2013 Completion of PhDs

image - 2013 Completion of PhDs - Thesis Topics

Dr Teresa Lee
Genetic and Environmental Influences on Neuropsychological Functioning in Later Life:  The Older Australian Twins Study 

Ageing is associated with cognitive decline.  While many areas of cognitive functioning are affected, there is relatively limited knowledge about the contributions of genetic (G) and environmental (E) factors to cognition.  This thesis looked at two specific areas of cognition.  Processing Speed (PS) and Executive Functions (EF).  PS is how long it takes to process information and to do a test.  Executive Functions are thinking processes which include complex attention and task planning.  Using data from OATS and genetic modeling, the first study looked at the extent of G influence (heritability) and E influences on multiple measures of PS and EF, and how they relate to General Cognitive Ability (GCA).  PS performances in several measures and GCA were explained by one common genetic factor, suggesting that they shared the same genes.  The results for EF in the second study, however suggested it has both G and E influences.  Differences in PS and EF were also both found to be related to differences in the memory of older people, but more so for PS.  These findings suggest PS can be assessed to investigate declines in general cognition as people age.  The last study in the thesis looked at the associations between three leisure activities (cognitive, physical and social) and various health/medical factors with cognitive performance.  A number of cardiovascular, frailty and sensory factors were identified that explained differences in cognitive function between identical twins.  Taken together, this research has identified important G influences and E factors that promote our understanding of mechanisms related to cognitive ageing.  The results also have practical implications for the development of targeted interventions to slow age-associated cognitive decline. 

Dr Teresa  Lee was awarded the 2013 UNSW Rising Star Award.

 

image - 2013 Completion of PhDs - Thesis TopicsDr Seyed Amir Hossein Batouli
Genetic and Environmental Influences on Brain Structure and Biochemistry in the Elderly: Data from the Older Australian Twins Study

Healthy brain functioning is an important part of healthy ageing.  Several brain features have shown links with healthy ageing; including brain size, brain white matter hyperintensity (WMH) and brain metabolites.  Age-related changes are influenced by both genetic and environmental factors, and this study looked at how they influence the structure and biochemistry of the brain.  Participants were recruited from the OATS Study (average age 72 years).  Firstly structural equation modeling was performed to compare MRI brain scan data from identical and fraternal twins.  The influences of age and sex on the heritability of these parameters were examined, as well as identifying any common genetic factors.  Estimations showed significant heritability of the brain size, WMH volume and brain biochemistry in the elderly.  Brain size heritability decreased with age, but WMH volume heritability increased.  There were no significant differences between males and females in the heritability of brain metabolites and WMH volumes, but the heritability of brain size was higher in males.  Also, common genetic factors were observed between the volumes and WMHs of different brain regions and also between the brain metabolites.  The results showed that the human brain is largely influenced by genetic factors in later life, but that this influence may diminish with increasing age, particularly for brain size.  As environmental factors may become more important in later life, it is suggested that healthy ageing may be optimized by enrichment of environmental conditions.

 

Dr Im Quah-Smithimage - 2013 Completion of PhDs - Thesis Topics
An Experimental and Clinical Study on the Effects of Laser Acupuncture in the Alleviation of Depressive Symptoms 

The World Health Organisation has in recent years declared depression as the number one cause of disability in the world.  Treatment options include pharmacotherapy, cognitive behavior therapy and supportive counseling.  The adverse effects of pharmacotherapy (a major deterrent to patient compliance) and recent literature reporting only 6-7% of depressed patients remit on pharmacotherapy are of concern.  Many patients suffering from depression turn to Complementary Medicine, including acupuncture for answers.  Empirically acupuncture has been helpful in treating depression, however, due to the heretogeneity of acupuncture in depression studies, results have been inconclusive.  Acupuncture’s adverse effects profile is minimal and it is well tolerated.  This project is a comprehensive investigation on the use of low intensity laser acupuncture (LA) in the treatment of depression based on the highly significant pilot study using LR14, CV14, HT7, LR8 acupoints.  The significant brain effects of these acupoints under LA in healthy and depressed subjects are identified and evaluated. Default mode network (DMN) modulation by LA and its relevance to depression is explored. The pilot clinical study was repeated with both clinician and self-reporting measures. An attempt is also made to identify the components of depression that improved with LA. The final experiment was to test the differential brain activation between LA and NA on the most significant acupoint within the treatment regime. The replication of the positive findings of the anti-depressant regime using LA has been further clarified by the fMRI studies: LA modulates the brain regions important in depression, including the DMN. There are wider brain regions stimulated with LA in depressed subjects (DS). Its stimulation of brain regions important in wellbeing and sense of self (identity) in healthy subjects (HS) does suggest maintenance LA may be helpful. Acupoint specificity was identified. Somatisation effects were significantly improved in the clinical study delivering a better quality of life. Transient fatigue was the only adverse effect reported. Further work on acupoint specificity in actual treatment regimes for different conditions is necessary. LA and NA both have commonality and specificity in their brain effects that need further exploration.

Im has just returned from the Neuroscience Research Institute at Gachon University, Incheon, Korea, where she is collaborating with Prof. Zhang Hee Cho and Dr. Richard Niemztow on the US Govt. $5.4M grant on the fMRI evidence for Battlefield Acupuncture’s brain effects in pain modulation.

 

Dr Nicola Gatesimage - 2013 Completion of PhDs
Psychological Wellbeing and Quality of Life in Mild Cognitive Impairment

Psychological wellbeing (PWB) and a high Quality of Life (QoL) are indicators of successful ageing.  With increasing numbers of older adults and their desire for positive ageing, along with projections of dementia prevalence and policy interest to reduce health expenditure, interest in PWB and QOL has risen significantly. Coupled with this has been the advancement of life style interventions as a means to preserve independence, improve cognition, and promote PWB. Evidence from epidemiological studies and clinical trials suggests that cognitive training (CT) and physical exercise (PE) interventions in adults with mild cognitive impairment (MCI) may improve cognition.   However, to date there has been limited investigation of QoL and PWB outcomes in these studies. Therefore, the first investigation was an empirical analyses of a theoretical 3-tiered model of PWB using cross sectional baseline data from the SMART trial.  The final model predicted 61% of the variance of PWB in MCI with memory concern and cognitive deficits identified as significant predictors of PWB, along with negative affect and QoL.  Following 26 weeks of SMART CT and PE intervention linear mixed model analyses revealed that mental health-related QoL and Purpose in Life subscale within PWB improved following combined intervention, and CT in isolation resulted in improved levels of Autonomy, and Self- Acceptance, both aspects of PWB.  By contrast, isolated PE had no significant benefit on any component of QoL or PWB.  Lastly, regression analyses indicated that improved cognitive performance following intervention was not associated with a reduction in memory concern or improvement in QoL or PWB.  The three investigations of this thesis demonstrated overall that PWB and QoL in MCI have multiple influences, that complex inter-relationships exist between negative affect, cognition and memory concern, and that interventions designed to improve cognition do not necessarily improve PWB.  Clinical implications from this research include recognising the importance of memory concern for PWB and QoL in MCI, the implementation of early intervention programmes in MCI, potential role of CT to improve aspects of PWB, and the development of PWB and QoL outcomes in future research studies.

 

Dr Chao Suoimage - 2013 Completion of PhDs
Brain plasticity stimulated by physical and cognitive exercise as revealed by multimodal magnetic resonance imaging

Alzheimer's Disease (AD) is a devastating and costly disorder that will become more common with the ageing of society. Accordingly, the delay, prevention and treatment of AD has risen as a top priority worldwide. Several lines of evidence suggest delay and prevention of AD may be possible through non-pharmacological lifestyle interventions.

This thesis has an interest in cognitive lifestyle, defined as lifelong habits of complex mental activity, and lifestyle-related physical activity, and their interventional counterparts, cognitive training and physical exercise. Extensive epidemiological research links these lifestyle factors with decreased dementia incidence and decreased cognitive impairment. Also, clinical trials evidence suggests that cognitive training and physical exercise can be effective at improving cognitive outcomes in healthy individuals as well as those with Mild Cognitive Impairment (MCI). However, the mechanisms by which these lifestyle factors or interventions lead to positive cognitive outcomes are largely unknown (systematically reviewed in Chapter 2).

This thesis therefore aimed at addressing these knowledge gaps using multimodal MRI. Three studies are presented, organized around two main themes. Firstly, potential neuroplastic mechanisms linked to cognitive lifestyle are investigated in Chapters 3 and 4. Secondly, the longitudinal effects of cognitive and physical training on brain structure, function and cognition in MCI is assessed in Chapter 5, in the setting of the Study of Mental Activity and Regular Training (SMART) Trial.

In Chapter 3, midlife managerial experience was revealed to be the key part of cognitive lifestyle linked to protection from hippocampal atrophy in late life. In Chapter 4, we extend this to MCI, finding that managerial experience is also linked to hippocampal morphometry, hippocampal functional networks, memory performance and subjective memory concerns. In Chapter 5 we found that cognitive training and physical resistance training stimulate distinct mechanisms: resting state hippocampal functional connectivity and posterior cingulate cortical thickness, respectively. Furthermore, these different types of brain plasticity were associated with different training-related therapeutic cognitive outcomes. Finally, in Chapter 6 we integrate these findings with the literature in terms of both long-term and short-term brain plasticity, discuss the limitations of current longitudinal MRI processing methods, and make recommendations about future research directions.

 

image - 2013 Completion of PhDsDr Michael Player
Neuroplasticity measured via brain stimulation in healthy and depressed subjects

Major Depressive Disorder (MDD) is a debilitating and pervasive illness with a lifetime prevalence of between 10-15% of the world’s population. The prevailing hypothesis of depression is the stress neurotrophic hypothesis, and is characterised by excessive levels of stress and glucocorticoids. Excessive stress and glucocorticoids result in detrimental changes to the structure and functioning of the brain, including effects upon neuroplasticity. Neuroplasticity allows the brain to differentially respond to stimuli, and adapt to changes in the environment. Impaired neuroplasticity is linked to a number of symptoms in depression. The thesis aims were to find a means to objectively test neuroplasticity in subjects suffering MDD, and to compare neuroplasticity with matched controls. A secondary aim was to discover if neuroplasticity changed with treatment for depression. To achieve these aims, three separate experiments were carried out. The aim of the first study was to find a conditioning protocol that induced robust and consistent increases in motor cortical excitability, thus providing a means of measuring neuroplasticity, in healthy subjects. The selected conditioning protocol would be used for measurement of neuroplasticity in healthy and depressed populations in two subsequent studies. Using the paired associative stimulation (PAS) protocol selected from study 1, the aim for study 2 was to compare neuroplasticity in depressed subjects with that of age and gender matched controls. By measuring motor cortical plasticity before and after PAS conditioning, this study provided one of the first objective demonstrations of impaired neuroplasticity in individuals with MDD that is not confounded by subject effort or motivation. In study 3, PAS-induced neuroplasticity was measured twice in the same subjects. The first measure was taken while subjects were depressed, the second, after a treatment course of transcranial direct current stimulation. This study showed a significant improvement in neuroplasticity and mood state after treatment, though change in mood did not correlate with change in neuroplasticity. This research supports a hypothesis of impaired neuroplasticity in depression. Thesis findings provide evidence of improved neuroplasticity and depressive symptoms after treatment, and thus provide important information about the pathophysiology and treatment of MDD.

 

Dr Jaemin Kimimage - 2013 Completion of PhDs
Directed differentiation of human embryonic stem cells into dopamine neurons

Parkinson’s disease (PD) is a neurodegenerative disease which is caused by many factors including progressive degeneration of dopamine (DA)-secreting neurons which reside in the midbrain substantia nigra (SN). Currently, there is no cure for treating PD and therefore, alternative treatment such as cell replacement therapy using human embryonic stem cells is required. A specific investigation on the derivation of DA neurons was carried out by using a three-dimensional (3D) environment via encapsulation. A detailed gene and protein expression analysis during neuronal differentiation showed earlier onset of midbrain DA (mdDA) neuronal markers and secreted higher DA level than the cells differentiated under conventional two-dimensional (2D) culture system. This data corresponds to the microarray data which revealed up-regulation of mRNA expressions that are involved in neuronal developments such as Wnt, hedgehog and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, a hESC reporter cell line which has been stably integrated with a plasmid vector that contains a human TH promoter tagged with an enhanced green fluorescent protein (eGFP) marker with no abnormal karyotype. Results from this study displayed a more effective differentiation towards neuroectoderm and DA neurons when differentiated under 3D environment. It is a very useful model to study the proliferation and directed differentiation of hESC to various lineages. This 3D system also allows the separation of feeder cells from hESC during the process of differentiation and also has potential for immune-isolation during transplantation studies. The derivation of hESC reporter cell line containing TH-tagged eGFP could be further utilised to isolate homogeneous population of DA neurons for possible transplantation studies or developmental pathway analysis in the future.

CHeBA Directors

Dr Sophia Dean

    Professor Perminder
    Sachdev AM

    Scientia Professor

Dr Sophia Dean

    Professor Henry Brodaty
    AO

    Scientia Professor

 

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