Volume 12, Number 1, September 2007 - Special Issue "The Multifaceted Aspects of Alzheimer's Disease: From Social to Molecular Problems" (Guest Editor: Patrizia Mecocci)

Page 1
Patrizia Mecocci
Preface: The Multifaceted Aspects of Alzheimer's Disease: From Social to Molecular Problems

Pages 3-9
Robert H. Binstock
Our Aging Societies: Ethical, Moral, and Policy Challenges
Abstract: The aging of industrialized nations poses grave ethical, moral, and policy challenges for health professionals and our societies. The demand for both acute and long-term health care for the elderly will increasingly strain the economic resources of older persons and our nations. These pressures generate a number of difficult issues for our aging societies. Three of the most important issues are: (1) How aggressive should curative medical treatment be for severely demented patients?; (2) How should the financial burden of long-term care be distributed between the public and private sectors?; (3) Should public policies establish old-age-based limits on acute medical care in order to conserve resources? These issues are complex, of great importance, and require substantial reflection and discussion by health care professionals and the public at-large.

Pages 11-22
Laura Fratiglioni, Hui-Xin Wang
Brain reserve hypothesis in dementia
Abstract: The concept of brain reserve refers to the ability to tolerate the age-related changes and the disease related pathology in the brain without developing clear clinical symptoms or signs. A considerable body of biological research has documented that a number of factors including education, work complexity, social network, and leisure activities may contribute to this reserve allowing cognitive function to be maintained in old ages. Epidemiological studies have also related these factors to the development of dementia, suggesting that intellectual challenges experienced across the whole life span may increase the brain reserve and be crucial for the occurrence of dementia symptoms in late life. This paper is a systematic review of the published epidemiological studies on this topic. The availability of numerous epidemiological and biological data investigating the reserve hypothesis in dementia permits some preliminary conclusions. High education, adult-life occupational work complexity, as well as a mentally and socially integrated lifestyle in late life could postpone the onset of clinical dementia and AD. The relevance of physical activity itself remains in debate, as most physical activities include also social and mental stimulation. Leisure activities with all three components - physical, mental and social - seem to have the most beneficial effect. Delaying dementia onset by five years would halve dementia prevalence and substantially decrease the number of dementia cases in the community.

Pages 23-35
Elena Mariani, Roberto Monastero, Patrizia Mecocci
Mild Cognitive Impairment: A Systematic Review
Abstract: MCI is a nosological entity proposed as an intermediate state between normal aging and dementia. The syndrome can be divided into two broad subtypes: amnestic MCI (aMCI) characterized by reduced memory, and non-amnestic MCI (naMCI) in which other cognitive functions rather than memory are mostly impaired. aMCI seems to represent an early stage of AD, while the outcomes of the naMCI subtypes appear more heterogeneous -including vascular dementia, frontotemporal dementia or dementia with Lewy bodies- but this aspect is still under debate. MCI in fact represents a condition with multiple sources of heterogeneity, including clinical presentation, etiology, and prognosis. To improve classification and prognosis, there is a need for more sensitive instruments specifically developed for MCI as well as for more reliable methods to determine its progression or improvement. Current clinical criteria for MCI should be updated to include restriction in complex AD; also the diagnostic and prognostic role of behavioral symptoms and motor dysfunctions should be better defined. A multidisciplinary diagnostic approach including biological and neuroimaging techniques may probably represent the best option to predict the conversion from MCI to dementia. In this review we discuss the most recent aspects related to the epidemiological, clinical, neuropathological, neuroimaging, biochemical and therapeutic aspects of MCI, with specific attention to possible markers of conversion to dementia.

Pages 37-52
Ezio Giacobini, Robert E. Becker
One hundred years after the discovery of Alzheimer's disease: A turning point for therapy?
Abstract: Following the introduction of cholinesterase inhibitors in 1986 and a 20-yr long period of successful clinical application in mild, moderate and severe patients, the treatment of AD has turned to modify the course of pathological processes thought to comprise the disease. Several active and passive vaccines are presently under investigation for efficacy, reducing beta-amyloid in the brain of patients with mild-moderately advanced disease. Three large international immunization trials are in progress in US and Europe on mild-moderate AD patients. Among these, the most advanced trial in time is the humanized antibody trial. In addition, drugs aiming to reduce tau phosphorylation (GSK3 inhibitors) are about to enter clinical phases of development. Due to intrinsic difficulties, the developments of gamma-and beta-secretase inhibitors have not yet reached clinical stages. Only one anti-amyloid-aggregation, an aminoglycan compound, and one anti-APO-E approach with rosiglitazone are currently in clinical testing. Stem-cell therapy and gene-replacing therapy remain experimental and far from clinical application. Based on experimental evidence that NGF (nerve growth factor) treatment could provide prolonged protection of the central cholinergic system , i.c.v. infusion of NGF , with genetically modified fibroblasts or gene therapy are under current investigation. NGF treatment could probably double the clinical effect of ChEIs in time. Given the level of scientific and clinical activity it is reasonable to expect that within the next five to ten years a new therapy for AD will, by blocking disease progression, both produce long term stabilization of at least 5 years in patients with AD and prevent or delay emergence in persons at risk for AD.

Pages 53-59
Clive Ballard, Susanne Sorensen, Samantha Sharp
Pharmacological Therapy for People with Alzheimer's Disease: The Balance of Clinical Effectiveness, Ethical Issues and Social and Healthcare Costs
Abstract: The drive for evidence based practice and cost-effective use of pharmacological therapies has advantages, but can also be problematic. These difficulties are particularly challenging in the context of long-term conditions, such as Alzheimer's disease. The complexity of the illness, the variable and complex pattern of service use and the difficulty of conducting long term clinical trials are extremely difficult to factor into a meaningful cost effectiveness model. In Alzheimer's disease, the additional impact on caregivers as well as the person with dementia should be considered. In the current article we give a brief overview of the clinical effectiveness of cholinesterase inhibitors for the treatment of Alzheimer's disease, discuss in detail the NICE appraisal of these treatments in the UK as a example of an attempt at a standardised evaluation of cost-effectiveness and discuss a proposed way forward to achieve a unified and consistent approach to the assessment of cost-effectiveness for anti-dementia therapies.

Pages 61-72
D. Allan Butterfield, Rukhsana Sultana 
Redox proteomics identification of oxidatively modified brain proteins in Alzheimer’s disease and mild cognitive impairment:  insights into the progression of this dementing disorder
Abstract: Alzheimer disease is a common age-related neurodegenerative disease characterized pathologically by senile plaque, neurofibrillary tangles, synaptic disruption, and progressive neuronal deficits. The senile plaques contain Abeta (1-42) and Abeta (1-40), that has been shown by a number of laboratories to induce oxidative stress and as well as neurodegeneration, although the exact mechanisms remained to be defined. Our laboratory showed an increased oxidative stress in AD and MCI brain as indexed by protein oxidation and lipid peroxidation. In the present review, we summarized our finding of oxidatively modified proteins using redox proteomics approach in AD and MCI brain to investigate the mechanism that may be involved in MCI and AD pathogenesis and discussed our finding in terms of AD progression and pathogenesis.

Pages 73-92
Alessandro Serretti, Paolo Olgiati, Diana De Ronchi
Genetics of Alzheimer's disease. A rapidly evolving field
Abstract: Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to the beta amyloid deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNFalpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environment factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs.

Pages 93-99
Cristina Lanni, Daniela Uberti, Marco Racchi, Stefano Govoni, Maurizio Memo
Unfolded p53: A potential biomarker for Alzheimer's disease
Abstract: The identification of biological markers of AD can improve diagnostic accuracy and therapy follow-up as well as provide information on the pathogenesis of the disease. We recently found that fibroblasts derived from AD patients expressed an altered conformational status of p53 and were less sensitive to p53-dependent apoptosis compared to fibroblasts from non-AD subjects. When investigating the mechanism of such alteration, we found that the exposure to nanomolar concentrations of amyloid-β (Aβ) 1-40 peptide induced the expression of an unfolded p53 protein isoform in fibroblasts derived from non-AD subjects. These data suggest that the tertiary structure of p53 and the sensitivity to p53-dependent apoptosis is influenced by low concentrations of soluble Aβ. On this basis, we hypothesized that low amounts of soluble Aβ induce early pathological changes at cellular level that may precede the amyloidogenic cascade. One of these changes is the induction of a novel conformational state of p53. If low amounts of Aβ peptide, not resulting in cytotoxic effects, are responsible for p53 structure changes, it could be possible to consider the unfolded p53 both as an agent participating to the early pathogenesis and as a specific marker of the early stage of AD.

Pages 101-109
Eugenio Mocchegiani and Marco Malavolta
Zinc dyshomeostasis, ageing and neurodegeneration: Iplications of A2M and inflammatory gene polymorphisms
Abstract: Zinc maintains brain functions because involved in glutaminergic transmission, in antioxidant response and in conferring biological activity to brain enzymes and growth factors. Zinc turnover is mediated by Metallothioneins (MT) which regulate the intracellular free zinc ions [Zn]i. Alterations in zinc homeostasis are associated to various brain dysfunctions, including brain inflammatory status, but little is known about its implication in the aging brain and neurodegeneration. Literature data in experimental animals suggest that zinc dyshomeostasis may occur in aging associated to a decline in brain functions. One of the causes may be an altered homeostasis of MT and other zinc-binding proteins, such as α2 macroglobulin (A2M), which are of protection against stress and inflammation during young/adult age but turn into being harmful in aging. In fact, despite total brain zinc content is unchanged in the brain of aged animals, with respect to the young/adult, the activity of some zinc dependent enzymes is impaired and large amount of zinc has been found in the core of Alzheimer's disease senile plaques. The role played by MT and A2M is reported in ageing and Alzheimer's disease and on some polymorphisms of A2M and inflammatory genes (cytokines and their receptors) because some of them may be affected by zinc, via MT homeostasis.

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