Dissertationen zum Thema „Awareness of cognitive decline“

Nous décrivons 6 études originales, menées sur le cohorte française INSIGHT-PreAD et la cohorte américaine ADNI, qui abordent différents aspects de l'association entre le niveau de conscience des patients du déclin cognitif (« awareness of cognitive decline » en anglais, ou ACD) et leur risque de maladie d'Alzheimer (MA). Nous avons utilisé des méthodes statistiques classiques et l'apprentissage automatique. Nous montrons qu'un déclin subtil est déjà présent dans la MA préclinique. Les patients peuvent remarquer ces changements précoces alors que ni son entourage ni les tests cognitifs ne le font. Cependant, l’entourage et les tests deviennent très vite des sources d'information plus fiables que le patient lui-même : au cours de la progression du stade préclinique au stade prodromal, l'ACD commence à décliner. Dans la MA prodromale, le patient est légèrement anosognosique, jusqu'à ce qu'il atteigne une anosognosie franche dans la démence MA. Le clinicien doit tenir compte de la plainte du patient, mais aussi la comparer à d'autres sources d'information plus fiables. Cela peut également aider à une meilleure sélection des sujets pour les études ciblant la MA pré-démentielle
We describe 6 original studies, conducted on INSIGHT-PreAD and ADNI cohorts, that address different aspects of the association between patients' level of awareness of cognitive decline (ACD) and their risk of Alzheimer’s disease (AD). We used both classical statistical methods and machine learning. We show that a subtle decline is already present in preclinical AD. Patients may notice these early changes when neither the informant nor cognitive tests do. However, the informant and tests very quickly become more reliable sources of information than the patient him/herself: during the progression from the preclinical to the prodromal stage, ACD begins to decline. In prodromal AD, the patient is mildly anosognosic, until he/she usually reaches clear anosognosia in AD dementia. The clinician should consider the patient's complaint but also compare it to other, more reliable sources of information. This may also help in a better subject selection for studies targeting pre-dementia AD

The initial chapters of this thesis describe the clinical and physiological aspects of hypoglycaemia, followed by a review of the literature on the effects of acute hypoglycaemia on cognitive function. The subsequent chapters describe original research studies in subjects with and without diabetes, which examine the effects of acute hypoglycaemia on aspects of cognitive function and the prevention of hypoglycaemia. In Studies 1 to 3, a hyperinsulinemic glucose clamp was used to either maintain euglycemia (blood glucose 4,5 mmol/l) or induce hypoglycaemia (2.6 mmol/l) in both healthy adults (n=20), and subjects with type 1 diabetes (n=16). A cognitive test battery was administered to examine aspects of attention, intelligence, motivation, affect and subjective cognition. Hypoglycaemia induced a significant deterioration in tests sensitive to both visual and auditory selective attention, and attentional flexibility deteriorated (Studies 1 and 2). Intelligence scores did not deteriorate during hypoglycaemia (Studies 1 and 2). In Study 3, hypoglycaemia increased task-irrelevant interference and self-focus of attention, but motivation declined to a similar extent during both study conditions. Hypoglycaemia produced a negative mood state with a significant fall in energy levels and a concomitant rise in anxiety (Study 3). Study 4 was an open-label, comparative study of the post-prandial glucodynamics of insulin lispro, when administered either 5 minutes before or 20 minutes after a high fat/high solid phase meal, in twelve subjects with type 1 diabetes. Administration of insulin lispro after the meal reduced the risk of early postprandial hypoglycaemia, without compromising postprandial glycaemic control. Therefore, the work in this thesis has demonstrated a different deterioration of attentional function in humans during hypoglycaemia with no effect on non-verbal reasoning skills. Furthermore, it would appear that the brain is not only less cognitively competent and more dysphoric during hypoglycaemia, it is also more self-aware and distracted when required to perform effortful processing.

Cognitive impairment in the elderly encompasses many forms, ranging from subtle impairments in otherwise cognitively healthy individuals through mild cognitive impairment and dementia. Brain structural and functional changes underlie the observed cognitive impairment. Complementary to the clinical observation, biomarkers have been proposed as in vivo indicators of the underlying pathophysiology and neurobiological changes in a sufficiently reliable manner that they could be used to detect, track, and predict the disease course over time. In this thesis we used a combination of epidemiological and clinic-based approaches to investigate the mechanisms underlying vascular cognitive impairment (VCI) and Alzheimer’s disease (AD) and to identify possible biomarkers that could help early diagnosis of such conditions. To do so, a set of circulating and cerebrospinal fluid (CSF) biomarkers were studied in healthy and cognitively impaired subjects. Then, these measures were related to grey matter (GM) volumes, white matter (WM) integrity and cognition. The first two studies are part of the population-based Barcelona-ASIA neuropsychology study. Study I aimed to compare the cognitive patterns of risk markers for cerebrovascular disease (CVD) with the cognitive profile in relation to novel and traditional vascular risk factors (VRF) in a community-dwelling sample. Biomarkers of inflammation, endothelial dysfunction and vascular thrombosis were selected. Results showed that VRF and circulating markers of inflammation and endothelial dysfunction predicted performance in several cognitive domains. Cognitive patterns of inflammatory markers overlapped those related to VRF. Markers of endothelial dysfunction predicted lower performance in verbal memory. Study II was designed to further explore the structural changes mediating the relationships between risk markers of CVD and cognition. For that purpose the same set of markers of risk for CVD were related to GM atrophy and WM integrity and cognition. The main finding was an association of inflammation and vascular thrombosis with WM integrity loss in cortico-subcortical pathways and association fibres of frontal and temporal lobes. As expected, none of the biomarkers was related to GM volume changes. Vascular thrombosis also predicted lower performance in processing speed. The third study is a memory clinic-based investigation that was conducted aiming to test the potential use of CSF biomarkers cut-offs as components for the diagnostic work-up in AD. We assessed GM and cognitive patterns in cognitively impaired subjects using CSF Aβ1-42, t-tau and p-tau181 cut-offs as grouping criteria. Results indicated that patients with abnormal CSF levels of t-tau and p-tau (but not Aβ1-42) showed impairment and signs of regional GM atrophy in brain regions characteristic for AD, compared to those with normal levels. More specifically, GM volume differences were found in temporal, inferior parietal, lateral occipital and widespread prefrontal regions. Studies I and II show that risk markers of inflammation and vascular thrombosis are related to a VCI profile for both cognitive patterns and structural brain changes. A microvascular damage of WM projections in fronto-subcortical pathways, but not GM atrophy, could mediate the association between these pathogenic processes and cognitive performance. Markers of endothelial dysfunction are related to a different cognitive pattern which is characteristic of both vascular and neurodegenerative mechanisms. Study III provides evidence that patients with abnormal CSF levels of t-tau and p-tau (but not Aβ1-42) show cognitive an AD profile according to GM density patterns and cognitive impairment. Taken together, these results suggest that, complementary to the clinical observation, plasma and CSF markers and structural imaging are well placed to improve early diagnosis of both VCI and AD.
El terme deteriorament cognitiu (DC) es refereix al contínuum de canvis cognitius associats a l’envelliment sa i patològic. El diagnòstic precoç de les persones amb DC és clau, ja que els tractaments són més eficaços quan s’inicien als inicis de la malaltia. Els biomarcadors s’han proposat com a eines pel diagnòstic precoç del DC i la demència. Es consideren indicadors in vivo de la patologia i s’han plantejat com a possibles eines pel diagnòstic, pronòstic i seguiment del DC i la patologia subjacent. L’objectiu general de la present tesi era explorar els mecanismes patofisiològics subjacents al deteriorament cognitiu vascular (DCV) i la (MA). Per aquest motiu, vàrem mesurar diversos biomarcadors sanguinis i de LCR en persones sanes i en persones amb diagnòstic de deteriorament cognitiu i vàrem relacionar-los amb canvis de l’estructura cerebral i de la cognició. L’objectiu final era identificar possibles biomarcadors pel diagnòstic precoç d’aquestes malalties. Els estudis I i II s’emmarquen dins del projecte Barcelona-ASIA Neuropsicologia i tenien com a objectiu estudiar la relació entre biomarcadors en plasma de malaltia vascular cerebral (MVC) i canvis estructurals i cognitius. Els resultats obtinguts mostren que els biomarcadors d’inflamació i trombosi vascular es relacionen amb un perfil de deteriorament cognitiu vascular tant a nivell cognitiu com estructural. La lesió microvascular dels tractes de SB còrtico-subcorticals mediaria l’associació entre aquests mecanismes i la cognició. Els marcadors de disfunció endotelial es relacionen amb un perfil cognitiu diferent, que és característic tant de processos vasculars com neurodegeneratius. L’estudi III té com a objectiu valorar el possible ús dels biomarcadors de líquid cefaloraquidi pel diagnòstic de la MA. En concret, vàrem estudiar els perfils estructurals i cognitius en persones amb deteriorament cognitiu emprant punts de tall de líquid cefaloraquidi com a criteri d’agrupació. Els resultats mostren que pacients amb DC i amb nivells patològics de t-tau i p-tau al LCR (però no d’Aβ1-42) presenten un perfil cognitiu i estructural de MA. En conclusió, els resultats obtinguts en la present tesi suggereixen que, complementaris a l’observació clínica, els biomarcadors de LCR i plasma, així com els indicadors de morfologia cerebral podrien ser d’ús pel diagnòstic precoç del DCL i la demència.

The foundations for later-life cognitive health are often laid decades prior to the first symptoms of cognitive decline, therefore preventative strategies should be implemented early in life. Structured resistance training shows promise at reducing dementia risk and has been associated with enhanced cognitive function and biomarker profiles. More specifically, intense acute resistance exercise and chronic resistance training may increase levels of growth factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1) and vascular endothelial growth factor (VEGF), which influence the proliferation and maintenance of neural and vascular tissue. Furthermore, biomarkers associated with suboptimal cognitive health (e.g., homocysteine) are decreased following longer-term resistance training. Although promising, the current literature is inconsistent, with varying resistance exercise regimens implemented, contributing to conflicting reported effects on cognition and biomarkers. The aim of the current thesis was to evaluate the impact of different strength training protocols on cognitive health. Four studies were conducted to examine acute response in growth factors following resistance exercise in young and older adults, and the chronic response in neurotrophic growth factors and cognitive function following resistance training in older adults. Chapters Four and Five explored the acute response in neurotrophic growth factors to intense resistance exercise in young or late middle-aged adults. Sixteen young adults were recruited (Chapter Four) to perform to-fatigue (i.e., maximal), high-volume acute resistance exercise bouts: i) traditional hypertrophy-based resistance exercise (i.e., three sets, 10 repetitions at 100% of 10 repetition maximum [RM]), or ii) traditional strength-based resistance exercise (i.e., five sets, five repetitions at 100% of 5RM). Levels of serum BDNF and blood lactate concentration (i.e., physiological marker of session intensity) were measured prior to and following exercise. Serum BDNF was increased (p<0.01; d=0.52) immediately post-hypertrophy resistance exercise when compared to strength resistance exercise. Change in serum BDNF levels were positively correlated (r=0.70; p<0.01) with change in blood lactate concentration immediately following hypertrophy-based resistance exercise only. The acute BDNF response to resistance exercise may not be consistent across the lifespan, and to-fatigue and high-volume resistance exercise is not practical in ageing adults. For this reason, Chapter Five explored the acute growth factor response to intense, yet pragmatic resistance exercise (i.e., submaximal and lower-volume) in 29 late middle-aged adults. Two resistance exercise sessions i) moderate-load (i.e., three sets, 10 repetitions at 70% of 1RM), or ii) high-load (i.e., five sets, five repetitions at 85% of 1RM) were performed in parallel groups (Chapter Six and Seven). Session intensity was determined by change in blood lactate concentration, and session rating of perceived exertion (sRPE). Serum samples were taken prior to and following exercise for later BDNF, IGF-1, and VEGF analysis. No acute changes in BDNF, IGF-1 or VEGF were observed. Changes in BDNF, IGF-1 or VEGF were not associated with changes in blood lactate concentration or sRPE. My findings provide evidence that to-fatigue, high-volume resistance exercise can increase acute levels of BDNF; however, under more practical resistance training scenarios (e.g., moderate volume, submaximal resistance exercise) this outcome is less likely to occur. Resting levels of BDNF, IGF-1, VEGF and homocysteine are important predictors for later life cognitive function in ageing adults; thus, Chapter Six explored changes in resting blood markers following a 12-week period of intense, lower-volume resistance training twice per week in 45 late middle-aged adults. Participants were randomised into one of three groups; i) moderate-load (i.e., three sets, 10 repetitions at 70% of 1RM), ii) high-load (i.e., five sets, five repetitions at 85% of 1RM), or iii) a non-exercising (i.e., no intervention) control group for comparison. Fasted levels of serum BDNF, IGF-1, VEGF, and plasma homocysteine were quantified from blood samples collected before and after the 12-week intervention. No differences were observed in BDNF, IGF-1, VEGF, or plasma homocysteine from pre- to post- intervention between groups. Despite an intense training stimulus, it is possible that the protocols implemented here were not of high enough volume to enhance growth factors. However, high-intensity and high-volume resistance exercise is not a practical training model in ageing adults. Chapters Four-Six placed a strong emphasis on the importance of physiology, and the levels of certain biomarkers, in regards to cognitive health. Therefore, it is essential to evaluate the functional outcomes of resistance training on cognitive health. As part of the randomised controlled trial introduced in Chapter Six, Chapter Seven explored the response in cognitive function following 12 weeks of intense resistance training in 45 late middle-aged adults. Participants were randomised into either i) moderate-load resistance training, ii) high-load resistance training, or iii) a non-exercising control group. Cognitive function was assessed using the CogState computerised cognitive battery, which evaluates performance within several cognitive domains. Greater delayed short-term memory (p=0.02) was observed in high-load and moderate-load groups when compared to the control, with no difference observed between resistance training groups. No other differences for changes in cognitive function between groups were observed. In cognitively healthy adults, 12 weeks of intense resistance training enhances short-term memory, a finding supporting the use of structured resistance training to promote physical and cognitive health. In conclusion, the findings presented in this thesis provide evidence that resistance exercise needs to be to-fatigue and high in volume to enhance BDNF levels. Intense resistance exercise in late middle-aged adults influences neither the acute nor chronic response in neurotrophic growth factors or homocysteine when resistance exercise is reduced in total volume. However, 12 weeks of intense resistance training enhances short-term memory in cognitively healthy adults, a relevant outcome that supports the hypothesis that resistance training can contribute to reducing dementia risk. These findings support the use of structured resistance training to promote full body health inclusive of physical and cognitive health.

Objectives: Gaining an informant’s perspective on cognitive decline has become an increasingly popular, and recommended practice, in the assessment of dementia. However, concern regarding the accuracy of such reports has been documented. The current study aimed to explore factors that might influence such reports, with a particular focus on informant burden. Design: Using a cross-sectional, single-group design, routinely collected data from 82 patient-informant dyads within a memory assessment service, was analysed. Univariate and multivariate analyses explored associations between informant-reported cognitive decline, demographic characteristics and clinical variables (including burden). Results: None of the demographic characteristics explored were associated with informant-reported cognitive decline. Informant reports were associated with patient cognitive functioning, as assessed by a standardised psychometric measure, and the final outcome of the assessment. Patient affective state and informant-reported burden interacted in influencing informant-reported cognitive decline. Informant-reported burden did not mediate the relationship between informant-reported cognitive decline and patient performance on a standardised psychometric measure. Conclusions: Findings suggest that informant subjective burden predicts informant-reported cognitive decline, and that patient affective state interacts with subjective burden in doing so. Clinical and empirical implications are discussed.

Dementia is a group of diseases that are caused by neurocognitive disorder. It is the second leading cause of death in older adults in the US. People who suffer from dementia experience memory loss and other cognitive or functional decline that is severe enough to interfere with their professional and social performance. In spite of the controversy on accuracy of diagnosis and debate on disclosure of dementia diagnosis results, it is important for patients and their families to know what to expect about the future development of cognitive decline. The course of dementia progression is highly diverse, and the symptoms vary differently from case to case. Amnesia, aphasia, agnosia, and apraxia can exist solely or in combination. The rate of cognitive decline, in the term of Clinical Dementia Rating Score, demonstrated different patterns on an individual level. However, in spite of the variety of symptoms, it is essential to map the cognitive decline to the severity of the impact of the symptoms on daily life. Clinical Dementia Rating SUM score (CDR SUM score) is a comprehensive evaluation based on cognition level. Trajectory modeling can provide a practical tool for physicians to make prognosis and medical trials. Furthermore, trajectory modeling can be a valuable reference for stakeholders to use in reimbursement decisions or policies on caregiving resource allocation. However, there is a gap in the current research to predict the trajectory for cognitive decline. In this research, we studied the typical pattern of CDR SUM scores and predicted a timeline for people with cognitive decline. The innovation and significance of this study is the development of multilevel and semiparametric models, and a simple and straightforward criterion for model evaluation and selection. The model we built showed robustness in both explaining the data and predictions. The study results revealed the factors associated with cognitive decline rate in terms of CDR SUM score, and gave implications on accurate CDR SUM score prediction by individual demographic and clinical profiles. The developed model can also be applied to other longitudinal studies in behavioral science, medical monitoring, and other time series related studies.

The six experiments reported in this thesis tested Endsley's (1995) three level theory of perception, comprehension and projection in SA alongside relevant cognitive theories, using a driving hazard perception test (HPT) of both hazard recognition and hazard anticipation as the main dependent measures. Experiments 1 and 2 tested the effects of training and expertise on the HPT, revealing a positive association between hazard anticipation and both SA training and expertise. Experiment 2 revealed a potentially complex relationship between expertise and recognition and anticipation. The effects of training Endsley's (1995) perception and comprehension levels of SA did not appear to be additive as predicted by that theory. Experiments 3 and 4 tested the effects of concurrent freeze probes and real time SA probes on the HPT. This revealed a negative effect of interruption and a positive effect of reorientation (revealing the rationale of the task) associated with the use of a freeze probe, in terms of hazard anticipation. Furthermore, these two effects appear to be mutually cancelling. It was also found that notification of forthcoming online probes does not ameliorate the negative effects of those interruptions in terms of hazard anticipation. Experiments 5 and 6 tested the effects of working memory interference in terms of visual-spatial, phonological and episodic buffer processing on the two HPT measures. This revealed more deleterious effects on hazard recognition associated with visual-spatial and episodic buffer interference than with phonological interference. It is argued that in terms of SA related visual processing during driving Milner and Goodale's (1992) dual pathway theory appears to have more explanatory power than Endsley's (1995) theory of SA.

The aims of this study were to assess neuropsychological function and change in participants with mild cognitive impairment (MCI).Further aims were to determine if platelet membrane secretase activity was higher in MCI participants compared to controls and to assess FOG-PET CT brain changes in MCI participants. METHODS Participants with MCI were recruited through a memory clinic. Controls with no evidence of cognitive impairment were also recruited. Participants undertook a neuropsychological test battery. MCI participants were reassessed through the memory clinic and a subset returned for in-depth neuropsychological testing on a yearly basis. Blood samples were collected for measurement of platelet membrane secretase activity and APOE genotyping. FOG-PET CT Brain scans were carried out on 36 MCI participants. Statistical analysis was performed using SPSS Version 17 for Windows. RESULTS 237 participants were recruited over a 2.5 year period; 139 MCI and 98 control participants. The MCI participants performed significantly worse than the controls on all cognitive tests, except one test of memory. Most MCI participants were categorised as amnestic multidomain; this was the group most likely to convert to dementia on follow-up. Age had the most significant effect on conversion, however. Conversion rate was 15.7% per year overall. There was no significant difference in platelet membrane secretase activity between the MCI and control groups. FOGPET CT Brain activity changes were seen in MCI participants and most changes correlated with previous literature of brain imaging. CONCLUSIONS MCI is a heterogeneous condition with most participants having multiple cognitive deficits on full assessment at baseline. Older participants with amnestic multidomain MCI are most likely to convert to dementia. Platelet membrane secretase activity cannot be advocated as a useful biomarker of MCI from the results of this study. Changes in FDG-PET and cognition produced some interesting associations that would need verified in larger studies.

Cognitive decline is the first outward sign of dementia and has a major public health impact on individuals and governments around the world. There is a well-established relationship between specific lifestyle behaviours and cognitive decline, but extremely limited research on the role of combined behaviours. The aim of this thesis was to examine the role of lifestyle behaviours (alcohol, smoking, physical activity and dietary choice) separately and in combination on cognitive functioning in midlife (age 43) and on 20-year cognitive decline from mid to later life using data from the MRC National Survey of Health and Development. Key findings were that high quality dietary choices made in midlife were associated with slower memory decline as compared to low quality dietary choices, and active levels of physical activity were associated with slower visual search speed decline compared to those who were inactive. Smoking was marginally associated with faster decline in visual search speed compared to non-smokers, but not with memory decline. Associations for these behaviours were independent of each other, as well as of a range of covariates. Cluster patterns of two and three healthy lifestyle behaviours showed a stronger positive association with verbal memory decline compared to no healthy lifestyle behaviours adopted in early midlife. These results provide further evidence of the effectiveness of healthy lifestyle behaviours adopted in early midlife. Public health interventions based on modifiable lifestyle behaviours represent high level priorities and should be regarded as an important line of defence against cognitive decline and dementia.

Alzheimer's disease (AD) is the most common form of dementia and results in progressive cognitive decline, particularly in regards to memory (National Institute on Aging, 2012). Prior research has shown sex differences in brain-atrophy rates of AD patients, with women experiencing a higher rate of progression in volume reduction (Skup et al., 2011). This suggests that there may also be differences in cognitive functioning between sexes, particularly in the rate of cognitive decline with a more rapid disease progression for dementing females compared to dementing males. The current study monitored memory function longitudinally in approximately 200 total participants, 100 with Mild Cognitive Impairment (MCI) or probable AD and 100 healthy controls enrolled in an aging study through the Arizona Alzheimer's Disease Research Consortium. Memory performance was evaluated with two memory tests, the Rey Auditory Verbal Learning Test (RAVLT; Rey, 1941) and the Brief Visuospatial Memory Test-Revised (BVMT-R; Benedict, 1997). Memory function was evaluated in participants with at least three data points over a five-year span. A multivariate regression model was used that includes controls for disease severity, age, age at disease onset, education, ethnicity, and medical comorbidities. Results indicated that females in the MCI and AD groups initially performed better than the males, but that over time, female scores had dropped significantly lower than male scores, suggesting a more rapid decline in females. Significant sex differences in cognitive decline may yield a deeper understanding of the development and progression of AD and aid in more effective and sex-specific treatment.

The older population is increasing, as is life expectancy. Technical devices are becoming more widespread and used for many everyday tasks. Knowledge about new technology is important to remain as an active and independent part of the society. However, if an old user group should have equal access to this technology, new demands will be placed on the design of interfaces and devices. With respect to old users it is and will be important to develop technical devices and interfaces that take the age-related decline in physical and cognitive abilities into account. The aim of this work was to investigate to what extent the age-related cognitive decline affects performance on different computer-related tasks and the use of different interfaces. With respect to the use of computer interfaces, two studies were conducted. In the first study, the information was presented with a hierarchical structure. In the second study the information was presented as a 3D-environment, and it was also investigated how an overview map could support navigation. The third study examined the age-related cognitive decline in the use of a small mobile phone display with a hierarchical information structure. The results from the studies showed that the most pronounced age-related difference was found in the use of the 3D-environment. Within this environment, prior experience was found to have the largest impact on performance. Regarding the hierarchical information structures, prior experience seemed to have a larger impact on performance of easy tasks, while age and cognitive abilities had a larger impact on performance of more complex tasks. With respect to navigation aids, the overview map in the 3D-environment did not reduce the age-differences; however, it contributed to a better perceived orientation and reduced the feeling of being lost.

The purpose of the present study was to investigate cognitive functioning in a group of 30 chronic pain patients (CPG) as compared to a group of 39 acute pain patients (APG). In order to assess cognitive performance, certain subtests were selected from the McCarron-Dial System (MDS) of Neuropsychological Evaluation. Specifically, a measure of haptic discrimination was used along with the Bender Visual Motor Gestalt Test. As such, completion of these subtests required a cortically mediated, central nervous system processing of sensory information. This particular method of assessment was chosen because it provided a nonverbal measure of higher-order cognitive performance. Additionally, the haptic measure provided separate scores for right and left hemispheric functioning. Data analysis revealed significantly poorer Bender performance among CPG members (t(69) = -5.09, E - •0004, two tailed). Further data analysis revealed that the CPG performed significantly poorer on certain of the haptic discrimination subtests. Specifically, both texture and configuration scores for the right hemisphere were significantly lower among CPG members (texture, p = -042 and configuration, p = .002). Subsequent analyses were conducted to determine predictive relationships between important variables. These data are discussed in terms of their clinical significance and importance for future research.

Olfactory impairment may be a nonspecific early finding in Alzheimer's disease. Many late onset depressives progress to irreversible dementias, but previous research has not identified specific markers for such decline. It was hypothesized that depression and olfactory identification impairment would predict cognitive loss in the elderly. In this study, elderly with and without depression and with and without baseline olfactory identification impairment were compared to evaluate cognitive changes at six-months and relationships between plasma cortisol (CORT) and homocysteine (HC) profiles and cognition. Subjects were 30 community-dwelling elderly (mean age 77 ± six years; 77%F/23%M) recruited by newspaper advertisement. Some had depression and cognitive difficulties, some did not. At baseline and six-month follow-up, subjects completed the Geriatric Depression Scale (GDS), Alzheimer's Disease Assessment Scale (ADAS), Folstein Mini-Mental State Examination (MMSE), Boston Naming Test (BNT), Cain Olfactory Identification Test, plasma levels for basal 8:00 A.M. CORT, post dexamethasone suppression test (DST) CORT, and HC. Subjects were divided into four groups based on median scores on the GDS (above median meaning depressed) and Cain Test (below median meaning impaired olfactory identification ability). Normals (NORMALS) had below median GDS scores and above median Cain scores, Depressed Only (DEP ONLY) had above median GDS scores and above median Cain scores, Olfactory Impaired Only (IMP ONLY) had below median GDS scores and below median Cain scores, and Depressed Olfactory Impaired (DEP/IMP) had above median GDS scores and below median Cain scores. Depressed subjects (DEP ONLY and DEP/IMP) performed significantly worse on baseline MMSE, ADAS and BNT; DEP/IMP subjects were the more cognitively impaired at baseline, and on follow-up showed a trend towards greater cognitive loss. IMP ONLY and DEP/IMP had higher baseline CORT levels and tended towards higher HC; furthermore, the DEP/IMP group showed the greatest baseline cognitive dysfunction and largest six-month loss of cognition. Plasma elevations in CORT and HC seem to be associated with olfactory identification impairment. Whether or not these elevations cause or result in dysfunction of the olfactory system in depressed elderly must be the subject for further research.

Technological advances over the past four decades have decreased the major complications or mortality in cardiac surgery. However, a significant number of patients suffer from adverse neurological and cognitive outcomes which, in turn, remain an important cause of postoperative morbidity and are responsible for an increasing proportion of perioperative deaths. Adverse neurological and cognitive outcomes after cardiac surgery are the result of multiple preoperative and/or intraoperative factors. While demographic, biomedical, and psychological disorders (e.g., anxiety and depression) represent preoperative variables associated with postoperative adverse outcomes, intraoperative cerebral hypoperfusion, microembolization and neuroinflammation that are related to cardiopulmonary bypass also represent a major cause of impairment after surgery. Despite a growing interest in adverse psychological outcomes after cardiac surgery, the psychobiological mechanisms underlying postoperative cognitive decline have to be investigated yet. In this dissertation, four studies are described, that were meant to examine cognitive decline and depression after cardiac surgery and some psychobiological mechanisms underlying the afore-mentioned phenomena. The main aim of Experiment I was to provide further evidence about the preoperative relationships among anxiety, depression, cognitive dysfunctions and risk-stratification scores, namely the Stroke Index and European System for Cardiac Operative Risk Evaluation, in patients undergoing cardiac surgery. It was found that both the risk-stratification scores showed significant correlations with cognitive performance, whereas only the European System for Cardiac Operative Risk Evaluation was significantly associated also with anxiety and depression. The main goal of Experiment II and III was to investigate the hemodynamic cerebral factors underlying cognitive decline after cardiac surgery. Experiment II was designed to examine whether cerebral hypoperfusion may represent a predictor of cognitive decline in patients undergone cardiac surgery after controlling for common demographic and biomedical risk factors. Experiment II showed that hypoperfusion in the left middle cerebral artery selectively predicted the incidence of cognitive decline after surgery, whereas blood flow velocity in the right middle cerebral artery was unrelated to postoperative cognitive decline. Hence, cardiac surgery patients with reduced left cerebral blood flow velocity preoperatively are at greater risk for postoperative cognitive decline. Left cerebral hypoperfusion may also represent an independent predictor of cognitive decline in cardiac surgery patients. Experiment III was designed to determine the effects of lateralization and type of microembolization on postoperative cognitive decline in patients who had undergone heart valve surgery. Experiment III showed that microembolization in the left middle cerebral artery significantly correlated with early and late (i.e., 3-month follow-up) postoperative cognitive decline, while microembolization in the right middle cerebral artery was unrelated to early and late cognitive decline. Moreover, an association between solid microemboli with early but not late postoperative cognitive decline was noted. In contrast, gaseous microembolization was related to both early and late cognitive decline. Given the relevant role played by depression as a risk factor for postoperative adverse clinical and cognitive outcomes, the main aim of the Experiment IV was to examine, postoperatively, whether electroencephalographic activity could reflect the influence of depression during an emotional imagery task requiring the subject being involved in a cognitive task (retrieval and imagery), which is emotionally laden. There was no difference between groups in resting electroencephalographic activity, whereas patients with depression showed a significant reduced frontal theta power during the emotional imagery task compared to those without depression. Also, a significant correlation was selectively found between frontal theta power and emotional reappraisal. Taken together these experiments provide a better understanding of the psychological and physiological mechanisms underlying postoperative cognitive decline and depression in cardiac surgery patients. In conclusion, the present thesis suggests the need for including preoperative and postoperative evaluation of cognitive and affective status as well as objective hemodynamic and/or electroencephalographic measures to accurately predict and/or treat patient’s dysfunctional psychological outcomes after cardiac surgery
Le innovazioni tecnologiche conseguite nella seconda metà del XX secolo hanno ridotto le complicazioni maggiori e la mortalità nei pazienti sottoposti a cardiochirurgia. Nonostante gli evidenti benefici clinici nella pratica medica, un numero significativo di pazienti presenta disfunzioni neurologiche e/o psicologiche nel periodo postoperatorio che, a loro volta, sono responsabili per l’incremento della mortalità perioperatoria e della morbidità postoperatoria. Tali disfunzioni neurologiche e cognitive in seguito a cardiochirurgia sono il risultato di diversi fattori preoperatori e/o intraoperatori. Mentre le variabili demografiche, biomediche e psicologiche (tra cui ansia e depressione) rappresentano importati fattori preoperatori associati allo stato di salute postoperatorio, l’ipoperfusione cerebrale, l’embolizzazione e/o i processi neuroinfiammatori associati al bypass cardiopolmonare durante la chirurgia rappresentano fattori di rischio intraoperatori per le disfunzioni neurologiche e cognitive postoperatorie. Sebbene vi sia un sempre crescente interesse nello studio delle disfunzioni psicologiche in seguito a cardiochirurgia, i meccanismi psicobiologici sottostanti il declino cognitivo postoperatorio devono ancora essere indagati. Perciò, nella presente tesi sono descritti quattro studi che, per prima cosa, avevano lo scopo di indagare l’entità del declino cognitivo e della depressione in seguito a cardiochirurgia e, in secondo luogo, miravano ad identificare alcuni fattori di stampo psicobiologico coinvolti nel declino cognitivo e depressione postoperatori. L’Esperimento I mirava, come scopo principale, a fornire nuove evidenze circa la relazione, nel periodo preoperatorio, tra ansia, depressione, disfunzioni cognitive e punteggi di rischio biomedico (lo Stroke Index e l’European System for Cardiac Operative Risk Evaluation) in pazienti in attesa di intervento cardiochirurgico. I risultati del presente studio hanno indicato che, mentre entrambi i punteggi di rischio biomedico erano associati allo stato cognitivo preoperatorio dei pazienti cardiochirurgici, solo l’European System for Cardiac Operative Risk Evaluation teneva in considerazione anche i fattori di rischio associati all’ansia e depressione. Lo scopo principale degli Esperimenti II e III era indagare l’associazione fra fattori emodinamici cerebrali perioperatori e disfunzioni cognitive in seguito a cardiochirurgia. L’Esperimento II è stato disegnato per indagare se l’ipoperfusione cerebrale preoperatoria potesse essere un predittore di declino cognitivo postoperatorio nei pazienti sottoposti a cardiochirurgia, anche dopo aver controllato per i più comuni fattori di rischio demografici e biomedici. L’Esperimento II ha mostrato che l’incidenza del declino cognitivo si associava selettivamente all’ipoperfusione nell’arteria cerebrale media sinistra, mentre la velocità di flusso ematico nell’arteria cerebrale media destra non correlava con il declino cognitivo postoperatorio. L’ipoperfusione cerebrale sinistra, quindi, sembra rappresentare un fattore di rischio indipendente per il declino cognitivo in pazienti sottoposti a cardiochirurgia. L’Esperimento III è stato disegnato per determinare il ruolo dell’asimmetria e della natura della microembolizzazione intraoperatoria sul declino cognitivo postoperatorio in pazienti sottoposti a chirurgia valvolare. L’Esperimento III ha mostrato che la microembolizzazione intraoperatoria nell’arteria cerebrale media sinistra correlava significativamente sia con il declino cognitivo nell’immediato postoperatorio (alle dimissioni) che a distanza nel tempo (a 3 mesi dall’intervento chirurgico), mentre gli eventi embolici nell’arteria cerebrale media destra non erano associati né al declino cognitivo immediato né a distanza nel tempo. Inoltre, i microemboli solidi correlavano significativamente con il declino cognitivo immediato ma non al follow-up di 3 mesi. Al contrario, è stata riscontrata un’associazione significativa tra gli eventi microembolici gassosi ed il declino cognitivo immediato e a 3 mesi di distanza dall’intervento chirurgico. Dato il ruolo rilevante giocato dalla depressione come fattore di rischio per le disfunzioni cognitive postoperatorie, lo scopo principale dell’Esperimento IV è stato quello di indagare, nel periodo postoperatorio, se e come la depressione potesse influenzare l’attività elettroencefalografica durante un compito di imagery emozionale, il quale, a sua volta, implica sia un’elaborazione di tipo cognitivo che emozionale. Sebbene nessuna differenza tra i gruppi sia stata riscontrata nell’attività elettroencefalografica a riposo, rispetto ai controlli non depressi, si osservava nei pazienti depressi una ridotta attività theta frontale durante il compito di imagery emozionale. Inoltre, una ridotta ampiezza della theta frontale si associava selettivamente a disregolazione emozionale (ridotta capacità di reappraisal). Questi esperimenti, considerati nel loro insieme, forniscono una migliore e più approfondita comprensione dei meccanismi psicologici e fisiologici sottostanti il fenomeno del declino cognitivo e depressione postoperatori in pazienti cardiochirurgici. In conclusione, la presente tesi suggerisce la possibilità di includere sia una valutazione cognitiva e affettiva pre e postoperatoria che misure emodinamiche e/o elettroencefalografiche oggettive in grado di predire e/o facilitare il trattamento delle disfunzioni psicologiche postoperatorie nei pazienti sottoposti a cardiochirurgia

At the present time, researchers have increasingly shifted their focus to earlier stages of dementia, such as subjective cognitive decline (SCD) and Mild Cognitive Impairment (MCI), to enable early diagnosis and/or intervention to prevent or slow future cognitive decline. Older people who perceive very mild cognitive difficulties but do not demonstrate objective evidence of cognitive impairment on neuropsychological testing are characterised as SCD. By contrast, those people who experience cognitive difficulties and demonstrate overt cognitive deficits on objective testing but remain functionally independent are characterised as MCI. These two groups are recognised as being at a higher risk of developing dementia compared to cognitively healthy older adults. Whilst functional capacity has typically differentiated MCI from dementia, it seems that mild changes in functioning are experienced even in MCI; however, this remains under-explored and relatively unclear. This research will therefore concentrate on exploring the nature, extent and impact of subtle functional change in the ‘at risk’ cohorts (SCD and MCI). Given that existing functional assessment tools have typically been designed for people with dementia and are therefore too gross, this research will also investigate a novel self-report questionnaire for measuring this early functional change and how clinical variables such as cognitive performance, physical health and psychosocial functioning correlate with downstream subjective functional change in individuals ‘at risk’ of dementia. The research will complement and extend the previous literature with respect to early functional change occurring in SCD and MCI and offer further support for the implementation of formal measurement tools in clinical practice in order to inform diagnosis, prognosis, and potential early intervention and psychoeducation.

The aim of the study is to investigate the current state of awareness of urban shrinkage inLiepājaby the key actors involved in the planning process. Last couple of hundred years have brought many transformations in urbanity that was always accompanied by the growth of the population and expansion of the city. However, the new patterns of urban development emerged in the last decades all over the globe, causing cities to lose the inhabitants resulting in urban shrinkage.Liepāja, the third largest city inLatvia, has lost a quarter of its population in last two decades and the trend continues. The long-term municipal planning document is being presented during this research in a light of which the research question is asked: “What is the current state of awareness of urban shrinkage inLiepājaby the key actors?” Utilising Flyvbjerg’s phronetic form of inquiry in combination with case study and repeated semi-structured interviews, the dominant planning views related to urban shrinkage are sought and analysed. The research identifies three underlying causalities that shape the decisions in planning and leave formidable consequences for the future of the city. The causalities identified and discussed in this paper are (1) the planning legacy; (2) the misconception; and (3) the political sensitivity of the urban shrinkage.

[Truncated abstract] Background: Dementia, largely due to Alzheimer's disease (AD), is a major public health problem. The early identification of disease is an important challenge for clinicians because treatment of AD is now available. A simple and accurate means of stratifying risk for AD and identifying early disease is needed so that risk factor modification and treatment can occur optimally. To date, despite many attempts, an accurate means of standardising an approach to the assessment of subtle cognitive symptoms has not been developed. A subjective complaint of poor memory has been identified as a possible marker for underlying brain disease. This study examines the utility of neuropsychological scores, homocysteine levels, APOE genotyping and brain imaging as predictors of cognitive decline in individuals with subjective memory complaint (SMC). Method Eighty subjects with SMC were recruited from memory clinics and the community (MC: 1). Forty-two control subjects were also examined (MC: 0). CAMDEX was used to describe baseline clinical features. The CAMCOG was used as a global test of cognition and was administered annually for four years. At baseline, neuropsychological testing was administered. Cranial CT scanning, measurement of plasma homocysteine and APOE genotyping were completed. Categorical variables were analysed using chi-square according to Pearson's method. Continuous data was analysed using Student's t-tests and Mann-Whitney tests. A logistic regression model was used to identify independent contributors to the presence of memory complaint. Participants were then matched for age, gender and time to follow-up (up for three years) to determine longitudinal predictors of cognitive decline. ... Baseline CAMCOG scores were greater in the control group (MC:0 = 98.3 ? 2.8, MC:1 94.2 ? 5.5, Z ?4.46, p 0.000). There were no differences in neuropsychological scores, concentration of total plasma homocysteine, APOE genotype or brain scan measurements. Using the Wald stepwise selection method, logistic regression could not be established due to non-convergence regardless of whether or not the continuous variables were re-coded into dichotomous variables. A matching process that created 32 pairs of controls/subjects allowed follow-up analysis. The controls showed significant improvement with time on the CAMCOG unlike subjects (mean ? SD, controls 1.5 ?-3.0, Z - 2.61, p 0.01, subjects 0.2 ? 3.2, Z ? 0.24, p 0.81). The logistic regression analysis showed that group membership could not be defined by any single independent variable. When group membership was abandoned and those with stable scores were compared to those who declined no clear meaningful independent predictors of decline apart from age were identified. Conclusions: Methodological issues such as small sample size and inadequate follow up duration were identified that may have precluded identification of predictive factors for cognitive decline. The results indicate that complaints of memory problems are not associated with established risk factors for Alzheimer's disease and fail to predict objective cognitive decline over three years. Future studies should continue trying to identify robust predictors of cognitive decline in later life.

Hypertension is prevalent in older adults and associated with impaired cognitive function compared to normotensive peers. The effect of antihypertensive therapy on preventing or reducing the rate of cognitive decline is unclear. The studies in this thesis examined the association of elevated blood pressure in older adults on changes in specific cognitive domains and tested the hypothesis that antihypertensive treatment reduces the rate of cognitive decline in older adults with mild hypertension. 507 older individuals (70-89 years) were recruited from a general practice population (250 normotensives, and 257 hypertensives who participated in an international, placebo- controlled trial of candesartan). Cognition was assessed annually for 3-5 years using a comprehensive computerised assessment battery and tests of executive function. Analysis of cognitive function at baseline showed hypertensive subjects performed worse than normotensives across a range of tasks (Chapter 3). Exploratory factor analyses were conducted on the baseline data to derive composite scores used to characterise five domains of cognition and reduce the number of statistical comparisons (Chapter 4). Regression analyses were performed for each participant to calculate individual slopes of decline on the five domains, to provide a sensitive method of analysing repeated assessment data with differential length of follow-up. The primary analysis showed that candesartan-based therapy reduced cognitive decline associated with hypertension on Attention and Episodic Memory, with a trend for Speed of Cognition; effect sizes were small-to-moderate. There were no effects on Working Memory or Executive Function (Chapter 6). The normotensive subjects showed less cognitive decline than the hypertensives (Chapter 7). These data suggest that the rate of cognitive decline associated with hypertension in older adults may be reduced by blood-pressure-lowering. Analysing individual slopes of decline on empirically-derived domains of cognition provides a sensitive and feasible methodology for assessing the effects.

Hearing loss (HL) is a common disorder of the elderly, and is associated with communication difficulties and social isolation. Most recently, HL has been inconsistently linked to cognitive decline and it has been postulated that HL may be an independent risk factor for dementia. The aim of this thesis is to determine whether HL is associated with cognitive decline during normal and/or pathological ageing by specifically investigating contributions from peripheral HL, central auditory processing and the psychosocial pathway. Results show that central auditory processing was linked with cognition during normal and pathological ageing, but there was no independent association with peripheral hearing levels or psychosocial factors. The prevalence of HL was not significantly higher in the patient sample compared with matched controls, nor did HL influence the cognitive profiles in normal ageing or neurodegeneration. There was, however, a statistically significant interaction between HL and decline in executive function only in participants with HL who were high performers at baseline, thereby suggesting that peripheral HL is not an independent risk factor for cognitive decline. Higher scores on central auditory processing were associated with better performance on a test of visual long term memory, after controlling for the effects of peripheral HL, and could predict decline in cognitive performance over time on the Short Cognitive Evaluation battery. In keeping with this, the severity of pathological cognitive impairment was closely related to central auditory processing performance, and patients with mild cognitive impairment recruited the right hemisphere for linguistic processing, which was corroborated with findings of increased grey matter in the right auditory association areas. In summary, it was concluded that the inconsistent findings in the literature may be due to differing influence of HL on normal and pathological cognitive ageing. Peripheral and central hearing changes may be a marker of impending neuronal decline or vulnerability to dementia in people with pathological cognitive impairment, but during healthy ageing, HL does not influence cognitive performance or increase the risk of developing dementia.

Background: Subjective cognitive decline (SCD), i.e., the self-perceived feeling of worsening cognitive function, may be the first notable syndrome of preclinical Alzheimer’s disease and other dementias. However, not all individuals with SCD progress. Stability of SCD, i.e., repeated reports of SCD, could contribute to identify individuals at risk, as stable SCD may more likely reflect the continuous neurodegenerative process of Alzheimer’s and other dementias. Methods: Cox regression analyses were used to assess the association between stability of SCD and progression to MCI and dementia in data derived from the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). Results: Of 453 cognitively unimpaired individuals with a mean age of 80.5 years (SD = 4.2), 139 (30.7 %) reported SCD at baseline. Over the study period (M = 4.8 years, SD = 2.2), 84 (18.5 %) individuals had stable SCD, 195 (43.1 %) unstable SCD and 174 (38.4 %) never reported SCD. Stable SCD was associated with increased risk of progression to MCI and dementia (unadjusted HR = 1.8, 95 % CI = 1.2–2.6; p < .01), whereas unstable SCD yielded a decreased progression risk (unadjusted HR = 0.5, 95 % CI = 0.4–0.7; p < .001) compared to no SCD. When adjusted for baseline cognitive functioning, progression risk in individuals with stable SCD was significantly increased in comparison to individuals with unstable SCD, but not compared to individuals without SCD. Conclusions: Our results, though preliminary, suggest that stable SCD, i.e., repeated reports of SCD, may yield an increased risk of progression to MCI and dementia compared to unstable SCD. Baseline cognitive scores, though within a normal range, seem to be a driver of progression in stable SCD. Future research is warranted to investigate whether stability could hold as a SCD research feature.

Cognitive decline and dementia are core features of Parkinson’s disease (PD) with major personal and socioeconomic impact. Identifying individuals at risk of cognitive decline and dementia is vital in order to optimise clinical management and develop novel therapeutics. However, biomarkers for cognitive decline remain a major unmet need. A large structured review undertaken as part of this thesis revealed discrete gait characteristics predicted cognitive decline and dementia in older adults but to date no such study has been conducted in PD. Thus, the primary aim of this thesis was to investigate gait as a clinical biomarker for cognitive decline in PD. Newly diagnosed PD participants (n=118) and controls (n=184) completed a detailed quantitative gait assessment under single and dual task conditions at baseline. Additionally, a comprehensive battery of neuropsychological assessments were completed at baseline, 18 and 36 months later. Mixed-effects models identified significant gait predictors of cognitive decline over three years. Baseline cognition was also explored as a predictor for cognitive decline. Finally, gait was collected in the free-living environment using a body-worn monitor (BWM) and cross-sectional analysis explored free-living gait-cognition associations. Original contributions to knowledge were that gait characteristics under single and dual task in an incident cohort of PD predicted decline in discrete cognitive domains over three years. Critically, in comparison to gait, baseline neuropsychological assessment performance did not predict cognitive decline. Additionally, cross-sectional analysis in early PD revealed discrete gait-cognition associations in free-living signifying future clinical utility for gait as a clinical biomarker. This thesis provides the first evidence for gait as a clinical biomarker for cognitive decline in PD. Discrete gait characteristics may provide a low cost clinical biomarker and make an important contribution to prognostic models of dementia risk in PD.

Nurse dissatisfaction occurs when the quality in communication of persons affected by a cognitive decline is impacted during the transmission process. It is necessary to understand the nurse’s perception of this situation and how alternative augmentative communication (AAC) patient-centered care intervention (PCCI) care planning provides the most advantageous strategy. The purpose of this Direct Practice Improvement (DPI) project is to understand how ten nurses perceived their level of dissatisfaction while communicating with patients with a cognitive decline before and after implementation of an AAC PCCI care plan intervention at a Long Term Care Home (LTCH) in Southeast Iowa. This project demonstrated the importance of implementing AAC PCCI care planning as a means to decrease nurse dissatisfaction when caring for individuals with cognitive decline. Their perception was measured prior and following implementation of the care plan. The project utilized Watson’s theory of human caring to support the perceptual and qualitative nature of this project. A case study framework using qualitative open-ended questions solicited the nurse’s personal perceptual view and experiences in answering the clinical questions. The data results of (N=10) nurse’s narratives were analyzed. A confidence interval of 95% provided statistical significance supporting AAC PCCI care planning implementation as a means to improve nurse satisfaction. The measurable practice outcome of this project’s AAC PCCI care planning implementation is effective in decreasing nurse dissatisfaction. A future recommendation is to provide a quantitative approach as a means to provide additional reliability.

The advancement in medical science has increased life expectancy in developed countries, which results in a rise in the elderly population. Consequently, age related health issues are also increasing and aging societies are continuously searching for new technologies to provide better healthcare services to the elderly population. One of the prominent health issues relates to the elderly population is cognitive impairment. The decline in cognitive health does not only affect day to day matters of the individual, but also creates difficulties for clinicians and caregivers in terms of providing necessary support to individuals suffering from cognitive disorder. Therefore, an early detection of cognitive impairment is very important, so that clinicians, caregivers, and individuals can take necessary measures to support a cognitively impaired person. In medical literature, the term Mild Cognitive Impairment (MCI) is recognized as a transitional phase between normal aging and dementia. Several studies show that in early stages of the disorder, signs are quite subtle. Hence, it is difficult to capture subtle signs through episodic medical workups. Studies in this domain also conclude that the deteriorated cognitive health significantly affects the ability of an elderly person to correctly perform routine life activities. Therefore, a continuous monitoring of the daily routine of the elderly can be helpful for clinicians to diagnose the early onset of MCI. Thanks to the recent advancement in the pervasive technology, which allows us to develop such systems which can continuously monitor daily routine of the elderly through a smart space. This thesis focuses on the detection of fine-grained anomalies found in the daily behavior of the subject; an elderly person who lives independently in a smart home. We particularly focused on those anomalies which reflect early onset of MCI. In order to model abnormal behavior, we have collaborated with neuro-science experts and clinicians. The medical model provides natural language descriptions of fine-grained anomalies. We proposed FABER, a novel technique for Fine Grained Abnormal BEhavior Recognition (FABER). FABER is a modular architecture and relies on artificial intelligence techniques for the recognition of abnormal behavior. FABER is developed with the objective to support clinicians for a proper diagnosis of MCI. In FABER, we have exploited a combination of statistical, symbolic, and hybrid techniques to infer fine-grained anomalies. Complex human activities are characterized by wide variability; a person can adopt several different patterns of simple actions to perform an activity. Simple actions are detected by various multi-modal sensors deployed in a smart space. For the sake of privacy, we do not consider audio and visual sensors. The data stream from multimodal sensors contain several activities performed by a smart home resident. FABER recognizes boundaries of activities i.e., the start and end time instants of an activity. We have considered various techniques to recognize boundaries of activities. These techniques include supervised machine learning such as Random Forest and hybrid techniques such as Markov logic network (MLN). After recognizing activities, the next step is the detection of fine-grained anomalies. We constructed a knowledge-base to recognize these fine-grained anomalies. For this purpose, we have represented knowledge using a symbolic technique: first-order logic. Knowledge is acquired from various sources: 1) experts provide us knowledge of abnormal behavior and other necessary information required for the detection of fine-grained anomalies such as a medical prescription to detect an anomaly missed medicine; 2) contextual information is acquired from multi-modal sensors which includes spatio-temporal information; 3) recognized activities are obtained from activity recognition module. In order to infer anomalies, natural language descriptions of fine-grained anomalies are translated into first-order logic rules. In an “if-then” rule, the antecedent is based on conditions defined by the clinical model for an anomaly and the consequent is a single class of fine-grained anomaly to be recognized. The clinical model also specifies seriousness level of each anomaly such as a critical anomaly or a non-critical anomaly. The critical anomaly alerts clinicians for a serious behavioral modification, whereas the non-critical anomaly indicates routine life errors that may occur due to negligence, hastiness or personal habits. In general, knowledge representation is a challenging task and depends on several factors. These factors include smart home layout, environmental conditions, personal habits of the subject, and physical health of the subject. In order to formulate rules, a knowledge engineer must understand the hidden relationship between these factors and the relevant anomaly class. Moreover, manually formulated rules are not seamlessly portable to different environments. In order to solve these issues, we have considered a rule induction technique, RIPPER, which automatically learns rules from a set of features. In this way, we can automatically generate anomaly detection rules for different environments while using same feature set for each environment. In order to evaluate the proposed framework, we have conducted experiments with two datasets: 1) a smart home lab data set in which actors simulated daily behavior of MCI patients; 2) a real home dataset in which a real patient performed activities. According to the directions of clinicians, we have selected three activities for the experimentation which includes taking medicines according to a medical prescription, preparing a meal during mealtime, and eating a meal during mealtime. The system periodically infers fine-grained anomalies, in our case we infer anomalies at the end of each day i.e., by 12:00 a.m. midnight. We have used k-fold cross validation to validate the performance of the system. In each fold, the data acquired for exactly one day serve as test set, whereas data acquired for the rest of days serve as training set.

With the growing prevalence of bilingualism in modern society, it has become increasingly important to understand how the ability to speak more than one language affects cognitive function across the lifespan. Although bilingualism has been associated with disadvantages in measures of language use, bilinguals appear to demonstrate superior executive functioning compared to monolinguals. This “bilingual advantage” has been found for several aspects of cognitive control, including attention, inhibition and conflict resolution. Based on the overlap between cognitive networks and brain regions affected by aging, it has been further proposed that cognitive control—and by extension, bilingualism—confers protective effects against cognitive decline associated with natural aging. Here, we review the behavioral performance of bilinguals on linguistic and cognitive control measures, as well as evaluating information on the neural correlates of bilingualism and its relation to cognitive control and cognitive decline. An assessment of the present literature suggests that, compared to monolingual performance, the bilingual advantage in cognitive control carries over to a reasonable protective effect against cognitive decline. However, the lack of integrated research in the field demonstrates a need for further exploration of the specific facets of bilingualism, its potential significance for neurodegenerative diseases (e.g., Alzheimer’s disease), and the role of bilingualism in cognitive reserve.

The relationship between consciousness and other perceptual and cognitive processes can be studied using psychophysical methods to present visual stimuli in the absence of conscious perception. Here we investigate several properties of continuous flash suppression and motion-induced interocular suppression, two versions of interocular suppression that allow the presentation of visual stimuli without reaching awareness for long periods of time. Taking advantage of prolonged interocular suppression, we explored whether suppression of a visual stimulus from awareness affects the generation of a negative afterimage or the formation of an explicit memory trace. Our results suggest that interocular suppression does not reduce afterimage formation. In contrast, performance in forced-choice discrimination of suppressed stimuli was at chance level, showing that explicit memory was completely impaired in the absence of awareness. Taken together, these findings support the idea that higher-level visual processes require awareness, whereas lower-level processes are more independent of awareness. Thus, visual awareness seems to arise gradually as visual information gets processed.
La relation entre la conscience et autres procédés perceptuelles et cognitifs peuvent être étudiés en utilisant des méthodes psychophysiques pour présenter des stimuli visuelles en absence de conscience perceptuelle. Dans ces études, nous explorons différentes propriétés de suppression continue avec flashs et de suppression interoculaire causé par mouvement, deux versions de suppression interoculaire qui permet la présentation de stimuli visuelles sans atteindre la conscience pour de longues périodes. Prenant avantage de la suppression interoculaire prolongée, nous avons recherché à savoir si la suppression d'un stimulus visuelle affecterait la création d'une après-image négative ou une formation d'une mémoire explicite. Nos résultats suggèrent que la suppression interoculaire ne réduit pas la formation d'une après-image. En contraste, la performance de la discrimination avec choix forcé était aléatoire pour les stimuli suppressés, démontrant que la mémoire explicite était complètement absente de la conscience. En conjoncture, ces résultats supportent l'idée que procédés visuels de niveaux plus élevé exigent conscience, alors que des procédés de bas niveau sont indépendants de la conscience. Ainsi, la conscience visuelle semble augmenter graduellement à mesure que le l'information visuelle est traiter.

The principal aim of the present study was to examine the longitudinal change in cognitive test performance in relation to major clinical CVDs and vascular risk factors in a population-based sample of older people. The analysis is based on a cohort of 809 men and 783 women aged 55-74 years which in 1987/8 was randomly selected from the general population of Edinburgh. The findings from the present study further add to those of previous investigations demonstrating a relationship between CVDs, vascular risk factors, and cognitive decline in older people. Specifically, they reveal that, even in the absence of overt stroke, clinical CVDs are associated with a greater cognitive decline in the elderly, independently of potential confounding by a wide range of vascular risk factors. Also, the relationships between several vascular risk factors and cognitive decline proved to be independent of co-existing vascular pathology. Based on these findings, further study is needed to determine the combined effects of CVDs and multiple risk factors on cognitive outcomes in samples of older people. In addition, what the likely pathological mechanisms are underlying cognitive decline associated with atherosclerotic disease and vascular risk factors risk factors needs to be addressed in future studies. From a perspective of preventing or delaying vascular-based cognitive decline and impairment, more research is required to assess the effectiveness of both individual and population-based strategies targeting vascular disease and risk factors in older age groups. Finally, further investigation is needed to address the potential impact of subtle cognitive deficits on indictors of the quality of life and the capability of self-maintenance of elderly vascular patients, on adherence to medical treatment and rehabilitation, and further cognitive decrements and survival.

Background. Research identifies isolation (being alone) as a risk factor for cognitive decline— yet it is possible that subjective dimensions of isolation are more critical. Potential risk factors are loneliness (the distress stemming from feeling alone) and cynical hostility (an attitude of distrust and cynicism). The present study examined the relationship between these factors and cognitive functioning and decline. Methods. Data came from the Health and Retirement Study, a nationally representative longitudinal study of US adults over 50. Loneliness was measured using the Hughes Loneliness Scale; cynical hostility was measured using items from the Cook-Medley Hostility Inventory. Cognitive functioning was indexed by the Telephone Interview for Cognitive Status. Regressions were conducted to examine loneliness and cynical hostility as predictors of cognitive function at baseline as well as cognitive decline over four and six-year periods. Models were adjusted for demographic characteristics, health behaviors, and isolation. Results. Loneliness, [f2=.003, t(52)=-3.75; p<.001] and cynical hostility, [f2=.002, t(52)=-2.98, p=.004] predicted cognitive function at baseline. Loneliness and cynical hostility each predicted cognitive decline over four [f2=.001, t(52)=-2.29; p=.026 f2=.003, t(52)=-3.98; p<.001 respectively] but not six years [t(52)= -.78; p=.439; t(52)= -1.29; p=.203 respectively]. Discussion. Loneliness and cynical hostility are correlates of lower cognitive function and risk factors for cognitive decline over four years. The absence of significant effects of loneliness and cynical hostility over six years could be attributed to low statistical power in these analyses. The effect sizes in this study are small, yet meaningful in the context of the personal and social costs associated with cognitive decline.

Ce travail a pour but de développer des outils statistiques pour l'étude du déclin cognitif général ou précédant le diagnostic de démence, à partir de données de cohorte en tenant compte du risque compétitif de décès et de la censure par intervalle. Le temps de démence est censuré par intervalle dans les études de cohortes car le diagnostic de démence ne peut être établi qu'à l'occasion des visites qui peuvent être espacées de plusieurs années. Ceci induit une sous-estimation du risque de démence à cause du risque compétitif de décès : les sujets déments sont à fort risque de mourir, et peuvent donc décéder avant la visite de diagnostic. Dans la première partie, nous proposons un modèle conjoint à classes latentes pour données longitudinales corrélées à un événement censuré par intervalle, en compétition avec le décès. Appliqué à la cohorte Paquid, ce modèle permet d'identifier des profils de déclin cognitif associés à des risques différents de démence et de décès. En utilisant cette méthodologie, nous comparons ensuite des modèles pronostiques dynamiques pour la démence, traitant la censure par intervalle, basés sur des mesures répétées de marqueurs cognitifs. Dans la seconde partie, nous conduisons une étude comparative afin de clarifier l'interprétation des estimateurs du maximum de vraisemblance des modèles mixtes et conjoints et estimateurs par équations d'estimation généralisées (GEE), couramment utilisés dans le contexte de données longitudinales incomplètes et tronquées par le décès. Les estimateurs de maximum de vraisemblance ciblent le changement individuel chez les individus vivants. Les estimateurs GEE avec matrice de corrélation de travail indépendante, pondérés par l'inverse de la probabilité d'être observé sachant que le sujet est vivant, ciblent la trajectoire moyennée sur la population des survivants à chaque âge. Ces résultats justifient l'utilisation des modèles conjoints dans l'étude de la démence, qui sont des outils prometteurs pour mieux comprendre l'histoire naturelle de la maladie
The purpose of this work is to develop statistical tools to study the general or the prediagnosis cognitive decline, while accounting for the selection by death and interval censoring. In cohort studies, the time-to-dementia-onset is interval-censored as the dementia status is assessed intermittently. This issue can lead to an under-estimation of the risk of dementia, due to the competing risk of death: subjects with dementia are at high risk to die and can thus die prior to the diagnosis visit. First, we propose a joint latent class illness-death model for longitudinal data correlated to an interval-censored time-to-event, competing with the time-to-death. This model is applied on the Paquid cohort to identify profiles of pre-dementia cognitive declines associated with different risks of dementia and death. Using this methodology, we compare dynamic prognostic models for dementia based on repeated measures of cognitive markers, accounting for interval censoring. Secondly, we conduct a simulation study to clarify the interpretation of maximum likelihood estimators of joint and mixed models as well as GEE estimators, frequently used to handle incomplete longitudinal data truncated by death. Maximum likelihood estimators target the individual change among the subjects currently alive. GEE estimators with independent working correlation matrix, weighted by the inverse probability to be observed given that the subject is alive, target the population-averaged change among the dynamic population of survivors. These results justify the use of joint models in dementia studies, which are promising statistical tools to better understand the natural history of dementia

The current dissertation used a gene x environment (G x E) approach to examine the independent and interactive effects of specific genetic variants and participation in physical and cognitive/social activities (PA and CSA) on cognitive performance in 4,764 participants of the Health and Retirement Study. Using three-wave data, three sets of multi-level growth models were conducted to examine baseline, longitudinal, and interactive effects of genotype (i.e., ApoE, COMT, and BDNF) and CSA/PA on performance across five cognitive measures: immediate, delayed and total word recall, and serial 7s and backwards counting. At baseline, the ApoE ε4 allele predicted worse performance in all measures except backwards counting, and the BDNF Met allele predicted better recall scores. The effect of COMT genotype was not significant. Higher CSA/PA predicted better performance on almost all measures. One significant G x E interaction was found between COMT x CSA for backwards counting. Longitudinally, participation in CSA moderated the effect of time on word recall in the ApoE and BDNF models. These results support the idea that genetic and environmental factors are mechanisms of cognitive aging, but also exemplify the variability seen in genetic association studies. Further research is needed to translate such findings into clinically relevant criteria that can be used to identify individual susceptibility to cognitive decline.

Nonalcoholic Fatty Liver Disease (NAFLD) is increasing in older adults, but no evidence exists on the longitudinal association between NAFLD and cognitive decline at old ages. The aim of this 7-year longitudinal study was to examine whether presence of NAFLD at baseline and/or its change (i.e. progression or regression) over the follow up predict the rate of cognitive decline over the same timeframe in older adults, independent of potential confounders. Participants included 457 community dwelling men and women aged 65 to 87 (mean ±SD: 70.9±4.1) years old, living near Bologna (Northern Italy). Global cognitive status was evaluated using Mini-mental State Examination (MMSE). Hepatic steatosis was assessed by abdominal ultrasound and categorized as absent, mild, moderate or severe. Participants were also classified into three subgroups according to their progression, stability or regression in hepatic steatosis over the follow up. Generalized estimating equation (GEE) models with 30 minus MMSE total score as the dependent variable with a Poisson distribution were used to test the longitudinal associations. Covariates included demographics, education, activities of daily living, alcohol, smoke, body mass index (BMI), waist circumference, hypertension, dyslipidemia, diabetes, insulin resistance and inflammation. As results, I found no significant association between baseline presence/severity of hepatic steatosis and either cross-sectional cognitive status or longitudinal rate of cognitive decline (P> .05). In addition, participants who underwent regression in the degree of hepatic steatosis over the follow-up presented accelerate cognitive decline over the same timeframe compared to the rest of the population, independent of covariates and even after adjusting for longitudinal change in BMI and waist circumference (P= .03). A nested sensitivity analysis confirmed this trend even when including only participants starting from moderate-severe hepatic steatosis at baseline. In conclusion, the present study suggests that in older adults NAFLD regression rather than progression is associated with accelerated cognitive decline.

In 2015 the number of people worldwide living with Dementia was 46.8 million, with approximately 50-75% of these cases being clinically defined as Alzheimer’s disease (AD). Despite extensive efforts, clinical trials have so far failed to yield a treatment that successfully addresses the underlying cause of AD. This lack of treatment has been suggested, in part, to be a result of late stage of intervention in current clinical trial design. For this reason, greater focus has been placed on preclinical trials and in turn both the identification of individuals at-risk for AD and, amongst these, those that are expected to decline over the course of a trial. While brain imaging to determine Aβ- amyloid burden has utility in identifying individuals with preclinical AD, further work needs to be conducted to determine what influences rates of change during these early disease stages. Of particular focus is the rate of decline in cognitive performance, as it is the primary outcome measure of efficacy in clinical trials. A number of genetic variants have been associated with cognitive performance, however additional research needs to be conducted to accurately understand the influence that genetic variation has on cognition in preclinical AD. Aims Initially the aim of this thesis was to assess the combined genetic influence of established AD risk genetic variants on preclinical cognitive performance, specifically using AD-risk effect-size weighted polygenic risk scores (PRSs) (Chapter 2). It was then aimed to evaluate the effects on cognitive rates of change in preclinical AD of genes with a priori evidence for association with cognition, both individually (Chapter 3) and then when combined (Chapter 4). The results of the preceding chapters informed the final aim which was to determine a novel method of weighting individual variants in genes associated with AD-risk and/or cognition, for use in a genetic risk score that would improve the prediction of preclinical cognitive rates of change (Chapter 5). Methods All studies presented in this thesis utilised data from the highly characterised Australian Imaging, Biomarkers and Lifestyle Study of Aging (AIBL). The AIBL study is a longitudinal cohort study collecting data at 18-monthly intervals, currently consisting of 7.5 years of follow up. Individuals investigated in this thesis had been Positron Emission Tomography (PET) imaged to determine neocortical amyloid burden. Further, all individuals were classified as Αβhigh or Αβlow based on tracer specific cut offs. In addition, a subset of these samples underwent lumbar puncture for CSF collection at the study baseline, and Aβ42, total-tau and phospho-tau were quantified. Finally, based on the AIBL neuropsychological test battery, three cognitive composites previously developed were calculated for all participants. The cognitive composites investigated were; verbal episodic memory, a statistically driven global cognition composite, and the Pre-Alzheimer’s Cognitive Composite. The AD-risk weighted PRS (Chapter 2) consisted of 22 genetic variants associated with AD classification, and was calculated by weighting individual variants based on their previously published associations with risk for AD. A statistically derived Cognitive Genetic Risk Profile (Cog-GRP), specifically driven by verbal episodic memory, was developed using a decision tree analysis (Chapter 4). Finally, a 27 genetic variant cognition weighted PRS (cwPRS), was developed and tested in a preclinical AD sample (Chapter 5). For the cwPRS, effect sizes for decline in a verbal episodic memory were determined individually for all variants in a reference sample. The resulting effect sizes were then used to calculate the cwPRS for each participant in a test sample (Chapter 5). For both the AD-risk weighted PRS (Chapter 2) and the cwPRS (Chapter 5), PRS calculations were conducted with both the inclusion and exclusion of the major genetic risk factor for, Apolipoprotein E (APOE). In all studies, linear mixed models were used to investigate associations between genetic factors, independent or in combination, and longitudinal rates of cognitive performance. Results In CN older adults the AD-risk weighted PRS, both including and excluding APOE, was positively correlated with brain and blood biomarkers, specifically; brain Aβ burden, CSF total-tau and phospho-tau (Chapter 2). When investigating cognitive performance, specifically in CN Αβhigh participants, significant associations with baseline and longitudinal cognition were only observed in the AD-risk weighted PRS with APOE (Chapter 2). When investigating gene variants previously reported to influence cognition, in CN Αβhigh participants, no independent associations were observed for any variant (Chapter 3). However, in the same sample, after interaction with APOE e4, significant associations were observed for variants in the Kidney Brain Expressed Protein (KIBRA) and Spondin-1 (SPON1) genes (Chapter 3). The combination of variants investigated in Chapter 3, with additional variants, resulted in the development of the Cog-GRP (Chapter 4). The Cog-GRP was able to delineate four groups: APOE ε4+ Risk, APOE ε4+ Resilient, APOE ε4- Risk, APOE ε4- Resilient, with the ε4+ Risk group reporting significantly faster decline in cognition than all other groups (Chapter 4). Finally, a PRS encompassing a combination of AD-risk genes (Chapter 2) and cognitive-risk genes (Chapters 3 and 4), weighted by episodic memory (cwPRS), was reported to be associated with preclinical longitudinal cognitive performance (Chapter 5). Further, these associations were observed irrespective of the presence or absence of APOE in the calculation of the cwPRS (Chapter 5). Conclusions The work presented in this thesis provides an in depth investigation of genetic influences in preclinical AD, particularly on cognitive performance. Importantly, it supports the hypothesis that there is are differences between the genetic architectures of AD-risk and AD progression. The results presented here support the use of combinatory approaches when investigating genetic influence. Finally, reported here is a novel method for PRS weighting, with the ability to predict preclinical cognitive performance in the presence and absence of APOE. Further investigation is required in cohorts with comparable data to the AIBL study, to validate the methods explored in this thesis, allowing for their eventual use in a clinical setting.

The tremendous ongoing growth of wireless digital communications has raised spectrum shortage and security issues. In particular, the need for new spectrum is the main obstacle in continuing this growth. Recent studies on radio spectrum usage have shown that pre-allocation of spectrum bands to specific wireless communication applications leads to poor utilization of those allocated bands. Therefore, research into new techniques for efficient spectrum utilization is being aggressively pursued by academia, industry, and government. Such research efforts have given birth to two concepts: Cognitive Radio (CR) and Dynamic Spectrum Access (DSA) network. CR is believed to be the key enabling technology for DSA network implementation. CR based DSA (cDSA) networks utilizes white spectrum for its operational frequency bands. White spectrum is the set of frequency bands which are unoccupied temporarily by the users having first rights to the spectrum (called primary users). The main goal of cDSA networks is to access of white spectrum. For proper access, CR nodes must identify the right cDSA network and the absence of primary users before initiating radio transmission. To solve the cDSA network access problem, methods are proposed to design unique second-order cyclic features using Orthogonal Frequency Division Multiplexing (OFDM) pilots. By generating distinct OFDM pilot patterns and measuring spectral correlation characteristics of the cyclostationary OFDM signal, CR nodes can detect and uniquely identify cDSA networks. For this purpose, the second-order cyclic features of OFDM pilots are investigated analytically and through computer simulation. Based on analysis results, a general formula for estimating the dominant cycle frequencies is developed. This general formula is used extensively in cDSA network identification and OFDM signal detection, as well as pilot pattern estimation. CR spectrum awareness capability can be enhanced when it can classify the modulation type of incoming signals at low and varying signal-to-noise ratio. Signal classification allows CR to select a suitable demodulation process at the receiver and to establish a communication link. For this purpose, a threshold-based technique is proposed which utilizes cycle-frequency domain profile for signal detection and feature extraction. Hidden Markov Models (HMMs) are proposed for the signal classifier. The spectrum awareness capability of CR can be undermined by spoofing radio nodes. Automatic identification of malicious or malfunctioning radio signal transmitters is a major concern for CR information assurance. To minimize the threat from spoofing radio devices, radio signal fingerprinting using second-order cyclic features is proposed as an approach for Specific Emitter Identification (SEI). The feasibility of this approach is demonstrated through the identification of IEEE 802.11a/g OFDM signals from different Wireless Local Area Network (WLAN) card manufactures using HMMs.
Ph. D.