Psychiatry - Theses

Recent developments in neuroscience have heightened the possibilities to tackle the prodromal stage of dementia. The purpose of this thesis is to identify the relationships between physical health, cognitive function, vascular risk burden and peripheral biomarker candidates in 108 older adults at risk of cognitive decline. The AIBL Active trial participants, aged 60 years and older (32 cases of MCI, 76 cases of SMC) with at least one cardiovascular risk factor present, completed a neuropsychological test battery and provided cross-sectional health data and physical activity information using a validated questionnaire and pedometer recordings. Cardiovascular parameters and blood tests determined if the participants met the clinical definition of metabolic syndrome that referred to a cluster of vascular and metabolic disturbances due to obesity and insulin resistance. This thesis utilised a preferred statistical standardisation of metabolic syndrome factors and obtained continuous variable (z-scores) to indicate the composite cardiovascular risk burden that addressed the progressive nature of the syndrome. Regression models adjusted for covariates examined the associations between the parameters and cognitive function. Almost two-thirds of participants met the national physical activity guidelines for older Australians with MCI or SMC (moderate-to-vigorous physical activity (MVPA) over 150 minutes per week), according to self-report (average 317 minutes/week). The pedometer estimated a mean of 6,926 steps/day for all participants. Participants with lower body mass index (BMI) and higher self-efficacy were 18% and 24% respectively more likely to meet the guideline recommendations. The risk severity of metabolic syndrome was inversely associated with pedometer tracked physical activity and the six-minute walk test, independent of global cognitive performance. The six-minute walk test has a stronger association with metabolic syndrome and may be a preferable assessment tool to evaluate exercise capacity compared to the timed-up-and-go test in participants at risk of cognitive decline. The metabolic syndrome components are traditional vascular and metabolic risk factors, but few cognitive studies have examined the combined risk severity. While cognitive tests scores were similar between the two groups with or without a clinical diagnosis of a metabolic syndrome, the continuous standardised z-scores for metabolic syndrome were associated with lower cognitive performance for global cognition and executive functions. Therefore, the combined risk burden (z-score) was more sensitive to cognitive associations than the presence or absence of the clinical syndrome. Multivariate regression analyses showed separate linear associations between vascular risk factors (fasting homocysteine, glucose and Framingham scores) and lower cognitive functions. The importance and originality of this thesis are that several peripheral biomarkers showed significant associations with cognition, including between increasing plasma tumour necrosis factor (TNF-alpha) and executive dysfunction and between increasing brain-derived neurotrophic factor (BDNF) and better global cognition. A model hypothesising the relationship between physical health, cognition, vascular risk factors and biomarkers is proposed. A higher cardiometabolic risk burden may point to opportunities for cognitive testing and lifestyle modification recommendation in older adults as individuals may experience cognitive changes. The findings in the peripheral biomarker analyses add to the evidence of associations between TNF-alpha, BDNF and cognitive deficits. Future longitudinal research will be needed to establish a direct link between health factors, biomarkers and cognitive decline in older adults at risk of cognitive deterioration.

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.

Psychiatry - Theses

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