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4.
Alzheimers Dement ; 16(11): 1481-1482, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33179841
6.
Int J Stroke ; : 1747493019871915, 2019 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-31543058

RESUMEN

The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action. © 2019 the Alzheimer's Association and the World Stroke Organisation. Published by Elsevier Inc. All rights reserved.

8.
Alzheimers Dement ; 15(7): 961-984, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31327392

RESUMEN

The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.


Asunto(s)
Fibrilación Atrial/diagnóstico , Encéfalo/fisiopatología , Demencia/prevención & control , Hipertensión/diagnóstico , Accidente Cerebrovascular/prevención & control , Fibrilación Atrial/tratamiento farmacológico , Barrera Hematoencefálica , Trastornos Cerebrovasculares/fisiopatología , Demencia/epidemiología , Salud Global , Humanos , Hipertensión/tratamiento farmacológico , Incidencia , Accidente Cerebrovascular/epidemiología
9.
Brain ; 141(7): 1917-1933, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29850777

RESUMEN

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-ß proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Neuronas Colinérgicas/fisiología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Colinérgicos/metabolismo , Colinérgicos/uso terapéutico , Neuronas Colinérgicas/metabolismo , Inhibidores de la Colinesterasa/metabolismo , Cognición/fisiología , Trastornos del Conocimiento/etiología , Humanos , Ovillos Neurofibrilares/metabolismo
12.
Alzheimers Dement (N Y) ; 3(4): 571-578, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29124116

RESUMEN

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 projections 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.

13.
Alzheimers Dement ; 2017 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-29028480

RESUMEN

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

15.
Alzheimers Dement ; 12(9): 1014-1021, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27238630

RESUMEN

Massive investment and technological advances in the collection of extensive and longitudinal information on thousands of Alzheimer patients results in large amounts of data. These "big-data" databases can potentially advance CNS research and drug development. However, although necessary, they are not sufficient, and we posit that they must be matched with analytical methods that go beyond retrospective data-driven associations with various clinical phenotypes. Although these empirically derived associations can generate novel and useful hypotheses, they need to be organically integrated in a quantitative understanding of the pathology that can be actionable for drug discovery and development. We argue that mechanism-based modeling and simulation approaches, where existing domain knowledge is formally integrated using complexity science and quantitative systems pharmacology can be combined with data-driven analytics to generate predictive actionable knowledge for drug discovery programs, target validation, and optimization of clinical development.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Modelos Neurológicos , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Simulación por Computador , Bases de Datos Factuales , Descubrimiento de Drogas/métodos , Humanos
17.
Methods Mol Biol ; 1303: 49-67, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26235059

RESUMEN

This chapter questions the prevailing "implicit" assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer's disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer's disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer's disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid-beta (Aß) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD.


Asunto(s)
Enfermedad de Alzheimer , Progresión de la Enfermedad , Biología de Sistemas/métodos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Humanos , Estudios Longitudinales , Proteómica
20.
Mol Aspects Med ; 43-44: 3-15, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26054567

RESUMEN

There exist many challenges hampering the discovery and development of effective interventions to prevent dementia. Three major trends have now intersected to influence the emerging interest in disease modifying therapies that may delay or halt dementia. The three crucial factors shaping this current focus are: (1) the emergence of the longevity revolution and the impact of a aging society, (2) the effects of the US Federal investment in research in advancing knowledge about the neurobiology of aging and dementia, and (3) the problem of US legislators and health policy makers to balance the allocation of evermore scarce research funding resources. The purpose of this essay is to provide a survey of the politics of science and to describe efforts to correctly manage the high level of expectations of both the patient and research communities. The perspective offered reviews the history and evolution of the ideas to treat or prevent dementia and Alzheimer's disease as a national strategic goal. The aim is to evaluate the interplay between science and formulation of public policy for setting research priority. We use the history of developing US National Institute of Aging's extramural research programs on brain aging and Alzheimer's disease (Khachaturian, 2006; 2007) as an initial case study.


Asunto(s)
Enfermedad de Alzheimer/epidemiología , Demencia/epidemiología , Política de Salud , Envejecimiento , Enfermedad de Alzheimer/patología , Investigación Biomédica , Demencia/patología , Humanos
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