Objective: To characterize the association between longitudinal changes in fasting serum glucose and changes in flourodeoxyglucose Positron Emission Tomography (FDG PET) measurements of regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD). A secondary objective was to investigate whether higher fasting serum glucose levels are associated with lower rCMRgl in younger adults within these same AD relevant brain areas. Methods: For the primary study, baseline, interim, and 4.4 ± 1.0-year follow-up fasting serum glucose and PET CMRgl were analyzed in 80 cognitively unimpaired, non-diabetic, 61.5 ± 5 year-old persons with a first-degree family history of AD, including 38 carriers and 42 non-carriers of the apolipoprotein E (APOE) ε 4 allele. An automated brain-mapping algorithm was used to characterize associations between changes in fasting serum glucose levels and changes in rCMRgl. Longitudinal changes in fasting serum glucose levels and their correlation with changes in six pre-selected neuropsychological test measures of memory, attention and processing speed were also assessed with linear regression. The secondary study included a cross sectional sample of 31 cognitively unimpaired, non-diabetic participants, 31.2 ±5.4 years of age. General linear model-based voxel-wise analyses were performed to examine the correlation between fasting serum glucose and rCMRgl. Results: In the primary study of older adults, average fasting serum glucose levels increased over longitudinal measurement, and changes in these levels were inversely associated with longitudinal CMRgl changes in the vicinity of brain regions preferentially affected by AD (p<0.05, corrected for multiple comparisons). Fasting serum glucose was also inversely associated with performance on a measure of visuospatial memory (p<0.05, corrected for multiple comparisons). In the younger sample, fasting serum glucose levels were inversely associated with rCMRgl in left frontal pole and right primary visual cortex regions (p<.05, corrected for multiple comparisons).Conclusions: In older adults, fasting serum glucose increases across time and is inversely related to rCMRgl in AD relevant regions and to visual memory test scores. This relationship between serum glucose and regional brain metabolism may begin in metabolically sensitive areas at a younger age.

Alzheimer’s disease is the most common cause of dementia and was responsible for over 2% of all deaths in Sweden 2012. One of the pathological hallmarks is amyloid plaques built by fibrillated Amyloid β. Luminescent conjugated oligothiophenes are known to stain and give characteristic fluorescence spectra when staining amyloid fibrils. Little is however known about the interactions between LCOs and fibrils. Studies have been performed on molecules more traditionally known to stain amyloid fibrils. Studies have also been performed on fibrils using limited proteolysis. So far no studies have been performed using LCOs combined with limited proteolysis in order to study the interaction pattern between LCOs and fibrils. Amyloid β is expressed and purified using a simple few step purification protocol. The amyloid β peptide was then fibrillated in several generations in order to select for a homogenous fibril structure. This purification protocol also has the ability to purify different oligomers of Amyloid β that are interesting from a toxicity point of view. In this thesis optical characteristics and limited proteolysis with mass spectrometry are being used to studies the interactions between LCOs and fibrillated amyloid β. The proteolytic pattern was suggestive of an accessible N-terminal and a hidden C-terminal of Amyloid β M1-42 in the fibril. It was also shown that the proteolysis cleavage pattern of Chymotrypsin is not disrupted when the LCO pKTAA was used to stain fibrils. The emission spectra from the two LCOs pATAA and pKTAA changes differently when subjected to continuous excitation indicative of conformational changes or chemical modification.

Autosomal-dominant mutations in the amyloid precursor protein (APP) gene increase the production and aggregation of toxic amyloid-β (Aβ) peptides and cause early-onset Alzheimer’s disease (AD). Noradrenergic cell loss is well documented in AD and has been posited to play a role in cognitive symptoms as well as disease progression. We investigated memory and affect, tissue levels of catecholamines, brain-derived neurotrophic factor (BDNF) mRNA and bioenergetic homeostasis in TgCRND8 mice that express a double mutant (K670N/M671L + V717F) human APP695 transgene. We found that TgCRND8 mice develop object memory impairment and behavioural despair, as well as reductions in noradrenaline and BDNF expression in the hippocampus and cortex, before the appearance of Aβ plaques. Animals with more advanced Aβ pathology exhibit disruptions in energetic status, along with diminished complex I+III activity in the electron transport chain. To test whether the AD-like phenotypes of TgCRND8 mice might be due to altered noradrenergic tone, pre-plaque mice were treated with dexefaroxan, an antagonist of presynaptic inhibitory α2-adrenoceptors that are highly expressed on both noradrenergic and cholinergic terminals. Effects of dexefaroxan were compared to those of rivastigmine, a cholinesterase inhibitor. Both dexefaroxan and rivastigmine improved behavioural phenotypes and BDNF expression without affecting tissue Aβ load. Drug treatments also restored complex I+III mitochondrial activity and increased ATP levels. Reductions in noradrenergic tone appear to underlie Aβ-induced functional impairment in TgCRND8 mice, in addition to BDNF deficits and bioenergetic stress. These studies suggest that α2-adrenoceptor targeting may warrant consideration as a therapeutic strategy in AD.

Autosomal-dominant mutations in the amyloid precursor protein (APP) gene increase the production and aggregation of toxic amyloid-β (Aβ) peptides and cause early-onset Alzheimer’s disease (AD). Noradrenergic cell loss is well documented in AD and has been posited to play a role in cognitive symptoms as well as disease progression. We investigated memory and affect, tissue levels of catecholamines, brain-derived neurotrophic factor (BDNF) mRNA and bioenergetic homeostasis in TgCRND8 mice that express a double mutant (K670N/M671L + V717F) human APP695 transgene. We found that TgCRND8 mice develop object memory impairment and behavioural despair, as well as reductions in noradrenaline and BDNF expression in the hippocampus and cortex, before the appearance of Aβ plaques. Animals with more advanced Aβ pathology exhibit disruptions in energetic status, along with diminished complex I+III activity in the electron transport chain. To test whether the AD-like phenotypes of TgCRND8 mice might be due to altered noradrenergic tone, pre-plaque mice were treated with dexefaroxan, an antagonist of presynaptic inhibitory α2-adrenoceptors that are highly expressed on both noradrenergic and cholinergic terminals. Effects of dexefaroxan were compared to those of rivastigmine, a cholinesterase inhibitor. Both dexefaroxan and rivastigmine improved behavioural phenotypes and BDNF expression without affecting tissue Aβ load. Drug treatments also restored complex I+III mitochondrial activity and increased ATP levels. Reductions in noradrenergic tone appear to underlie Aβ-induced functional impairment in TgCRND8 mice, in addition to BDNF deficits and bioenergetic stress. These studies suggest that α2-adrenoceptor targeting may warrant consideration as a therapeutic strategy in AD.

The prevalence of Alzheimer’s disease (AD) in Canada is on the rise, creating the need for evidence-based care practices designed to support individuals with AD and their care providers. Declines in memory, language, visual-spatial, executive abilities, and functional capacity associated with AD create the need for caregiver assistance during the completion of activities of daily living (ADLs). Unfortunately, assisting individuals with more advanced stages of AD is further complicated by communication breakdowns that occur in the dyad (i.e., caregiver and the individual with AD) established to meet a common goal: to complete ADLs. Clinically recommended communication strategies are the current solution used to support caregivers interacting with individuals with AD. However, there are limitations to these recommendations, including that the majority are based on caregiver experience, few are supported by empirical research, and little is known about which strategies are effective when assisting individuals with moderate to severe AD specifically during the context of completing ADLs. This dissertation presents novel research studies that systematically examined formal caregivers’ use of communication strategies while successfully assisting residents with moderate and severe AD during the completion of a representative ADL. Two observational studies and one focus group interview study were conducted to address our hypotheses and research objectives. Key findings from the studies comprising this dissertation were: (1) caregivers used a variety of verbal and nonverbal task-focused communication strategies when successfully assisting residents with AD during the completion of a representative ADL; (2) the task-focused communication strategies caregivers most frequently used were supported by empirical literature and included the use of one direction or idea (i.e., proposition) at a time, closed-ended questions, and paraphrased repetition; (3) when assisting residents with severe AD, caregivers used the resident’s name, one proposition, and paraphrased repetition significantly more than when assisting residents with moderate AD; and (4) the communication strategies that caregivers perceived to use in their care practice indicate that person-centered dementia care is a central aspect to facilitating the completion of ADLs. This research is an important step towards the development of evidence-based communication strategies for caregivers assisting individuals with AD during ADLs.

The prevalence of Alzheimer’s disease (AD) in Canada is on the rise, creating the need for evidence-based care practices designed to support individuals with AD and their care providers. Declines in memory, language, visual-spatial, executive abilities, and functional capacity associated with AD create the need for caregiver assistance during the completion of activities of daily living (ADLs). Unfortunately, assisting individuals with more advanced stages of AD is further complicated by communication breakdowns that occur in the dyad (i.e., caregiver and the individual with AD) established to meet a common goal: to complete ADLs. Clinically recommended communication strategies are the current solution used to support caregivers interacting with individuals with AD. However, there are limitations to these recommendations, including that the majority are based on caregiver experience, few are supported by empirical research, and little is known about which strategies are effective when assisting individuals with moderate to severe AD specifically during the context of completing ADLs. This dissertation presents novel research studies that systematically examined formal caregivers’ use of communication strategies while successfully assisting residents with moderate and severe AD during the completion of a representative ADL. Two observational studies and one focus group interview study were conducted to address our hypotheses and research objectives. Key findings from the studies comprising this dissertation were: (1) caregivers used a variety of verbal and nonverbal task-focused communication strategies when successfully assisting residents with AD during the completion of a representative ADL; (2) the task-focused communication strategies caregivers most frequently used were supported by empirical literature and included the use of one direction or idea (i.e., proposition) at a time, closed-ended questions, and paraphrased repetition; (3) when assisting residents with severe AD, caregivers used the resident’s name, one proposition, and paraphrased repetition significantly more than when assisting residents with moderate AD; and (4) the communication strategies that caregivers perceived to use in their care practice indicate that person-centered dementia care is a central aspect to facilitating the completion of ADLs. This research is an important step towards the development of evidence-based communication strategies for caregivers assisting individuals with AD during ADLs.

γ-Secretase plays a pivotal role in the production of neurotoxic amyloid β-peptide (Aβ), the principal component of amyloid plaques present in Alzheimer’s disease. It consists of a core complex of presenilin (PS), nicastrin, anterior pharynx-defective 1 (Aph-1), and presenilin enhancer 2 (Pen-2) proteins. PS harbors the catalytic aspartates required for regulated intramembrane proteolysis and the paralogs (PS1 and PS2) contribute to the assembly of distinct subpopulations of γ-secretases that may fulfill distinct roles. To characterize the molecular environments of distinct γ-secretases complexes in-depth quantitative comparisons were performed on 1) wild-type PS1 and its derivative carrying point mutations known to cause heritable early-onset AD in mice, and 2) PS1- or PS2-containing γ-secretase complexes equipped with N-terminal tandem-affinity purification (TAP) tags on PS paralogs in HEK293 cells. Isobaric labeling of co-purifying peptides for quantitative mass spectrometry revealed that γ-secretase complexes interact with other protein networks, including the cellular catenin-cadherin network, the molecular machinery that targets and fuses synaptic vesicles to cellular membranes, and the H+-transporting lysosomal ATPase macro-complex. The study revealed mature γ-secretase complexes containing PS1 or mutant PS1 to be indistinguishable in their protein composition, confirmed several previously proposed γ-secretase interactors, identified many novel interactors and uncovered a subset of proteins which can engage in robust interactions with γ-secretase complexes in individual cell types but may escape detection when whole brains are used as biological source materials. Interestingly, signal peptide peptidase (SPP), a Type II TM cleaving aspartyl protease, was pre-dominantly found to co-purify with PS2-containing γ-secretase complexes and could be shown not to influence their maturation but to affect cleavage or release of cellular Aβ. A model emerged from this work that suggests PS1 and PS2 paralogs may divide up the task of handling a broad range of membrane stubs at least in part by associating with different molecular environments.

No description available.

No description available.

Semantic knowledge was investigated in patients diagnosed with Dementia of the Alzheimer's Type (DAT) by means of an off-line probe question battery and an on-line measurement of semantic priming in a lexical decision task (LDT) that varied the stimulus onset asynchrony (SOA). The patients' performance on the detailed probe questions showed that their semantic deficit was confined primarily to animate concepts, characterized by visual descriptive features. In the primed LDT, demented patients demonstrated increased semantic priming compared to age-matched controls. A trend was also found indicating that for both normal controls and DAT subjects the priming magnitude decreased as the SOA increased. These results are interpreted in terms of a distributed representation of semantic knowledge that is impaired in demented patients.