healthy men and women estrogen-users performed better than estrogen non-users on Forward and Total Digit Span, which test attention and short-term memory, concomitant with their higher E2 levels. The estrogen-users performed better than the men and the non-users on Delayed Selective Reminding, a test of explicit verbal memory. Men and women with higher CRT levels performed worse on several explicit verbal memory tests compared to those with lower endogenous, CRT levels. In Study 2, male patients with AD performed better than estrogen non-using women with AD on several everyday memory tests, and women estrogen-users with AD performed similarly to the men. Both the men and estrogen-users had higher levels of E2 than the non-users. AD patients with higher endogenous levels of DHEAS performed better than those with lower levels on several everyday memory tests, and AD patients with higher CRT levels were impaired on one aspect of everyday spatial memory, Route Recall. In Study 3, no differences in hormone levels between AD patients and age-matched healthy elderly controls were found. The AD patients were most severely impaired on tasks involving explicit verbal recall compared to healthy controls, and least impaired on short-term memory and concentration tasks. The AD patients reported more dysphoric mood and mental dulling symptoms than healthy age-matched controls, but they did not report feeling less positive about the future. Taken together, these results suggest that higher levels of DHEAS and E2 are related to better memory performance in both healthy elderly men and women and in patients with AD, and higher CRT levels are associated with poorer explicit verbal memory performanc

Background: Dementia is a disease known to cause chronic deterioration of intellectual functions severe enough to interfere with the ability to perform activities of daily living. Alzheimer’s disease (AD) is the most frequent cause of dementia and is expected to have a substantial impact on the health care system as the Canadian population ages. Current therapies are ineffective at halting disease progression; thus, investigations examining risk factors for AD have become a popular avenue of research. A relationship between cerebrovascular disease and the risk of AD has been established, but the underlying mechanisms on how these morbidities are related remain unclear. The apolipoprotein E gene (ApoE) influences the development of AD with the apolipoprotein E-e4 allele (ApoE-e4) conferring increased risk. The underlying mechanism by which the ApoE-e4 allele influences AD is unclear. Since the ApoE-e4 allele is related to both AD and stroke, the impact of cerebral infarcts on AD may vary by ApoE-e4 allele status. Objective: The objective of this study was to assess if ApoE-e4 allele status modified the relationship between cerebral infarcts and AD. Methods: Secondary data from the Nun Study, a longitudinal clinico-pathologic study of aging representing 678 female participants 75+ years were used for this investigation. AD was diagnosed using criteria for clinical dementia and AD pathology. Dementia was diagnosed using standard criteria, including the Consortium to Establish a Registry for Alzheimer’s Disease battery of neuropsychological tests and performances on activities of daily living. AD pathology was diagnosed using a modified version of the National Institute on Aging and Reagan Institute criteria. Infarcts were identified during gross neuropathologic assessment at autopsy. Logistic regression was used to assess the relationship between AD and the presence, location, and size of cerebral infarcts. Regression models were then stratified by ApoE-e4 allele status to determine if this variable was a significant effect modifier. The relationship of ApoE-e4 allele status with AD, as well as presence of cerebral infarcts, was also explored. All regression models were adjusted for age at death, educational level, and, when appropriate, ApoE-e4 allele status. A sensitivity analysis using different definitions for the outcome AD was performed and showed that varying criteria for AD pathology did not change study results; however, the use of clinical dementia (regardless of pathology) as an outcome did produce significantly different results. Thus, the research questions were repeated using clinical dementia as an outcome. Results: The presence of cerebral infarcts was not significantly associated with AD; this relationship did not change when location and size of infarcts were examined. ApoE-e4 was significantly associated with an increased risk of AD. ApoE-e4 was not associated with presence of cerebral infarcts. ApoE-e4 did not modify the relationship between presence of cerebral infarcts and AD. When the outcome clinical dementia was investigated, presence of cerebral infarcts significantly increased the risk of dementia. This relationship remained when location and size of infarcts were analyzed. ApoE-e4 allele status slightly modified the relationship between presence of cerebral infarcts and dementia. Conclusions: The findings from this study suggest that individuals with severe AD pathology are unlikely to be affected by cerebral infarcts. Future studies should focus on examining levels of severity of AD pathology in relation to cerebral infarcts. Cerebral infarcts appear to have an impact on dementia and this relationship was found to slightly vary by ApoE-e4 status. Future studies are recommended to examine how ApoE interacts with a variety of age-related risk factors to increase the risk of AD.