For older adults, functional independent mobility is essential to well-being. Many care home residents have physical and cognitive impairments and use wheelchairs. Residents with difficulty self-propelling manual wheelchairs may benefit from power mobility; however, those with cognitive impairments may be precluded because of the potential for injury. My research goals were to apply novel power wheelchair technology to enable safe, independent mobility. Technology was developed to examine the value and implications of power mobility for residents with restricted mobility and mild or moderate cognitive impairments. The first study tested a prototype anti-collision wheelchair with a contact sensor skirt. Six single subject studies were completed. Distances travelled in manual and anti-collision wheelchairs were compared. Observational and interview data were collected. Focus groups (37 staff) and interviews (18 staff, six other residents, one spouse) were performed. Three of six residents were able or had potential to operate the prototype. One resident chose to use it beyond the study, and his mobility and well-being improved. Case analyses showed factors limiting prototype acceptance. Residents were unsatisfied with the appearance and slow speed, and found the interface frustrating to operate because of inadequate feedback. Social isolation and reduced autonomy restricted independence achievable with technology. Socialization and affective benefits of mobility were demonstrated in one case where prototype use was continually assisted. Residents and staff supported the anti-collision concept. On observation, the prototype compensated for absent or delayed responses of residents to obstacles below sensors and decreased injury risk. However, full sensor coverage of the environment was needed. The second study addressed acceptance and interface usability issues. A simulated collision-avoidance wheelchair with a multimodal feedback interface was evaluated. The interface provided audio, visual and haptic feedback to guide navigation away from obstacles. Through observations, interviews and questionnaires, five residents evaluated the device. High device acceptance and usability were found. The device was easy to use and assisted with performance of indoor mobility goals. Further research is necessary before power wheelchairs with new features are available for users; however, these results could play a fundamental role in shaping technology development and mobility interventions for this neglected population.

For older adults, functional independent mobility is essential to well-being. Many care home residents have physical and cognitive impairments and use wheelchairs. Residents with difficulty self-propelling manual wheelchairs may benefit from power mobility; however, those with cognitive impairments may be precluded because of the potential for injury. My research goals were to apply novel power wheelchair technology to enable safe, independent mobility. Technology was developed to examine the value and implications of power mobility for residents with restricted mobility and mild or moderate cognitive impairments. The first study tested a prototype anti-collision wheelchair with a contact sensor skirt. Six single subject studies were completed. Distances travelled in manual and anti-collision wheelchairs were compared. Observational and interview data were collected. Focus groups (37 staff) and interviews (18 staff, six other residents, one spouse) were performed. Three of six residents were able or had potential to operate the prototype. One resident chose to use it beyond the study, and his mobility and well-being improved. Case analyses showed factors limiting prototype acceptance. Residents were unsatisfied with the appearance and slow speed, and found the interface frustrating to operate because of inadequate feedback. Social isolation and reduced autonomy restricted independence achievable with technology. Socialization and affective benefits of mobility were demonstrated in one case where prototype use was continually assisted. Residents and staff supported the anti-collision concept. On observation, the prototype compensated for absent or delayed responses of residents to obstacles below sensors and decreased injury risk. However, full sensor coverage of the environment was needed. The second study addressed acceptance and interface usability issues. A simulated collision-avoidance wheelchair with a multimodal feedback interface was evaluated. The interface provided audio, visual and haptic feedback to guide navigation away from obstacles. Through observations, interviews and questionnaires, five residents evaluated the device. High device acceptance and usability were found. The device was easy to use and assisted with performance of indoor mobility goals. Further research is necessary before power wheelchairs with new features are available for users; however, these results could play a fundamental role in shaping technology development and mobility interventions for this neglected population.

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.

Attention is one of the most impaired cognitive functions in schizophrenia; however, the precise mechanisms underlying schizophrenia-related attention impairment are unclear. Progress in identifying these mechanisms has been hampered by using methods that are not designed to isolate specific cognitive processes. The purpose of the present dissertation was to investigate visual attention among patients with schizophrenia using the visual search paradigm — the dominant paradigm for studying attention in the cognitive sciences. Moreover, the current study used eye-tracking methodology to more finely examine the mechanisms underlying impaired visual search in this clinical population. This dissertation had three main objectives: (1) to investigate whether patients with schizophrenia have smaller and/or less dynamic visual spans, (2) to examine whether certain mechanisms guiding the visual selection of objects are impaired in schizophrenia, and (3) to determine the contribution of visual search performance to substitution test performance. Results indicated that patients’ visual spans are both smaller and less dynamic compared to healthy controls. On the other hand, selectivity for more informative distractors is intact in schizophrenia; however, impaired motion perception results in impaired target discrimination in the context of intact target selection. Results also indicated that visual search performance is a primary determinant of substitution test performance. Collectively, these data demonstrate, on one hand, an impairment among patients with schizophrenia in the distribution and flexible modulation of visual attention and, on the other hand, intact visual selective attention in the presence of strong bottom-up cues. The current data also demonstrate the important contribution of visual attention to a highly sensitive neuropsychological test and, by inference, to patients’ cognitive and real-world functioning.

Attention is one of the most impaired cognitive functions in schizophrenia; however, the precise mechanisms underlying schizophrenia-related attention impairment are unclear. Progress in identifying these mechanisms has been hampered by using methods that are not designed to isolate specific cognitive processes. The purpose of the present dissertation was to investigate visual attention among patients with schizophrenia using the visual search paradigm — the dominant paradigm for studying attention in the cognitive sciences. Moreover, the current study used eye-tracking methodology to more finely examine the mechanisms underlying impaired visual search in this clinical population. This dissertation had three main objectives: (1) to investigate whether patients with schizophrenia have smaller and/or less dynamic visual spans, (2) to examine whether certain mechanisms guiding the visual selection of objects are impaired in schizophrenia, and (3) to determine the contribution of visual search performance to substitution test performance. Results indicated that patients’ visual spans are both smaller and less dynamic compared to healthy controls. On the other hand, selectivity for more informative distractors is intact in schizophrenia; however, impaired motion perception results in impaired target discrimination in the context of intact target selection. Results also indicated that visual search performance is a primary determinant of substitution test performance. Collectively, these data demonstrate, on one hand, an impairment among patients with schizophrenia in the distribution and flexible modulation of visual attention and, on the other hand, intact visual selective attention in the presence of strong bottom-up cues. The current data also demonstrate the important contribution of visual attention to a highly sensitive neuropsychological test and, by inference, to patients’ cognitive and real-world functioning.

Introduction : Les individus présentant des troubles cognitifs légers ou Mild Cognitive Impairment (MCI) sont plus à risque de développer une maladie d’Alzheimer (MA) que le reste de la population âgée. Objectif : Cette étude repose sur le recours à un devis de type étude de cas multiples dont l’objectif est de contribuer à l’identification d’indices biologiques en quantifiant, à l’aide de la résonance magnétique spectroscopique (MRS), des changements métaboliques précoces chez les individus avec MCI, susceptibles d’évoluer vers la MA. Méthodologie : Huit individus MCI sont comparés à huit individus âgés normaux. Chaque participant est soumis à un examen MRS. Résultats : Parmi les huit participants MCI recrutés, l’un d’entre eux présente désormais un profil cognitif concordant avec une MA. L’analyse spectrale des métabolites de cet individu montre des ratios de glutamate plus élevés au niveau du cortex préfrontal gauche et de la régioncingulaire postérieure gauche. Bien qu’une diminution de NAA/Cr soit fréquemment observée chez la population MCI en voie d’évoluer vers la démence, les résultats obtenus ne démontrent rien en ce sens. Discussion/Conclusion : Le rôle du glutamate dans les processus neurodégénératifs est encore mal établi. L’augmentation de glutamate observée est contraire à la diminution habituellement observée au cours de la MA. Ces résultats sont toutefois explicables par l’existence possible d’excitotoxicité précoce chez les MCI en voie de d’évoluervers la démence. Cela pourrait aussi illustrer des mécanismes de compensation présents avant qu’un déclin cognitif ne soit objectivable. / Background: Mild cognitive impairment (MCI) characterizes individuals who present some cognitive impairment without criteria for dementia. Known as a highly plausible transitional stage between normal aging and Alzheimer’s disease (AD), the majority of individuals with MCI will eventually evolve to AD. Objective: The general aim of this multiple-cases study is to explore the contribution of magnetic resonance spectroscopy (MRS) to the neurochemical identification individuals with MCI in the process of evolving toward an AD. Methodology: Eight individuals were compared to eight age and education matched-controls. For each participant, MRS measures for XX neurometabolites were taken from the left prefrontal and left posterior cingulate gyrus. Results: Among all the MCI participants, one of them converted to AD during the time of the study. The spectral analysis of this participant showed higher glutamate/glutamine ratios in both regions. Although a reduction of Naa/Cr is often/generally observed among the MCI population moving/headed toward dementia, the obtained/experimental results show/demonstrate nothing in this sense. Discussion/Conclusion: The role of glutamate in pathological processes is not well-known. These results suggest the probable existence of excitotoxicity mechanisms in MCI subjects who will convert to AD, a mechanism that could express the presence of some compensatory processes. While reporting the challenge of MRS measures in this population, this study provide indications of its potential for the early detection of AD in a MCI population.

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Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.

Mild cognitive impairment (MCI) is a transition phase between normal aging and Alzheimer’s disease. Individuals with MCI show impairment in cognition as well as corresponding damage to areas of their brain. Performance on tasks such as discriminating objects with ambiguous features has been associated with damage to the perirhinal cortex, while scenes with structural (spatial) elements have been associated with damage to the hippocampus. In addition, attention is regarded as one of the first non-memory domains to decline in MCI. A relatively new MRI technique called diffusion tensor imaging (DTI) is sensitive to white matter microstructural integrity and has been associated with changes due to cognitive decline. 18 MCI (14 amnesic, 4 vascular) and 12 healthy matched controls were assessed in feature ambiguity, attention and structural learning to assess associated deficits in MCI. Associations with white matter microstructural integrity were then investigated. The MCI groups were discovered to perform worse than controls on the test of structural learning. In addition, altered attention networks were found in MCI and were associated with white matter microstructural integrity. No significant differences were found for feature ambiguity. These findings suggest there may be specific damage to the hippocampus while the perirhinal cortex may be preserved in MCI. Furthermore, dysfunction in attention was found to be associated with white matter microstructural integrity. These experimental tests may be useful in assessing dysfunction in MCI and identifying degeneration in white matter microstructural integrity. Further studies with larger sample sizes are needed to validate these findings.

Studies presented in this dissertation were conducted to gain more insight into the role of phospholipid asymmetry and amyloid-β (Aβ)-induced oxidative stress in brain of subjects with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). AD is a largely sporadic, age-associated neurodegenerative disorder clinically characterized by the vast, progressive loss of memory and cognition commonly in populations over the age of ~65 years, with the exception of those with familial AD, which develop AD symptoms as early as ~30 years-old. Neuropathologically, both AD and FAD can be characterized by synapse and neuronal cell loss in conjunction with accumulation of neurofibrillary tangles and senile plaques. Elevated levels of oxidative stress and damage to brain proteins, lipids, and nucleic acids are observed, as well. Likewise, aMCI, arguably the earliest form of AD, displays many of these same clinical and pathological characteristics, with a few exceptions (e.g., no dementia) and to a lesser extent. Studies in this dissertation focused on the contributions of oxidative stress to the exposure of phosphatidylserine (PtdSer) to the outer-leaflet of the lipid membrane, how and when PtdSer asymmetric collapse contributes to the progression of aMCI, AD, and FAD, and the role played by methionine-35 (Met-35) of Aβ in oxidative stress and damage, as measured in a transgenic mouse model of Aβ pathology. Normally, the PtdSer is sequestered to the cytosolic, inner-leaflet of the bilayer by the adenosine triphosphate (ATP)-dependent, membrane-bound translocase, flippase, which unidirectionally transports PtdSer inward against its concentration gradient. Oxidative stress-induced modification of flippase and/or PtdSer, however, leads to prolonged extracellular exposure of PtdSer on the outer membrane leaflet, a known signal for both early apoptosis and selective recognition and mononuclear phagocytosis of dying cells. Within the inferior parietal lobule (IPL) of subjects with aMCI and AD, a significant collapse in PtdSer asymmetry was found in association with increased levels of both pro- and anti-apoptotic proteins, Bax, caspase-3, and Bcl-2. Moreover, a significant collapse in PtdSer asymmetry was also found in whole brain of human double-mutant knock-in mouse models of Aβ pathology, together with significantly reduced Mg2+ATPase activity, representing flippase activity, and increased levels of pro-apoptotic caspase-3. Significant PtdSer externalization corresponded to the age at which significant soluble Aβ(1-42) deposition occurs in this particular mouse model (9 months), and not of plaque deposition (12 months), suggesting that elevated levels of Aβ(1-42), together with increasing oxidative stress and apoptosis, may contribute to altered PtdSer membrane localization. Also in this dissertation, transgenic mice carrying Swedish and Indiana mutations on the human amyloid precursor protein (APPSw,In) and APPSw,In mice carrying a Met35Leu mutation on Aβ were derived to investigate the role of Met-35 in Aβ(1-42)-induced oxidative stress in vivo. Oxidative stress analyses revealed that Aβ-induced oxidative stress requires the presence of Met-35, as all indices of oxidative damage (i.e., protein carbonylation, nitration, and protein-bound 4-hydroxy-2-trans-nonenal [HNE]) in brain of Met35Leu mice were completely prevented. Moreover, immunohistochemical analyses indicated that the Met35Leu mutation influences plaque formation, as a clear reduction in Aβ-immunoreactive plaques in Met35Leu mice was found in conjunction with a significant increase in microglial activation. In contrast, behavioral analyses suggested that spatial learning and memory was independent of Met-35 of Aβ, as Met35Leu mice demonstrated inferior water-maze performance compared to non-transgenic mice. Differential expression and redox proteomic analyses to pinpoint proteins significantly altered by the APPSw,In and Met35Leu mutations was performed, as well. Expression proteomics showed significant increases and decreases in APPSw,In and Met35Leu mouse brain, respectively, in proteins involved in cell signaling, detoxification, structure, metabolism, molecular chaperoning, protein degradation, mitochondrial function, etc. Redox proteomics found many of these same proteins to be oxidatively modified (i.e., protein carbonylation and nitration) in both APPSw,In and Met35Leu mouse brain, providing additional insights into the critical nature of Met-35 of Aβ for in vivo oxidative stress in a mammalian species brain, and strongly suggesting similar importance of Met-35 of Aβ(1-42) in brain of subjects with aMCI and AD. Taken together, studies presented in this dissertation demonstrate the role of oxidative stress-induced alteration of PtdSer asymmetry and Met-35 in Aβ-induced oxidative stress in aMCI, AD, and FAD brain.