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ItemMemory decline and Aβ amyloid as markers of neurodegeneration in preclinical Alzheimer's diseaseLim, Yen Ying ( 2013)Alzheimer’s disease (AD) is pathologically characterised by neurofibrillary tangles and beta-amyloid (Aβ) plaques. Clinically, it is characterised by a gradual decline in cognitive function, particularly in episodic memory. Current neuropsychological models emphasise the measurement of cognitive impairment to determine cognitive abnormality. However, as AD is a neurodegenerative disease, it has been suggested that the repeated assessment of cognitive function could provide important information about an individual’s performance over time, particularly as any changes in cognitive function in the very early stages of the disease are likely to be subtle. The overarching aim of this thesis was to investigate the relationship between a known marker of AD, Aβ amyloid, as determined by positron emission tomography (PET) neuroimaging using 11C-Pittsburgh Compound B, and decline in cognitive function as potential markers of neurodegeneration in the preclinical stages of AD. Additionally, the role of genetic polymorphisms in modifying the relationship between Aβ amyloid and cognitive decline were explored. First, the nature and magnitude of Aβ amyloid-related impairment in cognitive function was characterised cross-sectionally in both healthy older adults and adults with mild cognitive impairment (MCI). The data suggested that there were very small differences between healthy older adults with high and low levels of Aβ amyloid. Further, in adults with MCI, high Aβ amyloid was associated with a more focal impairment in episodic memory, but low Aβ amyloid was associated with additional impairments in executive function, attention and language, suggesting the presence of other underlying neurological or psychiatric processes. The relationship between Aβ amyloid and cognitive function in both healthy older adults and adults with MCI became clearer when studied prospectively. High levels of Aβ amyloid were associated with increased rates of cognitive decline, particularly in episodic memory, and this decline occurred at the same rate in both healthy older adults and in adults with MCI. High Aβ amyloid levels were also associated with higher risk of disease progression in both healthy older adults and adults with MCI. Carriage of the apolipoprotein E (APOE) ε4 allele did not moderate this relationship between Aβ amyloid and cognitive decline; although carriage of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele did. Low levels of Aβ amyloid were associated with stable cognitive function in both healthy older adults and adults with MCI, lending strength to the hypothesis that the underlying pathological process in adults with MCI and low Aβ amyloid is non-AD in nature. These findings have important implications for future clinical trials in AD as the data strongly suggest that healthy older adults with high levels of Aβ amyloid and objectively defined decline in memory are in the preclinical stages of AD, and are promising candidates for anti-amyloid therapies aimed at halting or modifying the neurodegenerative disease process in the early stages of the disease.
ItemCognitive impairment and vitamin B12Moore, Eileen Mary ( 2013)Vitamin B12 is an essential enzyme co-factor that is required for neuronal health. Vitamin B12 participates in two reactions in man, specifically; (i) the regeneration of methionine from homocysteine (Hcy), which supports cellular methylation reactions, and (ii) the re-arrangement of methylmalonic acid (MMA) to succinyl-CoA for metabolising odd-numbered fatty acids. Hcy and MMA levels are elevated in vitamin B12 deficiency (serum vitamin B12 levels <150ρmol/L). Elevated Hcy (serum level >12µmol/L) is a risk factor for cardiovascular disease (CVD) and Alzheimer’s disease (AD). Elevated MMA has been associated with a faster rate of brain volume loss and cognitive impairment. The prevalence of vitamin B12 deficiency increases in older age, and is associated with gastritis, achlorhydria, pernicious anaemia, terminal ileal resection, and use of medications that interfere with absorption. International studies have reported that deficiency amongst older adults is common; and, in over-50 year olds the prevalence is between 6.1% and 24.6%. A recent survey of over-50 year olds in Australia reported that vitamin B12 deficiency and subclinical low-normal levels (~150-250ρmol/L) were 6.3% and 29.0%, respectively. I studied vitamin B12 levels in 1,085 men and 1,125 women aged 20 to 97 years, of whom 176 (8.0%) were on vitamin B12 supplements. The age-adjusted prevalence of vitamin B12 deficiency was 3.6% amongst those who were not on vitamin B12 supplements. The prevalence of vitamin B12 deficiency rose to 5.2% in over-50 year olds, and 8.5% in over-65 year olds. The age-adjusted prevalence of subclinical low-normal vitamin B12 levels was 25.8% amongst those who were not on vitamin B12 supplements. The prevalence of subclinical low-normal vitamin B12 levels was 27.5% in over-50 year olds, and 28.7% in over-65 year olds. Vitamin B12 levels below 250ρmol/L are therefore common in a random sample of the Australian population and this is therefore likely to be the case with the population as a whole. The next objective of this study was therefore to investigate any association between serum vitamin B12 levels and neurological health. In the literature, vitamin B12 deficiency is associated with cognitive impairment. Also, subclinical low-normal serum vitamin B12 levels are reported to be associated with AD, vascular dementia, and Parkinson’s disease. In clinical trials, vitamin B12 therapy improved cognition in those who were already deficient. The lower limit of the reference range for serum vitamin B12 was originally statistically derived from a random sample of the haematologically normal adult population. The level chosen (~150ρmol/L) may not be adequate for maintaining neuronal health in later life, as AD, Parkinson’s disease, and vascular dementia have each been associated with serum vitamin B12 levels in the subclinical low-normal range. This study included 1,354 participants who had cognitive performance assessed within six months of having blood tests for serum vitamin B12 and red cell folate (RCF). Participants were recruited from four sources, namely; (i) the Prospective Research in Memory (PRIME) clinics study, (ii) the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing, (iii) patients who attended a geriatric specialist clinic in the Barwon region, or (iv) who were a patient of the Cognitive, Dementia and Memory Services (CDAMS) of the McKellar Centre between 2001 and 2011. The study group included 480 AD patients, 187 participants with mild cognitive impairment (MCI), 372 cognitively-intact participants with memory complaints, and 315 cognitively-intact participants without memory complaints. Cognitive performance was assessed by the Mini-Mental State Examination (MMSE). Participant’s cognitive performance was rated in one of four categories, namely; (i) most-impaired (MMSE <18, n=137), (ii) mildly-impaired (MMSE 18-23, n=240), (iii) minimally-impaired (MMSE 24-28, n=295), and (iv) not-impaired (MMSE >28, n=682). Annualised change in MMSE scores (ACMS) was calculated arithmetically for a sub-group of 1,307 participants who had at least two MMSE measurements taken at least six months apart. Four categories for the rate of cognitive decline were formed; (i) fast-decliners (ACMS <-3, n=119), (ii) moderate-decliners (ACMS <-1 to -3, n=233), (iii) slow-decliners (ACMS <0 to -1, n=197), and (iv) stable or improving (ACMS ≥ 0, n=758). In this study, models that were formed met the model assumptions of ordinal logistic regression (OLR). Serum vitamin B12 levels above 253ρmol/L were associated with better cognitive performance (odds ratio 1.63, 95% CI: 1.01-2.65, p-value 0.046). Very high RCF levels (>1,594nmol/L) were associated with a worse cognitive performance (odds ratio 0.57, 95% CI: 0.35-0.92, p-value 0.022). Also, each micromole per litre (µmol/L) increase in serum Hcy level was associated with a 5% increased likelihood of having a worse cognitive performance (odds ratio 0.95, 95% CI: 0.90-1.00, p-value 0.034). Serum Hcy levels >7.7µmol/L were associated with a faster rate of cognitive decline (odds ratio 0.48, 95% CI: 0.24-0.95, p-value 0.034). My findings indicate that better neurological health in later life is associated with serum vitamin B12 levels >253ρmol/L, RCF <1,594nmol/L, and serum Hcy <8.0µmol/L. Consideration should be given to revising the current reference ranges for these biochemical markers. The databases also allowed me to study the effects of other supplements. Calcium regulates neurotransmitter secretion at the synapse between neurons, so being on calcium supplements could be beneficial to cognition. Omega-3 fish oil is comprised of fatty acids that are a component of the lipid membranes in the brain. Supplementing omega-3 fatty acid levels may aid in the correct formation and repair of neuronal structures. In this study, better cognitive performance was associated with being on calcium supplements (odds ratio 1.90, 95% CI: 1.51-2.40, p-value <0.001) or omega-3 supplements (odds ratio 1.74, 95% CI: 1.26-2.41, p-value 0.001). Cognitive performance was not associated with being on vitamin E, diuretics, or proton pump inhibitors (PPI), or with having CVD, hypertension, anxiety, fractures, diverticular disease, gastro-oesophageal reflux disease (GORD), or resection of the distal ileum. A prospective, well-resourced, and sufficiently-powered intervention trial would provide further evidence for the need to revise the current reference ranges for serum vitamin B12, and to prove the efficacy of calcium and omega-3 supplements for improving cognition in later life. The rate of conversion to AD in the normal population is around 1-2%, therefore such a trial would need to recruit very large numbers (>1000) to show prevention. The latent period of effect of vitamin B12 on cognition is currently unknown. It is possible that, to be effective in preventing cognitive decline, intervention would need to commence early, in 50-60 year olds, and continue for years longer than has been studied previously. Previous studies have reported that patients with diabetes are at a greater risk for AD. In this study, cognitive performance was worse in 126 participants with diabetes compared to those without diabetes. An objective of this study was to assess whether being on metformin, or the levels of serum vitamin B12, and RCF, were associated with cognition in participants with diabetes. Metformin improves sensitivity to insulin, so is prescribed as a first line monotherapy for treating type II diabetes. In cell culture, metformin induces over-secretion of Aβ peptides, which form amyloid plaques that are in the brains of people with AD at autopsy. Also, metformin use induces vitamin B12 deficiency in up to 30% of its users via a drug interaction at the distal ileum that impedes absorption. In the literature, vitamin B12 and calcium supplements have been shown to reverse vitamin B12 deficiency induced by metformin. Better cognitive performance in participants with diabetes was associated with increasing vitamin B12 levels (p-value 0.043), decreasing RCF levels (p-value 0.025), and being on vitamin B12 supplements (odds ratio 3.40, 95% CI: 1.01-11.46, p-value 0.048). Participants with diabetes who were on calcium supplements showed a trend towards better cognitive performance, but the association did not reach significance (odds ratio 2.12, 95% CI: 0.98-4.58, p-value 0.056). Participants with diabetes who were on metformin had a worse cognitive performance than participants with diabetes who were not on metformin (odds ratio 0.45, 95% CI: 0.21-0.95, p-value 0.037). My findings indicate that worse cognition in patients with diabetes is associated with having a low serum vitamin B12 level or being on metformin. Vitamin B12 and calcium supplements are inexpensive, safe and effective; so should be considered for routine and adjunct therapy for improving the cognitive outcomes of patients with diabetes. Vitamin B12 deficiency is common; also subclinical low-normal vitamin B12 levels affect over one-quarter of adults, but are associated with cognitive impairment and a faster rate of cognitive decline. Patients with diabetes are a group with worse cognitive impairment; those on metformin may be in particular need of supplements.