Common Versus Uncommon Causes of Dementia

When patients present with a dementia syndrome at a young age, the experienced clinician will automatically include uncommon dementias in the diagnostic considerations, as familial uncommon dementias due to genetic mutations frequently present as early-onset dementias. This paper highlights why uncommon dementias due to genetic mutations, although marginal in terms of prevalence numbers in the total population, are of significance in the quest to unravel the underlying cause of common dementias such as Alzheimer\u27s disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementias (FTD) and vascular dementia (VaD)

PRKAG2 gene expression is elevated and its protein levels are associated with increased amyloid-β accumulation in the Alzheimer’s Disease brain

Increased amyloid-β (Aβ) accumulation associated with abnormal autophagy-lysosomal activity and nutrient kinase dysregulation are common features in Alzheimer’s disease (AD) brain. Recent studies have identified PRKAG2 and TIPRL genes that control nutrient kinase regulated autophagy, and here we determined if their expression is altered in postmortem AD brains. Gene and protein expression of TIPRL were unchanged. However, gene expression of PRKAG2 was increased 3-fold and its protein levels positively correlated with Aβ accumulation in the AD brain. In summary, our findings suggest that increased PRKAG2 is an important contributing factor to Aβ accumulation in the AD brain

A rapid absorbance-based growth assay to screen the toxicity of oligomer Aβ42 and protect against cell death in yeast

Multiple lines of evidence show that soluble oligomer forms of amyloid β protein (Aβ42) are the most neurotoxic species in the brain and correlates with the degree of neuronal loss and cognitive deficit in Alzheimer\u27s disease. Although many studies have used mammalian cells to investigate oligomer Aβ42 toxicity, the use of more simple eukaryotic cellular systems offers advantages for large-scale screening studies. We have previously established and validated budding yeast, Saccharomyces cerevisiae to be a simple and a robust model to study the toxicity of Aβ. Using colony counting based methods, oligomeric Aβ42 was shown to induce dose-dependent cell death in yeast. We have adapted this method for high throughput screening by developing an absorbance-based growth assay. We further validated the assay with treatments previously shown to protect oligomer Aβ42 induced cell death in mammalian and yeast cells. This assay offers a platform for studying underlying mechanisms of oligomer Aβ42 induced cell death using gene deletion/overexpression libraries and developing novel agents that alleviate Aβ42 induced cell death. © 2020 Neural Regeneration Research. All rights reserved

Impact of aging on the auditory system and related cognitive functions: A narrative review

Age-related hearing loss (ARHL), presbycusis, is a chronic health condition that affects approximately one-third of the world’s population. The peripheral and central hearing alterations associated with age-related hearing loss have a profound impact on perception of verbal and non-verbal auditory stimuli. The high prevalence of hearing loss in the older adults corresponds to the increased frequency of dementia in this population. Therefore, researchers have focused their attention on age-related central effects that occur independent of the peripheral hearing loss as well as central effects of peripheral hearing loss and its association with cognitive decline and dementia. Here we review the current evidence for the age-related changes of the peripheral and central auditory system and the relationship between hearing loss and pathological cognitive decline and dementia. Furthermore, there is a paucity of evidence on the relationship between ARHL and established biomarkers of Alzheimer’s disease, as the most common cause of dementia. Such studies are critical to be able to consider any causal relationship between dementia and ARHL. While this narrative review will examine the pathophysiological alterations in both the peripheral and central auditory system and its clinical implications, the question remains unanswered whether hearing loss causes cognitive impairment or vice versa

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

Multiple effects of physical activity on molecular and cognitive signs of brain aging: can exercise slow neurodegeneration and delay Alzheimer\u27s disease?

Western countries are experiencing aging populations and increased longevity; thus, the incidence of dementia and Alzheimer\u27s disease (AD) in these countries is projected to soar. In the absence of a therapeutic drug, non-pharmacological preventative approaches are being investigated. One of these approaches is regular participation in physical activity or exercise. This paper reviews studies that have explored the relationship between physical activity and cognitive function, cognitive decline, AD/dementia risk and AD-associated biomarkers and processes. There is now strong evidence that links regular physical activity or exercise to higher cognitive function, decreased cognitive decline and reduced risk of AD or dementia. Nevertheless, these associations require further investigation, more specifically with interventional studies that include long follow-up periods. In particular, relatively little is known about the underlying mechanism(s) of the associations between physical activity and AD neuropathology; clearly this is an area in need of further research, particularly in human populations. Although benefits of physical activity or exercise are clearly recognised, there is a need to clarify how much physical activity provides the greatest benefit and also whether people of different genotypes require tailored exercise regimes.Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.162

Sirtuin-1 mediates the obesity induced risk of common degenerative diseases: Alzheimer\u27s disease, coronary artery disease and type 2 diabetes

Obesity, especially at mid-life, is a major risk factor for atherosclerosis, insulin resistance and the metabolic syndrome, which in turn contrib- ute to coronary artery disease (CAD), Type 2 diabetes and Alzheimer’s disease (AD). The rise in overweight and obesity in all societies is prompting intense research into the causes and effects of the condition. Obesity disrupts many body systems including glucose and lipid me- tabolism, circadian rhythms and liver function. It also causes or increases inflammation and oxi- dative stress. Within cells, the endoplasmic re- ticulum (ER) appears to be particularly suscep- tible to such metabolic disruption. Sirtuin 1 (Sirt1) and leptin have received attention recently as they are central regulatory factors for the body’s metabolic pathways which interact at particular levels, for example lipid and Abeta metabolism. This mini-review discusses recent findings con- cerning obesity, lipid metabolism and the role of Sirtuin 1 and how all influence the ER. A greater understanding of obesity and its effects on me- tabolic control systems of the body are required, to develop pharmacological, dietary and lifestyle changes that will reduce the incidence of CAD, Type 2 diabetes and AD

Multiplex biomarkers in blood

Advances in the field of blood biomarker discovery will help in identifying Alzheimer\u27s disease in its preclinical stage, allowing treatment to be initiated before irreversible damage occurs. This review discusses some recent past and current approaches being taken by researchers in the field. Individual blood biomarkers have been unsuccessful in defining the disease pathology, progression and thus diagnosis. This directs to the need for discovering a multiplex panel of blood biomarkers as a promising approach with high sensitivity and specificity for early diagnosis. However, it is a great challenge to standardize a worldwide blood biomarker panel due to the innate differences in the population tested, nature of the samples and methods utilised in different studies across the globe. We highlight several issues that result in the lack of reproducibility in this field of research currently faced by researchers. Several important measures are summarized towards the end of the review that can be taken to minimize the variability among various centres

The acceleration of aging and Alzheimer’s disease through the biological mechanisms behind obesity and type II diabetes

The incidence of diabetes is predicted to increase to 21% by 2050. Currently, one third of US adults are obese and over 11% of these individuals have diabetes. Due to the growing need for therapeutic intervention to control and/or stabilize this increase in the incidence of diabetes in Western communities, gaining a comprehensive understanding of the association between obesity and Type 2 diabetes has become increasingly important to diabetes research. The increased cell senescence associated with diabetes has been associated with the limited ability of cells to divide, with indication of telomere shortening and genomic instability of the cells. Obese individuals have shorter telomeres suggesting an inverse relationship between adiposity and telomere length. The implication that Type 2 diabetes has on biological aging is of particular interest since telomere shortening in obesity and diabetes has been associated with an early risk for dementia and even progression to Alzheimer’s disease (AD). Lifestyle, nutrition and longevity are closely related and cellular senescence has been associated with telomere shortening and connected to longevity. Diet, cholesterol lowering drugs and exercise that control food intake and glucose tolerance in aging and diabetic individuals, via connections between liver circadian clocks and the suprachiasmatic nucleus in the brain, also have been shown to alter telomere lengths. Lifestyle interventions, such as diets low in fat and exercise, target the rise in obesity and associated telomere shortening by delaying or preventing the onset of Type 2 diabetes. The implementation of these anti-aging therapies early in life may prevent calorie overload and activation of calorie sensitive genes such as Sirtuin 1 (Sirt1). This may maintain telomere length and the control of obesity, which is linked to cardiovascular disease, diabetes and accelerates aging and AD