Identification of plasma lipid biomarkers in Alzheimer\u27s disease

Alzheimer’s disease (AD), the commonest form of dementia, is a chronic, progressive neurodegenerative disease which manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With an ageing population, there is predicted to be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Currently there is no cure for AD and while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. Attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis but provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestations develop. Research and understanding of AD pathology has been driven in recent years by advances in technologies, enabling the precise investigation of the lipidome; the repertoire of lipid species present in cells and tissues that reflect the net effect of gene and protein expression, which in turn are influenced by the cellular environment. Lipidomic studies have identified abnormal lipid metabolism as a key component of the pathological processes which lead to the development of AD. Therefore, lipidomic studies are crucial for advancing the understanding of AD pathology and for identifying potential therapeutic targets; these studies may also facilitate biomarker discovery. Many studies have reported abnormal lipid profiles in both AD plasma and brain tissue. This thesis investigated plasma lipid species using a “shotgun” lipidomics approach by electrospray ionisation tandem mass spectrometry (ESI/MS/MS). Additionally, Phospholipid Transfer Protein (PLTP); a protein involved in lipid metabolism was assayed using a commercial kit. The utility of these analytes as potential AD biomarkers was investigated by testing plasma samples from the highly characterised Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The study cohort comprised over 1000 participants at inception who were classified as either healthy control (n=733), mild cognitive impairment (MCI, n=125) or AD (n=204): Samples from the baseline and 18 month follow-up time points were utilised. Plasma PLTP activity levels were measured in a subset of the baseline samples (n=259). Lipid and PLTP measurements were analysed in conjunction with supplementary neuroimaging and blood biomarker data collected as part of the AIBL study. The thesis identified significant differences in several plasma lipids between clinical classification groups, including several ceramide, sphingomyelin (SM), phosphatidylethanolamine (PE), phosphatidylcholine (PC) and plasmalogen species. Additionally, a panel of lipids was identified which could distinguish AD participants from healthy controls with a sensitivity and specificity of 80%. Plasma PLTP activity was significantly lower in AD and MCI groups compared to healthy controls, and levels correlated with plasma Aβ in all groups and cerebral Aβ in the healthy controls. The results of this thesis validate and extend previous findings reported in the literature. The current findings provide evidence to indicate that several lipid species and PLTP show promise as potential blood biomarkers of AD. Further investigation using a targeted lipidomics platform and prospective longitudinal follow-up is warranted

Links Between Insulin Resistance, Lipoprotein Metabolism And Amyloidosis In Alzheimer\u27s Disease

The origins of premature brain aging and chronic disease progression are associated with atherogenic diets and sedentary lifestyles in Western communities. Interests in brain aging that involves non alcoholic fatty liver disease (NAFLD), the global stroke epidemic and neurodegeneration have become the focus of nutritional research. Atherogenic diets have been linked to plasma ceramide dysregulation and insulin resistance actively promoting chronic diseases and neurodegeneration in developed countries. Abnormal lipid signaling as observed in chronic diseases such as hypothyroidism, obesity and diabetes is connected to stroke and neurodegenerative diseases in man. Lipids that are involved in calcium and amyloid betahomeostasis are critical to cell membrane stability with the maintenance of nuclear receptors and transcriptional regulators that are involved in cell chromatin structure and DNA expression. Western diets high in fat induce hyperlipidemia, insulin resistance and other hormonal imbalances that are linked to alterations in brain calcium and lipid metabolism with susceptibility to various chronic diseases such as stroke. Nutrition and food science research identifies dietary components and lipids to prevent hyperlipidemia and calcium dyshomeostasis connected to neuroendocrine disease by maintaining astrocyte-neuron interactions and reversing hormonal imbalances that are closely associated with NAFLD, stroke and Alzheimer’s disease (AD) in global populations

Molecular Insights into Appetite Control and Neuroendocrine Disease as Risk Factors for Chronic Diseases in Western Countries

Environmental factors such as stress, anxiety and depression are important to consider with the global increase in chronic diseases such as cardiovascular diseases, cancer, stroke, obesity, diabetes and neurodegenerative diseases. Brain metabolic diseases associated with conditions such as obesity and diabetes require early intervention with diet, lifestyle and drug therapy to prevent diseases to various organs such as the liver with non alcoholic fatty liver disease (NAFLD) and other organs such as the heart, lungs thyroid, pancreas, brain, kidneys and reproductive systems. Behavioural stress and the molecular mechanisms that are involved in neuroendocrine diseases such as insulin resistance in obesity require attention since associated inflammatory processes early in the disease process have been associated with neurodegenerative diseases. Molecular neuroendocrine disturbances that cause appetite dysregulation and hyperphagia are closely linked to hyperinsulinemia, dyslipidaemia and reduced lifespan. The origins of metabolic diseases that afflict various organs possibly arise from hypothalamic disturbances with loss of control of peripheral endocrine hormones and neuropeptides released from the brain. Diet and drug therapies that are directed to the autonomic nervous system, neuroendocrine and limbic systems may help regulate and integrate leptin and insulin signals involving various neuropeptides associated with chronic diseases such as obesity and diabetes. The understanding of brain circuits and stabilization of neuroanatomical structures in the brain is currently under investigation. Research that is involved in the understanding of diet and drugs in the stabilization of brain structures such as frontostriatal limbic circuits, hypothalamus brainstem circuits and parasympathetic nervous system is required. Information related to neuropeptides and neurotransmitters that are released from the brain and their regulation by therapeutic drugs requires further assessment. The promise of appropriate diets, lifestyle and drugs that target the CNS and peripheral tissues such as the adipose tissue, liver and pancreas may improve the prognosis of chronic diseases such as obesity and diabetes that are also closely associated with neurodegeneration

Deletion Mutations in an Australian Series of HNPCC Patients

Hereditary non polyposis colorectal cancer (HNPCC) is characterized by the presence of early onset colorectal cancer and other epithelial malignancies. The genetic basis of HNPCC is a deficiency in DNA mismatch repair, which manifests itself as DNA microsatellite instability in tumours. There are four genes involved in DNA mismatch repair that have been linked to HNPCC; these include hMSH2, hMLH1, hMSH6 and hPMS2. Of these four genes hMLH1 and hMSH2 account for the majority of families diagnosed with the disease. Notwithstanding, up to 40 percent of families do not appear to harbour a change in either hMSH2 or hMLH1 that can be detected using standard screening procedures such as direct DNA sequencing or a variety of methods all based on a heteroduplex analysis

Meeting the nutritional needs of seniors via a seafood rich diet

Research has shown a gap in the market for information around the types of protein rich, bioavailable meals that would be suitable for seniors who are capable of, and have the facilities to prepare their own meals at home. Seniors can experience significantly more nutritional risk factors associated with chronic lifestyle conditions than the general population. Inadequate nutritional intake in older people is common, frequently overlooked, and results in many negative health outcomes including malnutrition. This study was a mixed methods, quasi experimental trial involving both qualitative and quantitative data collection methods. The main aim of the study was to develop a series of low cost, nutritionally balanced meals specifically designed to meet the needs of seniors

Effects of a high-fat, high-cholesterol diet on brain lipid profiles in apolipoprotein E ε3 and ε4 knock-in mice

Apolipoprotein E (ApoE) is important in facilitating the transport of lipids (cholesterol, phospholipids, and sulfatides) and plays a fundamental role in normal lipid metabolism. High cholesterol levels increases the risk of developing Alzheimer’s disease. In this study, we investigated the effects of a high-fat high cholesterol (HFHC) diet on brain lipid profiles in 95 young and aged APOE ε3 and ε4 knock-in mice to determine whether diet leads to altered brain levels of a number of glycerophospholipids, sphingolipids, cholesterol precursors, cholesterol, cholesterol oxidation products, and cholesterol esters. The results in this study revealed significant changes in lipid levels. The HFHC-enriched diet influenced the levels of cholesterol esters. A sharp increase in cholesterol ester levels, particularly in the aged APOE ε4 diet-enriched group, might be suggestive of abnormal acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT) activity and/or levels. Age exerts appreciable effects on the brain lipidome, especially with regard to polar lipid species

Diet, nutrients and metabolism: Cogs in the wheel driving Alzheimer's disease pathology?

Alzheimer's disease (AD), the most common form of dementia, is a chronic, progressive neurodegenerative disease that manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With a global ageing population, it is predicted that there will be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Global estimates put a direct cost for treating and caring for people with dementia at $US604 billion, an estimate that is expected to increase markedly. According to recent global statistics, there are 35.6 million dementia sufferers, the number of which is predicted to double every 20 years, unless strategies are implemented to reduce this burden. Currently, there is no cure for AD; while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. A greater understanding of AD pathophysiology is paramount, and attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis, but also provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets, including nutritional ones. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestation develops