The aging brain is prone to the development of pathology and dementia. With a rapidly growing elderly population diagnoses of neurodegenerative diseases, such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease are on the rise. Additionally, diabetes and obesity are linked to an increased risk of dementia. The convergence of this increasingly aged population with the obesity and diabetes epidemic give rise to new concerns regarding the future of prevention and treatment of neurodegenerative diseases. Our lab has previously shown that leptin, an adipokine involved in signaling satiety to the hypothalamus, can modulate the generation of the amyloid beta (Aβ) peptide (a toxic peptide associated with neurologic disease) and attenuate hyperphosphorylation of the tau protein (another peptide prone to forming large insoluble structures causing neurodegeneration). From these studies we have elucidated that leptin resistant mice (which develop severe obesity and type-2 diabetes mellitus) with knock-in mutations for the amyloid precursor protein (APP) and presenilin-1 (PS1) genes develop extensive vascular pathology and cognitive impairments. Interestingly, these mice do not display increased levels of amyloid deposition in the brain. Additionally, increased tau phosphorylation occurs in these mice with leptin resistance. As a follow up to this study db mice were transduced, via adeno-associated virus, with the tau P301L mutant to induce the development of tangle pathology. These mice displayed no cognitive deficits, yet they displayed increases in both tau phosphorylation and tangle count within the hippocampus. Collectively, these studies indicate leptin resistance, obesity, and type-2 diabetes mellitus promote the development of cerebrovascular and neurofibrillary tangle pathologies associated with neurodegeneration and dementia. These observations open many previously unexplored avenues for developing novel therapeutics to treat these devastating diseases.

Alzheimer's Disease (AD) is among the most prevalent of the dementias and it is anticipated that much of the care required for the dependent patient will be provided in the home setting by a caregiver. The purpose of this study was to identify the importance of needs related to caregiving and the level of satisfaction of those needs related to the caregivers of Alzheimer's victims. The theoretical framework for this study is Dorthea Orem's "Self-Care Deficit Theory."The sample was 18 caregivers who attended one of three Alzheimer's Support Group meetings held in three central Indiana cities. Human subjects rights were protected. The Home Caregiver Needs Survey (HCNS), Hileman, 1990, was used to identify the information, household, patient psychological needs of the and care needs, personal and caregivers of Alzheimer's patients and to determine if these needs are being adequately met. Findings included: (a) the caregivers perceived the need for information, patient care, personal, spiritual, psychological need to be somewhat important to important; teach, assist and support caregivers throughout the and (b) satisfaction of the needs indicated that the caregivers were somewhat satisfied to satisfied with the needs presented. Implications call for: (a) Nursing intervention to caregiving experience. (b) Home health care agencies and senior citizens action groups to lobby for support and programs to assist caregivers. / School of Nursing

This study investigated the utility of the cognitive measures of the Dean-Woodcock Neuropsychological Assessment System (D-WNAS) in the differential diagnosis of Alzheimer dementia (AD) from depression. Past research has found an overlap of symptoms in the early stages of AD and those found in geriatric depression. In both instances, patients are likely to report memory loss, attention deficits, and mood disturbances. As a result of this similarity, differentially diagnosing one from another is a vexing problem for the clinical practitioner. Although a number of screening measures have been offered, none have proven to be clinically useful. Some have proposed this is the result of reliance upon use of single-factor measures. Indeed, many have proposed a multiple factor assessment model would be of more utility in diagnosing AD and depression. Considering the importance of an accurate diagnosis in treatment, this study utilized a multiple factor cognitive model offered by the Dean-Woodcock Neuropsychological Assessment System to differentiate AD from depression.Specifically, subtest scores of the Woodcock-Johnson III - Tests of Cognitive Ability (WJ-III; cognitive measure of the Dean-Woodcock Neuropsychological Assessment System) were compared. Participants (n = 172) fell into one of three groups (i.e. Depressed, Demented, or Normal) based on the diagnoses of a board certified neurologist and neuropsychologist. Results showed clinical groups performed more poorly than normal participants on tests of the WJ-III. In addition, AD participants differed significantly from depressed participants on the Visual Matching and Spatial Relations tests of the WJ-III. However, in all, the WJ-III demonstrated a classification hit rate of less than 70%. Although groups were found to differ in specific ways, the classification hit rate of the WJ-III suggested it could not differentially diagnose AD from depression alone. / Department of Educational Psychology

No description available.

Die Liquordiagnostik ist neben der Anamnese, neuropsychologischen Testung und der Bildgebung eine wichtige Säule in der Demenzdiagnostik. Bisher diente sie vorrangig dazu, Demenzen von nicht-dementiellen Erkrankungen abzugrenzen. Die vorliegende Arbeit beschäftigt sich mit der Trennschärfe der Kombination der Liquormarker Aß 1-42, T-Tau und P-Tau in der Differenzialdiagnostik innerhalb verschiedener Demenzformen. So bestätigten wir die liquorgestützte Alzheimerdiagnose bei erhöhten Werten von T-Tau und P-Tau, sowie bei erniedrigtem Aß 1-42. Bei den alpha-Synucleinopathien ließ sich bei einem normalen Befund eine Demenz bei Parkinson von einer Lewy-Body-Demenz abgrenzen (Aß erniedrigt). Vaskuläre Demenzen ließen sich durch ein normales Liquorprofil vom M. Alzheimer trennen; nach ischämischen Schlaganfällen jedoch traten stark erhöhte Werte des neuronalen Destruktionsmarkers T-Tau auf (abhängig von Größe und Alter des Infarktes) sodass hier die Aussagekraft eines Liquorbefundes bei Z.n. Schlaganfall gemindert war. Eine Lumbalpunktion bei Infarktnachweis in Anamnese oder Bildgebung sollte in ausreichend zeitlichen Abstand erfolgen (abhängig von Infarktgröße bis 6 Monate). Eine korrekte Therapie hängt von einer korrekten Diagnose ab, diese kann durch Liquordiagnostik unterstützt werden.

Background: Alzheimer???s disease and related dementias (ADRD) are often improperly or under-diagnosed in primary care; yet, it is expected that community-based care will be an increasingly important source of support for ADRD patients. In Ontario, primary care has continued to expand its services to include health team models, such as family health teams (FHTs) to provide multidisciplinary collaborative care for patients. Within such teams, memory clinic teams have also been implemented, which are clinic days set up typically once or twice a month to provide interprofessional collaborative care specifically for ADRD patients by trained health care providers (HCPs). Objective: Little is known about the experience of HCPs who work in primary care memory clinic team settings to provide care for ADRD patients. This study explored these experiences. Specifically, questions were asked around the rewards, challenges and motivations with working in the memory clinic structure and providing support to ADRD patients. Methods: A phenomenological approach was used. One-on-one semi-structured interviews were completed with 12 interprofessional team members in two primary care memory clinic teams. Interviews were transcribed and analyzed using Colaizzi???s (1978) method of analysis. Results: Overall, seven subthemes were found which describe the HCP experience. The first two subthemes describe experiencing the journey with the patient and caregiver. HCPs want to support patients while maintaining the patient???s dignity. They also balance emotional dilemmas with responsibilities. The next two subthemes describe experiencing the journey with the team. HCPs feel valued and connected to their team members. The memory clinic structure offers unique care provider experiences. Lastly, three subthemes were found which describe the personal and professional rewards of the experience. HCPs found thrilling complexities within the patient population in the memory clinic and that working in the clinic they are able to experience ongoing learning opportunities. HCPs also described that the memory clinic offers personal and professional fulfillment. Discussion: HCPs described an overall positive experience working in the memory clinic to support ADRD patients. HCPs take pride in being able to support patients and caregivers. Knowing that they are making a difference and doing good work are motivations to continue to work with complex populations, such as ADRD patients. HCPs enjoy working in close proximity to one another, respect their team members, and enjoy learning from each other. Team members motivate each other to stay and work with the ADRD population in primary care memory clinics. HCPs reap many rewards associated with working in a ???tight-knit??? memory clinic team setting for ADRD patients. As the number of HCPs working in team settings continues to grow in Canada, it is important to look at the experiences of these teams to understand the rewards, challenges and motivations of team members. Conclusions: These findings provide more context in understanding how to motivate future HCPs to work with more complex populations such as ADRD patients. Future research should address the outcomes of these clinics by exploring patient and family caregiver experiences with specialized teams, as it is important to gain their experiences to enhance the care practices for these individuals.

No description available.

With societies aging all around the world, the global burden of degenerative diseases is expected to increase exponentially. From the perspective drug development, degenerative diseases represent an especially challenging class. Clinical trials, in this context often termed disease progression studies, are long, costly, require many individuals, and have low success rates. Therefore, it is crucial to use informative study designs and to analyze efficiently the obtained trial data. The development of novel approaches intended towards facilitating both the design and the analysis of disease progression studies was the aim of this thesis. This aim was pursued in three stages (i) the characterization and extension of pharmacometric software, (ii) the development of new methodology around statistical power, and (iii) the demonstration of application benefits. The optimal design software PopED was extended to simplify the application of optimal design methodology when planning a disease progression study. The performance of non-linear mixed effect estimation algorithms for trial data analysis was evaluated in terms of bias, precision, robustness with respect to initial estimates, and runtime. A novel statistic allowing for explicit optimization of study design for statistical power was derived and found to perform superior to existing methods. Monte-Carlo power studies were accelerated through application of parametric power estimation, delivering full power versus sample size curves from a few hundred Monte-Carlo samples. Optimal design and an explicit optimization for statistical power were applied to the planning of a study in Alzheimer's disease, resulting in a 30% smaller study size when targeting 80% power. The analysis of ADAS-cog score data was improved through application of item response theory, yielding a more exact description of the assessment score, an increased statistical power and an enhanced insight in the assessment properties. In conclusion, this thesis presents novel pharmacometric methods that can help addressing the challenges of designing and planning disease progression studies.

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.