Dissertations / Theses on the topic 'Cognitive impairment'

Background In our aging population the burden of dementia is increasing, necessitating the urgent identification of treatable risk factors. Small cross-sectional studies demonstrate associations between nonvalvular atrial fibrillation (NVAF), silent cerebral infarction and decreased cognitive function, but there are few longitudinal studies in this area. This thesis reports the results of a prospective longitudinal cohort study of cognitive decline in people with recent-onset NVAF compared to controls. To inform the thesis, an extensive literature review was undertaken . This included searches on NVAF and cognitive decline, NVAF and silent infarction, epidemiology of NVAF, other risk factors for cognitive decline, epidemiology of cognitive decline and the neuropsychological tests included in the CAFE battery. Methods 362 people over 60, screenedi n primary care, underwent baseline assessmenitn cluding a battery of neuropsychological tests, repeated at 12 months (n=304). Cases (n=175) with recent-onset NVAF, were matched for age, sex and GP practice with controls in sinus rhythm. Data were compared using SPSS software (version 11) with both parametric and non-parametric analysis. Results Baseline characteristics, including cognitive function, were similar for cases and controls. There was wide variation between individuals in change in performance on the neuropsychological tests over 12 months, with some improving and some deteriorating for each sub-test. Cases (NVAF) significantly (p<0.05) deteriorated in four subtests measuring attention/ non-verbal memory, and significantly (p<0.05) improved in two subtests measuring verbal memory. Controls significantly (p<0.05) deteriorated and improved in the same sub-tests as cases, but significantly (p<0.05) deteriorated in another three subtests measuring attention/non-verbal memory, and significantly (p<0.05) improved in another six subtests. Treatment with warfarin or aspirin did not appear to be associated with change in cognitive status. Conclusions At baseline there was no significant difference in cognitive function between cases in NVAF and controls in sinus rhythm. At follow-up there was no consistent relationship between NVAF and cognitive decline over 12 months, nor any apparent effect of antithrombotic therapy. Explanations include true independence of NVAF and cognitive decline, or too short a follow-up period. An additional follow-up at 36 months is underway to explore this further.

The clinical syndrome of heart failure is one of the leading causes of hospitalisation and mortality in older adults. Due to ageing of the general population and improved survival from cardiac disease the prevalence of heart failure is rising. Despite the fact that the majority of patients with heart failure are aged over 65 years old, many with multiple co-morbidities, the association between cognitive impairment and heart failure has received relatively little research interest compared to other aspects of cardiac disease. The presence of concomitant cognitive impairment has implications for the management of patients with heart failure in the community. There are many evidence based pharmacological therapies used in heart failure management which obviously rely on patient education regarding compliance. Also central to the treatment of heart failure is patient self-monitoring for signs indicative of clinical deterioration which may prompt them to seek medical assistance or initiate a therapeutic intervention e.g. taking additional diuretic. Adherence and self-management may be jeopardised by cognitive impairment. Formal diagnosis of cognitive impairment requires evidence of abnormalities on neuropsychological testing (typically a result ≥1.5 standard deviation below the age-standardised mean) in at least one cognitive domain. Cognitive impairment is associated with an increased risk of dementia and people with mild cognitive impairment develop dementia at a rate of 10-15% per year, compared with a rate of 1-2% per year in healthy controls. Cognitive impairment has been reported in a variety of cardiovascular disorders. It is well documented among patients with hypertension, atrial fibrillation and coronary artery disease, especially after coronary artery bypass grafting. This background is relevant to the study of patients with heart failure as many, if not most, have a history of one or more of these co-morbidities. A systematic review of the literature to date has shown a wide variation in the reported prevalence of cognitive impairment in heart failure. This range in variation probably reflects small study sample sizes, differences in the heart failure populations studied (inpatients versus outpatients), neuropsychological tests employed and threshold values used to define cognitive impairment. The main aim of this study was to identify the prevalence of cognitive impairment in a representative sample of heart failure patients and to examine whether this association was due to heart failure per se rather than the common cardiovascular co-morbidities that often accompany it such as atherosclerosis and atrial fibrillation. Of the 817 potential participants screened, 344 were included in this study. The study cohort included 196 patients with HF, 61 patients with ischaemic heart disease and no HF and 87 healthy control participants. The HF cohort consisted of 70 patients with HF and coronary artery disease in sinus rhythm, 51 patients with no coronary artery disease in sinus rhythm and 75 patients with HF and atrial fibrillation. All patients with HF had evidence of HF-REF with a LVEF < 45% on transthoracic echocardiography. The majority of the cohort was male and elderly. HF patients with AF were more likely to have multiple co-morbidities. Patients recruited from cardiac rehabilitation clinics had proven coronary artery disease, no clinical HF and a LVEF >55%. The ischaemic heart disease group were relatively well matched to healthy controls who had no previous diagnosis of any chronic illness, prescribed no regular medication and also had a LVEF >55%. All participants underwent the same baseline investigations and there were no obvious differences in baseline demographics between each of the cohorts. All 344 participants attended for 2 study visits. Baseline investigations including physiological measurements, electrocardiography, echocardiography and laboratory testing were all completed at the initial screening visit. Participants were then invited to attend their second study visit within 10 days of the screening visit. 342 participants completed all neuropsychological assessments (2 participants failed to complete 1 questionnaire). A full comprehensive battery of neuropsychological assessment tools were administered in the 90 minute study visit. These included three global cognitive screening assessment tools (mini mental state examination, Montreal cognitive assessment tool and the repeatable battery for the assessment of neuropsychological status) and additional measures of executive function (an area we believe has been understudied to date). In total there were 9 cognitive tests performed. These were generally well tolerated. Data were also collected using quality of life questionnaires and health status measures. In addition to this, carers of the study participant were asked to complete a measure of caregiver strain and an informant questionnaire on cognitive decline. The prevalence of cognitive impairment varied significantly depending on the neuropsychological assessment tool used and cut-off value used to define cognitive impairment. Despite this, all assessment tools showed the same pattern of results with those patients with heart failure and atrial fibrillation having poorer cognitive performance than those with heart failure in sinus rhythm. Cognitive impairment was also more common in patients with cardiac disease (either coronary artery disease or heart failure) than age-, sex- and education-matched healthy controls, even after adjustment for common vascular risk factors.

Insomnia is a common problem in older people, especially in patients with mild cognitive impairment (MCI) whose circadian rhythm is often compromised. Insomnia exerts such a toll on caregivers that it is frequently the primary reason for seeking to institutionalize their loved ones. Three different types of insomnia are recognized: sleep-onset or initial insomnia, sleep maintenance or middle insomnia, and early morning awakening or late insomnia. Nocturnal hypoglycemia, as a cause of middle insomnia, is the main focus of this case study. Other types of insomnia are also briefly reviewed. The management of insomnia is then discussed including sleep hygiene, the usefulness and potential drawbacks of dietary supplements, nonprescription over-the-counter preparations and prescription hypnotics. Sleep architecture is then briefly reviewed, emphasizing the importance of its integrity and the role of each sleep stage.

Participants with amnestic Mild Cognitive Impairment (aMCI) do not inevitably show cognitive decline or convert to Alzheimer’s disease (AD) supporting the hypothesis that secondary events are crucial in the conversion process. Research suggests that psychological stress is a risk factor for AD. Therefore, we proposed psychological stress will be associated with worsened cognitive decline, a clinical marker of advancing neurodegeneration. This was a longitudinal observational study assessing the association between the degree of psychological stress and cognitive decline in 134 aMCI participants and 69 control participants. We hypothesised that stress, as measured by the Recent Life Change Questionnaire (RLCQ), would be associated with worsened cognitive decline, as measured by the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR), over an 18 month follow-up period. Other secondary cognitive outcomes included the difference in change of the Montreal Cognitive Assessment score and the Trail Making Test Part B. Exploratory measures of stress included the Perceived Stress Scale and the presence of physical stressors. Hypothesised modulators of the stress response were assessed including mood, neuroticism, social support, and favoured coping style. Biological outcomes included changes in blood levels of inflammatory markers and salivary cortisol. Objective stressful life events occurring during the course of the study were associated with increased rates of cognitive decline across a range of measures in the aMCI group. Whereas, as predicted, psychological stress was not associated with cognitive decline in the control group. Presence of the ApoE ε4 allele was associated with an increased rate of cognitive decline and increased serum levels of the anti-inflammatory cytokine TGFβ was associated with a slower rate of cognitive decline in the aMCI group. We found that neither measures of mood nor potential modulators of stress exerted a consistent significant influence over rates of cognitive decline in the aMCI group.

Objectives: The main focus of this study was the investigation of cognitive dysfunction in schizophrenia, specifically memory and executive impairment, and the link this has with outcome in the illness. The hypotheses being that both memory impairment and executive dysfunction would be demonstrated and that cognitive dysfunction would be linked to outcome. An attempt was also made to replicate Liddle et al's (1987) finding of three syndromes of schizophrenic symptoms (Psychomotor Poverty, Reality Distortion and Disorganisation) and linking two of these factors to executive dysfunction. Design: A group of 70 patients with schizophrenia at varying stages of the Rehabilitation process completed a neuropsychological battery of assessments including tests of memory and executive function. Correlational analyses were carried out on results. A between group comparison of "successful" versus "unsuccessful" outcome in schizophrenia with 15 patients in each group was also carried out. Results: Memory impairment and executive dysfunction were found to be present and were disproportionately pronounced compared to overall level of cognitive impairment. The hypothesis that cognitive impairment would be linked to outcome was also substantiated in the between group analysis investigating "successful" versus "unsuccessful" outcome where two measures of executive assessments were demonstrated to be the best predictors of outcome. Finally, three Factors were identified through factor analysis, which corresponded closely to Liddle et al's (1987) 3 syndromes of schizophrenia. The hypothesis that the two Factors corresponding to Liddle's Psychomotor Poverty and Disorganisation would be linked to executive dysfunction was not supported. Conclusions: This study supports the increasing recognition that neuropsychological deficits are an integral part of schizophrenia and significantly associated with outcome in the illness. This has led to the development of cognitive remediation strategies with the aim of improving neurocognitive deficits to aid the rehabilitation process.

Background Combination antiretroviral therapy has dramatically improved the outlook for people living with HIV-infection worldwide. As such, the focus of care in well-treated individuals has shifted to the management of long-term comorbidities, such as cognitive impairment. However, the pathogenesis of cognitive impairment in virologically suppressed individuals is unclear. Aims To determine the prevalence, characteristics and understand the pathogenesis of cognitive impairment in well-treated HIV-positive individuals and to assess biomarkers for their ability to predict cognitive impairment and longitudinal changes in cognition. Methods Cross-sectional analysis of two European cohorts (POPPY and COBRA) and longitudinal analysis of the CHARTER cohort using blood, cerebrospinal fluid, clinical, cognitive and neuroimaging data with advanced statistical techniques including machine-learning. Results Firstly, cognitive impairment was prevalent in ~20% of successfully treated patients compared to ~5% in demographically comparable controls. However, it was mild, not clearly associated with symptoms and remained stable over time. Additionally, the prevalence depended on the diagnostic method used, with simulation data demonstrating that the commonly used ‘Frascati criteria’ classifies impairment in ~25-50% of a normative control population. Secondly, cognitive impairment in well-treated patients was predominantly associated with white matter microstructural injury rather than grey or white matter atrophy and using multivariate machine learning techniques could be predicted with up to 80% accuracy. Thirdly, greater exposure to efavirenz and nevirapine were associated with clinical and neuroimaging signals of CNS neurotoxicity. However, these results should be interpreted with caution given their cross-sectional nature and limited sample size (n=60). Nevertheless, they justify further, prospective study given that millions are prescribed these drugs worldwide. Conclusions Cognitive impairment was more prevalent in well-treated HIV-positive patients compared to well matched controls, with white matter microstructural injury sustained before sustained suppression of HIV-viraemia the likely pathogenic driver. Reassuringly however, this impairment was generally mild, asymptomatic and remains stable over time.

This thesis investigated the role of the amygdala in social cognition by examining variability in social-perceptual abilities within the normal population and via experiments with individuals who have Asperger's syndrome (AS). I found that a significant proportion of men from the general population had a fear recognition deficit akin to that seen in patients with bilateral amygdala lesion and that poor fear recognition was associated with poor theory of mind ability and with reduced activation of the amygdala and associated areas of the 'social brain'. Further experiments suggested a mechanism for these impairments - reduced fixation of the eye region of the face - similar to that exhibited by patient SM, who has suffered bilateral amygdala damage. Overall, I found that AS subjects also had a fear recognition deficit when compared with matched controls. However, there was great variability in responses, with scores ranging from normal to severely impaired. Again, an eyetracking experiment showed that low fear recognition was related to a reduced amount of time spent fixating the eyes. Informed by recent neurodevelopmental models of amygdala involvement in autistic- spectrum disorders, I conducted psychological, neurophysiological and neuroanatomical experiments in order to examine the cause of this failure to attend to the eyes in some AS subjects. As a whole, the findings support a 'hyper-active amygdala model', in which social stimuli induce an aversive level of arousal and so are avoided. I suggest that inattention to social stimuli, which could have a number of possible aetiologies, might be at the heart of a general route to social cognitive impairment, which could be shared by several distinct populations.

The concept of Mild Cognitive Impairment is a newly defined entity within the context of Parkinson’s Disease (PD-MCI) with recent development of diagnostic criteria, biomarker research programs and therapeutic strategies. However, it is well-established that MCI represents a heterogeneous entity with different clinical phenotypes, rates of progression, and perhaps underlying pathological processes. As such, while the application of the MCI construct has provided a framework for understanding cognitive decline in PD, additional research is required to validate and/or refine the proposed PD-MCI criteria, as well as to better understand its utilization, association with different PD phenotypes, neurobiological basis, and impact within the context of PD. The studies in this thesis set out to investigate these issues, highlighting the heterogeneity, challenges, and unmet needs regarding the utilization of PD-MCI. In particular, the following issues have been investigated: the exploration of specific MCI phenotypes that might be at higher risk of evolving into PDD; the utility of the proposed Movement Disorder Society (MDS) Task Force Level 1 PD-MCI criteria; the relationships between PD-MCI and clinical phenotypes in PD; and the clinical impact of PD-MCI on caregivers. In addition, a description about treatment options for cognitive impairment in PD will be discussed. Findings from the present thesis showed that additional research is required to validate and refine the proposed MDS Level 1 PD-MCI criteria, as well as to identify MCI phenotypes at risk of developing PDD. Specifically, the present thesis highlighted the importance of exploring the relationship between PD-MCI and heterogeneity in PD, in order for the concept of MCI to be utilized within the context of PD. In parallel, greater emphasis also needs to be placed on identifying specific MCI phenotypes that can be utilized within the prodromal stage of PD, where the neurodegenerative pathology and tissue loss are more likely to be modifiable. In this regard, a close examination regarding specific characteristics of MCI patients with RBD may be particularly relevant. As with treatments for PD-MCI patients, findings from this thesis suggest that it is important to take into account heterogeneity in PD when evaluating PD-MCI so as to better direct their specific management by taking into consideration the constellation of clinical symptoms that are likely to coexist and impact on quality of life. In addition, the need to include management of caregiver distress and associated sequelae should be emphasized alongside the management of PD-MCI patients as caring for PD-MCI patients can be associated with elevated levels of distress. Furthermore, the potential in the possibility of improving cognitive functioning with treatment for comorbid condition (e.g. sleep, depression, and hallucinations) should be explored in future studies.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2019
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 141-165).
Dementia comes second only to spinal cord injuries in terms of its debilitating effects; from memory-loss to physical disability. The standard approach to evaluate cognitive conditions are neuropsychological exams, which are conducted via in-person interviews to measure memory, thinking, language, and motor skills. Work is on-going to determine biomarkers of cognitive impairment, yet one modality that has been relatively less explored is speech. Speech has the advantage of being easy to record, and contains the majority of information transmitted during neuropsychological exams. To determine the viability of speech-based biomarkers, we utilize data from the Framingham Heart Study, that contains hour-long audio recordings of neuropsychological exams for over 5,000 individuals. The data is representative of a population and the real-world prevalence of cognitive conditions (3-4%). We first explore modeling cognitive impairment from a relatively small set of 92 subjects with complete information on audio, transcripts, and speaker turns. We loosen these constraints by modeling with only a fraction of audio (~2-3 minutes), of which the speaker segments are defined through text-based diarization. We next apply this diarization method to extract audio features from all 7,000+ recordings (most of which have no transcripts), to model cognitive impairment (AUC 0.83, spec. 78%, sens. 79%). Finally, we eliminate the need for feature-engineering by training a neural network to learn higher-order representations from filterbank features (AUC 0.85, spec. 81%, sens. 82%). Our speech models exhibit strong performance and are comparable to the baseline demographic model (AUC 0.85, spec. 93%, sens. 65%). Further analysis shows that our neural network model automatically learns to detect specific speech activity which clusters according to: pause followed by onset of speech, short burst of speech, speech activity in high-frequency spectral energy bands, and silence.
by Tuka Alhanai.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science

Cognitive impairment is common in multiple sclerosis (MS), with as many as 70% of patients with MS affected. Individuals with MS who experience cognitive deficits are less likely to be employed, and may have more difficulty performing independent activities of daily living. Most commonly, deficits are observed in processing speed, complex attention, and memory. Because lesion location varies widely among individuals, no clear pattern of cognitive dysfunction in MS has emerged. However, a number of risk and protective factors may influence the likelihood of individuals to develop and/or express dysfunction, though the contribution of each to specific domains of cognition has not been fully explored. Recently, support for the cognitive reserve hypothesis (i.e., enriching life experiences protect against cognitive decline despite disease burden) has emerged in the MS literature. The current study investigated the contributions of cognitive reserve to learning and memory functioning in MS and the interaction of cognitive reserve variables and risk factors known to impact cognitive functioning in individuals with MS. Finding revealed cognitive reserve protects against decline in the domains of processing speed and complex attention. Furthermore, indirect protective effects of cognitive reserve through these domains were observed for verbal learning and memory. Finally, in line with previous literature, cognitive dysfunction predicted employment status of the current sample. Clinical implications and future directions for intervention efforts are discussed.

Epilepsy is a highly prevalent neurological disorder affecting people from all walks of life. Psychosocial adjustment and psychological morbidity have been longstanding challenges for people with this clinical diagnosis. However, very little is known about the psychosocial correlates of psychological morbidity, such as anxiety and depression, among people with epilepsy in Hong Kong. Previous clinical studies suggest social cognitive impairment may contribute to the poor psychosocial integration of people with epilepsy. An important aspect of social cognition is the ability to attribute mental states to others so as to understand their behavior, desires, and intentions. This prerequisite for successful social interactions is termed mentalizing. This thesis reports two studies conducted to examine the psychosocial correlates of psychological morbidity among people with epilepsy, and their mentalizing ability with regard to the neuropsychological basis of mentalizing deficits that are specific to this neurological disorder. Study 1 examines the association of psychological morbidity with a broad array of personality traits and social skills in a sample of 54 local Chinese people with epilepsy. Participants completed the Temperament and Character Inventory (TCI), the Social Performance Survey Schedule (SPSS), and the Hospital Anxiety and Depression Scale (HADS) via semi-structured interviews. The findings showed that, independent of demographic and medical variables and perceived illness-related impact, three personality traits (harm avoidance temperament, self-directedness, and cooperation) and two subscales of interpersonal behaviors (both positive and negative social skills) are significant psychosocial predictors of adjustment among Chinese people with epilepsy. Study 2 examines the neuropsychological basis of mentalizing deficits in people with epilepsy. Thirty-nine right-handed local Chinese people with epilepsy and 38 matched healthy controls were recruited for this study. The eyes test and the faux pas test were employed to study the decoding and reasoning stages of mentalizing, respectively. The findings showed that, relative to the healthy controls, the participants with epilepsy were impaired in decoding and reasoning about the affective aspect of social materials; and at the same time, they were impaired in reasoning about the cognitive aspects of others’ mental states—that is, in inferring intentionality. Such a pattern of mentalizing deficits suggests a wider structural abnormality that may be implicated in the brains of people with epilepsy. In conclusion, epilepsy is associated with social cognitive impairment in emotion recognition and intentionality inference, involving both decoding and reasoning about the affective and cognitive aspects of others’ mental state, which may predispose people with epilepsy to maladaptive psychosocial adjustment and functioning. The significance and implications of the results are discussed.
published_or_final_version
Psychology
Doctoral
Doctor of Philosophy

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008.
Additional advisors: Paul D. Blanton, David G. Clark, Roy C. Martin, Virginia G. Wadley. Description based on contents viewed Feb. 9, 2009; title from PDF t.p. Includes bibliographical references (p. 63-76).

Thesis (Ph.D.)--University of Florida, 2004.
Typescript. Title from title page of source document. Document formatted into pages; contains 162 pages. Includes Vita. Includes bibliographical references.

Mild cognitive impairment (MCI) represents a state of high risk for dementia but is heterogeneous in its course. To date, the trajectories reflecting distinct developmental courses of cognition among patients with MCI, and their association with readily available clinical information, have not been well defined. Study 1 sought to identify the developmental trajectory of groups with distinct cognitive change patterns among a cohort of MCI patients. Study 2 was conducted to identify individual items/subtests of the Mini-Mental State Examination (MMSE) and demographic variables at baseline that predicted the identified trajectories of cognitive change from Study 1. One hundred and eighty-seven MCI patients were evaluated serially with the MMSE for up to 3.5 years. Five trajectories were identified and labeled based on their baseline MMSE score and course: 29-stable (6.4%); 27-stable (53.9%); 25-slow-decline (23.8%); 24-slow-decline (11.6%); 25-rapid-decline (4.2%). In multivariate logistic regression analysis, a model was established to dissociate patients with stable vs. declining trajectories. An equation derived from this model that included age, delayed recall, constructional praxis, attention, and orientation to time and floor predicted future cognitive decline with good accuracy (79.9%) and specificity (86.4%), and moderate sensitivity (67.2%). The identification of varying trajectories of cognitive change and predictors of cognitive decline from easily obtained baseline clinical information can help target at-risk groups for early interventions aimed at delaying the onset of dementia.
Les déficits cognitifs légers représentent un risque élevé pour le développement de la démence, mais le parcours vers cet état est hétérogène. À ce jour, les trajectoires reflétant des parcours distincts de développement de la cognition chez les individus avec un déficit cognitif léger et leur association avec des informations cliniques facilement accessibles ne sont pas bien définies. La première étude visait à identifier la trajectoire développementale de groupes avec des parcours distincts de changements cognitifs parmi une cohorte de personnes ayant un déficit cognitif léger. La deuxième étude visait à identifier des items/sous-tests du Mini-Mental State Exam (MMSE) et des variables démographiques mesurées au point de départ et qui prédisaient les trajectoires de changements cognitifs identifiées à la première étude. 187 patients avec des déficits cognitifs légers ont été évalués à plusieurs reprises avec le MMSE sur une période de 3,5 années. Cinq trajectoires ont été identifiées et nommées sur la base de leur score au MMSE au point de départ et le parcours : 29-stable (6.4%); 27-stable (53.9%); 25-déclin lent (23.8%); 24- déclin lent (11.6%); 25- déclin rapide (4.2%). Avec la régression logistique, un modèle a été établi afin de distinguer les patients ayant une trajectoire stable de ceux ayant une trajectoire déclinante. Une équation dérivée à partir de ce modèle et qui incluait l'âge, le rappel différé, la praxis, l'attention, l'orientation dans le temps et l'étage prédisait le déclin cognitif avec une justesse (79.9%), sensibilité (67.2%) et spécificité (86.4%). L'identification des différentes trajectoires de changements cognitifs et des variables explicatives du déclin cognitif à partir des informations cliniques facilement accessibles peut aider à identifier les groupes de personnes qui ont un risque élevé afin qu'ils reçoivent des interventions rapides qui ont pour but de retarder l'apparition de la démence.

Psychology
Ph.D.
Objective: Grit is a noncognitive trait related to perseverance and consistent pursuit of long-term goals. Research on grit and aging provides evidence that grit increases with age and may be protective of cognitive and everyday functioning. However, no studies to date have examined relations between concurrently measured grit, cognitive abilities, and everyday functioning. This study tested two hypotheses: 1) that grit would predict cognitive performance and that this relation would be moderated by clinical diagnosis of cognitive status (i.e., healthy vs. mild cognitive impairment; MCI), and 2) that grit would predict everyday functioning and that this effect would be mediated by compensatory strategy use. Methods: Sixty-one older adults were recruited from the Penn Memory Center’s National Alzheimer’s Coordinating Center (NACC) cohort, including forty healthy controls with normal cognition and twenty-one individuals with mild cognitive impairment (MCI). Participants completed tests of verbal episodic memory, executive functioning, grit, compensatory strategy use, and everyday functioning. Results: Grit was not associated with cognitive functioning in either domain. Instead, memory performance was predicted only by clinical status (healthy vs. MCI), and executive functioning was predicted by clinical status, depressive symptoms, and years of education. Grit was negatively associated with everyday functional difficulties; however, there was no indirect effect of compensatory strategy use. Additionally, grit was moderately correlated with depression symptoms (r = -0.41). Conclusions: Grit is predictive of preserved everyday functioning, but not cognitive functioning, in a sample of healthy older adults and individuals with MCI. Mechanisms explaining the role of grit on everyday function remain elusive, though secondary analyses support that grit also influences affective well-being and may have a weaker role in the context of cognitive impairment.
Temple University--Theses

Clinical trials seeking to improve cognitive performance are in dire need of biochemical biomarkers that reflect the processes taking place in the brain. In Down syndrome, this information is crucial to understand the progression of cognitive decline, or to evaluate the beneficial effects of a treatment, but there are few available biomarkers for this condition. We have analyzed the association between biomarkers (biochemical, genetic), executive functions, and cognitive decline, in the context of a clinical trial, taking into account extrinsic factors (education, diet) that may obscure the interpretation of the obtained results. We found that altered lipid profile or increased homocysteine concentrations in plasma are associated to worse executive functions. Additionally, increased plasma concentrations of amyloid peptides are associated to early dementia signs. I also optimized a new technique of tissue and cell culture to obtain neuronal precursors from the nasal olfactory epithelium for biomarker studies. The results of this study should provide with new tools to evaluate treatment efficacy and cognitive decline risk in the context of clinical trials in Down syndrome.
Els assajos clínics que cerquen la millora del rendiment cognitiu tenen la necessitat de disposar de biomarcadors que reflecteixin els processos que tenen lloc en el cervell. En la síndrome de Down aquesta informació és crucial per a entendre la progressió del declini cognitiu o per a avaluar els efectes beneficiosos d’un tractament però encara hi ha pocs biomarcadors disponibles per a aquesta afectació. Hem avaluat l’associació entre biomarcadors (bioquímics, genètics), funcions executives i declini cognitiu, en el context d’un assaig clínic, tenint en compte factors extrínsecs (educació, dieta) que poden afectar la interpretació dels resultats. Els nostres demostren que un perfil lipídic alterat o unes concentracions incrementades d’homocisteïna en plasma estan associats a pitjors funcions executives. També observem una associació entre concentracions incrementades de pèptids amiloides i signes primerencs de demència. També he optimitzat una nova tècnica de cultiu tissular i cel·lular per a obtenir precursors neuronals de l’epiteli olfactiu per a l’estudi de biomarcadors. Els resultats d’aquest estudi podrien proporcionar noves eines per a avaluar l’eficàcia de tractament i el risc de declini cognitiu en el context d’assaigs clínics en la síndrome de Down.

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.

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.

Parkinson’s disease is a neurodegenerative process with several motor and non-motor manifestations. Among non-motor symptoms, cognitive decline is a major cause of disability, and its neural bases are poorly understood. In recent years, multimodal neuroimaging techniques have proven to be useful tools in the investigation of the bases of cognitive impairment related to neurological diseases. The objective of this thesis was to evaluate the neuroimaging substrates of Parkinson’s disease-related cognitive and neuropsychiatric manifestations through a network approach, using state-of-the art magnetic resonance imaging techniques to assess associated connectivity and structural changes. In this work, two samples of Parkinson’s disease patients and healthy controls underwent neuropsychological evaluation as well as structural and functional magnetic resonance imaging. One of these samples included 121 Parkinson’s disease patients and 49 healthy controls. The data obtained were used in 2 studies addressing the resting-state functional connectivity changes associated with mild cognitive impairment in Parkinson’s disease; one using a graph-theory approach, and the second assessing large-scale intrinsic connectivity networks through an independent-component analysis/dual regression approach. A third was performed to assess connectivity disruptions in frontostriatal circuits associated with the presence of apathy in Parkinson’s disease. And a fourth study was made assessing cortical thickness changes associated with the presence of mild cognitive impairment in Parkinson’s disease. The second sample included the longitudinal evaluation of 17 Parkinson’s disease patients and 15 healthy controls, and the data obtained resulted in two studies regarding progressive cortical thickness and subcortical volumes in early-stage Parkinson’s disease patients. A seventh study, using subjects from both samples, was performed to evaluate microstructural white matter changes (using diffusion tensor imaging) and gray matter changes (through voxel-based morphometry) related to the presence of facial emotion recognition deficits in Parkinson’s disease. We have found that a high percentage of Parkinson’s disease patients had mild cognitive impairment. These patients showed altered patterns of resting-state functional connectivity characterized by the loss of long range connections and strengthening of local connectivity. From a graph-theory perspective, these changes translated as increased small-world coefficients, modularity and clustering coefficients, which correlated with visuospatial/visuoperceptual and memory performance. The study of large-scale networks showed that patients with mild cognitive impairment had reduced connectivity between the dorsal attention network and the right frontoinsular region, and that this reduction was associated with attention/executive deficits. Additionally, parieto-occipital regions that belong to the dorsal attention network showed reduced connectivity with anterior task­positive regions and loss of the normal anticorrelated pattern with the default mode network; furthermore, these posterior regions showed structural degeneration. Finally, these posterior structural and functional changes were associated with the presence of visuospatial/visuoperceptual deficits. The analysis of Parkinson’s disease patients with mild cognitive impairment revealed a pattern of cortical thinning predominating in parieto­occipito-temporal regions. The longitudinal analysis of progressive structural changes in early Parkinson’s disease revealed that these patients had more marked cortical thinning in frontotemporal regions, even before the onset of clinically evident cognitive manifestations. The functional analysis of a recognition memory network likewise showed signs of progressive connectivity changes without overt clinical deterioration. We conclude that different types of cognitive decline in Parkinson’s disease are associated with different patterns of resting-state functional connectivity, structural connectivity and GM structural changes involving distinct neural systems. Different techniques and different conceptual frameworks can provide useful information in the characterization of the neural bases of cognitive deficits associated with Parkinson’s disease.
La malaltia de Parkinson és un procés neurodegeneratiu que té diverses manifestacions motores i no motores. Entre les manifestacions no motores, el deteriorament cognitiu és una causa important i comú de discapacitat; al cap de 20 anys des de l’inici de la malaltia, més de 80% dels pacients desenvolupen demència. Tot i tenir una alta prevalença i representar un factor de pèrdua de qualitat de vida tant pels pacients com per als seus cuidadors, les bases neurals d’aquestes alteracions són poc conegudes. En els últims anys, les tècniques d’imatge multimodals han demostrat ser útils en la investigació de les bases dels dèficits cognitius associats a les malalties neurològiques, i alguns estudis previs han trobat alteracions cerebrals tant estructurals com funcionals en subjectes amb la malaltia de Parkinson. D’altra banda, el concepte de deteriorament cognitiu lleu (DCL), utilitzat per definir la presència d’un rendiment cognitiu inferior al esperat segons l’edat i el nivell educatiu – i un major risc de desenvolupament de demència – s’ha començat a aplicar en el context de la malaltia de Parkinson. A més, en estudis epidemiològics s’ha vist que la presència d’alguns tipus d’alteració cognitiva – concretament, aquells que tenen substrats neurals predominants en regions corticals posteriors, com són dèficits visuoespacials i visuoperceptius – indiquen una major probabilitat de desenvolupar demència. Al contrari, en els dèficits relacionats amb els desequilibris en la neurotransmissió dopaminèrgica (com són els dèficits d’atenció i executius), no s’ha trobat que siguin marcadors de pitjor pronòstic cognitiu. L’objectiu d’aquesta tesi va ser avaluar els substrats neuroanatòmics i neurofuncionals de les diferents alteracions cognitives i neuropsiquiàtriques relacionades amb la malaltia de Parkinson mitjançant un abordatge de xarxes, tot utilitzant tècniques avançades de ressonància magnètica per estudiar les disfuncions de la connectivitat cerebral. En aquesta tesi, es van utilitzar dues mostres de pacients amb malaltia de Parkinson i subjectes sans que es van sotmetre a avaluació neuropsicològica i de ressonància magnètica funcional i estructural. La primera d’aquestes mostres va incloure 121 malalts de Parkinson i 49 controls sans. Les dades obtingudes amb aquesta mostra han sigut utilitzades en cinc estudis (estudis 1, 2, 3, 4 i 5), tres dels quals van abordar la connectivitat funcional cerebral en repòs i les alteracions estructurals associats a la presència de DCL. Per definir la presència de DCL, en dos estudis (estudis 1 i 2) s’han avaluat els déficits en tres dominis cognitius (atenció/funcions executives, memòria i funcions visuoespacials/visuoperceptives); en l’altre estudi (estudi 3), s’ha utilitzat un mqtode de classificació d’acord amb les recents directrius proposades per la Movement Disorder Society Task Force, que consideren el rendiment en cinc dominis (atenció/memòria de treball, funcions executives, memòria, llenguatge i funcions visuoespacials/visuoperceptives). En els estudis 1 i 2, es van avaluar 66 pacients i 36 controls utilitzant tècniques d’avaluació de la connectivitat cerebral en repòs i les alteracions corresponents associats a la presència de DCL. Trenta cinc per cent dels pacients amb malaltia de Parkinson van complir criteris de DCL. Estudi 1: En aquest estudi, s’ha aplicat un abordatge de teoria de grafs per avaluar les alteracions globals de connectivitat. Per tal de reconstruir les xarxes cerebrals, la substància grisa cortical i subcortical s’ha dividit en 90 regions definides amb l’atles Automated Anatomical Labelling. Posteriorment, s’ha calculat la correlació temporal de l’activitat entre cada parell de regions, obtenint-se així una matriu representativa de la connectivitat funcional de tot el cervell. En un primer pas, s’han comparat directament aquestes matrius de correlació per tal d’avaluar el patró de reducció o augment de connectivitat en els diferents subgrups de pacients. Aquest anàlisi va revelar que els pacients amb DCL tenien reduccions de connectivitat, sobretot afectant les connexions interlobulars de llarga distància, així com alguns augments de connectivitat, sobretot en connexions mps curtes. Posteriorment, s’han utilitzat les matrius de correlació per calcular mesures globals i regionals de teoria de grafs. Concretament, s’han avaluat paràmetres que mesuren la integració (l’eficiència d’intercanvi d’informació entre distintes àrees cerebrals): el characteristic path length i l’eficiència global;i paràmetres de segregació, que mesuren la interconnectivitat local: el clustering coefficient i l’eficiència local. També s’ha avaluat el grau de modularitat de les xarxes cerebrals, és a dir, quant de bé aquestes xarxes es podien dividir en mòduls o comunitats de nodes densament interconnectats, amb poques connexions entre diferents mòduls. S’ha observat que els pacients amb DCL presentaven augments en les mesures de segregació i de modularitat. Les anàlisis de correlació han revelat que aquestes mesures es correlacionaven amb el rendiment en funcions visuoespacials/visuoperceptives i de memòria. En l’anàlisi de les mesures de centralitat dels nodes – és a dir, la importància que tenen en el tràfic d’informació dins de la xarxa –, s’ha observat que els nodes que solen ser més centrals en subjectes sans (els anomenats hubs cerebrals) perden centralitat en els pacients amb malaltia de Parkinson. Aquest resultat indica una reorganització d’aquestes xarxes caracteritzat per un augment del flux d’informació neural a travès de nodes que en subjectes sans són menys rellevants. Aquest estudi es va publicar a la revista Human Brain Mapping a l’any 2014 (Cognitive impairment and resting-state network connectivity in Parkinson’s disease). Estudi 2: s’ha utilitzat la mateixa mostra que en l’estudi 1. S’ha utilitzat, però, un altre tipus d’anàlisi amb l’objectiu d’estudiar els patrons de connectivitat dins d’un conjunt de xarxes cerebrals que, segons estudis previs, tenen un paper rellevant en els processos cognitius: la default mode network, la xarxa dorsal de l’atenció i la xarxa frontoparietal. Inicialment, s’ha realitzat un anàlisi de components independents amb les dades de ressonància magnètica funcional en repòs per tal d’identificar les xarxes d’interès a nivell grupal. Posteriorment, s’ha utilitzat la tècnica de dual regression per identificar les mateixes xarxes a nivell individual, i que permet comparacions entre els grups. En aquesta anàlisi, s’ha observat que els pacients amb DCL presentaven reduccions de connectivitat entre la xarxa dorsal de l’atenció i l’ínsula anterior i regions adjacents del lòbul frontal dret. En el grup de pacients, el nivell de connectivitat en aquestes regions es correlacionava amb el rendiment en el domini d’atenció/executiu. A més, s’ha vist que els pacients amb DCL presentaven un augment de connectivitat entre extenses àrees parieto-occipitals i la default mode network; aquestes disfuncions de connectivitat també estaven associats a pitjor rendiment cognitiu, però en aquest cas en el domini visuoespacial/visuoperceptiu. Com anàlisi addicional per definir les alteracions locals de connectivitat, es va realitzar una avaluació de les connexions entre els nodes individuals de les xarxes d’interès; per definir aquests nodes, s’han seleccionat a priori les coordenades disponibles en un estudi de referència. Aquesta anàlisi ha demostrat que els augments de connectivitat de regions corticals posteriors amb la default mode network en realitat estaven caracteritzats per una pèrdua del patró normal d’anticorrelació amb aquesta xarxa observat en controls sans. A més, s’ha vist que aquestes mateixes regions tenien menys connectivitat amb les altres xarxes avaluades. Finalment, s’han realitzat anàlisis complementaris per avaluar la presència de degeneració estructural de la substància grisa que pogués estar associada a les alteracions funcionals observades. L’anàlisi del gruix cortical va revelar la presència de reduccions en els pacients amb DCL en regions parieto-occipitals; aquestes reduccions estaven associades a les alteracions de connectivitat de la default mode network i amb el rendiment visuoespacial/visuoperceptiu. Aquest estudi es va publicar a la revista Human Brain Mapping a l’any 2014 (Functional brain networks and cognitive deficits in Parkinson's disease). Estudi 5: En el tercer estudi en que es va avaluar la connectivitat funcional en repòs, l’objectiu va ser investigar les alteracions en els circuits fronto-estriats en la malaltia de Parkinson amb apatia – un trastorn neuropsiquiàtric molt freqüent en pacients amb aquesta malaltia. Amb aquesta finalitat, es va utilitzar la mateixa mostra que en els dos primers estudis. Es van classificat els subjectes en apàtics o no-apâtics segons la puntuació en l’escala d’apatia de Starkstein. A més, es va tenir en compte la presència de trastorns depressius, que, a més de tenir una alta prevalença en la malaltia de Parkinson, freqüentment coexisteixen amb l’apatia i tenen manifestacions que s’hi solapen. Així doncs, també es va aplicar l’escala de depressió de Beck; la puntuació en els 11 ítems d’aquesta escala que representen els símptomes disfòrics, més específics de la depressió, es va utilitzar com a covariable en totes les anàlisis. Per a realitzar l’anàlisi de connectivitat funcional, es va parcel·lar l’estriat en 3 regions – límbica, executiva i sensorimotora. Així mateix, es va parcel·lar l’escorça frontal en 4 regions – límbica, executiva, rostral motora i caudal motora. Vint pacients (41%) es van classificar com apâtics (puntuació > 13 en l’escala d’apatia). L’anàlisi de connectivitat va revelar que la presència d’apatia estava acompanyada de reduccions, que principalment afectaven les regions límbiques tant del estriat com de l’escoroa prefrontal. Per tal d’avaluar si aquestes alteracions s’acompanyaven de degeneració de les estructures avaluades, es van realitzar anàlisis addicionals amb voxel-based morphometry de les estructures corticals i subcorticals, a més de volumetria i shape analysis dels nuclis del estriat. No s’han obtingut resultats significatius amb cap d’aquests abordatges. Aquest estudi està actualment en revisió en una revista indexada. Estudi 3: En aquest estudi, 90 pacients i 32 controls van ser estudiats mitjançant tècniques d’avaluació del gruix cortical. Trenta dos (52%) pacients van complir criteris de DCL. S’ha observat que el grup de pacients amb DCL presentava reduccions del gruix cortical en regions parieto-temporals, així com augment en mesures d’atròfia global tals com reducció del gruix cortical global i del volum de substància grisa, així com augment del volum ventricular. Les anàlisis de correlació van revelar que el rendiment en totes les proves neuropsicològiques estava associat a la pèrdua de gruix cortical posterior. Aquest estudi es va publicar a la revista Movement Disorders a l’any 2014 (Cortical thinning associated with mild cognitive impairment in Parkinson's disease). Per a la segona mostra de subjectes, es van reclutar 24 pacients amb malaltia de Parkinson inicial i 24 controls sans, els quals es van estudiar mitjançant ressonància magnètica estructural i funcional així com mitjançant exploració neuropsicològica. Disset pacients i 15 controls van ser avaluats longitudinalment, amb una segona avaluació després d’un seguiment mitjà de 35,5 mesos. Estudi 6: En el primer estudi fet amb aquesta mostra, es van incloure 17 pacients i 13 controls, i l’objectiu va ser estudiar la xarxa de memòria de reconeixement. Per això es va utilitzar una seqüència de ressonància magnètica funcional amb un paradigma de memòria de reconeixement que consistia en intentar reconèixer les 35 paraules prèviament apreses entre una llista de 70 paraules. Les dades obtingudes van ser avaluades a través de abordatges convencionals o model-based, així com a través de tècniques model-free (anàlisi de components independents). En la primera anàlisi, es va identificar el patró d’activació associat a la tasca. En l’anàlisi de components independents, també es van identificar els components associats a la tasca; les principals regions activades en la component més associada a la tasca es van utilitzar com a regions d’interès en un anàlisi subsegüent de canvis progressius de connectivitat. Es va trobar una correlació entre la activació de la component independent més associada a la tasca i el rendiment de memòria de reconeixement dels pacients. A més, l’avaluació longitudinal va revelar canvis progressius en la connectivitat entre els principals nodes d’aquesta xarxa, caracteritzats per la pèrdua de connectivitat entre regions frontoparietals i la preservació de la connectivitat frontofrontal (que en els controls sans s’havia reduït). Aquest estudi es va publicar a la revista Journal of Neurology, Neurosurgery and Psychiatry a l’any 2013 (Progressive changes in a recognition memory network in Parkinson's disease). Estudi 7: En aquest segon estudi fet amb la segona mostra, s’ha volgut analitzar el patró d’atròfia progressiva de la substància grisa en la malaltia de Parkinson inicial i la seva relació amb canvis neuropsicològics. Amb aquesta finalitat, les dades de setze pacients i 15 controls van ser avaluades amb tècniques de gruix cortical, volum de substància grisa a través de voxel-based morphometry i volumetria cortical i subcortical. Es van trobar reduccions progressives del gruix cortical en regions frontotemporals bilaterals. L’avaluació neuropsicològica va revelar que els pacients tenien pitjor rendiment en proves d’atenció i de velocitat psicomotora, però aquestes variables no es correlacionaven amb els canvis corticals. Aquest estudi es va publicar a la revista Movement Disorders a l’any 2012 (Progression of cortical thinning in early Parkinson's disease). Un últim estudi (estudi 4) es va realitzar amb subjectes de la primera i de la segona mostra. Es va seleccionar una submostra de 39 pacients i 23 controls amb la finalitat d’avaluar les alteracions de les substàncies blanca i grisa associats als dèficits de reconeixement d’emocions facials en la malaltia de Parkinson. Es van utilitzar imatges potenciades en difusió per l’estudi d’alteracions microestructurals de la substància blanca en els tractes llargs que connecten les estructures cerebrals involucrades en el processament emocional, mitjançant tècniques de imatge per tensor de difusió. A més, les imatges estructurals es van avaluar a través de voxel­based morphometry per estudiar les alteracions de volum de la substància grisa en les estructures cerebrals prèviament descrites com rellevants pel processament d’emocions. El rendiment en el reconeixement d’emocions facials es va mesurar mitjançant la prova d’Ekman. Els pacients amb la malaltia de Parkinson van obtenir un rendiment inferior als controls en la identificació de les emocions negatives (tristesa, ràbia, por i fàstic). L’anàlisi de correlacions va revelar que els dèficits d’identificació de tristesa correlacionaven amb els valors d’anisotropia fraccional –un paràmetre de la microestructura de la substància blanca– sobretot en el fascicle fronto-occipital inferior dret. L’anàlisi de substància grisa, per contra, va revelar que la identificació de tristesa correlacionava amb el volum de l’escoroa orbitofrontal dreta, amígdala i gir postcentral; la identificació de ràbia correlacionava amb el volum de substància grisa de l’estriat ventral, escorça infragenual i gir fusiform occipital dret; i la identificació de fàstic correlacionava amb volum de substància grisa en el còrtex cingulat anterior. Aquest estudi es va publicar a la revista Neuropsychologia a l’any 2012 (Structural correlates of facial emotion recognition deficits in Parkinson's disease patients). Tots aquests estudis ens permeten concloure que un alt percentatge de pacients amb malaltia de Parkinson tenen alteracions cognitives i compleixen criteris de DCL. L’anàlisi de neuroimatge mitjançant diferents estratègies demostra que la presència de DCL en la malaltia de Parkinson s’acompanya d’alteracions estructurals i funcionals. A més, diferents tipus de dèficit cognitiu es relacionen amb diferents patrons d’alteració. A nivell de connectivitat funcional en repòs, els pacients amb malaltia de Parkinson amb DCL presenten un patró predominant de reducció de connectivitat de llarg abast i augment de la connectivitat local, que es tradueix en un augment del caràcter modular i de segregació de les xarxes cerebrals. Així mateix, s’observa una reducció de connectivitat de components de xarxes de connectivitat intrínseca rellevants per al processament cognitiu, que es caracteritza per una reducció de connectivitat d’una xarxa involucrada en processos de l’atenció (xarxa dorsal de l’atenció) i la regió insular anterior dreta. Al mateix temps, s’observa una reducció de connectivitat de regions corticals posteriors amb regions cerebrals anteriors, que s’associa a atròfia cortical posterior i a la presència de dèficits en les funcions visuoespacials/visuoperceptives. L’anàlisi de la connectivitat funcional en repòs revela també que la presència d’apatia en la malaltia de Parkinson s’acompanya de reduccions en circuits fronto-estriats, que sobretot afecten els components del sistema de recompensa, és a dir, l’estriat ventral i l’escorça orbitofrontal. Els resultats de l’anàlisi d’alteracions microestructurals de la substància blanca associats al pitjor reconeixement d’emocions facials semblen indicar que els dèficits de connectivitat estructural també estan implicats en l’ocurrència dels dèficits cognitius en la malaltia de Parkinson. Finalment, en pacients amb malaltia de Parkinson inicial, s’han aportat evidències sobre el poder dels mètodes de neuroimatge per a detectar alteracions estructurals (pèrdua de gruix neocortical) i funcional fins i tot abans de l’inici de símptomes cognitius clínicament evidents. En conclusió, els resultats obtinguts en els diferents estudis d’aquesta tesi ens permeten concloure que distintes tècniques i diferents marcs conceptuals poden proporcionar informació útil per a la caracterització de les bases neurals dels dèficits cognitius i emocionals associats a la malaltia de Parkinson.

Cognitive impairments are a common feature of neurological and neuropsychiatric disorders, as well as of substance-abuse disorders. The impairments seen in these disorders can be caused by disruptions to common neural substrates, and therefore pharmacological agents can be repositioned from use in neuropsychiatric to neurological disorders, and vice versa. Together, these disorders have been estimated to comprise 13% of the global burden of disease. Indeed, an individual’s ability to successfully perform everyday activities can be limited by deficits in crucial cognitive functions such as attention, response inhibition, planning and working memory. Frontal-striatal networks in the brain have been shown to underlie these vital functions, which are modulated by neurotransmitters including acetylcholine, dopamine, and noradrenaline. Importantly, these functions are susceptible to pharmacological intervention with drugs such as physostigmine, modafinil, and atomoxetine. In order to explore the nature of a variety of forms of cognitive impairment, which were diverse in severity from mild to more severe, studies were carried out on amateur boxers and sleep-deprived doctors, as well as on patients with subarachnoid haemorrhage (SAH) and on patients with Parkinson’s disease (PD). Quantification of cognitive impairment is the crucial first step in determining which neural networks are involved, and thus which pharmacological agents would be suitable candidates for treatment. A longitudinal study was carried out using a comprehensive battery of well-validated cognitive tasks, in order to quantify the change in cognitive ability in healthy individuals who participated in amateur boxing. Subtle cognitive impairments, which were related to structural changes, were documented. Using existing understanding of pharmacological agents, novel treatments for cognitive impairments were explored in relation to sleep-deprived doctors, as well as to PD and SAH patients. A novel treatment for specific cognitive problems in PD was investigated: atomoxetine, a noradrenaline reuptake inhibitor. A double-blind placebo-controlled study revealed that atomoxetine may be a candidate for treatment of response inhibition impairments seen in PD. This finding is important as noradrenergic treatments are not currently used in PD, despite degeneration in the locus coeruleus, the main cortical source of noradrenaline. Another novel treatment explored was modafinil, a drug that has also been shown to modulate the noradrenergic system, as well as the dopaminergic system. Modafinil is currently licensed for use in narcolepsy and shift work sleep disorder. It was found that modafinil remediates task set-switching impairments and reduces impulsivity in sleep-deprived doctors. Furthermore, it was shown that modafinil might be a potential treatment for cognitive impairments found in neurological patients with SAH. In contrast to this, physostigmine, a cholinesterase inhibitor, did not seem to alter the cognitive symptoms investigated. To summarise, this thesis aims to quantify cognitive impairment in a range of groups, and to explore the potential use of existing pharmacological agents that could be repurposed to treat cognitive impairments in novel ways.

Cognitive impairment is a common consequence of cardiac surgery using cardiopulmonary bypass and embolisation of particulate and gaseous debris is believed to be the most important cause. Using a new generation of transcranial Doppler (TCD) ultrasonography the aim was to quantify gaseous and solid cerebral microemboli during different cardiac surgical procedures and to relate this to cerebral abnormalities identified using magnetic resonance imaging techniques. A substantial reduction in microembolic load was demonstrated with avoidance of cardiopulmonary bypass (CPB). The majority of microemboli detected during cardiac surgical procedure~ were gaseous and use of CPB was associated with a significantly higher proportion of solid microemboli - regarded as potentially more harmful. Reduction or elimination of aortic m~ipulation resulted in a significant reduction in intraoperative cerebral microembolisation with the potential for reduction of postoperative cerebral injury. Microemboli are not' only restricted to the intraoperative period and could be detected postoperatively following aortic valve replacement. Use ofa mechanical prosthesis is associated with significant increases in solid and gaseous microemboli. Functional magnetic resonance imaging (FMRI) performed serially in patients pre- and postoperatively demonstrated a significant overall reduction in taskassociated activation in the postoperative period. However, increased activation in certain regions of interest suggested a compensatory mechanism or adaptive change that may contribute to functional recovery after cerebral injury from microemboli. Then comparing off-pump and on-pump surgery, there was a significant reduction in prefrontal cerebral activation in patients undergoing on-pump surgery but preservation of cerebral activity following off-pump surgery. These changes in activation correlate with intraoperative microembolic load and were persistent at longer-term follow-up. Magnetic resonance spectroscopy of the frontal white matter showed no significant reductions in N-acetyl aspartate (NAA) levels - a marker of neuronal integrity. This was reassuring indicating that neuroaxonal damage is an unlikely explanation of the functional cerebral changes observed with FMRI. Careful assessment and further understanding of the pathophysiology of postoperative neurological injury would allow the development of targeted neuroprotective strategies aiming to reduce the rate and severity of this important complication

This PhD thesis examines the relationship between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). ALS is a rapidly progressive neurodegenerative movement disorder characterized by muscle weakness, spasticity and abnormal reflexes. In a very small subset of patients (5-15%), ALS is associated with FTD. Furthermore, a larger subset of patients who do not suffer from overt dementia, develop subtle deficits in cognition and behaviour (up to 50%). The changes have mostly been observed in the domains of executive functions, language and behavioural functioning. These observations have led some researchers to propose a continuum of dysfunction between ALS and FTD, ranging from an absence of neuropsychological abnormalities to mild, subclinical changes to a profile consistent with a full-blown FTD-syndrome in ALS. FTD consists of three subsyndromes; the first ‘executive-behavioural’ type, frontal variant FTD (fvFTD), is predominantly characterized by behaviour abnormalities, difficulties with using strategies and social judgement. In contrast, the other two types mainly involve problems with ‘language’, including a central degradation of knowledge for words, objects, people (semantic dementia; SD) as well as complications with speaking, spelling and the sounds of language (progressive non-fluent aphasia; PNFA). The current study aims to explore whether the cognitive-behavioural deficits found in nondemented ALS-patients can be classified as subclinical forms of the first two FTDsyndromes, i.e. fvFTD and SD. In addition, the study further examined whether executive and language impairments co-exist or rather occur independently. To answer the research questions, a battery of neuropsychological tests was employed, adapted to patients’ speech and motor disabilities, as well as behavioural questionnaires. The data revealed there was evidence of both executive and language involvement characteristic of FTD, albeit to a subtle extent. ALS-patients showed deficits on a test of Theory of Mind (ToM). On this test, participants were asked to judge the thoughts and feelings of another, using the direction of eye gaze, a cue considered to be important for social interaction. Results indicated that ALS patients had difficulties with affective ToM, i.e. recognizing feelings of others, and this effect was not driven by perceptual or attentional difficulties. In addition, patients exhibited a subtle deficit with empathy as well as a range of behavioural abnormalities. Furthermore, ALS-patients showed abnormal performance on a complex multi-modal semantic association task which involved assigning the correct picture iii to the sound of an object. This central deficit emerged in the presence of normal audio-visual information processing and episodic memory functions. Moreover, a category-specific deficit for man-made objects was detected in patients. Individual case-analyses showed that various subsets of patients were impaired on the language and executive tasks. These analyses also showed that executive and language problems can occur independently as well as simultaneously in patients with ALS. In addition, analysis of individual cases revealed that some patients’ performance on the decision making tasks was similar to that found in patients with either orbitofrontal or dorsolateral dysfunction, while there was little if any evidence of a pattern of impairment similar to that seen with anterior cingulate dysfunction. The observed difficulties with social cognition and semantic processing indicate that executive and language problems, characteristic of the two FTD syndromes, can be detected in patients with classical ALS.

This research volume examines the psychological adjustment of those diagnosed with either Mild Cognitive Impairment (MCI) or dementia. The first paper is a systematic review of the evidence of the use of Cognitive Behavioural Therapy (CBT) with people with dementia or MCI. Studies identified through database searches were reviewed. It was concluded that, although there is very modest evidence for the use of CBT to address depression, anxiety and acceptance among those with mild dementia or MCI, it is not possible to draw confident conclusions due to the lack of methodologically robust randomised controlled trials and the heterogeneity of existing studies. The second paper is an empirical paper of an exploration of patients’ experiences of receiving a diagnosis of MCI. Seven recently diagnosed MCI patients were interviewed about their diagnostic disclosure experiences. The interviews were analysed using Interpretative Phenomenological Analysis (IPA). Four super-ordinate themes emerged. These were ‘The test’: working it out for myself, Journey and Brakes, What’s wrong with me? and Decline and Loss. The use of multiple disclosure sessions and of pre and post assessment counselling is recommended. The third paper is a public dissemination summary of both the systematic review and the empirical paper.

The overall aim was to improve knowledge of the consequences of cognitive dysfunction in everyday life and of instruments to make these assessments. The thesis contains four studies each of different design using different populations. In study I, the relationship between cognitive function, ability to perform activities of daily living and perceived health-related quality of life were investigated in a population of 85-year-old individuals in the community of Linköping (n = 373). The study was part of the Elderly in Linköping Screening Assessment 85 (ELSA 85). Even mild cognitive dysfunction correlated with impaired ability to perform activities of daily living and lower health-related quality of life. In study II, the diagnostic accuracy and clinical utility of Cognistat, a cognitive screening instrument, were evaluated for identifying individuals with cognitive impairment in a primary care population. Cognistat has relatively good diagnostic accuracy with a sensitivity of 0.85, a specificity of 0.79 and a Clinical Utility Index (CUI) of 0.72. The corresponding values were 0.59, 0.91 and 0.53 for the Mini Mental State Examination (MMSE), and 0.26, 0.88 and 0.20 for the Clock Drawing Test (CDT). In study III, the aim was to develop an instrument measuring self-perceived or caregiver reported ability to perform everyday life activities in persons with suspected cognitive impairment or dementia and to perform psychometric testing of this instrument, named the Cognitive Impairment in Daily Life (CID). The CID was found to have good content validity. In study IV, experiences of cognitive impairment, its consequences in everyday life and the need for support in persons with mild cognitive impairment (MCI) or mild dementia and their relatives were explored. Interviews were performed with five people with MCI, eight people with mild dementia and their relatives (n = 13). The main finding was that persons with MCI and dementia experienced cognitive changes that could be burdensome and result in changed activity patterns. In conclusion, the findings support earlier research and show that cognitive dysfunction even at mild stages has an impact on everyday life and reduces perceived quality of life. To improve interventions for persons with cognitive impairment, it is important to assess not only cognitive function but also its consequences in everyday life activities.

One of the most significant complications of diabetes is retinopathy. Diabetic retinopathy (DR), a chronic progressive sight-threatening disease of the retinal microvasculature, is the leading cause of treatable blindness in the working age group. Another emerging complication of diabetes is cognitive impairment (Cl). The exact link between diabetes and Cl remains elusive. One theory is that microvascular changes in the brain may be responsible for change in cognition in diabetes. In this study, it was hypothesised that increased severity of DR was associated with impaired cognition (cerebro-microvascular disease) in individuals with Type 2 Diabetes (T2DM). 381 men and women with T2DM recruited to the South East London Diabetic Retinopathy Study were stratified by severity of DR (no/mild retinopathy and proliferative diabetic retinopathy (PDR)) and severity of diabetic maculopathy (non-clinically significant macular oedema (non-CSMO) and CSMO). Each subject underwent tests of cognitive function, psychosocial assessment, ophthalmic and physical examination. Bivariate analysis between categories of DR and maculopathy (ANOVA, Chi square) and ANCOVA for the cognitive scores by DR severity were conducted using SPSS v17. Severity of DR demonstrated an inverse relationship with Cl in patients with T2DM (fully adjusted model). No association was found between severity of maculopathy and Cl. Retinal arteriolar and venular dilation was associated with lower cognition scores in patients with no/mild retinopathy. Decreased levels of serum factor Apo A was associated with decreased cognition. Participants with Cl had consistently elevated risk of stroke compared to participants with no Cl, irrespective of their DR status. Cognition scores also varied by ethnic grouping; participants of ethnic minorities had significantly lower cognition scores than Caucasian participants.

Mild cognitive impairment (MCI) is a medical diagnosis that is conceptualized as existing on a continuum between normal cognitive aging and dementia. While a growing body of research has established the impact of this condition on family members' emotional well-being, as well as the quality of family relationships, the reciprocal impact of family dynamics and the family environment on illness course has received much less attention. Expressed emotion (EE) is a measure of the family emotional climate that has been established as being highly predictive of relapse and symptom exacerbation for a variety of mental health disorders. The recent integration of attribution theory with EE has offered new insights into the underlying attitudes and beliefs that give rise to it. This mixed methods study applied the attribution model of EE to test the validity of EE in predicting the illness course of MCI, and to identify family members' attributions regarding MCI-related behaviors and symptoms that underlie their EE status. The study sample included 57 family dyads consisting of a person with MCI and a family member providing primary care or assistance. The results of the ANCOVA did not support the hypothesis that EE status would predict changes in the non-cognitive features of MCI over time. However, methods of thematic analysis revealed four major themes, or care partner attributional stances: (a) non-blaming, (b) blaming, (c) variable, and (d) no identified. The analysis also revealed three subthemes, or attributional styles, within the variable stance: (a) ambivalent, (b) mixed, and (c) complex. These attributional stances and styles intersected with family EE status in notable ways and form the basis for future research in this area, as well as clinical interventions with these families that promote adaptation to the illness.
Ph. D.

Mild cognitive impairment (MCI), a term used to describe the transitional state between normal aging and established dementia, has been identified as a potentially effective time point at which to target interventions to prevent or slow the decline into dementia. An efficient way of identifying people with MCI is required as a first step in conducting large scale studies to develop and evaluate interventions targeted at this high risk population. The aim of the thesis was to investigate the effectiveness of a range of brief cognitive tests to be used for the purpose of identifying people with MCI in an efficient and accurate manner. A systematic review of the literature found that over 40 brief cognitive tests have been developed and tested to identify amnestic MCI (aMCI). However, the majority of these previous studies were conducted in secondary care settings and were at high risk of unblinding the assessment process, which may have exaggerated the diagnostic accuracy of the assessed tests. The Memory Alteration Test (M@T) and Test Your Memory test (TYM) were selected as potentially useful brief cognitive tests for aMCI and their validity was assessed within a cohort of older people recruited from the community, without prior knowledge of their cognitive status. A total of 472 older people were assessed for MCI according to the Petersen criteria using a standardised battery of neuropsychological tests. A prevalence of MCI of 16.5% was found within the assessed cohort and the M@T was found to be more accurate than the TYM at detecting aMCI, performing with a sensitivity of 85% and specificity of 84%. The ability of reaction time task derived measures to identify cognitive impairment within the cohort was also assessed. These were not as accurate at predicting cognitive status as the M@T. However, they did demonstrate some promising discriminative abilities and should be further explored as potentially useful alternatives to the traditionally used memory tests, which may be influenced by administrator bias, education level and language ability.

Reach and grasp are evolutionary conserved motor actions controlled by highly specialised neural pathways that have major nodes in the posterior parietal and premotor frontal cortices. Mild cognitive impairment is an important non-motor symptom of Parkinson’s disease (PD) and there is evidence that the risk of transition between PD mild cognitive impairment (PD-MCI) and Parkinson’s disease dementia (PDD) is dependent on which neurotransmitter systems within the brain are most dysfunctional. Studies of reach and grasp in PD subjects with normal cognition (PD-NC) suggest a greater dependence on visual feedback to guide reach and grasp compared with controls. The primary aim of this thesis is to explore how cognitive impairment influences reach and grasp in PD. Twenty two PD-NC, 23 PD-MCI, ten PDD and 19 controls reached and grasped for a target whilst wearing movement sensing equipment in four conditions: full vision, a darkened room with an illuminated target, with eyes closed at a natural speed and as quickly as possible in full vision. All PD subjects were tested whilst on. Kinematic parameters of reach and grasp were extracted from the movement data and analysed using standard statistical methods. Our results show a spectrum of change to kinematic reach parameters when reaching and grasping with eyes closed: PD-NC are disproportionately affected compared to controls and PDD are disproportionately affected compared to PD-NC. Parameters of reach and grasp were similar between PD-NC and PD-MCI in all conditions. These results have been discussed in the context of abnormal integration of sensorimotor functions and impaired spatial working memory in PD. Reaction time when reaching and grasping as quickly as possible is significantly associated with global cognition in the PD subjects after controlling for age, motor signs and disease duration. This supports a role for reaction time as a potential biomarker for cognitive impairment in PD.

The experiments presented in this thesis explored the possibility that an underlying cause of specific language impairment (SLI) may be a deficit in perceptual or cognitive information processing. The first three studies tested the hypothesis that children with SLI have impaired perception of the dynamic elements of visual and auditory stimuli, as proposed in the magnocellular hypothesis for developmental dyslexia. The experimental predictions were that a) children with SLI would have poor sensitivity to coherent motion (but not coherent form) stimuli relative to chronological-age matched controls; b) children with SLI would have poorer sensitivity than controls to slow (but not fast) rates of frequency modulation in a tone; c) sensitivity to slow rates of frequency modulation (FM) would correlate with children's performance on a set of tests of phonological skill. Overall, these predictions were not corroborated by the results, and the conclusion drawn from this set of studies is that a magnocellular impairment of the type reported in dyslexia is unlikely to be a causal factor in SLI. The second three studies used a grammaticality judgement task to focus on inflectional morphology, an area of language which poses particularly marked difficulty for many children with SLI. The findings from Study 4 suggested that children's performance on the grammaticality judgement task overall was strongly related to phonological discrimination ability, but was unaffected by the specific inflectional allomorph tested. The final two studies manipulated the information processing load of the grammaticality judgement task, in Study 5 to simulate (successfully) SLI-like performance in a group of typically developing children, and in Study 6 to attempt (unsuccessfully) to improve performance in a group of children with SLI. These results are compatible with the idea that the profile of language difficulties experienced by many children with SLI is due to a processing deficit in the early stages of language acquisition which interrupts the establishment of robust linguistic representations. The nature of this processing deficit is as yet unclear, though the current findings do not support the suggestion of a central auditory impairment. It is possible that a number of distinct deficits, such as poor phonological memory or reduced speed of processing, may produce a broadly similar linguistic profile in different individuals.

Background: Parkinson’s disease (PD) is often accompanied by non-motor complications, such as dementia, depression, and psychotic symptoms, which worsen the prognosis and increase the personal and socioeconomic burden of disease. Prevalence estimates of these complications are quite variable and are lacking for the outpatient care sector. Methods: As part of a larger, nationwide, cross-sectional epidemiological study in n=315 neurological outpatient settings in Germany, this paper estimates the frequency of dementia and cognitive impairment in n=873 outpatients meeting the UK Brain Bank criteria for idiopathic PD. Assessments were based on a clinical interview and neuropsychological assessments, including the Hoehn & Yahr rating and Unified Parkinson’s Disease Rating Scale (UPDRS). Cognitive impairment was assessed by the Mini-Mental State Exam (MMSE), Clock Drawing Test (CDT) and the Parkinson Neuropsychometric Dementia Assessment (PANDA) and the clinician’s diagnosis of dementia was based on the diagnostic criteria of DSMIV. Results Using standardized cutoff scores, the prevalence of cognitive impairment in the study sample as measured by various methods was 17.5% by MMSE (≤ 24), 41.8% by CDT (≥ 3), 43.6% by PANDA (≤ 14), and 28.6% met the DSM-IV criteria for dementia. All estimates increased with age and PD severity. Gender was an inconsistent contributor while illness duration had no significant impact on cognition. Multiple regression analyses revealed PD severity to be the strongest predictor of dementia risk (OR=4.3; 95 % CI: 2.1–9.1), while neuropsychiatric syndromes had independent, although modest additional contributions (OR=2.5, 95% CI: 1.6–3.8). Conclusion: Estimates of cognitive impairment and dementia in PD patients are largely dependent on the diagnostic measure used. Using established clinical diagnostic standards for dementia the overall rate on routine outpatient neurological care is 28.6%, but using more sensitive neuropsychological measures, rates for cognitive impairment might be up to 2-fold higher. The MMSE revealed strikingly low sensitivity. Neuropsychiatric syndromes, in addition to PD severity and age, have an independent – although modest – additional contribution to patients’ risk for cognitive impairment and dementia.

Neuropsychological tests are routinely undertaken at memory clinics to help diagnose Mild Cognitive Impairment (MCI) and Dementia. For those patients found to have MCI it would be clinically valuable to be able to distinguish patients at high risk of progressing to Dementia. The aim of this Thesis is to develop a prognostic algorithm using neuropsychological test performance, in order to estimate the probability of progressing to dementia in patients with MC!. The cohort providing data attended the BRACE memory clinic in Bristol, UK and comprises 643 MCI patients, 268 of whom were observed to progress to Dementia. To inform our analysis, a systematic search of the published literature and meta-analysis were conducted for an indication of which neuropsychological tests can distinguish those MCI patients at risk of progressing to dementia. This resulted in 38 articles fulfilling the inclusion criteria. A simulation experiment determined optimal methods for transforming the different types of estimate presented to a Diagnostic Odds Ratio (DOR) scale. Subsequently the meta-analysis revealed the most predominant domains associated with progression to dementia were Memory, Learning, and Language. Using the BRACE data, the best subset of neuropsychological tests to predict dementia was found to be compromising the tests of Mini Mental State Examination (MMSE), the Immediate Recall of the Story Test and the total score of Hopkins Verbal Learning Test (HVLT).

Rationale and study aims: Persons with mild cognitive impairment (MCI) experience declines in everyday functioning and cognitive performance greater than what is experienced in normal aging but less than that of dementia. Daily stress and daily memory complaints associated with cognitive deficits may contribute to greater psychological distress in the day-to-day experiences of persons with MCI. However, research examining the occurrence of daily stressors, daily memory complaints and psychological distress in MCI is limited, and it is not clear how the daily processes of stress and affect in persons with MCI compare to cognitively healthy older adults. This dissertation examined the occurrence of daily stressors, daily memory complaints, retrospective and daily well-being in persons with MCI compared to cognitively healthy controls. Main analyses examined whether daily stressors and daily memory complaints were associated with worse daily affect in MCI participants compared to controls, and whether increased daily stress was associated with a greater number of memory complaints. Methods: The study used a short-term repeated measures design, and included MCI and control participants recruited from a university-based memory clinic. The interviews consisted of a baseline interview and up to eight consecutive days of brief daily phone interviews. The interviews included both retrospective and daily measures of psychological well-being, daily stressors, daily memory complaints, and open-ended questions about daily experiences. Results: Persons with MCI reported a greater number of daily memory complaints and worse psychological distress, as measured by both retrospective and daily reports. There were no significant differences between MCI and control participants, however, in the frequency of daily stressors. In both unadjusted and adjusted analyses, on days when a participant reported more daily stressors, they had higher negative affect. The stress-negative affect relationship was stronger for MCI participants compared to controls. MCI and control participants who reported more memory complaints, on average, had higher negative affect. Discussion: Daily stressors were disproportionally associated with greater psychological distress in MCI participants as compared to cognitively healthy controls. Interventions targeting the potential distress associated with daily life may be beneficial for psychological well-being in persons with MCI. Future research should examine other potential mechanisms of distress in daily lives of persons with MCI in order to inform relatives and caregivers of persons with MCI, clinicians who give diagnoses to their patients, and individuals providing community support for individuals living with MCI.

The majority of schizophrenia patients exhibit significant, diffuse cognitive impairment. Understanding the course and nature of this impairment is essential to elucidating etiology and treatment. Previous studies have been unable to trace the course of cognition from infancy to adulthood and assess true developmental change. Cognitive deficits in individuals with subclinical psychotic experiences may provide important clues about clinical psychotic disorders. Yet, developmental change and the effects of age, sociodemographic and familial factors have not been examined. Moreover, while there is evidence for connection abnormalities in the brains of schizophrenia patients, little is known about the structure of cognitive functioning across the psychosis spectrum i.e. in subclinical psychotic experiences and clinical psychotic disorders. The first study examined the association between subclinical psychotic experiences and cognitive functioning in a general population sample. Adults with psychotic experiences showed significant verbal and memory, but not processing speed deficits. Only older adults with psychotic experiences showed medium to large verbal and memory deficits when adjusting for sociodemographic factors, psychiatric morbidity and cannabis use. First-degree relatives showed a significant verbal, but not memory impairment. The second and third studies used data from a longitudinal cohort to examine 1) the course of cognitive functioning from infancy to adulthood and 2) cognitive network structure in childhood and adulthood. Individuals with depression, psychotic experiences, affective psychotic disorder and non-affective psychotic disorder were compared to controls. Affective psychotic disorder, psychotic experiences and depression groups showed a degree of cognitive impairment across infancy and adulthood, but only those with non-affective psychosis showed large, progressive deficits across multiple domains. Individuals with non-affective, affective and subclinical psychosis also showed qualitative and quantitative abnormalities in cognitive network structure, with the two clinical groups showing larger, widespread anomalies. Controls showed increasing reliance on working memory between childhood and adulthood, while all other groups remained reliant on low-level cognitive processes. Altogether, these findings suggest that the course of cognitive impairment differs across the psychosis spectrum. Despite distinct profiles of impairment, abnormalities in cognitive network structure were seen across the spectrum, highlighting the importance of looking beyond cognitive deficits to how performance is achieved.