Toward common mechanisms for risk factors in Alzheimer's syndrome

The global strategic goal of reducing health care cost, especially the prospects for massive increases due to expanding markets for health care services demanded by aging populations and/or people with a wide range of chronic disorders-disabilities, is a complex and formidable challenge with many facets. Current projection s predict marked increases in the demand for health driven by both the exponential climb in the prevalence of chronic disabilities and the increases in the absolute numbers of people in need of some form of health care. Thus, the looming predicament for the economics of health care systems worldwide mandates the formulation of a strategic goal to foster significant expansion of global R & D efforts to discover and develop wide-ranging interventions to delay and/or prevent the onset of chronic disabling conditions. The rationale for adopting such a tactical objective is based on the premise that the costs and prevalence of chronic disabling conditions will be reduced by half even if a modest delay of 5 years in the onset of disability is obtained by a highly focused multinational research initiative. Because of the recent history of many failures in drug trials, the central thesis of this paper is to argue for the exploration-adoption of novel mechanistic ideas, theories, and paradigms for developing wide range and/or types of interventions. Although the primary focus of our discussion has been on biological approaches to therapy, we recognize the importance of emerging knowledge on nonpharmacological interventions and their potential impact in reducing health care costs. Although we may not find a drug to cure or prevent dementia for a long time, research is starting to demonstrate the potential contributes of nonpharmacological interventions toward the economics of health care in terms of rehabilitation, promoting autonomy, and potential to delay institutionalization, thus promoting healthy aging and reductions in the cost of care

Insulin levels are decreased in the cerebrospinal fluid of women with prodomal Alzheimer's disease

Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1-42) levels and cognitive score. Furthermore, total-tau/(Aβ1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1-42 ratio for early AD diagnosis in women

Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease

In spite of the fact that cholesterol does not pass the blood-brain barrier, hypercholesterolemia has been linked to increase Alzheimer's disease (AD) risk. Hypertension is another risk factor and angiotensin converting enzyme (ACE) activity is known to be increased in AD. Furthermore, a lower incidence of AD has been reported in patients taking anti-hypertensive drugs. Here we show that the levels of angiotensinogen (AGT) and ACE are increased in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and AD. Moreover, we show ACE activity in the CSF to be positively correlated with both plasma and CSF levels of 27-hydroxycholesterol (27-OH), an oxysterol known to pass through the BBB and taken up from the circulation by the brain. In addition, treatment of rat primary neurons, astrocytes, and human neuroblastoma cells with 27-OH resulted in increased production of AGT. Our results demonstrate that upregulation of renin-angiotensin system (RAS) in AD brains occurs not only at the enzymatic level (ACE) but also at the substrate level (AGT). The possibility that 27-OH is part of a mechanism linking hypercholesterolemia with increased brain RAS activity and increased AD risk is discussed

Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration: A translatable marker of synaptic degeneration

Synapse impairment is thought to be an early event in Alzheimer's disease (AD); dysfunction and loss of synapses are linked to cognitive symptoms that precede neuronal loss and neurodegeneration. Neurogranin (Ng) is a somatodendritic protein that has been shown to be reduced in brain tissue but increased in the cerebrospinal fluid (CSF) of AD patients compared to age-matched controls. High levels of CSF Ng have been shown to reflect a more rapid AD progression. To gauge the translational value of Ng as a biomarker, we developed a new, highly sensitive, digital enzyme-linked immunosorbent assay (ELISA) on the Simoa platform to measure Ng in both mouse and human CSF. We investigated and confirmed that Ng levels are increased in the CSF of patients with AD compared to controls. In addition, we explored how Ng is altered in the brain and CSF of transgenic mice that display progressive neuronal loss and synaptic degeneration following the induction of p25 overexpression. In this model, we found that Ng levels increased in CSF when neurodegeneration was induced, peaking after 2 weeks, while they decreased in brain. Our data suggest that CSF Ng is a biomarker of synaptic degeneration with translational value

Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer's disease: a potential early sign of AD

Background: Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer's disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers.Methods: Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) (N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (Aβ42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers.Results: In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype.Conclusion: We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated.</p

Peripheral electrical stimulation in Alzheimer's Disease: A randomized controlled trial on cognition and behavior

In a number of studies, peripheral electrical nerve stimulation has been applied to Alzheimer's disease (AD) patients who lived in a nursing home. Improvements were observed in memory, verbal fluency, affective behavior, activities of daily living and on the rest-activity rhythm and pupillary light reflex. The aim of the present, randomized, placebo-controlled, parallel-group clinical trial was to examine the effects of electrical stimulation on cognition and behavior in AD patients who still live at home. Repeated measures analyses of variance revealed no effects of the intervention in the verum group (n = 32) compared with the placebo group (n = 30) on any of the cognitive and behavioral outcome measures. However, the majority of the patients and the caregivers evaluated the treatment procedure positively, and applying the daily treatment at home caused minimal burden. The lack of treatment effects calls for reconsideration of electrical stimulation as a symptomatic treatment in A

Defeating Alzheimer's disease and other dementias: a priority for European science and society

Alzheimer’s disease (AD) is the leading cause of dementia, and because the primary risk factor for AD is old age, the prevalence of the disease is increasing dramatically with ageing populations worldwide. Even in high-income countries, the cost of medical care and associated societal burdens of dementia threaten to become overwhelming as more people live into old age. In view of the lack of progress in developing a cure for AD and the rapidly increasing costs of dementia, policy makers and governments have a powerful incentive to provide more resources to develop AD therapeutics. The Lancet Neurology Commission was formed with the overarching aim to provide information and expert recommendations to policy makers and political leaders about the growing problem of AD and related dementias of ageing. The past two decades have seen remarkable improvements in the quality of care for patients with AD, with a research-driven shift to more personalised and integrated team-oriented care. Epidemiological and genetic studies have identifi ed many factors that increase the risk of AD. Prevention studies have highlighted the possibility of targeting risk and protective factors to delay onset, with the promise of reducing the overall prevalence of dementia. However, no treatment is yet available to halt or reverse the underlying pathology of established AD. Indeed, an eff ective therapy for AD is perhaps the greatest unmet need facing modern medicine. Basic biomedical research has provided insights into the causes and pathogenesis of AD and other neurodegenerative diseases, but improved understanding of disease mechanisms will be needed to develop safe and eff ective disease-modifying treatments. Nonetheless, several drugs are currently in late phases of clinical development. The Commission considered a range of challenges that need to be addressed to reduce the burden of dementia, and these challenges are discussed in detail in the main sections of our report: health economics (section 1), epidemiology (section 2), prevention (section 3), genetics (section 4), biology (section 5), diagnosis (section 6), treatment (sections 7, 8), care (section 9), and ethics (section 10). In panel 1 we summarise the key fi ndings of the Commission, with recommendations about how patient care and related research—from basic to clinical— in AD and other dementias should be organised in the future. A concerted eff ort to tackle dementia is needed, with a substantial overall increase in government and private investment in the care of patients and the search for AD therapeutics. Europe is well placed to take the world lead, in partnership with international organisations, to develop new approaches to prevent or cure AD and other dementias and to provide models of compassionate care for patients. As the cost of care increases, funds must not be shunted from basic research, clinical research, and drug-discovery programmes. In fact, a substantial increase in long-term funding for multidisciplinary research programmes is absolutely essential to reduce the burden of individual suff ering and the enormous societal cost of AD. Only targeted increases in research investment will provide any hope of fi nding a cure for AD or developing strategies to delay the onset or slow the progression of the disease

The Electroencephalogram as a Biomarker Based on Signal Processing Using Nonlinear Techniques to Detect Dementia

Dementia being a syndrome caused by a brain disease of a chronic or progressive nature, in which the irreversible loss of intellectual abilities, learning, expressions arises; including memory, thinking, orientation, understanding and adequate communication, of organizing daily life and of leading a family, work and autonomous social life; leads to a state of total dependence; therefore, its early detection and classification is of vital importance in order to serve as clinical support for physicians in the personalization of treatment programs. The use of the electroencephalogram as a tool for obtaining information on the detection of changes in brain activities. This article reviews the types of cognitive spectrum dementia, biomarkers for the detection of dementia, analysis of mental states based on electromagnetic oscillations, signal processing given by the electroencephalogram, review of processing techniques, results obtained where it is proposed the mathematical model about neural networks, discussion and finally the conclusions

Alzheimer’s disease: diagnostics, prognostics and the road to prevention

Alzheimer’s disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected worldwide prevalence of >107 million cases by 2025. While biomarkers have been identified, which may correlate with disease progression or subtype for the purpose of disease monitoring or differential diagnosis, a biomarker for reliable prediction of late onset disease risk has not been available until now. This deficiency in reliable predictive biomarkers, coupled with the devastating nature of the disease, places AD at a high priority for focus by predictive, preventive and personalized medicine. Recent data, discovered using phylogenetic analysis, suggest that a variable length poly-T sequence polymorphism in the TOMM40 gene, adjacent to the APOE gene, is predictive of risk of AD age-of-onset when coupled with a subject’s current age. This finding offers hope for reliable assignment of disease risk within a 5-7 year window, and is expected to guide enrichment of clinical trials in order to speed development of preventative medicines