Investigating a sustainable means of detecting and monitoring Alzheimer’s disease risk via non-invasive biomarkers

Compelling evidence has identified the kynurenine pathway (KP) as an avenue to predict, diagnose, and measure the progression of neurodegenerative diseases. This provides promising directions for the development of novel and precise treatment options for individuals experiencing metabolic dysregulation and cognitive challenges. However, the complex interrelationship between the KP and Alzheimer’s disease (AD) risk has not been characterised, in part due to a lack of understanding of: i) How normal KP function is characterised across the lifespan; ii) A lack of evidence from ‘at-risk’ cohorts; and iii) The heterogeneous and unvalidated methods used and the incomplete datasets available. This thesis will address these research gaps by developing and applying validated targeted metabolomics approaches to assess the diagnostic accuracy of the KP as a non-invasive biomarker for AD risk across various sample types and cohorts. Outcomes from this research aims to show or predict the relationship between the KP and AD risk. There are three aims to this thesis that will be addressed across three studies: Aim 1: Appraise and characterise the existing literature on how KP metabolites are measured and establish a set of normative data; Aim 2: Identify and develop a validated analytical method to quantify KP metabolites in the liquid biopsies of healthy adults in a range of human biofluids going beyond blood samples; and Aim 3: Analyse KP metabolites in the serum and urine of older adults at risk and not at risk of AD and assess their responsivity to treatment from clinical trial data. The overarching aim of this thesis is to profile a variety of non-invasive and minimally invasive biofluids from healthy adults across the lifespan, as well as older adults at risk of AD, to characterise the relationship between the KP and AD risk. The purpose of this is to seed new directions for pragmatic biomarker discovery in the fields of AD risk prediction and the monitoring of responsivity to treatment. As an additional note, this thesis will benefit from using analytical methods which have been objectively validated for diagnostic accuracy, and controlling for sex differences, lifestyle factors, and inter-sample variation

What we need as we get older : needs assessment for the development of a community geriatrics service in an Australian context

Background: The aim of this study was to inform the development of a Community Geriatrics Service (CGS) that addressed the healthcare and social needs of community dwelling older people in an Australian context. Methods: Stakeholders (N = 108) took part in a ‘needs assessment’ involving 30-min semi-structured interviews with general practitioners (GPs; N = 49), and three 2-h focus groups (community engagement meetings; N = 59) with older people, informal caregivers, allied healthcare workers, and nursing home directors. Data were transcribed and thematically coded, mapped to source and weighted to the frequency that the theme was raised across sources. Results: Five themes informing CGS development and delivery emerged: active health conditions (management of behavioural and psychological symptoms of dementia, falls, multimorbidity, and other relevant conditions), active social challenges (patient non-compliance, need for aged care social workers, caregiver stress, elder abuse, social isolation, and stigma), referrals (availability of specialists, communication, specialist input, and advance care directives), access (lack of transport options, and inaccessibility of local geriatrics clinics and specialists), and awareness (lack of awareness, knowledge, and resources). Conclusions: The CGS will need to address access, referral processes and health system navigation, which were perceived by stakeholders as significant challenges. These findings warrant the development of a CGS with an integrated approach to aged care, pertinent for the health and social needs of the elderly

Effects of a high-prebiotic diet versus probiotic supplements versus synbiotics on adult mental health : the "gut feelings" randomised controlled trial

Background: Preliminary evidence supports the use of dietary interventions and gut microbiota-targeted interventions such as probiotic or prebiotic supplementation for improving mental health. We report on the first randomised controlled trial (RCT) to examine the effects of a high-prebiotic dietary intervention and probiotic supplements on mental health. Methods: “Gut Feelings” was an 8-week, 2 × 2 factorial RCT of 119 adults with moderate psychological distress and low prebiotic food intake. Treatment arms: (1) probiotic supplement and diet-as-usual (probiotic group); (2) high-prebiotic diet and placebo supplement (prebiotic diet group); (3) probiotic supplement and high-prebiotic diet (synbiotic group); and (4) placebo supplement and diet-as-usual (placebo group). The primary outcome was assessment of total mood disturbance (TMD; Profile of Mood States Short Form) from baseline to 8 weeks. Secondary outcomes included anxiety, depression, stress, sleep, and wellbeing measures. Results: A modified intention-to-treat analysis using linear mixed effects models revealed that the prebiotic diet reduced TMD relative to placebo at 8 weeks [Cohen’s d = −0.60, 95% confidence interval (CI) = −1.18, −0.03; p = 0.039]. There was no evidence of symptom improvement from the probiotic (d = −0.19, 95% CI = −0.75, 0.38; p = 0.51) or synbiotic treatments (d = −0.03, 95% CI = −0.59, 0.53; p = 0.92). Improved anxiety, stress, and sleep were noted in response to the prebiotic diet while the probiotic tentatively improved wellbeing, relative to placebo. No benefit was found in response to the synbiotic intervention. All treatments were well tolerated with few adverse events. Conclusion: A high-prebiotic dietary intervention may improve mood, anxiety, stress, and sleep in adults with moderate psychological distress and low prebiotic intake. A synbiotic combination of high-prebiotic diet and probiotic supplement does not appear to have a beneficial effect on mental health outcomes, though further evidence is required. Results are limited by the relatively small sample size

Normative Data on Serum and Plasma Tryptophan and Kynurenine Concentrations from 8089 Individuals Across 120 Studies: A Systematic Review and Meta-Analysis

In this systematic review and meta-analysis, a normative dataset is generated from the published literature on the kynurenine pathway in control participants extracted from case-control and methodological validation studies. Study characteristics were mapped, and studies were evaluated in terms of analytical rigour and methodological validation. Meta-analyses of variance between types of instruments, sample matrices and metabolites were conducted. Regression analyses were applied to determine the relationship between metabolite, sample matrix, biological sex, participant age and study age. The grand mean concentrations of tryptophan in the serum and plasma were 60.52 ± 15.38 μM and 51.45 ± 10.47 μM, respectively. The grand mean concentrations of kynurenine in the serum and plasma were 1.96 ± 0.51 μM and 1.82 ± 0.54 μM, respectively. Regional differences in metabolite concentrations were observed across America, Asia, Australia, Europe and the Middle East. Of the total variance within the data, mode of detection (MOD) accounted for up to 2.96%, sample matrix up to 3.23%, and their interaction explained up to 1.53%; the latter of which was determined to be negligible. This review was intended to inform future empirical research and method development studies and successfully synthesised pilot data. The pilot data reported in this study will inform future precision medicine initiatives aimed at targeting the kynurenine pathway by improving the availability and quality of normative data

[In Press] Effect of kava (Piper methysticum) on peripheral gene expression among individuals with generalized anxiety disorder : a post hoc analysis of a randomized controlled trial

Kava is a South Pacific plant-based medicine with anxiolytic properties, but little is known about the impact kava has on gene expression or whether gene expression can serve as a marker of kava response. This study aimed to determine whether kava treatment alters the expression of genes with physiological relevance to anxiety pathophysiology and whether the baseline expression of these physiologically relevant genes modifies the efficacy of kava treatment. In this post hoc analysis, we examined the expression of 48 genes relevant to the pathophysiology of anxiety collected from a double-blind randomized controlled trial that assessed the efficacy of kava treatment in generalized anxiety disorder. Peripheral blood gene expression was measured in 71 (34 kava, 37 placebo) adults at baseline and in 40 (19 kava, 21 placebo) after 8 weeks of treatment by reverse transcription polymerase chain reaction (PCR). Results revealed that kava decreased the expression of a subunit of the GABAA-rho receptor gene (GABRR2) and catechol-O-methyltransferase (COMT), a gene related to catecholamine metabolism. Kava efficacy was not found to be modified by baseline (pretreatment) expression of relevant genes. Although these results did not withstand statistical correction for multiple comparisons and require external validation, they support the notion that kava's mechanism of action includes interaction with GABAergic and catecholaminergic systems

Assessing dietary, exercise, and non-pharmacological modalities within psychiatric hospitals

The ‘Lifestyle Medicine’ approach may offer an effective strategy for improving the outcomes of psychiatric care when used alongside conventional biological and psychotherapeutic treatments. Lifestyle interventions may also be useful in inpatient psychiatric settings, as this context provides a unique setting for adopting lifestyle changes that can be translated following discharge. While the data revealed by the small-scale feasibility studies reporting on the design and implementation of these interventions within psychiatric settings are compelling and indicative of improved patient outcomes, the strength and nature of the relationship between lifestyle factors and psychiatric care provision and outcomes remain unclear. It is strongly suggested that future research should focus on identifying any relevant organisational and programmatic challenges in psychiatric care settings, hence provide clear guidelines to enhance health-promoting behaviours and develop relevant public healthcare standards

Brain function effects of exercise interventions for cognitive decline: a systematic review and meta-analysis

IntroductionExercise is recognized as a modifiable lifestyle factor that can mitigate cognitive decline and dementia risk. While the benefits of exercise on cognitive aging have been reported on extensively, neuronal effects in adults experiencing cognitive decline have not been systematically synthesized. The aim of this systematic review was to assess the effects of exercise on cognition and brain function in people with cognitive decline associated with dementia risk.MethodA systematic search was conducted for randomized controlled trials of ≥ 4 weeks exercise (aerobic, resistance, or mind-body) that assessed cognition and brain function using neuroimaging and neurophysiological measures in people with subjective or objective cognitive decline. Study characteristics and brain function effects were narratively synthesized, while domain-specific cognitive performance was subjected to meta-analysis. Study quality was also assessed.Results5,204 records were identified and 12 unique trials met the eligibility criteria, representing 646 adults classified with cognitive frailty, mild or vascular cognitive impairment. Most interventions involved 40-minute sessions conducted 3 times/week. Exercise improved global cognition (g = −0.417, 95% CI, −0.694 to −0.140, p = 0.003, I2 = 43.56%), executive function (g = −0.391, 95% CI, −0.651 to −0.131, p = 0.003, I2 = 13.28%), but not processing speed or general short-term memory (both p >0.05). Across fMRI and ERP studies, significant neuronal adaptations were found with exercise cf. control throughout the brain and were linked with improved global cognition, memory, and executive function. Cerebral blood flow was also found to improve with 24 weeks of exercise, but was not linked with cognitive changes.DiscussionThe cognitive improvements associated with exercise are likely driven by increased metabolic activity, cerebrovascular mechanisms, and neuroplasticity throughout the brain. Our paper shows the promise in, and need for, high-quality trials integrating cognitive and brain function measures to elucidate the functional relationship between exercise and brain health in populations with a high risk of dementia.Systematic review registrationPROSPERO, identifier: CRD42022291843

Use of complementary medicines and lifestyle approaches by people living with dementia : exploring experiences, motivations and attitudes

Background: Lack of effective treatments for chronic conditions is associated with high rates of complementary medicine (CM) use. However, little is known about CM use for dementia. Aims and Objectives: The aim of this study was to explore the experiences, motivations, and attitudes towards CM use by people living with dementia in an Australian setting. Design: This study had a qualitative research design; quantitative demographic information was also collected. Methods: In-depth interviews were conducted with people living with dementia and their caregivers (N = 18). A thematic (inductive) analysis approach was taken to interpret data. Results: Three in four participants used CM for dementia, spending ~AUD$100/ month (USD$70/month). Within three overarching themes, a range of sub-themes was identified: (1) CM knowledge and use: people living with dementia and caregivers understanding of CM, types of CM used, and CM usage patterns; (2) Self-determined reasons for use/non-use: maintain or improve quality of life, hope, management of dementia symptoms, level of awareness, willingness and evidence, perceptions on efficacy and safety of CM, experiences of conventional medicine, and holistic approach to wellness; (3) External determinants of use: information on CM, relationship influences on CM use, and experiences with General Practitioners (GPs) and CM. Conclusion: Findings highlight that CM use is widespread and positively viewed by people living with dementia and their caregivers. Decisions regarding CM use were based on personal opinions. Findings have important implications for conversations with health professionals regarding CM use by people living with dementia to improve communication, health literacy, and reduce the risk of adverse effects through polypharmacy. Implications for Practice: This study showed that CM is a valued approach for dementia management by people living with dementia, their families, and healthcare providers. Future international research is required to evaluate the efficacy and safety of these approaches and promote accurate advice in nursing care