Alzheimer’s disease (AD) is a devastating neurodegenerative disease with growing prevalence in our society. Patients suffering from this debilitating disorder also develop neuropsychiatric symptoms. Depression is one of the most frequently conveyed comorbidity; moreover, depression is also a risk factor associated with AD development. There is a complex interplay between the neurobiology of depression and AD, but their concomitant disease mechanisms remain largely unknown. Retraction of axons and dendrites has been reported to be a common occurrence in both illnesses, proposing the involvement of cytoskeletal dysfunction. Tau is a microtubule-associated protein that undergoes aberrant processing to form neurofibrillary tangles in neurodegenerative diseases such as AD. However, the role of tau in depression has not been well studied. The elucidation of pathophysiological mechanisms in depression is important to provide a more holistic understanding of AD pathogenesis. This study proposes the potential participation of tau phosphorylation in the pathogenesis of depression. In addition, this study will also investigate tau modifications under concomitant models of depression and AD. Primary cultures of hippocampal neurons were exposed to independent and cotreatments of corticosterone and β-amyloid (Aβ), to induce in vitro models of depression and AD, respectively. Sprague Dawley rats were subcutaneously injected with corticosterone for 14 days to induce an in vivo model of depression. Tau phosphorylation, aggregation and interaction with microtubules were examined. Results demonstrated that in both in vitro and in vivo models of corticosterone-induce depression, tau underwent increased phosphorylation at residues S396 and S404. Phosphorylated tau showed decreased interactions with microtubules and increased vulnerability to aggregate. Furthermore, the in vivo model of depression illustrated an altered localization of tau in the CA3 region of the hippocampus. Co-treatment of corticosterone and Aβ exacerbated aberrant tau phosphorylation and aggregation. In conclusion, this study provides evidence for the role of tau in depression, suggesting the occurrence of abnormal tau phosphorylation as an early event in the pathogenesis. Additionally, the pathophysiology of depression and AD may involve similar mechanisms in tau phosphorylation and aggregation. This study provides insight into the neurobiological linkages between depression and AD, and emphasizes the importance of tau-targeted interventions in neuropsychiatric disorders. / published_or_final_version / Anatomy / Master / Master of Philosophy

This thesis describes the development of magnetic resonance imaging (MRI) techniques to visualise neurofibrillary tau pathology in transgenic mice. Neurofibrillary pathology is a prominent pathological feature of Alzheimer's disease (AD) and is closely correlated to cognitive impairment and dementia. 19F and 1H MRI methods were developed with a 4.7 T preclinical system. To facilitate these experiments, RF saddle coils were designed and constructed that show good agreement with theoretical SNR calculations and produce uniform B1 fields. A copper wire surface coil, incorporating active decoupling electronics, was built to increase the sensitivity of 19F and 1H mouse brain experiments. A stripline transmission line resonator (TLR) was also developed as a surface coil receiver and because it does not need tuning and matching adjustments, it reduces experimental set up times significantly. An ultra-short echo time (UTE) pulse sequence was developed for imaging 19F compounds, designed to attach to sites of tau pathology in the brain and which were known to exhibit very short T2 relaxation times. Ex vivo, 19F MRI experiments using these compounds indicated low penetration of the blood brain barrier and a tendency for precipitation. An RF spoiled, short TE 3D gradient echo pulse sequence was optimised to produce artefact-free T1-weighted images of the mouse brain. Measurements from a preliminary study using high resolution, T1-weighted MRI showed that the ventricular areas of a control mouse were not appreciably different from those of a transgenic mouse. Software was developed to generate automated T2 brain maps from spin echo MRI data sets and was used to compare T2 relaxation times between a control and a transgenic mouse. This experiment showed that the T2 relaxation times of the tau transgenic mouse brain were prolonged when compared to those of a control mouse.

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Most demented individuals are now cared for at home by family members. The present study examined the coping strategies employed by family caregivers, their perception of burden, and the internal dialogues employed by caregivers to stressful events. Sixteen (13 females, 3 males) participants with an average age of 67.4 years were interviewed. Results indicate that caregivers who spend less hours per week caring for their care receiver perceived less overall burden and caregivers who subjectively felt that they were coping with their role tended to use more coping strategies. Caregivers' internal dialogues and comments concerning problems coping with Alzheimer's patients are included.

Subcortical hyperintensities (SH) are believed to be observable signs of cerebrovascular disease, indicating some form of subcortical vasculopathy. Also commonly referred to as leukoariosis, these hyperintense signals on proton density, T2-weighted and fluid attenuated inversion recovery magnetic resonance images, are commonly observed phenomena in Alzheimer’s disease patients and elderly persons. Several SH sub-types with differential brain-behavior associations have been proposed in the scientific literature: periventricular, deep white, cystic fluid filled lacunar-like infarcts and perivascular Virchow-Robin spaces. This study will present Lesion Explorer (LE): a comprehensive tri-feature MRI-based processing pipeline that effectively and reliably quantifies SH sub-types in the context of additional brain tissues volumetrics in a regionalized manner. The LE pipeline was validated using a scan-rescan procedure. Finally, the LE pipeline was applied in a cross-sectional study of Alzheimer’s disease patients and normal elderly controls. Brain-behavior relationships were demonstrated with regional SH volumes and executive functioning, speed of mental processing, and verbal memory.

This secondary data analysis of the Health and Retirement Study – Aging, Demographics, and Memory Study (ADAMS) examines the relationship between subjective cognition and objective performance, depression, and anxiety in cognitive impairment with no dementia (CIND) and dementia. With a cross-sectional design, this study consists of 480 older adults between ages 72-105. Participants completed the Mini-Mental State Examination. The Wechsler Memory Scale- Revised Logical Memory I/II measured memory. Anxiety and depression were measured by the Neuropsychiatric Inventory. Subjective memory was measured by the HRS Self-report Memory and Informant Questionnaire on Cognitive Decline in the Elderly. Independent t-tests and Pearson correlation analysis were employed to determine differences between the dementia and non-dementia groups. Results demonstrated that the CIND group had significantly better general cognition; more severe cognitive/memory problems in the dementia group showed weaker relationships between general cognition and memory performance; anxiety/depression were weakly related in CIND and moderately related in dementia.

Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. These enzymes are associated with the pathology of neurologic disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS). In particular, AChE and BuChE accumulate in B- amyloid (AB) plaques and tau neurofibrillary tangles in the AD brain. Thus, imaging cholinesterase activity associated with plaques and tangles in the brain has the potential to provide definitive diagnosis of AD during life. This would be advantageous since, at present, confirmation of AD relies on detecting pathology through post-mortem examination of the brain. In a similar respect, BuChE is associated with the characteristic lesions in MS brain and thus, is a promising target for diagnosis and monitoring of pathology in this disease. It is hypothesized that cholinesterase-binding radiopharmaceuticals can be used in SPECT or PET imaging to visualize these enzymes associated with AD and MS pathology in the living brain. Several classes of cholinesterase ligands were synthesized and exhibited potent binding and specificity towards AChE and BuChE using enzyme kinetic analysis. These compounds were rapidly radiolabelled with 123I and purified. Radiolabelled molecules accumulated in vitro in areas known to contain cholinesterase activity in transgenic AD mice and post-mortem human AD brain tissues, using autoradiography. Furthermore, cholinesterase activity associated with AB plaques was visualized in human and transgenic mouse AD brain tissues. An enzyme kinetic approach was employed to determine critical residues in the BuChE active site gorge for ligand binding. In particular, residues pertaining to the peripheral site of the enzyme were identified and found to be involved in the binding of various ligands. These results are crucial for optimizing the enzyme binding properties of cholinesterase imaging agents. Finally, PET imaging of a transgenic mouse model of AD was performed as a vanguard for pre-clinical evaluation of cholinesterase imaging agents. PET imaging identified similar characteristics between this AD mouse model and the human condition. This is a promising approach for evaluation of cholinesterase imaging agents. Radioligands specific for cholinesterases have the potential to provide a noninvasive means for early diagnosis of neurological diseases using brain scanning.