The purpose of this thesis was to improve the understanding of what cognitive functions are important for driving performance, investigate the impact of impaired cognitive functions on drivers with brain injury, and study adaptation strategies relevant for driving performance after brain injury. Finally, the predictive value of a neuropsychological test battery was evaluated for driving performance. Main results can be summarized in the following conclusions: (a) Cognitive functions in terms of attentional and dynamic working memory-related functions are relevant for driving performance. (b) Neuropsychological impairments in information processing speed, divided and focused attention, requiring working memory, are associated to limitations in driving performance. In addition, qualitative aspects of driving problems especially impaired anticipatory attention appeared to constrain driving performance. (c) A neuropsychological test battery assessing speed of information processing and attention in terms of working memory predicted driving performance. In addition, cognitive factors are relevant for interpretation of driving problems qualitatively. (d) Driving speed adjustment and anticipatory attention were adaptive strategies for driving after brain injury. Interest in driving, motivation for driving safely, and driving experience appeared also relevant for driving after brain injury. (e) Collaboration between medical, neuropsychological and driving expertise is recommended for a total evaluation of driving performance after brain injury. Anticipatory attention was considered a working memory based attentional system, directing the processing resources flexibly and appropriately between the different information processing components. Thus, anticipatory attention demonstrated qualitatively that working memory is a prominent function in a real driving context.

One in nine North American women will be diagnosed with breast cancer in their lifetime and most will receive chemotherapy as part of their treatment. Although advances in treatment have increased survivorship, some research suggests chemotherapy results in cognitive deficits in a subset of recipients, a condition known as chemo-fog, thereby compromising quality of life. However, inconsistencies in methodology and neuropsychological assessment have complicated comparison of findings. The first objective of this thesis was to review the methodological issues with an emphasis on the quantitative techniques typically employed. A comparison of group and individual based analyses found negligible effects for both univariate and multivariate approaches while individual based analyses identified severe declines in function in a subset of participants. A standardized-regression based (SRB) approach was recommended as the method of choice. Furthermore, it was recommended that the number of tests be limited since comprehensive batteries can complicate identification due to increased risk of misclassification. Therefore, the second goal of the thesis was to evaluate the sensitivity of a reduced battery to the declines associated with chemo-fog. A comprehensive neuropsychological battery comprising 23 tests was compared to a subset of nine tests. SRB analyses demonstrated that a more selective battery was equally useful and may be appropriate for identification of chemo-fog. Given the variability in the composition of neuropsychological test batteries, the final aim of this thesis was to compare the structure of the theoretical cognitive domains with ones identified through exploratory factor analyses (principle axis factoring) to evaluate the convergence between the two. The results demonstrated there is statistical support for the conceptual framework that underlies the composition of the domains. The contributions of this thesis include providing methodological guidelines for those conducting future research in this area to ensure that results are comparable across studies and are meaningful, and evaluating the utility of a screening battery to facilitate identification of chemo-fog. In addition, it was demonstrated that despite the lack of professional guidelines informing the selection and construction of neuropsychological test batteries, there is statistical evidence to support the practice of grouping tests into domains based on theoretical grounds.

One in nine North American women will be diagnosed with breast cancer in their lifetime and most will receive chemotherapy as part of their treatment. Although advances in treatment have increased survivorship, some research suggests chemotherapy results in cognitive deficits in a subset of recipients, a condition known as chemo-fog, thereby compromising quality of life. However, inconsistencies in methodology and neuropsychological assessment have complicated comparison of findings. The first objective of this thesis was to review the methodological issues with an emphasis on the quantitative techniques typically employed. A comparison of group and individual based analyses found negligible effects for both univariate and multivariate approaches while individual based analyses identified severe declines in function in a subset of participants. A standardized-regression based (SRB) approach was recommended as the method of choice. Furthermore, it was recommended that the number of tests be limited since comprehensive batteries can complicate identification due to increased risk of misclassification. Therefore, the second goal of the thesis was to evaluate the sensitivity of a reduced battery to the declines associated with chemo-fog. A comprehensive neuropsychological battery comprising 23 tests was compared to a subset of nine tests. SRB analyses demonstrated that a more selective battery was equally useful and may be appropriate for identification of chemo-fog. Given the variability in the composition of neuropsychological test batteries, the final aim of this thesis was to compare the structure of the theoretical cognitive domains with ones identified through exploratory factor analyses (principle axis factoring) to evaluate the convergence between the two. The results demonstrated there is statistical support for the conceptual framework that underlies the composition of the domains. The contributions of this thesis include providing methodological guidelines for those conducting future research in this area to ensure that results are comparable across studies and are meaningful, and evaluating the utility of a screening battery to facilitate identification of chemo-fog. In addition, it was demonstrated that despite the lack of professional guidelines informing the selection and construction of neuropsychological test batteries, there is statistical evidence to support the practice of grouping tests into domains based on theoretical grounds.

The integrity of brain white matter is vital for the interneuronal signalling between distinct brain regions required for normal cognitive function. White matter integrity is compromised with ageing and could contribute to age-related cognitive decline. Chronic cerebral hypoperfusion is thought to underlie the development of white matter pathology and cognitive changes, often seen in the elderly. Additionally, the development of regional hypoperfusion and white matter damage are thought to be early events in Alzheimer’s disease (AD) pathogenesis. This thesis set out to test the hypothesis that chronic cerebral hypoperfusion underlies the development of white matter pathology and cognitive decline and also that chronic cerebral hypoperfusion causes the development of Ab pathology in AD. The first aim was to investigate the impact of hypoperfusion on the development of white matter damage and different aspects of cognition in a mouse model of chronic cerebral hypoperfusion. Two studies were undertaken to address this. The first study examined the temporal development of pathology following hypoperfusion induced by bilateral carotid artery stenosis (BCAS) using microcoils Hypoperfusion was induced in wild type (WT) mice and the pathological changes examined at one week, two weeks, one month and two months. Hypoperfused animals developed a diffuse and widespread white matter pathology, present from one week, which occurred predominantly in the myelin component of white matter; this was accompanied by minimal axonal damage. A second study examined the impact of hypoperfusion on different aspects of spatial memory and further investigated pathological changes in the model at one and two months. Behavioural testing revealed a significant impairment in spatial working memory but not episodic memory or spatial reference memory in hypoperfused animals. In the same mice, pathological assessment indicated that there was a significant increase in levels of myelin damage and elevated levels of microglial activation as compared to shams. These results demonstrate that modest reductions in cerebral blood flow are sufficient to cause the development of white matter damage and the development of cognitive deficits. The second aim was to investigate the impact of hypoperfusion on the development of white matter and amyloid pathology in a mouse model (3xTg-AD) of AD. To address this, using 2 different sizes of microcoils (0.18mm and 0.16mm internal diameter) BCAS of varying severities was induced in 3xTg-AD mice and white matter and Ab pathology were assessed at one month. Circle of Willis (CoW) architecture was also compared between WT and 3xTg-AD mice. Overall white matter pathology was not exacerbated in experimental 3xTg-AD mice with BCAS induced by 0.18mm coils. However with a greater level of stenosis (0.16mm coil) ischaemic damage to neuronal perikarya was present in most experimental animals. In addition to ischaemic damage, localised areas of severe white matter pathology were also observed in conjunction with subtle changes to white matter Ab levels. Hypoperfusion did not impact on the development of intraneuronal Ab pathology, other than in the presence of ischaemic damage when levels were reduced. Comparison of CoW architecture between WT and 3xTg-AD mice revealed strain specific differences in the presence and morphology of the posterior communicating artery which may explain the lack of pathology in 3xTg-AD mice as compared to WT following BCAS induced using 0.18mm dia. microcoils. The third aim was to investigate whether white matter protein composition changed with age and also whether ageing conferred increased vulnerability to hypoperfusion. To address this, white matter protein levels were compared between young (3-4 months) and old (12-13 months) 3xTg-AD mice. White matter pathology was compared between sham and hypoperfused animals in the aged cohort. Levels of myelin basic protein and 2', 3'-cyclic nucleotide 3'- phosphodiesterase were found to be significantly increased whilst levels of myelin associated glycoprotein were significantly reduced with ageing. These results suggest that changes in myelin protein composition may contribute to the development of age related white matter pathology. White matter pathology was not exacerbated in aged hypoperfused animals following one month of hypoperfusion as compared to shams. The results presented within the thesis demonstrate that chronic cerebral hypoperfusion precipitates the development of selective white matter damage and impacts on cognition. Also it has been shown that where hypoperfusion is severe enough to cause ischaemic damage to neuronal perikarya and localised areas of severe white matter pathology, alterations in white matter Ab levels can occur. Hypoperfusion does not impact on APP processing or on intraneuronal levels of APP or Ab, other than in the presence of ischaemic damage to neuronal perikarya, when levels are reduced. These findings highlight the importance of early intervention strategies in the treatment of vascular risk factors which can lead to hypoperfusion and the development of white matter damage and a decline in cognitive function in later life. These findings also suggest that repair or prevention of white matter damage may be an appropriate strategy for the attenuation of cognitive decline following onset of hypoperfusion. This thesis also highlights some of the limitations of animal models of human disease.

The aim of this study is to establish a brief screening tool to classify PD patients as PD with normal cognition (PD-N), PD patients with mild cognitive impairment (PD-MCI) and PD patients with dementia (PD-D). There has been emerging evidence that the MoCA (Montreal Cognitive Assessment) shows potential for the brief assessment of cognition to differentiate among PD patients. One possible solution to further improve the discrimination among PD-D, PD-MCI and PD-N groups is to examine Instrumental Activities of Daily Living (IADL) measures in conjunction with the MoCA. A convenience sample of 162 patients suffering from PD and 53 volunteer control subjects were examined in a movement disorders center. Extensive neuropsychological testing was done to classify the PD patients into PD-N, PD-MCI or PD-D. The 24 patients were diagnosed as PD-D based on the Movement Disorders Society Task Force criteria. For PD-MCI, two criteria were used: 1.5SD:2 in one-domain (1.5 SD below the norms on two measures in at least one of four cognitive domains) and 1.5SD:1 in two-domains (1.5 SD below normative data in at least one measure but in two domains) which made a diagnosis of 34 and 39 PD-MCI patients respectively. The remaining patients were classified as PD-N. For both the MCI criteria, the results suggest that 1) for discriminating PD-MCI from PD-N, the MoCA is a sufficiently suitable screening measure that is not improved by adding ADL measures, 2) for distinguishing PD-D from PD-MCI, the MoCA and the full ADL-IS questionnaire can be administered to a patient suffering from PD. When time is limited and depending on the possibility of answering the questions regarding the ADL-IS items, the MoCA along with the Muddled and Complex Medication ADL-IS items should be administered. When no scores are obtained for Muddled, then MoCA along with Complex Medication ADL-IS item is sufficient to discriminate PD-D from PD-MCI. However, if no scores are obtained for Complex Medication item, then an average of four ADL-IS items should be taken along with the MoCA. This attractive brief screening tool helps in detection of cognitive impairment in the elderly.

Individuals with mild cognitive impairment (MCI) show variable impairment in autobiographical memory function, source memory function and reduced integrity in the brain’s default mode network (DMN). There is overlap between the DMN, such as the medial posterior cortical hub, and brain regions that are active when participants recall autobiographical memories. To assess the association between autobiographical memory and the DMN, 14 MCI and eleven age and education-matched healthy control participants were assessed using the autobiographical memory interview (AMI) and underwent resting state fMRI scans. The same participants underwent a test of source memory which assessed both recognition and source memory. The MCI group showed significantly increased semantic as well episodic memory impairments using the AMI, evident across the lifespan for episodic memory but not for childhood semantic memory. Significantly poorer DMN connectivity, using a goodness of fit index (GOF) of the DMN template, was evident in the MCI group. MCI participants showed poorer performance on both recognition and source memory relative to HC participants. A modest association between AMI semantic memory (r=0.4) scores, but not episodic memory scores (r=0.09), and DMN connectivity was found in these participants. For future study the predictive value of MR imaging in the DMN of MCI participants should be explored.

The studies presented in this work were completed with the goal ofgaining greater insight into the roles of protein oxidation in brain aging and age-relatedcognitive impairment. Aging is associated with the impairment of physiological systemssuch as the central nervous system (CNS), homeostatic system, immune system, etc.Functional impairments of the CNS is associated with increased susceptibility to developmany neurodegenerative diseases such as Alzheimer's diseases (AD), Parkinson's disease(PD), and amyotrophic lateral sclerosis (ALS). One of the most noticeable functionalimpairments of the CNS is manifested by cognitive decline. In the past three decades, thefree radical theory of aging has gained relatively strong support in this area. Excessiveproduction reactive oxygen species (ROS) was demonstrated as a contributing factor inage-related memory and synaptic plasticity dysfunction. This dissertation use proteomicsto identify the proteins that are oxidatively modified and post-translationally altered inaged brain with cognitive impairment and normal aging brain.Ongoing research is being pursued for development of regime to preventoxidative damage by age-related oxidative stress. Among which are those that scavengefree radicals by antioxidants, i.e. ??-lipoic acid (LA), and protecting the brains byreducing production of neurotoxic substance, i.e. reducing production of amyloid ??(A??).Therefore, proteomics were also used to identify the alteration of specific proteins in agedbrain treated with LA and antisense oligonucleotides again amyloid protein precursor.This dissertation provides evidences that certain proteins are less oxidatively modifiedand post-translationally altered in cognitively impaired aged brain treated with LA andantisense oligonucleotides against the A?? region of amyloid precursor protein (APP)(AO).Together, the studies in this dissertation demonstrated that increased oxidativestress in brain play a significant role in age-related cognitive impairment. Moreover, suchincreased oxidative stress leads to specific protein oxidation in the brain of cognitiveimpaired subject, thereby leading to cognitive function impairment. Moreover, thefunctional alterations of the proteins identified by proteomics in this dissertation mayleads to impaired metabolism, decline antioxidant system, and damaged synapticcommunication. Ultimately, impairment of these processes lead to neuronal damages andcognitive decline. This dissertation also show that several of the up-regulated andoxidized proteins in the brains of normal aging mice identified are known to be oxidizedin neurodegenerative diseases as well, suggesting that the expression levels of certainproteins may increase as a compensatory response to oxidative stress. This compensationwould allow for the maintenance of proper molecular functions in normal aging brainsand protection against neurodegeneration.

Objective: The purpose of this dissertation was to determine whether measures of reaction time inconsistency (RTI) can be applied clinically to detect cognitive impairment in older adults. Methods: Data were obtained from the Victoria Longitudinal Study (VLS), a longitudinal study of healthy aging, and PREVENT, a multivariate study of risk factors for Alzheimer’s disease. Study 1 examined effects of task complexity and computational approach on the association between RTI and physical and cognitive functioning in participants of the VLS. Study 2 assembled normative data from the VLS and standardized RTI data from an independent VLS cohort against these normative data. Significant Study 1 findings were replicated in Study 2 using the obtained RTI T-Scores, and the clinical utility of results were evaluated using stratum specific likelihood ratios (SSLRs). Study 3 replicated Study 2 analyses in data from PREVENT. Results: Results of Study 1 identified four operationalizations of RTI from a choice reaction task that yielded consistent significant associations with cross-sectional cognitive performance. Consistent associations were not observed between these scores and cognitive change or performance on measures of physical functioning. Study 2 replicated Study 1 findings in an independent sample using RTI T-Scores. SSLRs supported the clinical utility of measures of RTI for detecting prevalent cognitive impairment. Study 3 replicated findings from Study 2, but SSLRs indicated that only low RTI scores yielded associations of sufficient reliability for clinical interpretation. Consistent with Study 1 and Study 2, associations between RTI T-Scores and measures of physical function were nonsignificant. Conclusions: Low RTI T-Scores were shown across two samples to be associated with a clinically meaningful reduction in the odds of cognitive impairment. Further research is needed in order to clarify the utility of high RTI scores for positive prediction of cognitive impairment. / Graduate

One in nine North American women will be diagnosed with breast cancer in their lifetime and most will receive chemotherapy as part of their treatment. Although advances in treatment have increased survivorship, some research suggests chemotherapy results in cognitive deficits in a subset of recipients, a condition known as chemo-fog, thereby compromising quality of life. However, inconsistencies in methodology and neuropsychological assessment have complicated comparison of findings. The first objective of this thesis was to review the methodological issues with an emphasis on the quantitative techniques typically employed. A comparison of group and individual based analyses found negligible effects for both univariate and multivariate approaches while individual based analyses identified severe declines in function in a subset of participants. A standardized-regression based (SRB) approach was recommended as the method of choice. Furthermore, it was recommended that the number of tests be limited since comprehensive batteries can complicate identification due to increased risk of misclassification. Therefore, the second goal of the thesis was to evaluate the sensitivity of a reduced battery to the declines associated with chemo-fog. A comprehensive neuropsychological battery comprising 23 tests was compared to a subset of nine tests. SRB analyses demonstrated that a more selective battery was equally useful and may be appropriate for identification of chemo-fog. Given the variability in the composition of neuropsychological test batteries, the final aim of this thesis was to compare the structure of the theoretical cognitive domains with ones identified through exploratory factor analyses (principle axis factoring) to evaluate the convergence between the two. The results demonstrated there is statistical support for the conceptual framework that underlies the composition of the domains. The contributions of this thesis include providing methodological guidelines for those conducting future research in this area to ensure that results are comparable across studies and are meaningful, and evaluating the utility of a screening battery to facilitate identification of chemo-fog. In addition, it was demonstrated that despite the lack of professional guidelines informing the selection and construction of neuropsychological test batteries, there is statistical evidence to support the practice of grouping tests into domains based on theoretical grounds.

Cognitive impairment no dementia (CIND) is conceptualized as a stage of cognitive decline between normal aging and onset of dementia. As persons with CIND are at high risk of developing dementia, efforts to determine early predictors of cognitive decline are warranted to advance both clinical knowledge and practice. Recent evidence suggests persons with CIND may have changes in vascular function compared to non-impaired peers, which may have clinical potential to differentiate those with and without CIND. The purpose of this study is to determine whether vascular functioning, examined both by individual indicators and as an aggregate vascular factor, will be associated with cognitive impairment. It is expected that the individual vascular indicators of hypertension, diabetes, stroke, and heart problems will be related to cognitive status classification, with poorer vascular function being more strongly associated with CIND as compared to the control group. Further, it is expected that examining the aggregate vascular factor in a multivariate approach will be more strongly associated with cognitive status than examining the vascular indicators individually. Data for this study were collected in the Victoria Longitudinal Study (VLS), a large-scale longitudinal, sequential study of community-dwelling older adults in Victoria, British Columbia. Cognitive group status was determined by a distributional approach based on scores on 5 cognitive reference measures. The associations between all vascular factors and cognitive status groups were assessed using chi-square analyses. Univariate analyses were then carried out using ordinal logistic analysis. A multivariate approach using discriminant analysis was then used to determine if cognitive status group membership was associated with vascular function based on linear combinations of vascular indicators. Contrary to expected results, we did not find a significant association between any of the vascular indicators (i.e., blood pressure classification, severity of stroke, severity of heart troubles, and severity of diabetes) and the cognitive status classifications. Further, group membership was not associated with any of the individual vascular markers, or by a multivariate combination of the indicators. Several reasons for this study’s findings include discrepant definitions of cognitive impairment in the literature, sample characteristics (i.e. high education, low base rate of vascular problems), and methodological considerations. Future research objectives should address the longitudinal association of vascular function and cognitive status. / Graduate