The AUstralian multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention study (AU-ARROW): A study protocol for a single-blind, multi-site, randomized controlled trial.

INTRODUCTION: The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World-Wide FINGERS (WW-FINGERS). As part of WW-FINGERS, the Australian AU-ARROW study mirrors aspects of FINGER, as well as US-POINTER. METHOD: AU-ARROW is a randomized, single-blind, multisite, 2-year clinical trial (n = 600; aged 55-79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION: The finalized AU-ARROW protocol is expected to allow development of an evidence-based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights: Study protocol for a single-blind, randomized controlled trial, the AU-ARROW Study.The AU-ARROW Study is a member of the World-Wide FINGERS (WW-FINGERS) initiative.AU-ARROW's primary outcome measure is change in a global composite cognitive score.Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests.Leading to development of an innovative treatment plan to reduce cognitive decline.

Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.

CONTEXT: In preclinical Alzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy deficit that leads to the accumulation of free radicals, which increases inflammation and damages neurons. When glucose utilization is impaired, ketone bodies offer an alternative energy source. Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue. Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy. OBJECTIVE: This systematic review and meta-analysis aims to review the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD. DATA SOURCES: A comprehensive search of electronic databases was performed on August 12, 2019, to retrieve all publications meeting the inclusion criteria. Alerts were then set to identify any publications after the search date up until January 31, 2021. DATA EXTRACTION: Data were extracted by 2 authors and assessed by a third. In total, 410 publications were identified, of which 16 (n = 17 studies) met the inclusion criteria. DATA ANALYSIS: All studies assessing change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase. Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) noncarriers (n = 2 studies). One study reported an increase in regional cerebral blood flow in APOE ε4 noncarriers and another reported an increase in energy metabolism in the brain. CONCLUSION: MCFA supplementation increases circulating ketone body levels, resulting in increased brain energy metabolism. Further research is required to determine whether this MCFA-mediated increase in brain energy metabolism improves cognition. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019146967.

Plasma metabolites associated with biomarker evidence of neurodegeneration in cognitively normal older adults.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently has no cure. Identifying biochemical changes associated with neurodegeneration prior to symptom onset, will provide insight into the biological mechanisms associated with neurodegenerative processes, that may also aid in identifying potential drug targets. The current study therefore investigated associations between plasma neurofilament light chain (NF-L), a marker of neurodegeneration, with plasma metabolites that are products of various cellular processes. Plasma NF-L, measured by ultrasensitive Single molecule array (Simoa) technology (Quanterix) and plasma metabolites, measured by mass-spectrometry (AbsoluteIDQ® p400HR kit, BIOCRATES), were assessed in the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort comprising 100 cognitively normal older adults. Metabolites belonging to biogenic amine (creatinine, symmetric dimethylarginine, asymmetric dimethylarginine; ADMA, kynurenine, trans-4-hydroxyproline), amino acid (citrulline, proline, arginine, asparagine, phenylalanine, threonine) and acylcarnitine classes were observed to have positive correlations with plasma NF-L, suggesting a link between neurodegeneration and biological pathways associated with neurotransmitter regulation, nitric oxide homoeostasis, inflammation and mitochondrial function. Additionally, after stratifying participants based on low/high brain amyloid-ß load (Aß ±) assessed by positron emission tomography, while creatinine, SDMA and citrulline correlated with NF-L in both Aß- and Aß+ groups, ADMA, proline, arginine, asparagine, phenylalanine and acylcarnitine species correlated with NF-L only in the Aß+ group after adjusting for confounding variables, suggesting that the association of these metabolites with neurodegeneration may be relevant to AD-related neuropathology. Metabolites identified to be associated with plasma NF-L may have the potential to serve as prognostic markers for neurodegenerative diseases, however, further studies are required to validate the current findings in an independent cohort, both cross-sectionally and longitudinally.

Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies.

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-ß peptide (also known as Aß or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aß peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aß.

The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men.

Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer's disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TèP), compared to baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores were observed when comparing testosterone treatment with placebo. In group B (PèT) a significant increase was observed from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment. Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo treatment. Our findings indicate a modest improvement on global cognition with testosterone treatment. Larger clinical trials with a longer follow- up and with the inclusion of blood and brain imaging markers are now needed to conclusively determine the significance of testosterone treatment.

The role of type 2 diabetes in neurodegeneration.

A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised neuropathologically by the accumulation of extracellular beta amyloid (Aß) peptide aggregates and intracellular hyper-phosphorylated tau protein, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. Although the precise mechanism remains unclear, T2D can exacerbate these neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism and CNS insulin resistance are features of both AD and T2D. Cell culture and animal studies have indicated that the early accumulation of Aß may play a role in CNS insulin resistance and impaired insulin signalling. From the viewpoint of insulin resistance and impaired insulin signalling in the brain, these are also believed to initiate other aspects of brain injury, including inflammatory and oxidative stress processes. Here we review the clinical and experimental pieces of evidence that link these two chronic diseases of ageing, and discuss underlying mechanisms. The evaluation of treatments for the management of diabetes in preclinical, and clinical studies and trials for AD will also be discussed.

Testosterone replacement therapy in older male subjective memory complainers: double-blind randomized crossover placebo-controlled clinical trial of physiological assessment and safety.

Testosterone replacement therapy (TRT) has been investigated in older men as a preventative treatment against Alzheimer's disease and dementia. However, previous studies have been contradictory. We assessed TRT physiological effects in 44 older men (aged 61 ± 7.7 years) with subjective memory complaints using a double blind, randomized, crossover, placebo-controlled study. Participants were randomized into 2 groups, one group received transdermal testosterone (50 mg) daily for 24 weeks, followed by a 4 week wash-out period, then 24 weeks of placebo; the other group received the reverse treatment. Blood evaluation revealed significant increases in total testosterone, free (calculated) testosterone, dihydrotestosterone, and a decrease in luteinizing hormone levels (p<0.001) following TRT. Although there were significant increases in red blood cell counts, hemoglobin and prostate specific antigen levels following TRT, they remained within normal ranges. No significant differences in plasma amyloid beta, estradiol, sex hormone binding globulin, insulin levels, body fat percentage, or body mass index were detected. This is the first carefully controlled study that has investigated the influence of TRT in Indonesian men on blood biomarkers linked to dementia risk. Our study suggests TRT is safe and well-tolerated in this Indonesian cohort, yet longitudinal studies with larger cohorts are needed to assess TRT further, and to establish whether TRT reduces dementia risk.

Distinct distribution of GLUT4 and insulin regulated aminopeptidase in the mouse kidney.

The physiological importance of the insulin responsive glucose transporter GLUT4 in adipocytes and muscle in maintaining glucose homeostasis is well established. A key protein associated with this process is the aminopeptidase IRAP which co-localizes with GLUT4 in specialized vesicles, where it plays a tethering role. In this study, we investigated the distribution of both GLUT4 and IRAP in the kidney to gain insights into the potential roles of these proteins in this organ. Both IRAP and GLUT4 immunostaining was observed in the epithelial cells of the proximal and distal tubules and thick ascending limbs in the cortex, but very little overlap between GLUT4 and IRAP immunoreactivity was observed. GLUT4 staining was consistent with a vesicular localization, whereas IRAP staining was predominantly on the luminal surface. In the principal cells of the inner medulla collecting duct (IMCD), IRAP immunoreactivity was detected throughout the cell, with limited overlap with the vasopressin responsive water channel aquaporin-2 (AQP-2). AQP-2 levels were observed to be two-fold higher in IRAP knockout mice. Based on our results, we propose that GLUT4 plays a role in shunting glucose across epithelial cells. In the kidney cortex, IRAP, in concert with other peptidases, may be important in the generation of free amino acids for uptake, whereas in the principal cells of the inner medulla IRAP may play a localized role in the regulation of vasopressin bioactivity.

Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting millions of people worldwide. Apart from age, the major risk factor identified so far for the sporadic form of AD is possession of the epsilon4 allele of apolipoprotein E (APOE), which is also a risk factor for coronary artery disease (CAD). Other apolipoproteins known to play an important role in CAD such as apolipoprotein B are now gaining attention for their role in AD as well. AD and CAD share other risk factors, such as altered cholesterol levels, particularly high levels of low density lipoproteins together with low levels of high density lipoproteins. Statins--drugs that have been used to lower cholesterol levels in CAD, have been shown to protect against AD, although the protective mechanism(s) involved are still under debate. Enzymatic production of the beta amyloid peptide, the peptide thought to play a major role in AD pathogenesis, is affected by membrane cholesterol levels. In addition, polymorphisms in several proteins and enzymes involved in cholesterol and lipoprotein transport and metabolism have been linked to risk of AD. Taken together, these findings provide strong evidence that changes in cholesterol metabolism are intimately involved in AD pathogenic processes. This paper reviews cholesterol metabolism and transport, as well as those aspects of cholesterol metabolism that have been linked with AD.

Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons.

Development of appropriate dendritic arbors is crucial for neuronal information transfer. We show, using seizure-related gene 6 (sez-6) null mutant mice, that Sez-6 is required for normal dendritic arborization of cortical neurons. Deep-layer pyramidal neurons in the somatosensory cortex of sez-6 null mice exhibit an excess of short dendrites, and cultured cortical neurons lacking Sez-6 display excessive neurite branching. Overexpression of individual Sez-6 isoforms in knockout neurons reveals opposing actions of membrane-bound and secreted Sez-6 proteins, with membrane-bound Sez-6 exerting an antibranching effect under both basal and depolarizing conditions. Layer V pyramidal neurons in knockout brain slices show reduced excitatory postsynaptic responses and a reduced dendritic spine density, reflected by diminished punctate staining for postsynaptic density 95 (PSD-95). In behavioral tests, the sez-6 null mice display specific exploratory, motor, and cognitive deficits. In conclusion, cell-surface protein complexes involving Sez-6 help to sculpt the dendritic arbor, in turn enhancing synaptic connectivity.

Androgens in the etiology of Alzheimer's disease in aging men and possible therapeutic interventions.

Animal experiments and cell biology studies have provided evidence that both estrogens and androgens can play a protective role against Alzheimer's disease (AD) related neurodegeneration. Males who become hypogonadal in later life often report problems with their memory. Lower than normal testosterone levels have also been detected in patients prior to the onset of AD, as well as in younger late-onset male AD patients, when compared to appropriate controls. The results of some small clinical trials suggest that testosterone can improve cognitive function in andropause. Although such improvement in cognitive function is subtle, patients on testosterone replacement therapy have reported memory improvements in both declarative and procedural domains. In contrast, there is no clinical evidence to date which suggest that the hormone dihydroepiandrosterone (DHEA) can improve cognitive function. Rises in the levels of the gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), have been associated with AD, but the clinical effects of reducing their levels remain to be determined. We hypothesize that androgens, gonadotropin modulators, or perhaps selective androgen receptor modulators may be useful components of therapy aimed at preventing the onset or delaying the progression of AD in male patients.

Reproductive hormones modulate oxidative stress in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by gradual cognitive decline, impairments in speech and language, and dysfunction in the sensorimotor systems, culminating in complete reliance on nursing care. Oxidative stress, caused by an imbalance in the pro-oxidant/antioxidant mechanisms in the body, has been implicated in AD pathogenesis, as in many other age-associated diseases such as atherosclerosis, Parkinson disease, and amyotrophic lateral sclerosis. Although the hormones estrogen, progesterone, testosterone, and luteinizing hormone are best known for their roles in reproduction, many studies show these hormones have other roles, including neuroprotection. Changes in the levels of these hormones that occur in reproductive senescence are hypothesized to increase risk of AD, as a result of reduced protection against oxidative insults. The Abeta peptide, overproduction of which is thought to be a key pathogenic event in the development of AD, is neurotoxic, most likely due to its ability to promote oxidative stress. The reproductive hormones are known to influence Abeta metabolism, and this review discusses the beneficial and detrimental effects these hormones have on Abeta production and oxidative stress, and their relevance in potential AD therapies.