Alzheimer Disease: Pennsylvania

Iacono KT, Brown AL, Greene MI, Saouaf SJ. · University of Pennsylvania, Department of Pathology and Laboratory Medicine, 252 John Morgan Building, 36th & Hamilton Walk, Philadelphia, PA 19104-6082, USA. · Exp Mol Pathol. · Pubmed #17945211 links to  free full text

Abstract: The immunoglobulin superfamily member CD147 plays an important role in fetal, neuronal, lymphocyte and extracellular matrix development. Here we review the current understanding of CD147 expression and protein interactions with regard to CD147 function and its role in pathologic conditions including heart disease, Alzheimer's disease, stroke and cancer. A model linking hypoxic conditions found within the tumor microenvironment to upregulation of CD147 expression and tumor progression is introduced.

Seabrook GR, Ray WJ, Shearman M, Hutton M. · Department of Alzheimer's Research, Merck Research Laboratories, West Point, PA 19486, USA. · Mol Interv. · Pubmed #17932415 links to  free full text

Abstract: The precise pathological events that cause cognitive deficits in Alzheimer's disease remain to be determined. The most widely held view is that accumulation of amyloid beta peptide initiates the disease process; however, with more than eighteen amyloid-based therapeutic candidates currently in clinical trials, the targeting of amyloid alone may not be sufficient to improve functional deficits over the course of the disease. Alternative targets, such as the tau protein and apolipoprotein E, have thus been increasingly investigated, and in the future, therapeutic strategies will likely address events that are upstream of a more broadly construed pathological cascade that includes but is not limited to the generation and accumulation of amyloid beta. Consideration of such events provides the basis for an "indirect amyloid hypothesis," for which data are beginning to emerge. Although it is clinically defined by simple post-mortem criteria, Alzheimer's disease likely has a complex etiology, and effective treatments for this disease will become ever more urgent as the world's population ages.

Mathis CA, Lopresti BJ, Klunk WE. · Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. · Nucl Med Biol. · Pubmed #17921032 links to  free full text

Abstract: Imaging agents capable of assessing amyloid-beta (Abeta) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Abeta plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Abeta imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional Abeta plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Abeta plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

Anandatheerthavarada HK, Devi L. · Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA · Neuroscientist. · Pubmed #17911214 No free full text.

Abstract: Growing evidence suggests that mitochondrial dysfunction is one of the key intracellular lesions associated with the pathogenesis of Alzheimer's disease (AD). Mitochondria, the powerhouses of the cell, participate in a number of physiological functions that include calcium homeostasis, signal transduction, and apoptosis. However, the pathophysiological mechanisms underlying the decline of mitochondrial vital functions leading to the dysfunction of mitochondria during AD are not well understood. Recent literature has observed the accumulation of Alzheimer's amyloid precursor protein (APP) and its C-terminal-cleaved product beta-amyloid (Abeta) in the mitochondrial compartment. Furthermore, evidence also implicates that the accumulation of full-length APP and Abeta in the mitochondrial compartment has a causative role in impairing mitochondrial physiological functions. Here, we review the mode of mitochondrial transport of full-length APP and Abeta and its pathological implications in bringing about mitochondrial dysfunction as seen in AD.

Kuller LH. · University of Pittsburgh, GSPH, 130 North Bellefield Avenue, Room 550, Pittsburgh, PA 15213, USA. · Curr Atheroscler Rep. · Pubmed #17877925 No free full text.

Abstract: The incidence and prevalence of dementia are increasing. Dementia is a major cause of disability. Alzheimer's disease (AD) is the most common type of dementia. There are no good prevention or treatment options. Experimental animal and laboratory studies have suggested that cholesterol metabolism in the brain is important in the causal pathway for dementia, possibly by modifying amyloid metabolism. A few studies have showed a possible relationship between mid-life blood cholesterol levels and risk of dementia, including AD. Case-control studies report that patients with AD were less likely to use lipid-lowering drugs, especially statins. Longitudinal epidemiology studies have not demonstrated a decreased risk of AD among statin users versus nonusers. Two clinical trials of statin therapy to reduce cardiovascular disease have not shown any reduction in risk of cognitive decline or dementia. The results of two secondary prevention trials will be reported shortly. In spite of negative studies, the possibility remains that statin therapy may reduce risk of dementia and AD. Primary prevention trials are difficult and expensive and will likely not be done in the United States.

Woodruff-Pak DS, Gould TJ. · Temple University and Albert Einstein Healthcare Network, USA. · Behav Cogn Neurosci Rev. · Pubmed #17715584 No free full text.

Abstract: Nicotinic acetylcholine receptors (nAChRs) play a role in a variety of diseases of the central nervous system including Alzheimer's disease (AD) and schizophrenia. There is great interest in evaluating disease-related nA ChR changes, and pharmacological treatment of nAChR deficits is a promising therapy. In AD, 7 nAChRs remain relatively stable, contrasting to 4 2 nAChRs that are lost in substantial numbers. -amyloid, a major neuropathology in AD, blocks 4 2 and 7 nAChRs. Agonists selective to 7nAChRs are neuroprotective against--amyloid. Paradoxically, 7nAChRs may function as receptors for -amyloid. These results indicate 7 nAChR antagonists may be appropriate therapy in AD. In schizophrenia, 7 nAChRs are significantly reduced in hippocampus and neocortex. The exceptionally high rate of smoking in schizophrenics is likely a form of self-medication. Therapy with 7 nAChR agonists relieves some schizophrenic symptoms. Despite disparities in etiology and symptomatology, AD and schizophrenia share a target for therapeutic intervention--7 nAChRs.

Ballatore C, Lee VM, Trojanowski JQ. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104-4283, USA. · Nat Rev Neurosci. · Pubmed #17684513 No free full text.

Abstract: Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.

Hills ID, Vacca JP. · Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. · Curr Opin Drug Discov Devel. · Pubmed #17659479 No free full text.

Abstract: Over the last six years, numerous research groups in both academia and industry have synthesized inhibitors of beta-amyloid cleaving enzyme-1 (BACE-1) in the hope of developing a therapy to halt or even reverse the progression of Alzheimer's disease. While several compounds have been demonstrated to be potent in vitro inhibitors of BACE-1, only a small subset of these compounds are able to satisfy other practical considerations essential for the development of a preclinical drug candidate. These considerations include selectivity of the inhibitor toward BACE-1 over other enzymes, cellular activity, and in vivo activity in an animal model. This review will summarize the recent development of BACE-1 inhibitors with particular focus placed on inhibitors that address some of the requirements necessary for a practical drug candidate.

Komatsu H, Liu L, Murray IV, Axelsen PH. · The Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Biochim Biophys Acta. · Pubmed #17632073 No free full text.

Abstract: The fully developed lesion of Alzheimer's disease is a dense plaque composed of fibrillar amyloid beta-proteins (Abeta) with a characteristic and well-ordered beta-sheet secondary structure. Because the incipient lesion most likely develops when these proteins are first induced to form beta-sheet structure, it is important to understand factors that induced Abeta to adopt this conformation. In this review, we describe the application of polarized attenuated total internal reflection infrared FT-IR spectroscopy for characterizing the conformation, orientation, and rate of accumulation of Abeta on lipid membranes. We also describe the application and yield of linked analysis, whereby multiple spectra are fit simultaneously with component bands that are constrained to share common fitting parameters. Results have shown that membranes promote beta-sheet formation under a variety of circumstances that may be significant to the pathogenesis of Alzheimer's disease.

Manuel SL, Rahman S, Wigdahl B, Khan ZK, Jain P. · Department of Microbiology and Immunology, Center for Cancer Biology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA. · Front Biosci. · Pubmed #17485377 No free full text.

Abstract: Dendritic cells are the most potent antigen presenting cells and have long been recognized as key regulators of the immune system, linking both stimulatory and inhibitory components of normal immunity. While DCs are fully characterized with respect to primary and secondary immune responses, their unique role in coordinating central and peripheral tolerance is just emerging. It is increasingly evident that the failure of DCs ability to maintain tolerance can lead to autoimmune and/or inflammatory diseases. However, existing literature highlighting participation of DCs in several autoimmune phenomena is scattered and remains underappreciated. This review is a comprehensive account of current knowledge characterizing the role of DCs in various autoimmune diseases including psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, and diabetes. Additionally, it provides a rare description of DCs participation in various neuroinflammatory disorders including multiple sclerosis, HAM/TSP, Alzheimer disease and prion-associated diseases. Finally, a detailed description of the possible mechanisms of DC involvement in regulating immune response towards self versus non-self is discussed. Overall, the goal of this review is to establish DCs in the interface of tolerance and autoimmunity and generate a global interest in this field in order to exploit DC potential for the therapy of inflammatory diseases.

Koldamova R, Lefterov I. · Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, USA. · Curr Alzheimer Res. · Pubmed #17430243 No free full text.

Abstract: Studies, ranging from epidemiological to in vitro and in vivo experimental settings have provided convincing evidence that different aspects of brain lipid metabolism may influence Alzheimer disease pathogenesis through effects on beta-amyloid deposition and clearance. It has been demonstrated that transcription factors called nuclear liver X receptors (LXR) and their responsive genes provide natural regulatory mechanisms and influence AD pathogenesis through their modulatory effects on intracellular cholesterol content, cholesterol efflux and possibly via anti-inflammatory mechanisms. Here, we provide a brief summary of the approaches undertaken by different groups that lead to the nowadays working model of LXR and ABCA1 regulatory role in brain amyloidogenesis and amyloid clearance and we highlight the therapeutic potential of LXR agonists.

Kettl P. · Penn State College of Medicine, Hershey, PA 17033, USA. · J Clin Psychiatry. · Pubmed #17388717 No free full text.

Abstract: OBJECTIVE: Alzheimer's disease is a chronic process of gradual deterioration of cognitive ability. While this is clearly a tragedy for the individual and the family, the prolonged nature of the disease allows the clinician an opportunity to plan for progressive stages of the disease including the final stages of care. This article reviews opportunities for assisting families in the care of their ill relatives with Alzheimer's disease. DATA SOURCES: Review articles on end-of-life care and Alzheimer's disease obtained on a search from Ovid on March 2, 2006. Only English-language review articles were included in the search. STUDY SELECTION: Articles were included in the review if they offered clinically relevant material for assisting families in end-of-life care in Alzheimer's disease. Articles between 1998 and 2006 were included. Approximately 10% of the articles listed were included in the review. DATA SYNTHESIS: Clinicians should discuss with family members choices to be made at the end of life in Alzheimer's disease care and work with the family to ensure these wishes are followed. The geriatric psychiatrist plays a central role in these discussions. Other members of the health care team, including nursing care, hospice care, and social work coordinators, all coordinate efforts to deliver optimal end-of-life care. This leads not only to better and more humane care, but also to a cost savings in America's burgeoning health care budget. CONCLUSION: Geriatric psychiatrists can play a central role in assisting families in managing end-of-life care in Alzheimer's disease.

Arenth PM, Ricker JH, Schultheis MT. · Department of Physical Medicine & Rehabilitation and the Center for the Neural Basis of Cognition, University of Pittsburgh, PA 15213, USA. · Clin Neuropsychol. · Pubmed #17366277 No free full text.

Abstract: Functional Near-Infrared Spectroscopy (fNIRS) is a neuroimaging technique that utilizes light in the near-infrared spectrum (between 700 and 1000 nm) to detect hemodynamic changes within the cortex when sensory, motor, or cognitive activation occurs. FNIRS principles have been used to study brain oxygenation for several decades, but have more recently been applied to study cognitive processes. This paper provides a description of basic fNIRS techniques, and provides a review of the rehabilitation-related literature. The authors discuss strengths and weaknesses of this technique, assert that fNIRS may be particularly beneficial to neurorehabilitation of cognitive disabilities, and suggest future applications.

Shaw LM, Korecka M, Clark CM, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Nat Rev Drug Discov. · Pubmed #17347655 No free full text.

Abstract: Rapid progress towards understanding the molecular underpinnings of neurodegenerative disorders such as Alzheimer's disease is revolutionizing drug discovery for these conditions. Furthermore, the development of models for these disorders is accelerating efforts to translate insights related to neurodegenerative mechanisms into disease-modifying therapies. However, there is an urgent need for biomarkers to diagnose neurodegenerative disorders early in their course, when therapy is likely to be most effective, and to monitor responses of patients to new therapies. As research related to this need is currently most advanced for Alzheimer's disease, this Review focuses on progress in the development and validation of biomarkers to improve the diagnosis and treatment of Alzheimer's disease and related disorders.

Geerts H. · In Silico Biosciences Inc, 686 Westwind Drive, Berwyn, PA 19104, USA. · IDrugs. · Pubmed #17285465 No free full text.

Abstract: (R)-flurbiprofen, the R-enantiomer of racemic flurbiprofen, is undergoing development by Myriad Genetics Inc, under license from Encore Pharmaceuticals Inc, for the potential treatment of Alzheimer's disease (AD). Devoid of any direct cyclooxygenase inhibition, which is associated with the more toxic S-enantiomer of flurbiprofen, (R)-flurbiprofen appears to modulate gamma-secretase, the enzyme that cleaves the C-terminal portion of the malignant Abeta(1-42) peptide out of amyloid precursor protein. In murine models of AD, (R)-flurbiprofen lowered brain levels of Abeta(1-42), and chronic dosing reduced brain amyloid pathology and prevented defects in learning and memory. In a phase II clinical trial in AD, (R)-flurbiprofen was determined to be most effective in a subset of patients who had high blood concentrations of the drug (> 75 microg/ml). These patients demonstrated a benefit in cognitive and behavioral performance that ranged from 36 to 48%, and statistical significance was achieved for two out of three trial endpoints. Compared with placebo, (R)-flurbiprofen also significantly reduced the incidence of psychiatric problems and the average time to a first psychiatric incidence. (R)-flurbiprofen has been generally well tolerated at high doses in clinical trials. Two pivotal phase III clinical trials in AD are underway in more than 2400 patients. The compound had also been under development for the treatment of prostate cancer; however, this indication was discontinued after disappointing phase IIa trial results.

Caltagarone J, Jing Z, Bowser R. · Department of Pathology, University of Pittsburgh School of Medicine, BST S-420, 200 Lothrop St., Pittsburgh, PA 15261, USA. · Biochim Biophys Acta. · Pubmed #17215111 links to  free full text

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that results from a loss of synaptic transmission and ultimately cell death. The presenting pathology of AD includes neuritic plaques composed of beta-amyloid peptide (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau, with neuronal loss in specific brain regions. However, the mechanisms that induce neuronal cell loss remain elusive. Focal adhesion (FA) proteins assemble into intracellular complexes involved in integrin-mediated communication between the extracellular matrix and the actin cytoskeleton, regulating many cell physiological processes including the cell cycle. Interestingly, recent studies report that integrins bind to Abeta fibrils, mediating Abeta signal transmission from extracellular sites of Abeta deposits into the cell and ultimately to the nucleus. In this review, we will discuss the Abeta induced integrin/FA signaling pathways that mediate cell cycle activation and cell death.

Connor JR, Lee SY. · Department of Neurosurgery, G.M. Leader Family Laboratory for Alzheimer's Disease Research, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. · J Alzheimers Dis. · Pubmed #17119292 No free full text.

Abstract: An imbalance in brain iron status has been established in Alzheimer's Disease (AD). This iron imbalance can impact plaque formation, amyloid processing, and expression of and response to inflammatory agents. In a more general sense, a deregulation of iron homeostasis underlies the generation of reactive oxygen species leading to oxidative damage. Thus, loss of iron homeostasis can be central to the pathogenic events in AD. Recently a number of studies have begun to investigate the frequency of mutations in the HFE gene in AD. Mutations in the HFE gene occur more frequently in Caucasians than any other mutation. The two most common mutations of HFE are the C282Y (2% of the total population) and the H63D (9%. Mutations in this gene are associated with loss of iron homeostasis, alterations in inflammatory responses and in its most severe form, a clinical disorder known as Hemochromatosis. The C282Y mutation is more frequently associated with Hemochromatosis and the frequency of the H63D mutation is receiving increasing attention in neurodegenerative disorders. This review summarizes the data on HFE mutations in neurodegenerative disorders and what is known about HFE in the brain and the cell biology underlying the HFE mutation.

DeKosky ST. · Alzheimer Disease Research Center, Department of Neurology, University of Pittsburgh, Pttsburgh, Pennsylvania 15213, USA. · Neurology. · Pubmed #17101928 No free full text.

Abstract: Incidence and prevalence of Alzheimer Disease (AD) will rise in a accelerating fashion through the middle of the 21st century. Increased understanding of the pathological cascades in AD, and the knowledge that the initial brain changes begin years prior to clinical manifestations, have led to initiation of trials to prevent AD. With many of the designs being used or contemplated, prevention trials will involve repeated cognitive and functional assessments over years, require cooperation and collaboration of both the subject and a partner or proxy, and represent a substantial time and resource investment by the research team. Compliance with the study regimen and adherence to the protocol are thus major foci for study efficiency and success. In this section methods by which compliance and adherence can be optimized are discussed. Research on the effectiveness of these and other evolving methods will be of help in assuring success of such large scale studies in the future.

Huang HC, Klein PS. · Department of Medicine (Hematology-Oncology), 364 Clinical Research Building, University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19104-6148, USA. · Curr Drug Targets. · Pubmed #17100579 No free full text.

Abstract: Alzheimer's disease (AD) is a common neurodegenerative disorder that presents clinically as inexorable cognitive impairment and decline in performance of activities of daily living. AD is characterized pathologically by neuronal depopulation, extracellular amyloid plaques, and intraneuronal accumulation of neurofibrillary tangles (NFTs). Accumulation of these polypeptide aggregates is generally believed to be integral to the pathogenesis of AD. Recent evidence implicates the protein kinase glycogen synthase kinase 3 (GSK-3) in the regulation of both of these processes. GSK-3 has long been studied as one of several tau protein kinases, and has more recently been shown to be involved in the generation of Abeta peptides. GSK-3 activity may also promote cell death and conversely, inhibition of GSK-3 has been associated with increased cell survival under a variety of cytotoxic conditions. Thus drugs that target GSK-3 could attack AD pathogenesis on multiple fronts simultaneously. Here we will briefly review the molecular understanding of AD pathogenesis as it stands at this point, and then discuss the emerging role of GSK-3 in regulating these processes.

Ikonomovic MD, Abrahamson EE, Isanski BA, Debnath ML, Mathis CA, Dekosky ST, Klunk WE. · Department of Neurology and Psychiatry, University of Pittsburgh, Pennsylvania 15213, USA. · Methods Enzymol. · Pubmed #17046656 No free full text.

Abstract: Postmortem pathological diagnosis and basic research investigations of neurodegenerative disorders rely on histochemical staining procedures developed specifically to visualize abnormal protein conformation. In Alzheimer's disease (AD), two major pathological hallmarks are required to confirm the clinical diagnosis. Both consist of abnormally aggregated proteins that share the structural and histological properties common to all amyloid deposits. Amyloid-beta peptide (Abeta) of extracellular senile plaques (SP) and hyperphosphorylated tau of intracellular neurofibrillary tangles (NFT) are assembled in the abnormal beta-pleated sheet (amyloid-like) structural conformation that can be visualized with histological staining procedures using Congo red or its derivatives. These histochemical dyes bind amyloid with high affinity and allow easy detection of amyloid structure in postmortem brain samples. This chapter focuses on the development and application of a histological protocol using the compound X-34, a highly fluorescent derivative of Congo red, for sensitive detection of pathological amyloid structures in histopathological investigations of postmortem brain tissue. This procedure provides a simple and effective method for detailed fluorescent visualization of the localization and distribution of the majority of currently known major histopathological structures in AD, including compact cored, neuritic, and diffuse-appearing SP, NFT, dystrophic neurites, neuropil threads, and cerebrovascular amyloidosis.

Johnson CM, Sullivan-Marx EM. · Living Independently for Elderly (LIFE) Program, University of Pennsylvania School of Nursing, Philadelphia, USA. · Geriatr Nurs. · Pubmed #17045130 No free full text.

Abstract: This article provides an introduction to the field of art therapy and the potential it can offer to address the emotional needs of the frail elderly. Two case studies are discussed, and examples of artwork are provided. The case studies and artwork were created under the guidance of an art therapist at a Program of All-Inclusive Care for the Elderly (PACE) site in an urban African American community. This article explores how art making addresses the specific developmental tasks of the elderly in a culturally competent manner. Included are practical considerations in the choice of art media and directives for working with elderly clients, as well as resources for further information on the use of art in therapy.

Rosano C, Newman AB. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA. · Neurol Res. · Pubmed #16945212 No free full text.

Abstract: Several recent studies demonstrate associations between cardiovascular disease and its risk factors and the incidence of Alzheimer's disease. This review will examine the evidence for these associations and possible pathogenetic pathways. Clinical relevance and implications of these associations will also be discussed.

Ganguli M. · Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and Graduate School of Public Health, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16917196 No free full text.

Abstract: In 1907, Alzheimer's single case report of presenile dementia led to the condition being recognized as a rare disease of middle-aged people. In 1964, Roth and colleagues reported an epidemiologic survey showing that the same condition was in fact a relatively common disease of the elderly. In 1987, Katzman introduced the concept of brain reserve, suggesting how individuals could have Alzheimer disease pathology in their brains without clinically manifesting the disease. In 1999, Petersen described mild cognitive impairment (MCI) as an amnestic state, since broadened to include other cognitive deficits, which, in the majority of patients, was a prelude to the development of full-blown Alzheimer disease or other dementia. MCI today is in some ways analogous to Alzheimer disease a century ago. We recognize and describe MCI clinically, among patients with memory complaints, but we do not know its distribution, outcomes, and risk factors in the elderly population at large. All population-based studies to date have found MCI to be an unstable and heterogeneous entity with a far wider range of outcomes than in the clinical setting, including reversion to normal in a substantial proportion. However, these studies thus far have been purely descriptive, and retro-fitted on to existing studies of dementia, using measurements not necessarily appropriate for the assessment of MCI. This review will address what is known and what has yet to be determined about MCI from the perspectives of the classic 7 uses of epidemiology.

Lee VM, Trojanowski JQ. · The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · J Alzheimers Dis. · Pubmed #16914864 No free full text.

Abstract: The landmark description of neurofibrillary tangles (NFTs) and senile plaques as the pathological hallmarks of an unusual form of dementia 100 years ago by Alois Alzheimer launched the quest to understand a neurodegenerative disorder that now has become a scourge in the 21st Century due to the unprecedented increase in human life expectancy since 1900. Indeed, while there are many benefits to individuals and society as a whole that will accrue from the remarkable gains in longevity since 1900, the risk of developing Alzheimer's disease (AD) increases exponentially with advancing age beyond the 7th decade of life. Hence, the prevalence of AD will rise inexorably in the coming decades unless effective interventions are developed to delay the onset or progression of AD. Widespread international recognition of the urgency of this problem has accelerated research to discover meaningful therapies for AD, and growing evidence implicates impairments of axonal transport in mechanisms underlying AD due to pathological alterations in tau, the building block proteins of NFTs. This brief review summarizes insights into mechanisms whereby pathological alterations in tau impair axonal transport resulting in neurodegeneration and how these insights are being exploited now to develop novel therapeutic interventions for the treatment of AD.

Geerts H, Grossberg GT. · In Silico Biosciences Inc, Berwyn, PA 19312, USA. · J Clin Pharmacol. · Pubmed #16809810 No free full text.

Abstract: The search for effective treatments of Alzheimer's disease (AD) is one of the major challenges facing modern medicine. Acetylcholinesterase (AChE) inhibitors (AChEIs) are effective for the treatment of mild to moderate AD, and memantine, an N-methyl-D-aspartate (NMDA) inhibitor, has been approved for moderate to severe AD. Galantamine is of particular interest because it has a dual mechanism of action: it is postulated to be both an AChEI and an allosteric modulator of nicotinic receptors. Modulation of NMDA and nicotinic receptors by memantine and galantamine may provide an optimal combination therapy for AD. The cholinergic and glutamatergic neurotransmitter systems, which share a close functional relationship, may play a role in the pathogenesis of AD. Close examination of the pharmacology of the 2 compounds suggests that galantamine can augment memantine's glutamatergic noise suppression while simultaneously enhancing the physiologic glutamatergic signal. The link between these systems suggests that AD therapies, which capitalize on this relationship, may be more effective in improving cognition than approaches focusing on a single system.