Antioxidant clinical trials in mild cognitive impairment and Alzheimer's disease

Alzheimer's disease (AD) is a highly disabling progressive neurodegenerative disorder characterized by a steadily growing number of patients, by the absence of a cure for the disease and by great difficulties in diagnosing in the preclinical phase. Progresses in defining the complex etiopathogenesis of AD consider oxidative stress a core aspect as far as both AD onset and progression are concerned. However, clinical trials of antioxidants in AD have brought conflicting conclusions. In this review, we report the main results of clinical trials with antioxidants in mild cognitive impairment (MCI) and AD. Although available data do not warrant the doubtless use of antioxidants in AD, they are characterized by extremely poor comparability and the absence of a substantial clinical benefit of antioxidants in AD is not disproved to date. Furthermore, the role of vascular damage that contributes to oxidative stress in AD should be addressed in testing antioxidant treatments. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

Towards a whole-body systems [multi-organ] lipidomics in Alzheimer's disease

Preclinical and clinical evidence suggests that docosahexaenoic acid (DHA), an omega-3 fatty acid derived from diet or synthesized in the liver, decreases the risk of developing Alzheimer’s disease (AD). DHA levels are reduced in the brain of subjects with AD, but it is still unclear whether human dementias are associated with dysregulations of DHA metabolism. A systems biological view of omega-3 fatty acid metabolism offered unexpected insights on the regulation of DHA homeostasis in AD [1]. Results of multi-organ lipidomic analyses were integrated with clinical and gene-expression data sets to develop testable hypotheses on the functional significance of lipid abnormalities observed and on their possible mechanistic bases. One surprising outcome of this integrative approach was the discovery that the liver of AD patients has a limited capacity to convert shorter chain omega-3 fatty acids into DHA due to a deficit in the peroxisomal d-bifunctional protein. This deficit may contribute to the decrease in brain DHA levels and contribute to cognitive impairment.     

New approaches for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.     

Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice

Progressive memory loss and cognitive dysfunction are the hallmark clinical features of Alzheimer's disease (AD). Identifying the molecular triggers for the onset of AD-related cognitive decline presently requires the use of suitable animal models, such as the 3xTg-AD mice, which develop both amyloid and tangle pathology. Here, we characterize the onset of learning and memory deficits in this model. We report that 2-month-old, prepathologic mice are cognitively unimpaired. The earliest cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Abeta in the hippocampus and amygdala. Plaque or tangle pathology is not apparent at this age, suggesting that they contribute to cognitive dysfunction at later time points. Clearance of the intraneuronal Abeta pathology by immunotherapy rescues the early cognitive deficits on a hippocampal-dependent task. Reemergence of the Abeta pathology again leads to cognitive deficits. This study strongly implicates intraneuronal Abeta in the onset of cognitive dysfunction.     

Nerve growth factor gene delivery: animal models to clinical trials

Cell death is the final common pathway of cognitive decline in Alzheimer's disease (AD). Nervous system growth factors, or neurotrophic factors, are substances naturally produced in the nervous system that support neuronal survival during development and influence neuronal function throughout adulthood. Notably, in animal models, including primates, neurotrophic factors prevent neuronal death after injury and can reverse spontaneous neuronal atrophy in aging. Thus, neurotrophic factor therapy has the potential to prevent or reduce ongoing cell loss in disorders such as AD. The main challenge in clinical testing of neurotrophic factors has been their delivery to the brain in sufficient doses to impact cell function, while restricting their delivery to specific sites to prevent adverse effects from broad distribution. This article reviews progress in evaluating the therapeutic potential of growth factors, from early animal models to human clinical trials currently underway in AD.     

Genetic background modifies CNS‐mediated sensorimotor decline in the AD‐BXD mouse model of genetic diversity in Alzheimer's disease

Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD‐BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD‐BXDs and the relationship to cognitive decline in these mice. We found that age‐ and AD‐related declines in coordination, balance and vestibular function vary significantly across the panel, indicating genetic background strongly influences the expressivity of the familial AD mutations used in the AD‐BXD panel and their impact on motor function. Although young males and females perform comparably regardless of genotype on narrow beam and inclined screen tasks, there were significant sex differences in aging‐ and AD‐related decline, with females exhibiting worse decline than males of the same age and transgene status. Finally, we found that AD motor decline is not correlated with cognitive decline, suggesting that sensorimotor deficits in AD may occur through distinct mechanisms. Overall, our results suggest that AD‐related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease.     

Crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system: A relevance for Alzheimer's disease?

Alzheimer's disease (AD) is a neurodegenerative disorder which accounts for 60–70% of the 50 million worldwide cases of dementia and is characterised by cognitive impairments, many of which have long been associated with dysfunction of the cholinergic system. Although the M₁ muscarinic acetylcholine receptor (mAChR) is considered a promising drug target for AD, ligands targeting this receptor have so far been unsuccessful in clinical trials. As modulatory receptors to cholinergic transmission, the endocannabinoid system may be a promising drug target to allow fine tuning of the cholinergic system. Furthermore, disease-related changes have been found in the endocannabinoid system during AD progression and indeed targeting the endocannabinoid system at specific disease stages alleviates cognitive symptoms in numerous mouse models of AD. Here we review the role of the endocannabinoid system in AD, and its crosstalk with mAChRs as a potential drug target for cholinergic dysfunction.     

Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders

Neurodegenerative diseases are devastating mental illnesses without a cure. Alzheimer's disease (AD) characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. Although tremendous progress has made in understanding the basic biology in disease processes in AD and PD, we still do not have early detectable biomarkers for these diseases. Just in the United States alone, federal and nonfederal funding agencies have spent billions of dollars on clinical trials aimed at finding drugs, but we still do not have a drug or an agent that can slow the AD or PD disease process. One primary reason for this disappointing result may be that the clinical trials enroll patients with AD or PD at advances stages. Although many drugs and agents are tested preclinical and are promising, in human clinical trials, they are mostly ineffective in slowing disease progression. One therapy that has been promising is ‘stem cell therapy’ based on cell culture and pre-clinical studies. In the few clinical studies that have investigated therapies in clinical trials with AD and PD patients at stage I. The therapies, such as stem cell transplantation – appear to delay the symptoms in AD and PD. The purpose of this article is to describe clinical trials using 1) stem cell transplantation methods in AD and PD mouse models and 2) regenerative medicine in AD and PD mouse models, and 3) the current status of investigating preclinical stem cell transplantation in patients with AD and PD.     

Déficit cognitif léger : mythe ou réalité ?

The concept of mild cognitive impairment, MCI, has been proposed by Petersen and described like a state between the cognitive changes of normal aging and very early dementia. However, MCI appears to be a heterogeneous clinical syndrome in term of etiological factors, clinical patterns or clinical course. New criteria of MCI are proposed for use in clinical research. Identification of patients at risk for Alzheimer disease, AD, is an important goal. Ongoing clinical and neuroimaging (magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT),¹⁸F flouorodeoxyglucose-photo emission tomography (FDG-PET)) studies are focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to AD.     

Pharmacological therapy in Alzheimer's disease. Current clinical practice in The Netherlands

Pharmacological therapy in Alzheimer's disease. Current clinical practice in The Netherlands. Dementia affects 195,000 patients of 65 years and older in The Netherlands currently. Rivastigmine and galantamine, both cholinesterase inhibitors, and memantine, an NMDA (N-methyl-D-aspartate) antagonist, are licensed for the treatment of AD. In clinical practice, these drugs have limited effects on cognitive and other symptoms of dementia. We describe the practical care of some patients treated with these drugs and discuss the pros and cons of pharmacotherapy in AD. Extensive knowledge of the drugs, other treatment options and of dementia are necessary for good clinical practice in the treatment of these patients and the counselling of their caregivers.     

Cholinergic foundations of Alzheimer's disease therapy

Cholinesterase inhibitors (ChEI) represent the drug of choice for Alzheimer's disease (AD) treatment. They produce significant improvement on cognitive as well as non-cognitive function for a period up to 1 year during the first 3 years following clinical diagnosis. The magnitude of cognitive improvements is similar for different ChEI, however, differences are seen with regard to incidence and severity of side effects, optimal ChE inhibition, pharmacokinetic properties and mode of administration.     

The study of Alzheimer’s disease biomarkers

Alzheimer’s disease (AD) is by far the most common dementing illness of late life and is increasing with the ever-growing number of older adults, in particular, in developed countries. The disease is often referred to as the “Long-Goodbye” because the person with the illness slowly becomes lost to everyone a long time before the body finally gives out. Being able to detect AD earlier on during the course of the disease offers better prospects for the future, for AD individuals, their families and friends as well as on the economy, as a whole. Unfortunately, such a detection technique is not yet, available. However, there are a number of promising biological markers (biomarkers) that correlate well with clinical cognitive tests of individuals and/or postmortem histopathological manifestations of the disease, especially when at least two markers are used for the diagnosis. Biosensors are tools that combine a biochemical binding element to a signal conversion unit and are already being used in the study of some AD biomarkers. However, their use in clinical diagnosis remains a challenge. Introduction of nanotechnology leading to nanobiosensors has several potential advantages over other clinical and/or existing analytical tools, including increased assay speed, flexibility, reduced cost of diagnostic testing, potential to deliver molecular diagnostic tools to family general practitioners, and other health care systems. Even more important, nano-based assays have the potential to detect target proteins at attomolar concentration level. They are, therefore, being increasingly exploited for the detection of early metabolic changes associated with diseases. Because brain damage is irreversible, the use of nanotechnology is particularly important in AD and other neurodegenerative disorders. Nanosensors can also facilitate and enable pointofcare-testing (POCT). This article reviews the basic biochemical processes that lead to AD pathology, current biomarkers for AD, and the current role of nanosensor technology for the study of AD biomarkers. Furthermore, it discusses the huge potential of nanosensing to deliver new molecular diagnostic strategies to AD research.     

1-H MRS changes in dorsolateral prefrontal cortex after donepezil treatment in patients with mild to moderate Alzheimer's disease

Magnetic resonance spectroscopy (MRS) noninvasively provides information on the concentration of some cerebral metabolites in vivo. Among those measurable by proton magnetic resonance spectroscopy (1H-MRS), N-acetyl-aspartate (NAA) is decreased, and myo-inositol (ml) and choline (Cho) levels are increased in patients with Alzheimer's disease (AD). Donepezil, an acetylcholinesteraze inhibitor, has proven effect on cognitive symptoms in patients with AD. In previous studies, treatment response was associated with an increase of NAA and NAA/Cr in the parietal lobe and hippocampi. Correlation of longitudinal changes of 1H-MRS detectable metabolites in dorsolateral prefrontal cortex (DLPFC) with clinically observable changes is a poorly researched topic. The objective of this non-interventional study is to assess whether changes in 1H-MRS measurable metabolites correlate with clinical outcome after donepezil treatment. Twelve patients with mild to moderate AD were evaluated during 26 weeks of donepezil treatment. 1H-MRS parameters in DLPFC were assessed before and after 26 weeks of donepezil treatment. Cognition was assessed with Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog). A significant increase in NAA/Cr ratio and significantly lower decrease in mI/Cr ratio were found in AD patients with positive treatment response. The results of this study indicate possible modest donepezil effect on prevention of neuronal functional deterioration in DLPFC which correlates with clinical outcome and point the use of 1HMRS as technique of help in assessment of drug effect.     

The role of cholesterol in Alzheimer's neuro-pathogenesis]

Alzheimer's Disease (AD) is the most common neurodegenerative disorder in western societies affecting up to 15 million individuals worldwide.It leads to death after a progressive memory deficit and cognitive impairment accompanied by the appearance of two pathological hallmarks in specific brain areas: neurofibrillary tangles and amyloid plaques. Cholesterol homeostasis may play a key role in AD pathogenesis and this is supported by the demonstration that cholesterol-rich membrane domain, so-called Rafts,are disorganized in affected brains. Retrospective clinical studies indicate that individuals chronically treated with cholesterol synthesis inhibitors,statins, are at lower risk of developing AD but current literature is conflicting with regard to the neuroprotective effects of statins on cognitive impairment.Before recommending statins for prevention and/or treatment of AD it is important to investigate more the role of cholesterol levels in neurodegenerative disorders.     

Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

Alzheimer’s disease(AD)is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks.Diagnosis of AD is difficult,particularly in early stages of the disease,and largely consists of cognitive assessments,with only one in four patients being correctly diagnosed.Development of novel therapeutics for the treatment of AD has proved to be a lengthy,costly and relatively unproductive process with attrition rates of90%.As a result,there are no cures for AD and few treatment options available for patients.Therefore,there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications.Here,we discuss the use of induced pluripotent stem cells(iPSCs),which can be derived from adult cells,as a method of recapitulation of AD phenotype in vitro.We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy,toxicology and disease modelling.At present,a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications.However,whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field,it is one with immense potential that is likely to reach fruition within the next few years.     

Conflict of evidence: carotenoids and other micronutrients in the prevention and treatment of cognitive impairment

Cognitive impairment is a common age-related disorder which affects in the stadium and type Alzheimer's Disease (AD) a steadily growing number of patients. AD is not curable and is not being easily diagnosed in its preclinical phase. This work aims at highlighting the complex though promising rationale for the use of selected micronutrients against age-related cognitive impairment and its progression. The advances made in the last decades in both defining the etiopathogenesis of cognitive impairment and in revealing mechanisms of action underlying possible preventive effects of several vitamins and micronutrients--likely related to antioxidant activity and modulation of cellular signaling--is being accompanied by conflicting results of most clinical trials. Therefore, available data do not currently support the use of substances such as carotenoids, polyphenols, vitamin D, curcumin, vitamin E, vitamin C, or lipoic acid in AD prevention and/or treatment. This might be partly due to the fact that cognitive impairment and especially AD are extremely complex disorders. The main obstacle to the inclusion of micronutrients among anticognitive impairment drug strategies, however, is that studies conducted so far are poorly comparable and probably underestimate of the role of vascular damage in age-related cognitive impairment. A possible clinical benefit of these substances in AD is not disproved to date, thus further better designed studies are needed.     

ROCK, PAK, and Toll of synapses in Alzheimer's disease

Alzheimer’s disease is a neurodegenerative disorder where the cognitive deficit is the hallmark symptom reflecting the progression of the disease. Synaptic dysfunction is a sensitive parameter of the AD pathology. Rho GTPases and the Rho kinases, ROCK1/2, and PAK1-3, are important regulators of synaptic plasticity, especially in maintaining the actin cytoskeleton of dendritic spines. Recent studies have revealed that β-amyloid oligomers can inhibit PAK and stimulate ROCK-mediated signaling. Both of these effects enhance the disassembly of synaptic actin filaments and ultimately evoke synaptic loss. Brain tissue in AD recognizes the β-amyloid peptide oligomers as foreign protein particles and mounts an inflammatory defense via Toll-like receptor (TLR) signaling which causes synaptic impairment. We will review here the dysfunction of ROCK, PAK, and Toll signaling associated with AD pathology. The protection of synapses in AD may provide new therapeutic approaches to combatting the cognitive impairment in AD.     

Stem cell therapy for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late. Stem cells have improved characteristics of self-renewal, proliferation, differentiation, and recombination with the advent of stem cell technology and the transformation of these cells into different types of central nervous system neurons and glial cells. Stem cell treatment has been successful in AD animal models. Recent preclinical studies on stem cell therapy for AD have proved to be promising. Cell replacement therapies, such as human embryonic stem cells or induced pluripotent stem cell–derived neural cells, have the potential to treat patients with AD, and human clinical trials are ongoing in this regard. However, many steps still need to be taken before stem cell therapy becomes a clinically feasible treatment for human AD and related diseases. This paper reviews the pathophysiology of AD and the application prospects of related stem cells based on cell type.