Alzheimer Disease: US Mid-Atlantic

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.

Mattson MP. · Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. · Ann N Y Acad Sci. · Pubmed #19076369 links to  free full text

Abstract: Glutamate's role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis, and neuron survival in the developing and adult mammalian nervous system. Cell-surface glutamate receptors are coupled to Ca(2+) influx and release from endoplasmic reticulum stores, which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF), which, in turn, modifies neuronal glutamate sensitivity, Ca(2+) homeostasis, and plasticity. Neurotrophic factors may modify glutamate signaling directly, by changing the expression of glutamate receptor subunits and Ca(2+)-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins, and antiapoptotic Bcl-2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer's disease to psychiatric disorders. By enhancing neurotrophic factor signaling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signaling and protect against neurological disorders.

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.

Mattson MP, Ashery U. · Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. · Trends Biochem Sci. · Pubmed #19008105 links to  free full text

Abstract: In Alzheimer's disease (AD), neurons suffer dysfunction and death associated with aberrant tau phosphorylation and subsequent neurofibrillary tangles. A new study reveals a surprising neuroprotective role for a truncated p73 isoform (DeltaNp73). Aged mice with reduced DeltaNp73 levels exhibit tau pathology and cognitive deficits, and DeltaNp73 reduction in mice with amyloid pathology causes extensive tangle formation and neuron death. These findings provide a novel animal model of AD and a potential therapeutic role for DeltaNp73 inducers.

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.

Schmitz T, Chew LJ. · Center for Neuroscience Research, Children's Research Institute, Washington, D.C., USA. · ScientificWorldJournal. · Pubmed #18979053 links to  free full text

Abstract: Myelin abnormalities that reflect damage to developing and mature brains are often found in neurological diseases with evidence of inflammatory infiltration and microglial activation. Many cytokines are virtually undetectable in the uninflamed central nervous system (CNS), so that their rapid induction and sustained elevation in immune and glial cells contributes to dysregulation of the inflammatory response and neural cell homeostasis. This results in aberrant neural cell development, cytotoxicity, and loss of the primary myelin-producing cells of the CNS, the oligodendrocytes. This article provides an overview of cytokine and chemokine activity in the CNS with relevance to clinical conditions of neonatal and adult demyelinating disease, brain trauma, and mental disorders with observed white matter defects. Experimental models that mimic human disease have been developed in order to study pathogenic and therapeutic mechanisms, but have shown mixed success in clinical application. However, genetically altered animals, and models of CNS inflammation and demyelination, have offered great insight into the complexities of neuroimmune interactions that impact oligodendrocyte function. The intracellular signaling pathways of selected cytokines have also been highlighted to illustrate current knowledge of receptor-mediated events. By learning to interpret the actions of cytokines and by improving methods to target appropriate predictors of disease risk selectively, a more comprehensive understanding of altered immunoregulation will aid in the development of advanced treatment options for patients with inflammatory white matter disorders.

Rapoport SI. · Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Building 9, Room 1S128, 9 Memorial Drive, Bethesda, MD 20892, USA. · Prostaglandins Leukot Essent Fatty Acids. · Pubmed #18973997 No free full text.

Abstract: Metabolic cascades involving arachidonic acid (AA) and docosahexaenoic acid (DHA) within brain can be independently targeted by drugs, diet and pathological conditions. Thus, AA turnover and brain expression of AA-selective cytosolic phospholipase A(2) (cPLA(2)), but not DHA turnover or expression of DHA-selective Ca(2+)-independent iPLA(2), are reduced in rats given agents effective against bipolar disorder mania, whereas experimental excitotoxicity and neuroinflammation selectively increase brain AA metabolism. Furthermore, the brain AA and DHA cascades are altered reciprocally by dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats. DHA loss from brain is slowed and iPLA(2) expression is decreased, whereas cPLA(2) and COX-2 are upregulated, as are brain concentrations of AA and its elongation product, docosapentaenoic acid (DPA). Positron emission tomography (PET) has shown that the normal human brain consumes 17.8 and 4.6 mg/day, respectively, of AA and DHA, and that brain AA consumption is increased in Alzheimer disease patients. In the future, PET could help to determine how human brain AA or DHA consumption is influenced by diet, aging or disease.

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.

Becker RE, Greig NH, Giacobini E. · Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · J Alzheimers Dis. · Pubmed #18953116 No free full text.

Abstract: Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, and lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice.

Lee HB, DeLoatch CJ, Cho S, Rosenberg P, Mears SC, Sieber FE. · Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-5371, USA. · Crit Care Clin. · Pubmed #18929940 No free full text.

Abstract: Recent increase in both the elderly population and associated incidence of dementia are of critical importance to patient care in ICUs in the United States. Identification of pre-existing cognitive impairment, such as mild cognitive impairment and dementia, could prevent delirium and associated morbidity and mortality in the ICU. Additionally, noncognitive behavioral symptoms, such as depression, psychosis, agitation, and catastrophic reactions, are common in patients with pre-existing cognitive impairment. Detection and management of noncognitive behavioral symptoms associated with MRI and dementia in ICU leads to improved delivery of life-saving critical care.

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.

Miller DB, O'Callaghan JP. · Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA. · Metabolism. · Pubmed #18803966 No free full text.

Abstract: How early-life events "set the stage" for adult disease has emerged as a research focus. Historically, the epidemiology of disease risk factors has centered on adult life, with little scrutiny of early-life events. Here we review the concept that events in early life may contribute to late-life neurodegenerative disease development, with a focus on Parkinson disease (PD) and Alzheimer disease (AD). Suspect events in early life include infections, stress, poor nutrition, and environmental factors such as chemical and pesticide exposure. Adiposity appears to contribute to both PD and AD; and because early-life events contribute to the development of obesity, linkages may exist between early determinants of obesity and the subsequent development of these neurologic diseases. Many now suggest a life-course approach for determining the relative contributions of genetic and environmental factors in any chronic disease. This requires determining when during the life course that a given exposure has its greatest effect and how exposures may accumulate over the life span. The data for PD and AD suggest that a number of insults occurring early in life may lead or contribute to these diseases. More definitive knowledge of the key risk factors involved will be needed to implement intervention and preventative strategies early in life to dampen or prevent any adverse late-life outcomes.

Becker RE, 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 #18690832 links to  free full text

Abstract: Recently, a number of Alzheimer's disease (AD) multi-center clinical trials (CT) have failed to provide statistically significant evidence of drug efficacy. To test for possible design or execution flaws we analyzed in detail CTs for two failed drugs that were strongly supported by preclinical evidence and by proven CT AD efficacy for other drugs in their class. Studies of the failed commercial trials suggest that methodological flaws may contribute to the failures and that these flaws lurk within current drug development practices ready to impact other AD drug development [1]. To identify and counter risks we considered the relevance to AD drug development of the following factors: (1) effective dosing of the drug product, (2) reliable evaluations of research subjects, (3) effective implementation of quality controls over data at research sites, (4) resources for practitioners to effectively use CT results in patient care, (5) effective disease modeling, (6) effective research designs. New drugs currently under development for AD address a variety of specific mechanistic targets. Mechanistic targets provide AD drug development opportunities to escape from many of the factors that currently undermine AD clinical pharmacology, especially the problems of inaccuracy and imprecision associated with using rated outcomes. In this paper we conclude that many of the current problems encountered in AD drug development can be avoided by changing practices. Current problems with human errors in clinical trials make it difficult to differentiate drugs that fail to evidence efficacy from apparent failures due to Type II errors. This uncertainty and the lack of publication of negative data impede researchers' abilities to improve methodologies in clinical pharmacology and to develop a sound body of knowledge about drug actions. We consider the identification of molecular targets as offering further opportunities for overcoming current failures in drug development.

Castellani RJ, Nunomura A, Lee HG, Perry G, Smith MA. · Department of Pathology, University of Maryland, Baltimore, MD, USA. · J Alzheimers Dis. · Pubmed #18688087 No free full text.

Abstract: Identification of phosphorylated tau as the major protein component of neurofibrillary tangles (NFTs) led to the concept that phosphorylated tau was inherently toxic and, as such, intimately involved in Alzheimer's disease (AD) pathogenesis. While superficially logical, this construct ignores a number of key findings in AD, including i) that NFTs are encountered in viable neurons until late stage disease; ii) that NFTs persist within the neuronal cytoplasm for decades; iii) that NFTs are encountered, sometimes in significant numbers, in cognitively intact elderly; and iv) that neurons with NFTs contain normal content and structure of microtubules. Experimental data in transgenic animal models has further demonstrated that NFTs accumulate in neurons in spite of tau suppression and behavior normalization. These data call into question the inherent toxicity of phosphorylated tau, seemingly leaving the only viable hypothesis of the ad hoc "toxic intermediate" phosphorylated tau concept. However, since we also know that phosphorylated tau sequesters redox active heavy metals and protects against oxidative stress, here we suggest that phosphorylated tau serves a protective role against cellular toxicity.

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.

Puentes WJ. · University of Medicine & Dentistry of New Jersey, School of Nursing, Stratford, NJ 08084-1350, USA. · J Gerontol Nurs. · Pubmed #18649823 No free full text.

Abstract: When the psychodynamics of simple reminiscence, the kind of reminiscence used to manage anxiety, are disrupted, individuals can become stuck on certain memories and begin to obsess or ruminate about them. Generally, obsessive reminiscence is identified as nonpurposive and dysfunctional. However, interpreting the content of obsessive reminiscence within an associational trends framework demonstrates that useful diagnostic information can be gleaned from obsessive reminiscence.This information can be incorporated into the treatment plan to enhance the quality of care delivered to clients, as well as clients'interpersonal relationships.

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.

Hodes RJ, Buckholtz N, Cahan V, Morrison-Bogorad M. · National Institute on Aging, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD, USA. · Alzheimers Dement. · Pubmed #18631998 No free full text.

Abstract: The public Alzheimer's disease (AD) research enterprise began in earnest in the mid-1970s with the creation by Congress of the National Institute on Aging at the National Institutes of Health. Today, AD research is a maturing field of study, with federal effort seeking to encourage the creativity and insights of individual investigators, and targeting special areas for emphasis. It is inspired by the legacy of our friend and colleague Leon Thal, whose innovative and collaborative approach to scientific research serves as a guidepost as we move toward the discovery of new and effective ways to prevent AD or slow its progression. This article describes the progress to date and potentially promising areas of study from the vantage point of the National Institute on Aging.

Oh ES, Troncoso JC, Fangmark Tucker SM. · Department of Medicine, The Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Ave., Baltimore, MD 21205, USA. · Neuromolecular Med. · Pubmed #18543125 links to  free full text

Abstract: Amyloid plaques are composed primarily of amyloid-beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) and are considered to play a pivotal role in Alzheimer's disease (AD) pathogenesis. Presently, AD is diagnosed after the onset of clinical manifestations. With the arrival of novel therapeutic agents for treatment of AD, there is an urgent need for biomarkers to detect early stages of AD. Measurement of plasma Abeta has been suggested as an inexpensive and non-invasive tool to diagnose AD and to monitor Abeta modifying therapies. However, the majority of cross-sectional studies on plasma Abeta levels in humans have not shown differences between individuals with AD compared to controls. Similarly, cross-sectional studies of mouse plasma Abeta have yielded inconsistent trends in different mouse models. However, longitudinal studies appear to be more promising in humans. Recently, efforts to modify plasma Abeta levels using modulators have shown some promise. In this review, we will summarize the present data on plasma Abeta in humans and mouse models of AD. We will discuss the potential of modulators of Abeta levels in plasma, including antibodies and insulin, and the challenges associated with measuring plasma Abeta. Modulators of plasma Abeta may provide an important tool to optimize plasma Abeta levels and may improve the diagnostic potential of this approach.

Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA. · Department of Pathology, University of Maryland, Baltimore, Maryland, USA. · J Neuropathol Exp Neurol. · Pubmed #18520771 No free full text.

Abstract: Identification of amyloid-beta and tau as the major protein components of senile plaques and neurofibrillary tangles, respectively, led to an exponential increase in investigations of these proteins and their corresponding metabolic pathways in Alzheimer disease (AD). The presumptions inherent in most studies and in the dogma of the amyloid cascade concept are that these hallmark lesions in AD brains contain molecules that drive the disease process, and that the proteinaceous accumulations are themselves toxic. On the other hand, the lesions of AD are, by definition, end-stage, and their relationship to the clinical disease is inconsistent; this has long been known but, generally, has not been acknowledged until relatively recently. Some recent attempts to address the etiology and pathogenesis of AD discard the pathology and focus on the interplay between invisible toxic intermediates, that is, amyloid-beta oligomers and the synapse. The concept that the hallmark lesions may be nontoxic (something we have long suggested) is slowly gaining acceptance. We favor the interpretation that senile plaques and neurofibrillary tangles represent a host response to an upstream pathophysiologic process, and that the therapeutic targeting of lesions, including toxic intermediates, will succeed only in the event that the host response is directly deleterious. Therefore, renewed efforts aimed at elucidating fundamental age-related processes such as oxidative stress and/or inflammatory mediators are warranted.

Crawley JN. · Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Porter Neuroscience Research, Center Building 35, Room 1C-903, Mail Code 3730, Bethesda, Maryland 20892-3730, USA. · Cell Mol Life Sci. · Pubmed #18500642 links to  free full text

Abstract: The neuropeptide galanin and its receptors are localized in brain pathways mediating learning and memory. Central microinjection of galanin impairs performance of a variety of cognitive tasks in rats. Transgenic mice overexpressing galanin display deficits in some learning and memory tests. The inhibitory role of galanin in cognitive processes, taken together with the overexpression of galanin in Alzheimer's disease, suggests that galanin antagonists may offer a novel therapeutic approach to treat memory loss in Alzheimer's patients.

Lyketsos CG, Szekely CA, Mielke MM, Rosenberg PB, Zandi PP. · Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A. · Int Psychogeriatr. · Pubmed #18498669 No free full text.

Abstract: This synthetic review presents an approach to the use of biomarkers for the development of new treatments for Alzheimer's disease (AD). After reviewing the process of translation as applied to AD, the paper provides a general update on what is known about the biology of the disease, and highlights currently available treatments. This is followed by a discussion of future drug development for AD emphasizing the roles that biomarkers are likely to play in this process: (1) define patients who are going to progress rapidly for the purpose of trial enrichment; (2) differentiate disease and therapeutically relevant AD subtypes; (3) assess the potential activity of specific therapies in vivo or ex vivo; and (4) measure the underlying disease state, so as to (a) detect disease and assess drug response in asymptomatic patients, (b) serve as a secondary outcome measure in clinical trials of symptomatic patients, and (c) decide if further development of a treatment should be stopped if not likely to be effective. Several examples are used to illustrate each biomarker utility in the AD context.

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.

Butts BD, Houde C, Mehmet H. · Apoptosis Research Group, Merck Research Laboratories, RY80Y-215, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. · Cell Death Differ. · Pubmed #18483490 links to  free full text

Abstract: Apoptosis plays a crucial role in brain development by ensuring that only appropriately growing, migrating, and synapse-forming neurons and their associated glial cells survive. This process involves an intimate relationship between cell-cell interactions and developmental cues and is further impacted by environmental stress during neurogenesis and disease. Oligodendrocytes (OLs), the major myelin-forming cells in the central nervous system, largely form after this wave of neurogenesis but also show a selective vulnerability to cell death stimuli depending on their stage of development. This can affect not only embryonic and early postnatal brain formation but also the response to demyelinating pathologies. In the present review, we discuss the stage-specific sensitivity of OL lineage cells to damage-induced death and how this might impact myelin survival and regeneration during injury or disease.