Alzheimer Disease: US Mid-Atlantic

Baranov D, Bickler PE, Crosby GJ, Culley DJ, Eckenhoff MF, Eckenhoff RG, Hogan KJ, Jevtovic-Todorovic V, Palotás A, Perouansky M, Planel E, Silverstein JH, Wei H, Whittington RA, Xie Z, Zuo Z, Anonymous00067. · Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Anesth Analg. · Pubmed #19372347 No free full text.

Abstract: In order to review the current status of the potential relationship between anesthesia and Alzheimer's disease, a group of scientists recently met in Philadelphia for a full day of presentations and discussions. This special article represents a consensus view on the possible link between Alzheimer's disease and anesthesia and the steps required to test this more definitively.

McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ, Anonymous00019. · Department of Neurology, Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University School of Medicine, 338 Krieger Hall, 3400 N Charles St, Baltimore, MD 21218-2685, USA. · Arch Neurol. · Pubmed #11708987 links to  free full text

Abstract: An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.

Van Lee R, Meagher B, Fritz P, Penfield S. · Booz Allen Hamilton, McLean, VA, USA. · Alzheimers Dement. · Pubmed #19328452 No free full text.

Abstract: There are many groups and organizations across the government, private, and nonprofit sectors that are passionately engaged in the fight against Alzheimer's disease (AD), but they have constraints on their funding and scope and, therefore, cannot tackle the problem holistically. Addressing the complexities of this epidemic strategically will require the collective efforts of committed stakeholders. Individuals and organizations must work together to identify mutual interests and forge new relationships and partnerships. Through this network of stakeholders, known as a megacommunity, individual members can support and expand their objectives and impact through the combined knowledge and resources in the megacommunity network. Leaders Engaged on Alzheimer's Disease (LEAD) is an example of a megacommunity tackling the toughest issues facing AD patients and their families. LEAD is currently comprised of more that thirty individuals and organizations committed to sharing information and coordinating action across organizational boundaries.

Ryan JM, Schneider G, Jacobsen JS. · Neuroscience Global Clinical Research and Development, Wyeth Research, Collegeville, PA, USA. · Alzheimers Dement. · Pubmed #19328445 No free full text.

This publication has no abstract.

Martin BK, Breitner JC, Evans D, Lyketsos CG, Meinert CL. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md, USA. · Am J Med. · Pubmed #17349436 No free full text.

This publication has no abstract.

Janson CG. · UMDNJ-Robert Wood Johnson Medical School, Camden, NJ 08103, USA. · Neurology. · Pubmed #16116144 No free full text.

This publication has no abstract.

Geldmacher DS. · Department of Neurology, University of Virginia Health System, P.O. Box 800394, Charlottesville, VA 22908, USA. · Clin Geriatr Med. · Pubmed #15062493 No free full text.

This publication has no abstract.

Radebaugh TS, Ward-Robinson J. · Khachaturian, Radebaugh & Associates, Inc., Patomac, Maryland 20854-3009, USA. · Alzheimer Dis Assoc Disord. · Pubmed #12351912 No free full text.

This publication has no abstract.

Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S. · Neurotez, Inc., Bridgewater, New Jersey 08807, USA. · J Alzheimers Dis. · Pubmed #19387109 No free full text.

Abstract: Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Perry DP. · Chairman, ACT-AD Coalition, Washington, DC, USA. · Alzheimers Dement. · Pubmed #19328455 No free full text.

Abstract: The aging of the baby boom generation continues to put more Americans at increased risk for Alzheimer's disease (AD). The need for meaningful treatment options to fight the destruction caused by AD has never been greater. This article highlights the pivotal role that the U.S. Food and Drug Administration will play in making the review of emerging AD therapies a national priority and ways that various stakeholders are engaging with regulators to meet the challenges posed by the growing AD epidemic.

Petanceska S, Ryan L, Silverberg N, Buckholtz N. · Division of Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Alzheimers Dement. · Pubmed #19328442 No free full text.

This publication has no abstract.

Fick DM, Kolanowski A, Beattie E, McCrow J. · School of Nursing, The Pennsylvania State University, University Park, PA 16802, USA. · J Gerontol Nurs. · Pubmed #19326827 No free full text.

Abstract: Delirium is a disorder of acute onset with fluctuating symptoms and is character ized by inattention, disorganized thinking and altered levels of consciousness. The risk for delirium is greatest in individual with dementia, and the incidence of both is increasing worldwide because of the aging of our population. Although s clinical trials have tested interventions f delirium prevention in individuals without dementia, little is known about the m anisms for the prevention of delirium i early-stage Alzheimer's disease (AD). Th purpose of this article is to explore ways o preventing delirium and slowing the ra of cognitive decline in early-stage AD enhancing cognitive reserve. An agenda for future research on interventions to prevent delirium in individuals with early-stage AD is also presented.

Fotuhi M, Mohassel P, Yaffe K. · Center for Memory and Brain Health, LifeBridge Health Brain & Spine Institute, Sinai Hospital of Baltimore, Baltimore, MD 21209, USA. · Nat Clin Pract Neurol. · Pubmed #19262590 No free full text.

Abstract: Long-chain omega-3 fatty acids could have neuroprotective properties against dementia, which is becoming a major global public health issue. We conducted a systematic review of the literature to establish the association between eating fish (a source of long-chain omega-3 fatty acids) or taking long-chain omega-3 fatty acid supplements and the risk of cognitive decline or Alzheimer disease (AD). We identified eleven observational studies and four clinical trials. All three observational studies that used cognitive decline as an outcome reported significant benefits, whereas only four of eight observational studies that used incidence of AD or dementia as an outcome reported positive findings. None of four small clinical trials provided convincing evidence for the use of this approach in the prevention or treatment of any form of dementia. In summary, the existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). This apparent dichotomy might reflect differences in study designs with regard to participants, dosages, the ratio of long-chain omega-3 to omega-6 fatty acids, or the choice of outcome measurements. Large clinical trials of extended duration should help to provide definitive answers.

Rosso A, Mossey J, Lippa CF. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Am J Alzheimers Dis Other Demen. · Pubmed #19230121 No free full text.

Abstract: Alzheimer's disease is a common problem in our elderly population. Although research is leading to improvements in our understanding of the underlying biology, we still have little understanding of the environmental risk factors associated with this disorder. Caffeine, an easily modifiable environmental factor, may have a protective effect on the likelihood of developing Alzheimer's disease. This article reviews the association between caffeine from both a biologic and epidemiologic perspective. Further studies are needed to determine whether caffeine consumption could have a major affect on the development of Alzheimer's disease or age-related cognitive decline.

Manolio TA. · National Human Genome Research Institute, Building 31, Room 4B-09, 31 Center Drive, MSC 2154, Bethesda, MD 20892-2154, USA. · Pharmacogenomics. · Pubmed #19207024 No free full text.

Abstract: In the past 3 years, genome-wide association (GWA) studies have revolutionized the discovery of genetic variants associated with complex diseases. These studies present unique challenges in their conduct; particularly in the need for meticulous quality control of genotyping and for sample sizes large enough to withstand the severe penalty for multiple comparisons necessitated by testing hundreds of thousands of SNPs. They also present unique opportunities in the unprecedented detail with which they characterize an individual's genome and the potential for relating that information to any trait consistent with that person's informed consent. Such data exceed the abilities of any single group of investigators to mine them fully and by NIH policy are distributed to qualified investigators agreeing to specified terms of use. This report describes collaborative programs of the National Human Genome Research Institute's Office of Population Genomics for facilitating collection, analysis, interpretation, and dissemination of these data so that their research value can be maximized.

Shie FS, Nivison M, Hsu PC, Montine TJ. · Division of Mental Health and Substance Abuse Research, National Health Research Institutes, No.35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, R.O.C. · Curr Med Chem. · Pubmed #19199928 No free full text.

Abstract: Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Although the etiology of AD remains unclear, microglia-mediated neuroinflammation is believed to play an important role in its pathogenesis. Microglial activation occurs in AD and is characterized by apparent phagocytic activity and by increased production and secretion of several cytokines, chemokines, reactive oxygen and nitrogen species, prostaglandin (PG)E2, and neurotrophic factors. Microglial activation can be neuroprotective through the release of neurotrophic factors and by phagocytosing Abeta, a critical neurotoxic component in AD brain. Concurrently, microglial activation causes elevated inflammatory responses that lead to paracrine damage to neurons. Therefore, a well-controlled microglial activation that diminishes microglial-mediated oxidative damage while promoting neuronal protection may be the key for AD therapy. Peroxisome proliferator-activated receptor gamma (PPARgamma) has recently gained increasing attention in AD due to its function as a molecular target for non-steroidal anti-inflammatory drugs (NSAIDs). In this review, we will discuss the role of PPARgamma in microglial innate immunity in AD and how pharmacological manipulation of microglial activation using PPARgamma ligands might facilitate the treatment of AD.

Becker RE, Unni LK, Greig NH. · Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. · Curr Alzheimer Res. · Pubmed #19199879 No free full text.

Abstract: Commercial priorities have been identified as negative factors in drug development. We trace the problem to inattention to sound clinical pharmacology practices. When properly applied, clinical pharmacology and associated drug development sciences can, hand in hand, facilitate success in commercial drug development.

Wei H, Xie Z. · Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA. · Curr Alzheimer Res. · Pubmed #19199872 No free full text.

Abstract: While anesthetics are indispensable clinical tools generally safe and effective, in some situations there is grown concern about selective neurotoxicity of these agents; the clinical significance is unclear as of yet. The mechanisms for inhalational anesthetics mediated cell damage are still not clear, although a role for calcium dysregulation has been suggested. For example, the inhaled anesthetic isoflurane decreases endoplasmic reticulum (ER) calcium concentration and increases that in the cytosol and mitochondria. Inhibition of ER calcium release, via either IP(3) or ryanodine receptors, significantly inhibited isoflurane neurotoxicity. Neurons made vulnerable to calcium dysregulation by overexpression of mutated presenilin-1 (PS1) or huntingtin (Q-111) proteins showed enhanced apoptosis upon isoflurane exposure. Sevoflurane and desflurane were less potent than isoflurane in altering intracellular calcium, and produced less apoptosis. Short exposures to inhalational anesthetics may provide neuroprotection by preconditioning via a sublethal stress, while prolonged exposures to inhalational anesthetics may induce cell damage by apoptosis through direct cytotoxic effects.

Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. · Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA. · Physiol Rev. · Pubmed #19126755 links to  free full text

Abstract: The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

Coico R, Woodruff-Pak DS. · Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA. · J Alzheimers Dis. · Pubmed #19096163 No free full text.

Abstract: This timely special issue of the Journal of Alzheimer's Disease provides the opportunity to examine interfaces between basic science and clinical medicine using animal models to develop more effective therapies for the treatment and, ideally, prevention of Alzheimer's disease (AD). That some patients with AD enrolled in a clinical trial to inoculate against amyloid-beta (Abeta) experienced a misdirected polarization of Th cells reminds us that our knowledge of T cell biology, immune regulation, and the precise functional properties of adjuvants is incomplete. We review this knowledge and consider the advantages of the rabbit for immunological studies. The langomorph species is proximate to primates on the phylogenetic scale, its amino acid sequence of Abeta is 97% identical to the human Abeta sequence, and the rabbit model system is extensively characterized on a form of associative learning with parallels in normal aging in rabbits and humans that is severely impaired in human AD. Cholesterol-fed rabbits treated with Abeta immunotherapy generate high titer anti-Abeta responses. The cholesterol-fed rabbit model of AD with its close parallels to human genetics and physiology, along with its validity from molecular to cognitive levels as a model of human AD, provides a promising vehicle for development of immunotherapies.

Iijima K, Iijima-Ando K. · Laboratory of Neurodegenerative Diseases and Gene Discovery, Farber Institute for Neurosciences, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA. · J Alzheimers Dis. · Pubmed #19096154 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of senile dementia, and a cure is desperately needed. The amyloid-beta42 (Abeta42) has been suggested to play a central role in the pathogenesis of AD. However, the mechanism by which Abeta42 causes AD remains unclear. To understand the pathogenesis and to develop therapeutic avenues, it is crucial to generate animal models of AD in genetically tractable organisms. Drosophila is a well-established model system for which abundant genetic tools are available. Moreover, its well organized brain permits the study of complex behaviors such as learning and memory. We have established transgenic flies that express human Abeta42 in the nervous system. These flies developed age-dependent short-term memory impairment and neurodegeneration. In this review, we will first describe transgenic Abeta42 fly models and discuss the unique features of this system compared to mouse AD models. Secondly, we will discuss the usage of the fly models to evaluate currently proposed therapeutic strategies. Thirdly, we will briefly review the results of a genetic screen for modifiers of Abeta42 toxicity in the fly model. Finally, we will discuss how to dissect the complex mechanisms of Abeta42 toxicity focusing on its aggregation propensity using the fly model system.

Woodruff-Pak DS. · Department of Psychology, Temple University, Philadelphia, PA 19122, USA. · J Alzheimers Dis. · Pubmed #19096153 No free full text.

Abstract: This Special Issue of the Journal of Alzheimer's Disease (JAD) provides an overview of animal models of Alzheimer's disease (AD). Very few species spontaneously develop the cognitive, behavioral, and neuropathological symptoms of AD, yet AD research must progress at a more rapid pace than the rate of human aging. In recent years, a variety of models have been created--from tiny invertebrates with life spans measurable in months to huge mammals that live several decades. The fruit fly, Drosophila melanogaster, is a powerful genetic tool that has recently emerged as a model of AD with neural features and assessable learning and memory. Transgenic mice are the most widely used animal models of AD and have yielded significant research breakthroughs. Accelerated aging seen in the SAMP8 mouse is a non-transgenic model with great utility. Rat models provided early evidence about the deleterious impact of amyloid-beta (Abeta) on neurons and continue to provide insights. Rabbits, as langomorphs, are more closely related to primates than are rodents and have conserved the sequence of Abeta in humans (as have canines and non-human primates). The hypercholesterolemic rabbit is an excellent AD model. The aging canine develops AD neuropathology spontaneously and is especially suitable for tests of therapeutics. Non-human primates are invaluable for the development of therapeutics translating to humans. Each animal model has limitations and strengths, but used together in complementary fashion, animal models for research on AD are essential for rapid progress toward a cure.

Pritchard JF. · Development and Regulatory Services, MDS Pharma Services, Renaissance Blvd, King of Prussia, PA 19406, USA. · BMC Neurosci. · Pubmed #19090998 links to  free full text

Abstract: Despite rapid progress in our understanding of disease mechanisms and an exploding list of new targets for therapeutic intervention, drug discovery and development remains a highly risky business. Understanding the risk involved requires appreciation of the differing perspectives of risk held by the various stakeholders involved in drug research. Risk can be reduced by thoughtful management of drug candidate selection, careful planning and program execution by a team of engaged experts, and disciplined decision making. Drug development is particularly challenging for treatments of neurodegenerative diseases such as Alzheimer's disease, in which translation from animal models of efficacy to human success is poor or unknown, the timelines for clinical study are long, and the markers of efficacy are still evolving. Despite this there are several therapies in clinical development that hold the promise of influencing this disease through novel and possibly synergistic mechanisms.

Block ML. · Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Campus, Richmond, VA 23298, USA. · BMC Neurosci. · Pubmed #19090996 links to  free full text

Abstract: At present, available treatments for Alzheimer's disease (AD) are largely unable to halt disease progression. Microglia, the resident macrophages in the brain, are strongly implicated in the pathology and progressively degenerative nature of AD. Specifically, microglia are activated in response to both beta amyloid (Abeta) and neuronal damage, and can become a chronic source of neurotoxic cytokines and reactive oxygen species (ROS). NADPH oxidase is a multi-subunit enzyme complex responsible for the production of both extracellular and intracellular ROS by microglia. Importantly, NADPH oxidase expression is upregulated in AD and is an essential component of microglia-mediated Abeta neurotoxicity. Activation of microglial NADPH oxidase causes neurotoxicity through two mechanisms: 1) extracellular ROS produced by microglia are directly toxic to neurons; 2) intracellular ROS function as a signaling mechanism in microglia to amplify the production of several pro-inflammatory and neurotoxic cytokines (for example, tumor necrosis factor-alpha, prostaglandin E2, and interleukin-1beta). The following review describes how targeting NADPH oxidase can reduce a broad spectrum of toxic factors (for example, cytokines, ROS, and reactive nitrogen species) to result in inhibition of neuronal damage from two triggers of deleterious microglial activation (Abeta and neuron damage), offering hope in halting the progression of AD.

Gold CA, Budson AE. · University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ, USA. · Expert Rev Neurother. · Pubmed #19086882 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by a constellation of cognitive disturbances, the earliest and most prominent being impaired episodic memory. Episodic memory refers to the memory system that allows an individual to consciously retrieve a previously experienced item or episode of life. Many recent studies have focused on characterizing how AD pathology impacts particular aspects of episodic memory and underlying mental and neural processes. This review summarizes the findings of those studies and discusses the effects of current and promising treatments for AD on episodic memory. The goal of this review is to raise awareness of the strides that cognitive neuroscientists have made in understanding intact and dysfunctional memory. Knowledge of the specific memorial processes that are impaired in AD may be of great value to basic scientists developing novel therapies and to clinical researchers assessing the efficacy of those therapies.