Melbourne School of Psychological Sciences - Theses
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ItemThe effect of vascular risk factors in dementia of the Alzheimer's type( 2016)The influence of vascular risk factors on Alzheimer’s disease and its clinical presentation is an area of intense scientific debate. There is now growing evidence to suggest that the presence of vascular risk factors in early-stage Alzheimer’s disease might accelerate its clinical presentation. Previous studies have also demonstrated that clinically healthy individuals with vascular risk factors perform below expectations on cognitive assessment. Further, the burden of vascular risk factors might be a predictor of future cognitive decline. However, the relationship between vascular risk factors and cognitive deterioration in healthy older adults has not been clearly established. The aim of this study was to investigate the relationship between vascular risk factors and cognitive function in a large cohort of 768 cognitively healthy older individuals drawn from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. This thesis addresses four main questions: (1) is there a difference in cognitive performance between individuals with and without vascular risk factors?, (2) does the presence of vascular risk factors affect the rate of cognitive change? (3) does the number of vascular risk factors influence cognition? and (4) does the presence of vascular risk factors increase the likelihood of developing Mild Cognitive Impairment? Participants were aged between 60–95 years, (M= 69.9 ± 6.9). All participants underwent a comprehensive baseline assessment and three additional serial assessments were repeated at 18-month intervals over a 54-month period. By the end of the study period, 172 individuals had withdrawn from the cohort. Of the remaining 596 participants, 43 had attracted a classification of Mild Cognitive Impairment. The sample was divided into subgroups of those with and without vascular risk factors. Participants in the vascular risk factors sub-group had at least one of the following risk factors: (1) hypertension, (2) diabetes, (3) dyslipidaemia, (4) Body Mass Index > 30 kg/m², (5) chronic kidney disease, (6) smoking history of more than 20 cigarettes per day for more than one year, and (7) elevated homocysteine levels (males>16.2 μmol/L; females>13.6 μmol/L). This thesis comprises a series of analyses. For the first analysis, demographic characteristics of individuals with and without vascular risk factors was compared. The data suggested that vascular risk factors were associated with older age (F (1, 712) = 8.1, p = 0.005), lower level of education (χ2 (1, n =711) = 7.8, p = 0.005) and apolipoprotein E ε4 carriage (χ2 (1, n = 714) =6.9, p = 0.009). In the second analysis, a statistically significant difference in cognitive performance between individuals with and without vascular risk factors was identified (F (4, 669) = 4.28, p = 0.002; partial eta square = 0.03). The results revealed that participants with vascular risk factors demonstrated poorer performance on variables that assessed visual cognition and executive functions than participants without vascular risk factors. In the third analysis, from a longitudinal perspective, five specific neuropsychological tests were subjected to a linear mixed model adjusted for age and apolipoprotein E ε4 carriage. The presence of vascular risk factors was associated with increased rates of cognitive decline on measures of verbal fluency (F (2, 1096.8) = 3.03, p < 0.05) and visuospatial skills (F (1204.6, 1) = 1.055; p < 0.05). The relationship between vascular risk factors and cognitive decline became more evident in the fourth analysis when the neuropsychological test battery was reduced into cognitive composite measures. Participants with vascular risk factors showed significantly greater decline on measures of verbal (F (624.016, 1) = 7.2; p = 0.01) and visual (F (1775.533, 1) = 6.89; p = 0.01) memory, as well as on visuospatial skills (F (1204.6, 1) = 1.055; p = 0.03) and executive functions (F (1821.035, 1) = 4.48; p = 0.03). No difference was found in the language composite measure. In the fifth analysis, higher vascular risk factor burden was associated with increased rates of cognitive decline, suggesting the presence of a dose-response relationship. In individuals with three or more vascular risk factors, a higher magnitude of decline on tasks that measure executive functions (Cohen's d = 0.35), visuospatial skills (Cohen's d = 0.35) and visual memory (Cohen's d = 0.47) was identified. No dose-response relationship was found in either the language or verbal memory cognitive domains. The sixth analysis focused on the group of participants who attracted a diagnosis of MCI over the 54 months. The data showed that there was a significant difference in the vascular risk factor burden distribution between individuals who remain cognitively stable and those who transition to Mild Cognitive Impairment (X² (2) = 44.88, p < 0.001), with greater risk factor burden observed in the latter. The interaction effect between clinical classification and presence/absence of vascular risk factors on the cognitive composite factors was further investigated. The only cognitive variable that showed a statistically significant difference was the visuospatial skill composite (1, 513) = 5.52; p = 0.019; partial eta square = 0.011). Finally, the analysis showed that vascular risk factors increased the likelihood of developing Mild Cognitive Impairment by 39%. In conclusion, the data suggest that vascular risk factors confer a degree of cognitive vulnerability on cognitively healthy older adults. This effect appears to be selective, impacting executive functions and visuospatial cognition but not language and verbal memory. Executive functions and visuospatial cognition are complex cognitive domains and share extensive distributed networks, which may increase their susceptibility to vascular risk factors over time. Based on the overall findings of this research, we propose that vascular risk factors – in combination with genetic and demographic factors – contribute to a reduction of brain reserve, precipitating an earlier onset of cognitive decline in the transition to Mild Cognitive Impairment. This implies that individuals who suffer from several risk factors may have less brain reserve and may therefore be more susceptible to developing dementia. Vascular risk factors are preventable for at least 95% of people with relatively simple changes in diet and lifestyle. The findings from this thesis contribute to a developing literature suggesting that decreases in vascular risk may reduce susceptibility for dementia and cognitive decline in later life.
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ItemAssessment of the effects of transcranial direct current stimulation (tDCS) on neurophysiologic, cognitive, and behavioral outcome measures( 2016)Transcranial Direct Current Stimulation (tDCS) is a form of non-invasive brain stimulation that serves to modulate brain activity via the passing of a weak, electrical current through the head. Despite public and clinical excitement, the effects of tDCS reported in the literature have been inconsistent. Accordingly, the reliability of this device remains unclear. The purpose of this PhD was to explore the consistency and reliability of inter- and intra-subject tDCS effects. First, I conducted research exploring the effects of four tDCS parameters (polarity, current density, electrode location, and stimulation-to-task relationship) on simple visual motor reaction time (smRT). 150 individuals were assigned to one of 5 experimental groups (2 mA anodal, 2 mA cathodal, 1 mA anodal, 1 mA cathodal, or sham) across 3 different conditions (M1 target with the reference over an orbitofrontal, bilateral, or extracephalic location). Participants received 20min stimulation while undertaking an smRT task 5min preceeding, during, and 5min following stimulation. Results revealed tDCS demonstrated no significant effect on any smRT parameter. In my next study, 30 participants underwent 7min of anodal, cathodal, or sham stimulation using a bilateral M1 electrode montage. Participants undertook an smRT task for 5min preceeding, during, and 20min following stimulation: however, the cueing stimulus utilized was auditory rather than visual. As before, this experiment produced null results. Next, 2 participants undertook 8 separate sessions of 1min cathodal tDCS utilizing a bilateral M1 montage. Participants undertook an smRT task for 1min preceding, during, and following stimulation. Again, this experiment produced null-results. To determine a cognitive measure reliably amenable to stimulation, I next conducted a quantitative review of every inter-lab replicated cognitive task in the tDCS literature. Of the 59 analyses exploring 52 outcome measures across three-tiers of inclusion stringency (gleaned from 138 studies), none demonstrated a significantly reliable response to tDCS. To determine a physiologic outcome measure amenable to stimulation, I conducted a second quantitative review of every inter-lab replicated physiologic outcome measure in the tDCS literature. Of the 31 measures (gleaned from 145 studies), only 1 reached statistical significance: motor evoked potential (MEP) amplitude modulation. At the time of the analysis, no data had been generated exploring intra-subject reliability of this outcome. In my final study, I explored the effect of multiple identical tDCS sessions on MEP amplitude modulation within individuals. 14 participants each underwent 9 sessions of 10min tDCS (3 anodal, 3 cathodal, 3 sham). MEP amplitudes were measured prior to and for 30min following stimulation. Results demonstrated tDCS effects on MEP amplituted are highly variable within individuals across sessions. Group-wide analysis demonstrated no significant effect of tDCS on MEP amplitude compared to sham. Regression analysis demonstrated modulation of MEP amplitude may be explainable by regression-to-the-mean and non-experimental variables. Based on the experimental investigations conducted and the comprehensive reviews of the existing literature, there is currently insufficient evidence that tDCS produces a reliable effect. In the conclusion, I explore potential explanations for the current state of the tDCS literature and suggest future directions for this tool.