Alzheimer Disease: Pennsylvania

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.

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.

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.

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.

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.

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.

Praticò D. · Department of Pharmacology, Temple University, School of Medicine, Philadelphia, PA 19140, USA. · Ann N Y Acad Sci. · Pubmed #19076432 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disease associated with dementia in the elderly. Although the initiating events are still unknown, it is clear that AD, at least in its sporadic form, results from the combination of genetic risk factors with different epigenetic events. Among them, a growing body of evidence suggests that an imbalance between free radical formation and destruction is involved in AD pathogenesis. This concept originally derived from the free radical hypothesis of aging, which states that the age-related accumulation of free radicals results in damaged cell components. The fact that age is a key risk factor in AD provides support for this hypothesis. There is a long list of surrogate markers, which includes lipid, DNA, and protein oxidation, of oxidant stress-mediated injury that have been reported as elevated in the AD brain. Moreover, epidemiologic studies show that dietary intake of natural or synthetic products with a putative antioxidant effect, such as (but not only) vitamin E, reduces the risk of AD. On the other hand, antioxidative intervention studies in animal models of AD-like amyloidosis show a significant reduction in amyloid beta deposition and behavioral improvements. However, a randomized clinical trial of vitamin E supplementation in AD patients shows only a marginal positive effect. Another study reports no effect of vitamin E on the rate of progression of AD in subjects with mild cognitive impairment. This article will review both promises and caveats of the available data and propose future directions to be taken for addressing them.

Venneti S, Wiley CA, Kofler J. · Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. · J Neuroimmune Pharmacol. · Pubmed #19052878 No free full text.

Abstract: Microglial activation is an important pathogenic component of neurodegenerative disease processes. This state of increased inflammation is associated not only with neurotoxic consequences but also neuroprotective effects, e.g., phagocytosis and clearance of amyloid in Alzheimer's disease. In addition, activation of microglia appears to be one of the major mechanisms of amyloid clearance following active or passive immunotherapy. Imaging techniques may provide a minimally invasive tool to elucidate the complexities and dynamics of microglial function and dysfunction in aging and neurodegenerative diseases. Imaging microglia in vivo in live subjects by confocal or two/multiphoton microscopy offers the advantage of studying these cells over time in their native environment. Imaging microglia in human subjects by positron emission tomography scanning with translocator protein-18 kDa ligands can offer a measure of the inflammatory process and a means of detecting progression of disease and efficacy of therapeutics over time.

Zhao WQ, Townsend M. · Alzheimer's Research, Merck Research Laboratories, West Point, PA 19486, USA. · Biochim Biophys Acta. · Pubmed #19026743 No free full text.

Abstract: Characterized as a peripheral metabolic disorder and a degenerative disease of the central nervous system respectively, it is now widely recognized that type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and amyloidogenesis. Several recent studies suggest that this is not an epiphenomenon, but rather these two diseases disrupt common molecular pathways and each disease compounds the progression of the other. For instance, in AD the accumulation of the amyloid-beta peptide (Abeta), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. Studying these processes at a cellular level suggests that insulin resistance and Abeta aggregation may not only be the consequence of excitotoxicity, aberrant Ca(2+) signals, and proinflammatory cytokines such as TNF-alpha, but may also promote these pathological effectors. At the molecular level, insulin resistance and Abeta disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. Thus both disease processes contribute to overlapping pathology, thereby compounding disease symptoms and progression.

Klunk WE, Mathis CA. · Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. · Curr Opin Neurol. · Pubmed #18989113 links to  free full text

Abstract: PURPOSE OF REVIEW: This review will focus on the coming proliferation of amyloid-beta imaging tracers and give an opinion on how the Alzheimer's disease field can develop a systematic means of evaluating which tracers are useful and how the useful tracers compare to each other. RECENT FINDINGS: Several new tracers have been reported to be useful for human amyloid-beta imaging. The most recent of these are labeled with fluorine-18. Compared with the 20 min half-life of carbon-11 used in the most widely used tracer, Pittsburgh Compound-B, the 110 min half-life of fluorine-18 allows for wider utilization in research and clinical settings. SUMMARY: It is likely that more than one fluorine-18-labeled tracer will come into common use. The use of preclinical and clinical 'bridging studies' to [C-11]Pittsburgh Compound-B could be a means to determine whether the sizable body of knowledge already gained in [C-11]Pittsburgh Compound-B studies can be applied to the understanding of these new tracers and to form a basis for the comparison among them. This approach could save resources and help sort out a potentially bewildering onslaught of new amyloid-beta imaging tracers.

Caldwell JD, Jirikowski GF. · Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA. · Horm Metab Res. · Pubmed #18956301 No free full text.

Abstract: New and more active concepts of steroid binding globulin action are emerging from recent research. As a result, examination of steroid levels in aging humans and the role of steroid binding globulins need to be re-visited. This review will discuss the possibility that sex hormone binding globulin (SHBG) plays an active role in the aging process. It will discuss the changes in blood levels of SHBG in aging humans in association with sexual activity, prostate hypertrophy and cancer, uterine leiomyoma, breast cancer, obesity and particularly the relationship between SHBG and HDL-cholesterol, Alzheimer's disease, osteoporosis, and cardiovascular disease. Starting with the idea that SHBG is an active participant in steroid action demands a re-evaluation of data demonstrating a primary change in blood SHBG levels in association with various pathologies. Here we discuss the postulate that SHBG may act at its own receptor at the plasma membrane level to influence other receptors such as scavenger receptors and HDL-cholesterol receptors. We will also suggest that SHBG is a critical marker for mating and thus may be an important physiological molecule in control of aging.

Praticò D. · Department of Pharmacology, Temple University, School of Medicine, Philadelphia, PA 19140, USA. · Trends Pharmacol Sci. · Pubmed #18838179 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia. In its sporadic form, AD results from the combination of genetic factors with different epigenetic events. Among them, oxidative metabolic reactions and their by-products have been consistently implicated in AD pathogenesis and represent the biological basis for the 'oxidative stress hypothesis' of AD. Numerous studies demonstrate that different biomarkers of oxidative-stress-mediated events are elevated in the AD brain. Studies in animal models of the disease with antioxidants report significant improvements of their AD-like phenotype. Although epidemiologic studies show that dietary intake of antioxidants reduces the risk of AD, clinical trials with antioxidants show only a marginal positive or no effect. These conflicting results have created a wave of criticism towards the oxidative stress hypothesis of AD. Here, I review the available data and discuss the necessary paths for a fair reappraisal of the hypothesis.

Vosler PS, Brennan CS, Chen J. · Department of Neurology, University of Pittsburgh School of Medicine, S-507, Biomedical Science Tower, Pittsburgh, PA 15213, USA. · Mol Neurobiol. · Pubmed #18686046 No free full text.

Abstract: Calpain is a ubiquitous calcium-sensitive protease that is essential for normal physiologic neuronal function. However, alterations in calcium homeostasis lead to persistent, pathologic activation of calpain in a number of neurodegenerative diseases. Pathologic activation of calpain results in the cleavage of a number of neuronal substrates that negatively affect neuronal structure and function, leading to inhibition of essential neuronal survival mechanisms. In this review, we examine the mechanistic underpinnings of calcium dysregulation resulting in calpain activation in the acute neurodegenerative diseases such as cerebral ischemia and in the chronic neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, prion-related encephalopathy, and amylotrophic lateral sclerosis. The premise of this paper is that analysis of the signaling and transcriptional consequences of calpain-mediated cleavage of its various substrates for any neurodegenerative disease can be extrapolated to all of the neurodegenerative diseases vulnerable to calcium dysregulation.

Kuller LH, Lopez OL. · Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. · Alzheimers Dement. · Pubmed #18632006 No free full text.

Abstract: One of Dr Leon Thal's major contributions to Alzheimer's disease (AD) research was the network of clinical trials and his strong commitment to finding effective therapies for both the prevention and treatment of AD in the population. AD and dementia research has matured since the inception of the Alzheimer's Disease Center program from a primary social service problem to clinical-pathologic correlates and better definition of disease to evaluation of measures of cognition, in vivo images of the brain, and then to measures of beta amyloid and tau in vivo and relationship to clinical dementia. Unfortunately, we still do not know the etiology of AD or the relationship to other brain abnormalities such as vascular disease and Lewy bodies. We also do not have good preventive or treatment strategies. Both are badly needed. The critical question is whether this field is ready for a major change in focus from primarily a descriptive science to analytical, longitudinal studies testing new research hypotheses that will lead to better preventive and treatment approaches.

Balin BJ, Little CS, Hammond CJ, Appelt DM, Whittum-Hudson JA, Gérard HC, Hudson AP. · Department of Pathology, Microbiology, Immunology and Forensic Medicine, Philadelphia PA 19131, USA. · J Alzheimers Dis. · Pubmed #18487846 No free full text.

Abstract: Sporadic, late-onset Alzheimer's disease (LOAD) is a non-familial, progressive neurodegenerative disease that is now the most common and severe form of dementia in the elderly. That dementia is a direct result of neuronal damage and loss associated with accumulations of abnormal protein deposits in the brain. Great strides have been made in the past 20 years with regard to understanding the pathological entities that arise in the AD brain, both for familial AD ( approximately 5% of all cases) and LOAD ( approximately 95% of all cases). The neuropathology observed includes: neuritic senile plaques (NSPs), neurofibrillary tangles (NFTs), neuropil threads (NPs), and often deposits of cerebrovascular amyloid. Genetic, biochemical, and immunological analyses have provided a relatively detailed knowledge of these entities, but our understanding of the "trigger" events leading to the many cascades resulting in this pathology and neurodegeneration is still quite limited. For this reason, the etiology of AD, in particular LOAD, has remained elusive. However, a number of recent and ongoing studies have implicated infection in the etiology and pathogenesis of LOAD. This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a "trigger or initiator" in the pathogenesis of this disease.

Sharer J. · Indiana University of Pennsylvania, Indiana, PA, USA. · Medsurg Nurs. · Pubmed #18429537 No free full text.

Abstract: The early evening exacerbation of behavioral symptoms in sundowning has been recognized by medical professionals as a challenge. The circadian, hormonal, physiological, and environmental correlations with sundowning behaviors are described.

Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS. · Wyeth Research, Collegeville, PA 19426, USA. · Neurodegener Dis. · Pubmed #18322388 No free full text.

Abstract: BACKGROUND: In a phase 2a clinical trial of AN1792 (Study 201), a potential immunotherapeutic agent for use in Alzheimer's disease (AD), approximately 6% of the treated AD patients (18/300) developed meningoencephalitis (ME). OBJECTIVE: To elucidate potential immune mechanisms of treatment-induced ME. METHODS: Peripheral blood mononuclear cells obtained from patients who received AN1792 were stimulated in vitro either with beta-amyloid (Abeta) or various overlapping peptides of Abeta(1-42), followed by quantification of cytokine-secreting cells by enzyme-linked immunosorbent spot assay. RESULTS: A significant difference in the quality of the T-cell responses between patients in Study 201 and those in earlier studies of AN1792 was noted. T-cell responses specific to the carboxy terminus of Abeta elicited from patients' peripheral blood mononuclear cells in an earlier multiple dose study (Study 102) were Th2 biased, while those from Study 201 were biased toward a proinflammatory Th1 response. Antibody responses in both studies were quantitatively and qualitatively similar (as determined by epitope mapping). The addition of polysorbate 80 to the formulation used in Study 201 is the most likely explanation for the difference in the T-cell response. CONCLUSION: ME following injection of AN1792 may be related to immune response differences driven by a formulation change. To address this, a novel peptide-carrier protein conjugate using an amino-terminal fragment of Abeta (ACC-001) has been developed to avoid potentially harmful T-cell responses, while maintaining a similar antibody response to that of AN1792. Immunotherapeutic trials using this treatment approach in AD patients are in progress.

Doty RL. · Smell and Taste Center and Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Ann Neurol. · Pubmed #18232016 No free full text.

Abstract: Environmental agents, including viruses, prions, and toxins, have been implicated in the cause of a number of neurodegenerative diseases, most notably Alzheimer's and Parkinson's diseases. The presence of smell loss and the pathological involvement of the olfactory pathways in the formative stages of Alzheimer's and Parkinson's diseases, together with evidence that xenobiotics, some epidemiologically linked to these diseases, can readily enter the brain via the olfactory mucosa, have led to the hypothesis that Alzheimer's and Parkinson's diseases may be caused or catalyzed by agents that enter the brain via this route. Evidence for and against this concept, the "olfactory vector hypothesis," is addressed in this review.

Buxbaum LJ, Haaland KY, Hallett M, Wheaton L, Heilman KM, Rodriguez A, Gonzalez Rothi LJ. · Moss Rehabilitation Research Institute, Philadelphia, Pennsylvania 19141, USA. · Am J Phys Med Rehabil. · Pubmed #18209511 No free full text.

Abstract: Limb apraxia is a common disorder of skilled, purposive movement that is frequently associated with stroke and degenerative diseases such as Alzheimer disease. Despite evidence that several types of limb apraxia significantly impact functional abilities, surprisingly few studies have focused on development of treatment paradigms. Additionally, although the most disabling types of apraxia reflect damage to gesture and/or object memory systems, existing treatments have not fully taken advantage of principles of experience known to affect learning and neural plasticity. We review the current state of the art in the rehabilitation of limb apraxia, indicate possible points of contact with the learning literature, and generate suggestions for how translational principles might be applied to the development of future research on treatment of this disabling disorder.

Abel T, Zukin RS. · Department of Biology, University of Pennsylvania, 204G Lynch Laboratories, 433 South University Avenue, Philadelphia, PA 19104-6018, USA. · Curr Opin Pharmacol. · Pubmed #18206423 links to  free full text

Abstract: Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition, and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington's disease, Parkinson's disease, anxiety and mood disorders, Rubinstein-Taybi syndrome, and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological, and psychiatric disorders.

Shaw LM. · Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Neurosignals. · Pubmed #18097156 links to  free full text

Abstract: There is a pressing need to develop effective prevention and disease-modifying treatments for Alzheimer's disease (AD), a dreaded affliction whose incidence increases almost logarithmically with age starting at about 65 years. A key need in the field of AD research is the validation of imaging and biochemical biomarkers. Biomarker tests that are shown to reliably predict the disease before it is clinically expressed would permit testing of new therapeutics at the earliest time point possible in order to give the best chance for delaying the onset of dementia in these patients. In this review the current state of AD biochemical biomarker research is discussed. A new set of guidelines for the diagnosis of AD in the research setting places emphasis on the inclusion of selected imaging and biochemical biomarkers, in addition to neuropsychological behavioral testing. Importantly, the revised guidelines were developed to identify patients at the earliest stages prior to full-blown dementia as well as patients with the full spectrum of the disease. The Alzheimer's Disease Neuroimaging Initiative is a multicenter consortium study that includes as one of its primary goals the development of standardized neuroimaging and biochemical biomarker methods for AD clinical trials, as well as using these to measure changes over time in mildly cognitively impaired patients who convert to AD as compared to the natural variability of these in control subjects and their further change over time in AD patients. Validation of the biomarker results by correlation analyses with neuropsychological and neurobehavioral test data is one of the primary outcomes of this study. This validation data will hopefully provide biomarker test performance needed for effective measurement of the efficacy of new treatment and prevention therapeutic agents.

Clark CM, Davatzikos C, Borthakur A, Newberg A, Leight S, Lee VM, Trojanowski JQ. · Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. · Neurosignals. · Pubmed #18097155 No free full text.

Abstract: The increasing prevalence of Alzheimer's disease and the devastating consequences of late-life dementia motivates the drive to develop diagnostic biomarkers to reliably identify the pathology associated with this disorder. Strategies to accomplish this include the detection of altered levels of tau and amyloid in cerebrospinal fluid, the use of structural MRI to identify disease-specific patterns of regional atrophy and MRI T(1)rho to detect disease-related macromolecular protein aggregation, and the direct imaging of amyloid deposits using positron emission tomography and single photon emission computerized tomography. Success will facilitate the ability to reliably diagnose Alzheimer's disease while the symptoms of brain failure are mild and may provide objective measures of disease-modifying treatment efficacy.