http://alzres.com The latest research articles published by Alzheimer's Research & Therapy 2012-02-13T00:00:00Z Dementia, a major cause of disability and institutionalization in older people, poses a serious threat to public health and to the social and economic development of modern society. Alzheimer's disease (AD) and cerebrovascular diseases are the main causes of dementia; most dementia cases are attributable to both vascular and neurodegenerative brain damage. No curative treatment is available, but epidemiological research provides a substantial amount of evidence of modifiable risk and protective factors that can be addressed to prevent or delay onset of AD and dementia. Risk of late-life dementia is determined by exposures to multiple factors experienced over the life course, and the effect of specific risk/protective factors depends largely on age. Moreover, cumulative and combined exposure to different risk/protective factors can modify their effect on dementia/AD risk. Multidisciplinary research involving epidemiology, neuropathology, and neuroimaging has provided sufficient evidence that vascular risk factors significantly contribute to the expression and progression of cognitive decline (including dementia) but that active engagement in social, physical, and mentally stimulating activities may delay the onset of dementia. However, these findings need to be confirmed by randomized controlled trials (RCTs). A promising strategy for preventing dementia is to implement intervention programs that take into account both the life-course model and the multifactorial nature of this syndrome. In Europe, there are three ongoing multidomain interventional RCTs that focus on the optimal management of vascular risk factors and vascular diseases. The RCTs include medical and lifestyle interventions and promote social, mental, and physical activities aimed at increasing the cognitive reserve. These studies will provide new insights into prevention of cognitive impairment and dementia. Such knowledge can help researchers plan larger, international prevention trials that could provide robust evidence on dementia/AD prevention. Taking a step in this direction, researchers involved in these European RCTs recently started the European Dementia Prevention Initiative, an international collaboration aiming to improve strategies for preventing dementia. http://alzres.com/content/4/1/6 Francesca Mangialasche Miia Kivipelto Alina Solomon Laura Fratiglioni Alzheimer's Research & Therapy 2012, null:6 2012-02-13T00:00:00Z doi:10.1186/alzrt104 Preventative measures for AD and dementia Mangialasche and colleagues address current epidemiological research and intervention studies to identify promising preventative strategies for Alzheimer's disease (AD) and dementia; considering the need for randomized controlled trials to confirm these findings. /content/figures/alzrt104-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 6 2012-02-13T00:00:00Z XML Alzheimer's disease (AD) is a cognitive disorder with a number of complex neuropathologies, including, but not limited to, neurofibrillary tangles, neuritic plaques, neuronal shrinkage, hypomyelination, neuroinflammation and cholinergic dysfunction. The role of underlying pathological processes in the evolution of the cholinergic deficit responsible for cognitive decline has not been elucidated. Furthermore, generation of testable hypotheses for defining points of pharmacological intervention in AD are complicated by the large scale occurrence of older individuals dying with no cognitive impairment despite having a high burden of AD pathology (plaques and tangles). To further complicate these research challenges, there is no animal model that reproduces the combined hallmark neuropathologies of AD. These research limitations have stimulated the application of 'omics' technologies in AD research with the goals of defining biologic markers of disease and disease progression and uncovering potential points of pharmacological intervention for the design of AD therapeutics. In the case of sporadic AD, the dominant form of dementia, genomics has revealed that the ε4 allele of apolipoprotein E, a lipid transport/chaperone protein, is a susceptibility factor. This seminal observation points to the importance of lipid dynamics as an area of investigation in AD. In this regard, lipidomics studies have demonstrated that there are major deficits in brain structural glycerophospholipids and sphingolipids, as well as alterations in metabolites of these complex structural lipids, which act as signaling molecules. Peroxisomal dysfunction appears to be a key component of the changes in glycerophospholipid deficits. In this review, lipid alterations and their potential roles in the pathophysiology of AD are discussed. http://alzres.com/content/4/1/5 Paul Wood Alzheimer's Research & Therapy 2012, null:5 2012-02-01T00:00:00Z doi:10.1186/alzrt103 Lipidomic findings in AD Current applications of lipidomic technologies and the potential roles of lipid deficits and alterations in the pathophysiology of Alzheimer's disease (AD) are discussed by Wood. /content/figures/alzrt103-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 5 2012-02-01T00:00:00Z XML Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disease that is the second most common form of dementia affecting individuals under age 65. The most common pathological subtype, FTLD with transactive response DNA-binding protein with a molecular weight of 43 kDa inclusions (FTLD-TDP), is often caused by autosomal dominant mutations in the progranulin gene (GRN) encoding the progranulin protein (PGRN). GRN pathogenic mutations result in haploinsufficiency, usually by nonsense-mediated decay of the mRNA. Since the discovery of these mutations in 2006, several groups have published data and animal models that provide further insight into the genetic and functional relevance of PGRN in the context of FTLD-TDP. These studies were critical in initiating our understanding of the role of PGRN in neural development, degeneration, synaptic transmission, cell signaling, and behavior. Furthermore, recent publications have now identified the receptors for PGRN, which will hopefully lead to additional therapeutic targets. Additionally, drug screens have been conducted to identify pharmacological regulators of PGRN levels to be used as potential treatments for PGRN haploinsufficiency. Here we review recent literature describing relevant data on GRN genetics, cell culture experiments describing the potential role and regulators of PGRN in the central nervous system, animal models of PGRN deficiency, and potential PGRN-related FTLD therapies that are currently underway. The present review aims to underscore the necessity of further elucidation of PGRN biology in FTLD-related neurodegeneration. http://alzres.com/content/4/1/4 Alexandra Nicholson Jennifer Gass Leonard Petrucelli Rosa Rademakers Alzheimer's Research & Therapy 2012, null:4 2012-01-23T00:00:00Z doi:10.1186/alzrt102 Progranulin protein and FTLD Recent data involving progranulin protein (PGRN) biology and frontotemporal lobar degeneration (FTLD), and the necessity of further elucidation of PGRN biology in FTLD-related neurodegeneration, is discussed by Nicholson and colleagues. /content/figures/alzrt102-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 4 2012-01-23T00:00:00Z XML Recent trials of statins produced no benefit for subjects with Alzheimer's disease. These negative studies add to a growing list of negative clinical trials. These data point to a need for reevaluating the pathophysiology of late-onset Alzheimer's disease. Late-onset Alzheimer's disease might result from the cumulative effects of at least four different factors: β-amyloid accumulation, cardiovascular disease, aging and the associated loss of synaptic plasticity, and inflammation. Successful therapy of subjects with overt dementia might require approaches targeting all four pathophysiological domains. http://alzres.com/content/4/1/3 Benjamin Wolozin Alzheimer's Research & Therapy 2011, null:3 2012-01-16T00:00:00Z doi:10.1186/alzrt101 /content/figures/alzrt101-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 3 2012-01-16T00:00:00Z XML Resting-state functional magnetic resonance imaging (fMRI) is emerging as an interesting biomarker for measuring connectivity of the brain in patients with Alzheimer's disease (AD). In this review, we discuss the origins of resting-state fMRI, common methodologies used to extract information from these four-dimensional fMRI scans, and important considerations for the analysis of these scans. Then we present the current state of knowledge in this area by summarizing various AD resting-state fMRI studies presented in the first section and end with a discussion of future developments and open questions in the field. http://alzres.com/content/4/1/2 Prashanthi Vemuri David Jones Clifford Jack Alzheimer's Research & Therapy 2011, null:2 2012-01-10T00:00:00Z doi:10.1186/alzrt100 fMRI as an Alzheimer's disease biomarker Vemuri and colleagues discuss the use of resting-state functional magnetic resonance imaging (fMRI) as an emerging Alzheimer's disease biomarker and consider future developments and open questions in the field. /content/figures/alzrt100-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 2 2012-01-10T00:00:00Z XML Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology. http://alzres.com/content/4/1/1 Helena Chui Zheng Ling Reed Reed Vinters Harry Mack Wendy Alzheimer's Research & Therapy 2011, null:1 2012-01-04T00:00:00Z doi:10.1186/alzrt98 Vascular risk factors and AD Current studies fail to show a positive association between vascular risk factors and an increase in Alzheimer's disease (AD) pathology, as discussed in an evidence-based review by Chui and colleagues. /content/figures/alzrt98-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 1 2012-01-04T00:00:00Z XML Although the molecular mechanisms underlying the pathogenesis of Alzheimer's disease and other related neurodegenerative diseases remain unclear, accumulation of misfolded proteins, neuroinflammation, mitochondrial dysfunction and perturbed calcium homeostasis have been identified as key events leading to neuronal loss during neurodegeneration. Evidence for 'druggable' targets for each of these key mechanisms was presented by the Alzheimer's Drug Discovery Foundation-funded investigators at the 12th International Conference on Alzheimer's Drug Discovery, Jersey City, NJ, 26-27 September 2011 http://www.worldeventsforum.com/addf/addrugdiscovery. http://alzres.com/content/3/6/36 Rachel Lane Diana Shineman Howard Fillit Alzheimer's Research & Therapy 2011, null:36 2011-12-20T00:00:00Z doi:10.1186/alzrt99 /content/figures/alzrt99-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 36 2011-12-20T00:00:00Z XML Patient-reported outcome (PRO) measures are used to evaluate disease and treatments in many therapeutic areas, capturing relevant aspects of the disorder not obtainable through clinician or informant report, including those for which patients may have a greater level of awareness than those around them. Using PRO measures in mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) presents challenges given the presence of cognitive impairment and loss of insight. This overview presents issues relevant to the value of patient report with emphasis on the role of insight. Complex activities of daily living functioning and executive functioning emerge as areas of particular promise for obtaining patient self-report. The full promise of patient self-report has yet to be realized in MCI and prodromal AD, however, in part because of lack of PRO measures developed specifically for mild disease, limited use of best practices in new measure development, and limited attention to psychometric evaluation. Resolving different diagnostic definitions and improving clinical understanding of MCI and prodromal AD will also be critical to the development and use of PRO measures. http://alzres.com/content/3/6/35 Lori Frank William Lenderking Kellee Howard Marc Cantillon Alzheimer's Research & Therapy 2011, null:35 2011-12-09T00:00:00Z doi:10.1186/alzrt97 Patient self-report measures The uses of, and issues associated with, patient-reported outcome measures in mild cognitive impairment and prodromal Alzheimer's disease are discussed by Frank and colleagues. /content/figures/alzrt97-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 35 2011-12-09T00:00:00Z XML Recent progress in molecular imaging has provided new important knowledge for further understanding the time course of early pathological disease processes in Alzheimer's disease (AD). Positron emission tomography (PET) amyloid beta (Aβ) tracers such as Pittsburgh Compound B detect increasing deposition of fibrillar Aβ in the brain at the prodromal stages of AD, while the levels of fibrillar Aβ appear more stable at high levels in clinical AD. There is a need for PET ligands to visualize smaller forms of Aβ, oligomeric forms, in the brain and to understand how they interact with synaptic activity and neurodegeneration. The inflammatory markers presently under development might provide further insight into the disease mechanism as well as imaging tracers for tau. Biomarkers measuring functional changes in the brain such as regional cerebral glucose metabolism and neurotransmitter activity seem to strongly correlate with clinical symptoms of cognitive decline. Molecular imaging biomarkers will have a clinical implication in AD not only for early detection of AD but for selecting patients for certain drug therapies and to test disease-modifying drugs. PET fibrillar Aβ imaging together with cerebrospinal fluid biomarkers are promising as biomarkers for early recognition of subjects at risk for AD, for identifying patients for certain therapy and for quantifying anti-amyloid effects. Functional biomarkers such as regional cerebral glucose metabolism together with measurement of the brain volumes provide valuable information about disease progression and outcome of drug treatment. http://alzres.com/content/3/6/34 Agneta Nordberg Alzheimer's Research & Therapy 2011, null:34 2011-12-02T00:00:00Z doi:10.1186/alzrt96 Molecular imaging progress in AD Nordberg reviews recent progress in molecular imaging and functional biomarkers, which can provide valuable information for early Alzheimer's disease (AD) detection, assessing disease progression, and the development of new therapeutics. /content/figures/alzrt96-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 34 2011-12-02T00:00:00Z XML Because the pathologic processes that underlie Alzheimer's disease (AD) appear to start 10 to 20 years before symptoms develop, there is currently intense interest in developing techniques to accurately predict which individuals are most likely to become symptomatic. Several AD risk prediction strategies - including identification of biomarkers and neuroimaging techniques and development of risk indices that combine traditional and non-traditional risk factors - are being explored. Most AD risk prediction strategies developed to date have had moderate prognostic accuracy but are limited by two key issues. First, they do not explicitly model mortality along with AD risk and, therefore, do not differentiate individuals who are likely to develop symptomatic AD prior to death from those who are likely to die of other causes. This is critically important so that any preventive treatments can be targeted to maximize the potential benefit and minimize the potential harm. Second, AD risk prediction strategies developed to date have not explored the full range of predictive variables (biomarkers, imaging, and traditional and non-traditional risk factors) over the full preclinical period (10 to 20 years). Sophisticated modeling techniques such as hidden Markov models may enable the development of a more comprehensive AD risk prediction algorithm by combining data from multiple cohorts. As the field moves forward, it will be critically important to develop techniques that simultaneously model the risk of mortality as well as the risk of AD over the full preclinical spectrum and to consider the potential harm as well as the benefit of identifying and treating high-risk older patients. http://alzres.com/content/3/6/33 Deborah Barnes Sei Lee Alzheimer's Research & Therapy 2011, null:33 2011-11-25T00:00:00Z doi:10.1186/alzrt95 Accurately predicting AD risk In light of recent research, Barnes and Lee consider the current limitations and future directions in identifying individuals at increased risk of developing symptomatic Alzheimer's disease (AD). /content/figures/alzrt95-toc.gif Alzheimer's Research & Therapy 1758-9193 ${item.volume} 33 2011-11-25T00:00:00Z XML