Genetic Risk for Alzheimer\u27s Disease Alters the Five-Year Trajectory of Semantic Memory Activation in Cognitively Intact Elders

Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer\u27s disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N = 24) and non-carriers (N = 21). All participants, ages 65–85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy

The effects of resistance training on cognition and brain health in older adults at risk for diabetes: A pilot feasibility study

Type 2 diabetes is associated with neurocognitive deficits and increased risk for dementia, with high prevalence of diabetes occurring in old age. There are many known risk factors for diabetes, including physical inactivity, obesity, and prediabetes. Studies show that individuals who are at risk for diabetes (i.e., have one or more risk factors) already experience some brain deficits seen in diabetes. One way to combat these deficits is aerobic exercise; however, the effects of resistance exercise in this population are relatively unknown. The objectives of this thesis were to report on the current evidence of brain deficits in prediabetes, and to assess the feasibility and preliminary efficacy of resistance training to improve cognition and brain health (structure and function) in older adults at risk for diabetes. A systematic review of cross-sectional and longitudinal studies assessing brain dysfunction in prediabetes was conducted, as well as a 26-week pilot feasibility randomized controlled trial of resistance exercise among older adults at risk for diabetes (i.e., those living with prediabetes and/or obesity). The systematic review found that adults with prediabetes may experience deficits in structural connectivity, but whether deficits in brain volume and cerebrovascular health are present is somewhat inconclusive and may be due to inconsistencies across study methodologies. Results from the pilot feasibility trial found that resistance exercise, compared to balance and stretching exercise, may improve selective cognitive functions, mainly task-switching, selective attention, and response inhibition. Resistance exercise also led to less age-related decline in total brain volume, less hippocampal atrophy, and increased functional activation patterns that mimic that of younger adults and healthy older adults. When assessing feasibility, study adherence, retention, and self-reported enjoyment were high, but recruitment was shown to be challenging. As such, important recruitment recommendations for improving future trials are included in this thesis. In conclusion, resistance exercise may lead to some improvements in cognition and brain health in older adults at risk for diabetes, however a full-scale, powered RCT is needed to further explore these possible effects

A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs: a Dissertation

Depression and stimulant drug addiction each result in massive losses of health, productivity and human lives every year. Despite decades of research, current treatment regimes for depression are ineffective in approximately half of all patients. Therapy available to stimulant drug addicts is largely ineffective and moreover, dedicated treatments for drug dependence (including abuse of cocaine) are non-existent. Thus, there is a pressing need to further understanding of the molecular mechanisms underlying these disorders in order to develop novel, targeted therapeutic strategies. Chromatin remodeling, including changes in histone acetylation, has been proposed to play a role in both the etiology and treatment of depression and stimulant abuse. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate numerous cellular processes, including transcription, cell cycle progression and differentiation. Moreover, histone acetylation has been shown to regulate hippocampal neurogenesis, a cellular response associated with the pathogenesis and treatment of depression and stimulant abuse (Hsieh et al., 2004, Yamaguchi et al., 2004, Fischer et al., 2007). Ultimately, such basic cellular processes impact higher order function, namely cognition and emotion. Indeed, recent studies suggest that HDAC activity in selected forebrain regions, including ventral striatum and hippocampus, modulate stimulant- and antidepressantinduced behavior (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). These reports highlight an association between chromatin remodeling and diverse behavioral changes, including changes induced by the pleiotropic HDAC inhibitor, sodium butyrate (SB), (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). However, behavioral, brain-metabolic and molecular effects of SB treatment in the context of rodent models of depression, dopaminergic sensitization and repeated cocaine administration remained unclear. The work described in this thesis illustrates the potential for chromatin modifying drugs in mechanisms underlying the experimental pharmacology of depression and stimulant addiction. Specifically, the data presented here support the view that treatment with the short chain fatty acid, sodium butyrate enhances: (1) antidepressant-like behavioral effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (2) locomotor sensitization induced by repeated administration of the dopamine D1/D5 receptor agonist SKF82958; and(3) brain metabolic activation upon repeated cocaine administration as evidenced by fMRI in awake rats. Furthermore, this report provides evidence that these treatment paradigms will result in chromatin modification changes associated with active transcription, in addition to increased mRNA levels of plasticity-associated genes, including brain-derived neurotrophic factor (BDNF) at key brain regions implicated in the pathogenesis of depression and stimulant addiction. To date, little is known regarding the underlying mechanisms of action mediating the enhancing effects of sodium butyrate on the various antidepressant- and stimulantrelated paradigms. Our findings underscore the potential of chromatin-modifying drugs to profoundly affect the behavioral response of an animal to antidepressant and stimulant drugs and warrants consideration in the context of developing novel therapeutic strategies

Effects of post-encoding processing on deliberate and intrusive memory for traumatic material

Following a traumatic event, some individuals might experience distressing involuntary thoughts and imagery, as seen in post-traumatic stress disorder. It is crucial to understand the complex factors that contribute to the occurrence and subsequent treatment of these intrusions. Whilst it has been shown that various factors during the immediate aftermath of an event can alter successful memory storage, little is known about how such post-encoding processes influence intrusive memories for traumatic material. Accordingly, unitary accounts suggest that intrusions behave like strong voluntary memories, whereas a dual representation view predicts that they behave in a complementary way. This thesis investigated post-encoding processing for traumatic material using behavioural and functional magnetic resonance imaging (fMRI) methods. First, I examined methodologies for assessing intrusive memories in a laboratory setting, demonstrating that short video clips as an analogue trauma induced more intrusions than negative static images. Utilising this method in Chapter 3, I investigated memory for videos immediately followed by either a short break or a second, unrelated video. In two similar experiments, differences between conditions were non-significant. However, when collapsing data across the two studies to gain more power, I showed that deliberate memory performance was significantly reduced for videos immediately followed by another video compared to videos followed by a short break, suggesting disrupted consolidation for the first video. Chapter 4 examined the effects of brief wakeful rest following viewing of traumatic material, a technique thought to enhance consolidation. Here, I demonstrated that, compared to a working memory task, brief wakeful rest decreased intrusive memories and had different effects on deliberate and intrusive memory. In Chapter 5, I used fMRI to show that activity in medial temporal lobe structures, during encoding and its immediate aftermath, predicts deliberate memory, whereas amygdala activity during encoding is associated with memory intrusions. The findings from this thesis highlight the importance of the period in the aftermath of trauma and how its modulation can alter deliberate and intrusive memory in different ways

Investigating the Relationship Between Vascular Health, Gait, and Cognition in Community-Dwelling Older Adults Without Dementia

Cardiovascular disease (CVD) risk factors contribute to neuropathological changes within regions of the brain that are involved with both cognitive and motor control processes, and have been identified as potentially modifiable dementia and gait dysfunction risk factors. Exercise training is a corner-stone treatment for vascular risk factor control, and evidence suggests that physical and cognitive training can benefit cognition and gait; however, the exercise training modality that can provide the greatest cognitive benefit remains elusive. Therefore, the purpose of this thesis was three-fold: (i) to determine whether CVD risk factors and gait were associated with cognitive functioning, (ii) to determine whether blood pressure dipping status was associated with cognitive and gait impairments in community-dwelling older adults, and iii) to examine the impact of a dual-task gait training and aerobic exercise (DAE) on cognition, gait, and vascular health. Cumulative CVD risk was an independent predictor of executive functioning. Cross-sectional differences in cognition and usual and dual-task gait were observed between older adults with preserved blood pressure dipping and non-dippers. Last, 26-weeks of DAE training improved cognition and usual and dual-task gait, and the improvements in cognition were maintained for at least 6 months after the exercise program. The management of traditional and novel CVD risk factors should be a primary aim of prevention strategies aimed at mitigating cognitive decline. Although DAE training can benefit cognition and gait, further work is required to unequivocally determine the efficacy of DAE training as a method to improve brain health in older adults without dementia

The Effects of Exercise on Cognition, Mobility, and Neuroimaging Outcomes in Older Adults without Dementia

Cognitive decline is increasing with the aging population and, at present, there is no effective pharmacologic treatment available. Exercise interventions may impart protection against cognitive decline. A novel exercise approach is multiple-modality exercise (MME; aerobic, resistance, and balance exercise) with mind-motor training. Mind-motor training is a promising intervention in the study of cognitive function. Combining MME with mind-motor training may improve or maintain cognition and provide prevention of dementia early in the course of cognitive decline. Individuals with subjective cognitive complaints (SCC) comprise an at-risk group early in the spectrum of cognitive decline that could be targeted for prevention. The objectives of this thesis were to report on the current state of evidence regarding the effects of MME in cognition and neuroimaging outcomes in older adults without dementia, and determine whether MME with mind-motor training benefit cognition, mobility, and neuroimaging outcomes in older adults with SCC. A scoping review of MME studies in older adults without dementia was conducted, as well as a 24-week randomized controlled trial (RCT) with a 28-week no-contact follow-up in community-dwelling older adults with SCC. Main findings were as follows: the scoping review concluded that although MME may improve cognition and neuroimaging outcomes compared to controls, confounding factors may account for these effects given that MME does not seem to evoke similar effects when compared to other interventions. Results from an RCT revealed that 24 weeks of MME with mind-motor training showed trends for greater improvements in global cognitive functioning and memory. These trends were confirmed after a 28-week no-contact follow-up. For mobility outcomes, MME alone was effective in improving gait performance under usual and dual-task conditions, while MME and mind-motor training did not seem to impart benefits to mobility. An exploratory study of memory and neuroimaging data revealed that MME and mind-motor training yielded greater benefits than MME alone in visuospatial memory, with changes in functional connectivity in brain areas of motor function and in brain regions relevant to Alzheimer’s disease risk. In conclusion, MME with mind-motor training is a promising strategy to improve cognition with potential to invoke neuroplasticity associated with improved memory, and reduce dementia risk

The clinical utility of multidisciplinary rehabilitation in individuals with Huntington’s Disease

Background Huntington’s disease (HD) is a chronic neurodegenerative disorder characterised by a progressive loss of cognitive function, motor control and psychiatric features. Individuals also display a variety of systemic features. Progressive neuronal dysfunction and neuronal cell death are thought to underlie the onset and progression of many clinical features of HD. Despite scientific progress, there is still no cure or disease modifying therapy for HD, and available pharmaceutical agents only provide partial relief of motor and psychiatric features. An emerging body of evidence indicates that lifestyle enrichment may delay the onset and progression of clinical features, and exert favourable effects on neuropathological aspects of HD. Few studies have evaluated the effects of lifestyle enrichment strategies like multidisciplinary rehabilitation on the clinical features of HD. Moreover, no study has evaluated the effects of multidisciplinary rehabilitation on neuropathological aspects of HD. Aims The initial aim of this thesis was to determine factors that contribute to features of the disease that negatively impact on activities of daily living such as mobility and balance (Chapter 2), and to identify, using a literature review, a rehabilitation strategy that could positively impact on these features of HD (Chapter 3). These studies informed our ultimate aim which was to investigate the clinical utility of multidisciplinary rehabilitation on clinical and neuropathological features of HD (Chapters 4, 5 and 6) Methods In study 1 (Chapter 2), 22 participants were assessed using a battery of balance, mobility, cognitive tests, assessments of muscle strength and body composition measures. Data was . then statistically examined using stepwise linear regression to identify factors that contribute to balance and mobility impairments in individuals with manifest HD. In study 2 (Chapter 3), a systematic search of journal databases was made from inception to July 2014 for studies reporting on resistance exercise in patients with neurodegenerative disorders. Selected studies were abstracted and critically appraised using a quality control checklist. For the intervention studies, (3 and 4 Chapters 4 and 5), 20 participants with manifest HD were randomly assigned to either a control or training group. Individuals randomised to the intervention group were provided with a nine month multidisciplinary intervention comprising once weekly supervised clinical exercise, thrice weekly home based exercise and fortnightly occupational therapy, while those randomised to the control group were asked to continue with their standard care and daily activities. Participants were assessed using motor, cognitive, psychological, body composition and quality of life measures at baseline and at the completion of the intervention. In study 5 (Chapter 6), 15 participants with manifest HD were assessed using magnetic resonance imaging and a battery of cognitive assessments after nine months of multidisciplinary rehabilitation to see whether such a therapy is capable of inducing favourable changes in brain structure and cognitive function. Results The main factors that contribute to mobility and balance impairments in patients with manifest HD were found to be lower limb muscle weakness and a loss of cognitive function (Study 1). Systematic evaluation of the effects of resistance exercise for neurodegenerative disorders showed that it is beneficial for multiple sclerosis and Parkinson’s disease. In particular, improvements in muscle strength, mobility, balance, clinical disease progression, fatigue, functional capacity, quality of life, disease biology, electromyography activity, mood, skeletal muscle volume and architecture were reported in individuals with multiple sclerosis or Parkinson’s disease (PD) after resistance exercise. The most robust effects of resistance exercise were found for muscle strength outcomes, and were more pronounced in individuals with PD (Study 2). The multidisciplinary rehabilitation intervention studies conducted as part of this thesis significantly improved isometric and isokinetic muscle strength, self-perceived balance, body mass, lean tissue mass and fat mass in patients with HD (Studies 3 and 4). Moreover, multidisciplinary rehabilitation also increased grey matter (GM) volume in the caudate nucleus and dorsolateral prefrontal cortex of patients. The significant increases in GM volume were accompanied by, and correlated to, a significant improvement in performance in verbal learning and memory. Conclusions The work presented here shows that lower extremity muscle weakness and a loss of cognitive function significantly contribute to impairments in mobility and balance. This work also shows that strength training has favourable effects on motor function, including strength, mobility and balance, as well as other clinical features in similar neurodegenerative disorders, and thus should be integrated into multidisciplinary rehabilitation interventions for HD. In addition, this study provides evidence that multidisciplinary rehabilitation can significantly improve aspects of motor control, cognitive function and body composition. Finally we show, for the first time, that multidisciplinary rehabilitation can increase GM volume in structures known to degenerate in HD, and that such increases are functionally related to changes in verbal learning and memory. Future work is urgently required to confirm and expand on these exciting findings, particularly with respect to the neurorestorative properties of multidisciplinary rehabilitation

Neurobiological, attentional and memory changes in posttraumatic stress disorder

This dissertation aimed at investigating the role of fear learning and encoding mechanisms in the development and maintenance of anxiety and trauma-related disorders in two studies. In study 1, we combined functional resting state connectivity with skin conductance data of cued and contextual fear conditioning in 119 healthy individuals. In study 2, we applied simultaneous high-density electroencephalography (EEG) with eye-tracking during free picture viewing (including traumatic cues in neutral contexts) and memory tests of the same materials in 20 patients with post-traumatic stress disorder (PTSD) and 20 trauma controls who did not develop PTSD (NPTSD). In study 1, we hypothesized that increased functional connectivity of the default mode network (DMN) (1) with the amygdala and frontal control regions would be associated with a decrease in the magnitude of cue aversive learning, and (2) that another DMN connectivity pattern including the hippocampal formation, would negatively correlate with the strength of contextual conditioning indices. The main result of this study is that two different DMN patterns were identified in which stronger connectivity linked to lower differential SCRs during fear and anxiety was learning. One was related to cue conditioning and involved the amygdala and the medial prefrontal cortex, and one was associated with context conditioning and included the hippocampal formation and sensorimotor areas. In the second study, we expected an early perceptual bias on trauma-related cues at the expense of the context in PTSD compared to NPTSD as visible in the modulation of polarity/amplitudes of the visual C1 and in eye tracking early fixation measures. Referring to the memory performance we expected the PTSD group to better retrieve pictures requiring a more elemental/unitary strategy (aka where the association between cues and contexts was kept constant) and consequently in being especially worse than NPTSD in retrieving cue-context modified associations. We finally expected encoding strategies to account for the memory performance. In the simultaneous EEG-eye-tracking task we found that the PTSD but not the NPTSD group oriented more towards traumatic but not neutral cues at the expense of the context. These outcomes were present at the first stages of information processing as indicated by the changes in polarity of the C1 component of the EEG and predicted the following associative memory performance. Different resting-state connectivity patterns within the DMN could emerge in association with individual predispositions of learning fear and anxiety. Because of the recognized clinical implications of these learning mechanisms in trauma and anxiety disorders, our findings highlight the relevance of brain connectivity differences as possible biomarkers already at rest and in healthy individuals, for example in healthy populations with high exposure to traumatic events (such as medical personal, rescue workers, police officer, soldiers) in order to reduce vulnerability and/or promote resilience to develop PTSD. An hippocampal processing impairment is probably responsible for the memory deficits in PTSD but possibly promoted from the strongly biased encoding strategy of the cues versus contexts, which also it is helpful in explaining intrusions and hyperarousal symptoms in a more complex perspective. Moreover, increasing awareness encoding used strategies could help existing therapies (e.g. cognitive behavioral and exposure therapy) in modifying faster the appraisal and memory of the trauma through trained restructuring of events and contextual representations

Acute effects of alcohol on trauma memories

Memory disturbances following a trauma are a characteristic feature of posttraumatic stress disorder. Despite alcohol’s frequent involvement in real-life traumatic events, our understanding of its contribution to trauma-related symptoms is unclear. The research in this thesis aimed to determine the way in which alcohol intoxication during a traumatic experience might influence memory for the event. Experiment 1 showed that alcohol impaired recognition associated with recollection with greater reductions as dose increased (0, 0.4, 0.6, 0.8g/kg); in contrast, recognition associated with familiarity was preserved. Experiments 2 and 3 utilised an analogue trauma film to examine how low (0.4g\kg) and high (0.8g/kg) doses of alcohol affected intrusive imagery and explicit memory for the footage. Alcohol during encoding resulted in a dose-dependent inverted U-shaped curve on intrusive imagery, with increased intrusions only following a low dose. Explicit memory for the footage was reduced in a dose-dependent linear manner. In addition, experiment 3 concurrently assessed same- and shifted-view object location recognition to determine the mechanisms that might underpin alcohol’s effects on trauma memory. Results showed that a low dose of alcohol selectively impaired shifted-view recognition, thought to rely on an allocentric representation. However, same-view recognition was preserved, suggesting a spared egocentric representational system. In contrast, the high dose disrupted both same- and shifted-view recognition, suggesting a global disruption in both memory systems. Experiment 4 examined the effects of alcohol (0.4/kg) on contextual fear acquisition and extinction and both same- and shifted-view recognition. Fear acquisition was unaffected by alcohol, whilst extinction learning was impaired with persistent conditioned responses throughout extinction. Alcohol-induced reductions in extinction learning were highly correlated with decreases in shifted-view recognition, supporting the role of contextual encoding in extinction. The findings of these studies suggest that alcohol dose-dependently influences trauma memories and this could result in a distinct set of trauma-related symptoms

Physical activity is associated with reduced Implicit learning but enhanced relational memory and executive functioning in young adults

Accumulating evidence suggests that physical activity improves explicit memory and executive cognitive functioning at the extreme ends of the lifespan (i.e., in older adults and children). However, it is unknown whether these associations hold for younger adults who are considered to be in their cognitive prime, or for implicit cognitive functions that do not depend on motor sequencing. Here we report the results of a study in which we examine the relationship between objectively measured physical activity and (1) explicit relational memory, (2) executive control, and (3) implicit probabilistic sequence learning in a sample of healthy, college-aged adults. The main finding was that physical activity was positively associated with explicit relational memory and executive control (replicating previous research), but negatively associated with implicit learning, particularly in females. These results raise the intriguing possibility that physical activity upregulates some cognitive processes, but downregulates others. Possible implications of this pattern of results for physical health and health habits are discussed