Young blood products:emerging treatment for Alzheimer's disease?

Alzheimer's disease is the most common neurodegenerative disorder and no disease-modifying treatment is currently available.Research has shown that while brain neurogenesis continues in adult life,it declines with age.Using parabiosis,plasma transfusions and direct administration of neural growth factors,animal studies have demonstrated the positive impact of exposure to young blood products on neurogenesis and synaptic plasticity in an aging brain.The hippocampus and the sub-ventricular zones were identified as the main regions affected.Promising findings have prompted researchers to experiment their effects in subjects with an established neurocognitive disorder,such as Alzheimer's disease.They argued that modification of brain vasculature,reactivation of adult neural stem cells,and remodeling of their synaptic activity/plasticity may lead to cognitive enhancement and increased neurogenesis.One pilot human study found that young donor plasma infusion protocols for adults with Alzheimer's disease were safe and feasible;however,no statistically significant improvements in cognition were detected.There is a need to conduct additional placebo-controlled human studies in larger samples.Future studies should focus on identifying an optimal age at which an intervention in humans may yield significant cognitive enhancement,as well as determining the types of transfusions with the best efficacy and tolerability profiles.     

Is inhibition of the renin–angiotensin system a new treatment option for Alzheimer's disease?

Findings from longitudinal and cross-sectional studies suggest an association between high blood pressure and dementia, and in turn the use of antihypertensives has been suggested to reduce incidence of dementia. Alzheimer's disease, the most common cause of dementia, is characterised in part by the deposition of amyloid beta protein (Abeta) in the brain. Reduction of Abeta load is now a major therapeutic strategy. In recent years the renin-angiotensin system, already of recognised importance in the pathogenesis of hypertension, has become a source of interest in the pathogenesis of Alzheimer's disease. This review explores molecular, genetic, and clinical studies that might help explain the relation between the renin-angiotensin system, hypertension, and Alzheimer's disease and whether treatment with angiotensin converting enzyme (ACE) inhibitors and similar treatment strategies have a part to play in the management of the disease.     

Can we do better in developing new drugs for Alzheimer's disease?

The past 30 years have seen multiple attempts at demonstrating the safety and efficacy of drugs for Alzheimer's disease (AD), predominantly to improve symptoms. Only five drugs (tacrine, donepezil, rivastigmine, galantamine, memantine) have obtained regulatory approval in most countries. Their cost-effectiveness from a societal perspective has not been universally recognized, and anybody who thinks these drugs are useful for individual patients will have to agree that the improvement above the starting point of treatment is moderate. Most of the benefit has been in slowing down progression of symptoms rather than a readily detectable improvement above baseline. There have also been attempts at arresting progression of AD, but all have failed until now. Should we change our approach to developing new drugs for AD so as to move forward? This review will highlight some options to consider in the development of future drugs for AD, with emphasis on strategies to prevent AD or arrest its progression.     

Resveratrol--a boon for treating Alzheimer's disease?

Resveratrol, a red wine polyphenol, is known to protect against cardiovascular diseases and cancers, as well as to promote antiaging effects in numerous organisms. It also modulates pathomechanisms of debilitating neurological disorders, such as strokes, ischemia, and Huntington's disease. The role of resveratrol in Alzheimer's disease is still unclear, although some recent studies on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of Alzheimer's disease pathology. Emerging literature indicates that mechanisms of aging and Alzheimer's disease are intricately linked and that these mechanisms can be modulated by both calorie restriction regimens and calorie restriction mimetics, the prime mediator of which is the SIRT1 protein, a human homologue of yeast silent information regulator (Sir)-2, and a member of NAD+-dependent histone deacetylases. Calorie restriction regimens and calorie restriction-mimetics trigger sirtuins in a wide variety of organisms, ranging from bacteria to mouse. In a mouse model of Huntington's disease, resveratrol-induced SIRT1 was found to protect neurons against ployQ toxicity and in Wallerian degeneration slow mice, resveratrol was found to protect the degeneration of neurons from axotomy, suggesting that resveratrol may possess therapeutic value to neuronal degeneration. This paper mainly focuses on the role of resveratrol in modulating AD pathomechanisms.     

Why do so many drugs for Alzheimer's disease fail in development? Time for new methods and new practices?

Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.     

Employing new cellular therapeutic targets for Alzheimer's disease: a change for the better?

Alzheimer's disease is a progressive disorder that results in the loss of cognitive function and memory. Although traditionally defined by the presence of extracellular plaques of amyloid-beta peptide aggregates and intracellular neurofibrillary tangles in the brain, more recent work has begun to focus on elucidating the complexities of Alzheimer's disease that involve the generation of reactive oxygen species and oxidative stress. Apoptotic processes that are incurred as a function of oxidative stress affect neuronal, vascular, and monocyte derived cell populations. In particular, it is the early apoptotic induction of cellular membrane asymmetry loss that drives inflammatory microglial activation and subsequent neuronal and vascular injury. In this article, we discuss the role of novel cellular pathways that are invoked during oxidative stress and may potentially mediate apoptotic injury in Alzheimer's disease. Ultimately, targeting new avenues for the development of therapeutic strategies linked to mechanisms that involve inflammatory microglial activation, cellular metabolism, cell-cycle regulation, G-protein regulated receptors, and cytokine modulation may provide fruitful gains for both the prevention and treatment of Alzheimer's disease.     

Colonic diverticular disease: A new risk factor for Parkinson's disease?

BackgroundColonic diverticular disease is a chronic gastrointestinal disorder. Previous studies have suggested that chronic gastrointestinal tract is involved in the pathophysiology of Parkinson's disease.ObjectThis study investigated the potential link between colonic diverticular disease and risk of Parkinson's disease.MethodsData in this nationwide population-based cohort study were obtained from the National Health Insurance Research Database. Patients with colonic diverticular disease were identified from among 23.22 million insured Taiwanese residents who had been diagnosed between 2000 and 2005 and were aged ≥20 years (n = 23367). The comparison cohort included patients without colonic diverticular disease, matched by sex, age, and all comorbidities with the colonic diverticular disease patients cohort (n = 23367). Using univariable and multivariable Cox proportional hazard regression models, we estimated the adjusted hazard ratio (aHR) for PD with a 95% confidence interval (CI) after adjusting for age, sex, and all of comorbidities.ResultsThe risk of Parkinson's disease was higher in the CDD cohort than in the comparison cohort (HR = 1.27, 95%CI = 1.10–1.47). Compared with patients aged ≥65 years without CDD, the CDD patients in the equal age group had a 1.25-fold increased risk of PD (95% CI = 1.07–1.46).ConclusionColonic diverticular disease may be associated with an increased risk of Parkinson's disease. Thus, the risk of this neurodegenerative disease should be considered in patients with colonic diverticular disease.     

GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer's disease?

Alzheimer's disease (AD) is the most common form of dementia affecting more than 15 millions individuals worldwide. While the cause is unknown, there are two major neuropathological abnormalities present in the brains of patients with AD, the extracellular senile plaques and the intracellular neurofibrillary tangles. There is strong evidence that glycogen synthase kinase-3 (GSK-3) plays an important role in AD being involved in the regulation of these neuropathological hallmarks. Increased activity and/or overexpression of this enzyme in AD is associated with increased tau hyperphosphorylation and alterations in amyloid-beta processing that are thought to precede the formation of neurofibrillary tangles and senile plaques, respectively. Furthermore, over activity of GSK-3 is also involved in neuronal loss. These data clearly identify GSK-3 inhibitors as one of the most promising new approaches for the future treatment of AD and a reduction of the aberrant over activity of this enzyme might decrease several aspects of the neuronal pathology in AD. In this review, we provide an overview of the rationale for the development of GSK-3 inhibitors for the treatment of AD, discussing the risks and benefits of this approach.     

Is hemochromatosis a risk factor for Alzheimer's disease?

Excess iron accumulation in the brain is a consistent observation in Alzheimer's Disease. Iron affects amyloid precursor protein (AbetaPP) processing and promotes deposition of Abeta. Iron is also among the most potent biological toxins because of its ability to react with oxygen to form reactive oxygen species. Consequently, elucidation of the mechanisms associated with maintaining brain iron homeostasis is fundamentally important to understanding the underlying pathogenesis in AD. The iron overload disorder, Hemochromatosis, is the most common genetic disorder (1:200) so a significant percentage of AD patients can be expected to carry this mutation. Heterozygotes for this mutation also have an increased, but sub-clinical iron burden. Given the high percentage of the population who are at significant risk for iron overload, we propose that the hemochromatosis mutation be considered as a confounding factor when evaluating the contribution of genetic associations with AD and treatment strategies and efficacy. Two recent papers and new evidence presented here that the protein associated with hemochromatosis is expressed on blood vessels, choroid plexus and the ependymal cells in the brain are offered as support for this proposal.     

Direct oral anticoagulants: a new therapy against Alzheimer's disease?

正More than 40 million people worldwide are thought to be affected by Alzheimer's disease(AD).Of these,estimated less than10% develop symptoms usually well before the age of 65,due to familial(hereditary) AD predisposition(Sierksma et al.,2020).AD is a multifactorial disorder,which includes a multitude of progressive degenerations in the brain parenchyma,but also in the vascular and hemostatic system.Currently,     

Adult ADHD: A new disease?

Objectives: Until recently, it was believed that attention deficit and hyperactivity disorder (ADHD) are outgrown by the end of adolescence and the beginning of adulthood. The purpose of this review is to describe the characteristics of the disease in adults, depict comorbidities that accompany it, and expand the scope over methods of diagnosis and treatment of these ages. Methods: A search was conducted in the PubMed/MEDLINE database for relevant key words ‘ADHD’, ‘attention deficit’, ‘hyperactivity’ and ‘adult’. Secondary search parameters were ‘comorbid’, ‘prevalence’, ‘epidemiology’, ‘therapy’ and ‘drug therapy’. Search was limited to ‘English’ and ‘Humans’. Results: Over the years, the persistent nature of the disorder has been clarified, elucidating prevalence rate, gender differences and subtype shifts among adult ADHD population. Nevertheless, even today, there is only limited awareness of the existence of the disorder across one's lifespan, its consequences and the appropriate treatment. Conclusions: Our results emphasise the growing awareness of adult psychosocial impairments due to ADHD symptoms and comorbidities, as well as the need for further collaboration among practitioners and mental health-care professionals to better identify the condition and allow for effective treatment.