Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of AD

  • c. ad
  • century ad
  • chiralpak ad
  • early ad
  • familial ad
  • first century ad
  • fourth century ad
  • infantile ad
  • mild ad
  • moderate ad
  • period ad
  • possible ad
  • probable ad
  • second century ad
  • seventh century ad
  • severe ad
  • sixth century ad
  • sporadic ad

  • Terms modified by AD

  • ad brain
  • ad case
  • ad extra
  • ad family
  • ad group
  • ad groups
  • ad hoc
  • ad hoc basis
  • ad hoc methods
  • ad hoc network
  • ad hoc questionnaire
  • ad hoc way
  • ad intra
  • ad libitum
  • ad libitum access
  • ad libitum feeding
  • ad pathogenesis
  • ad pathology
  • ad patient
  • ad risk
  • ad severity
  • ad skin
  • ad subject
  • ad therapy
  • ad treatment
  • ad vector

  • Selected Abstracts

    Magnetic resonance spectroscopy (MRS) and its application in Alzheimer's disease

    Pravat K. Mandal
    Abstract Magnetic resonance spectroscopy (MRS) is a noninvasive tool to measure the chemical composition of tissues (in vivo) and characterize functional metabolic processes in different parts of the human organs. It provides vital biological information at the molecular level. Combined with magnetic resonance imaging (MRI), an integrated MRI/MRS examination provides anatomical structure, pathological function, and biochemical information about a living system. MRS provides a link between the biochemical alterations and the pathophysiology of disease. This article provides a comprehensive description of the MRS technique and its application in Alzheimer's disease (AD) research. This review is a primer for students and researchers seeking a firm theoretical understanding of MRS physics as well as its application in clinical AD research. © 2007 Wiley Periodicals, Inc. Concepts Magn Reson Part A 30A: 40,64, 2007. [source]

    Think Globally, Publish Virtually, Act Locally: A U.S.-Saudi International Museum Partnership

    Paul Michael Taylor
    ABSTRACT This paper examines an on-going cooperative project between the National Museum of the Kingdom of Saudi Arabia and the National Museum of Natural History, Smithsonian Institution, undertaken within the framework of the International Partnership Among Museums (IPAM) program of the American Association of Museums. The project,Written in Stone: Epigraphy from the National Museum of Saudi Arabia,is a virtual Web exhibition of inscriptions dating from the late second millennium B.C. to the nineteenth century AD. It is undoubtedly representative of many special-purpose cooperative projects (for exhibitions, research, or other purposes) that are taking place across international boundaries between pairs or groups of museums in various countries. Such collaborations provide examples of how partner institutions can take advantage of the opportunities that globalization and standardization of museum practices offer. [source]

    Cancer risk from diagnostic radiology in a deliberate self-harm patient

    L. J. Norelli
    Norelli LJ, Coates AD, Kovasznay BM. Cancer risk from diagnostic radiology in a deliberate self-harm patient. Objective:, Patients who engage in recurrent deliberate self-harm (DSH) behaviours have increased morbidity and mortality and use emergency services more than others. Unrecognized iatrogenic injury may play a role. Specifically, we call attention to the potential danger of cumulative radiation exposure. Method:, Case presentation and discussion. Results:, A 29-year-old woman with multiple episodes of deliberate foreign body ingestion received over 400 diagnostic radiology examinations during a 12 year period. The patient's calculated total radiation dose reached an average of 20.5 mSv per year, a dose comparable to atomic bomb survivors and nuclear industry workers, populations in which there is a significant excess cancer risk. Conclusion:, Patients with recurrent self-injurious behaviours, frequent users of healthcare services who often undergo repeated medical assessment and treatment, are likely at higher risk for iatrogenic adverse events. Multiple diagnostic radiology examinations have recently come under scrutiny for causing increased lifetime risk of cancer. Healthcare providers, in particular psychiatrists and emergency department physicians, should consider the cumulative risks of radiological procedures when assessing and treating patients with DSH. [source]

    Trends in prevalence of Alzheimer's disease and vascular dementia in a Japanese community: the Hisayama Study

    A. Sekita
    Sekita A, Ninomiya T, Tanizaki Y, Doi Y, Hata J, Yonemoto K, Arima H, Sasaki K, Iida M, Iwaki T, Kanba S, Kiyohara Y. Trends in prevalence of Alzheimer's disease and vascular dementia in a Japanese community: the Hisayama Study. Objective:, To examine secular trends in the prevalence of Alzheimer's disease (AD) and vascular dementia (VD) in a general Japanese population. Method:, Four cross-sectional examinations were conducted among residents of a Japanese community aged ,65 in 1985, 1992, 1998 and 2005. Results:, The age- and sex-adjusted prevalence of all-cause dementia significantly increased with time (6.0% in 1985, 4.4% in 1992, 5.3% in 1998 and 8.3% in 2005; P for trend = 0.002). A similar trend was observed for AD (1.1%, 1.3%, 2.3% and 3.8% respectively; P for trend < 0.001), while the age- and sex-adjusted prevalence of VD and other/unclassified dementia showed J-shaped patterns (for VD: 2.3%, 1.5%, 1.5% and 2.5%, respectively, P for trend = 0.82; for other/unclassified dementia: 2.6%, 1.7%, 1.5% and 2.0%, P for trend = 0.26). The prevalence of AD was likely to increase with time from 1985 to 2005 among subjects aged 75 or older. The ratio of the prevalence of VD to that of AD decreased with time (2.1 in 1985, 1.2 in 1992, 0.7 in 1998 and 0.7 in 2005). Conclusion:, Our findings suggest that the prevalence of all-cause dementia and AD significantly increased over the past two decades in the general Japanese population. [source]

    The Effects of Ambulance Diversion: A Comprehensive Review

    Julius Cuong Pham MD
    Objectives To review the current literature on the effects of ambulance diversion (AD). Methods The authors performed a systematic review of AD and its effects. PubMed, EMBASE, the Cochrane database, societal meeting abstracts, and references from relevant articles were searched. All articles were screened for relevance to AD. Results The authors examined 600 citations and reviewed the 107 articles relevant to AD. AD is a common occurrence that is increasing in frequency. AD is associated with periods of emergency department (ED) crowding (Mondays, mid-afternoon to early evening, influenza season, and when hospitals are at capacity). Interventions that redesign the AD process or that provide additional hospital or ED resources reduce diversion frequency. AD is associated with increased patient transport times and time to thrombolytics but not with mortality. AD is associated with loss of estimated hospital revenues. Short of anecdotal or case reports, no studies measured the effect of AD on ED crowding, morbidity, patient and provider satisfaction, or EMS resource utilization. Conclusions Despite its common use, there is a relative paucity of studies on the effects of AD. Further research into these effects should be performed so that we may understand the role of AD in the health system. [source]

    An algorithm for the pharmacological treatment of depression

    J. Spijker
    Spijker J, Nolen WA. An algorithm for the pharmacological treatment of depression. Objective:, Non-response to treatment with antidepressants (AD) is a clinical problem. Method:, The algorithm for pharmacological treatment of the Dutch multidisciplinary guideline for depression is compared with four other algorithms. Results:, The Dutch algorithm consists of five subsequent steps. Treatment is started with one out of many optional ADs (step 1); in case of non-response after 4,10 weeks, best evidence is for switching to another AD (step 2); next step is augmentation with lithium as the best option (step 3); the next step is a monoamine oxidase inhibitor (MAOI) (step 4); and finally electroconvulsive therapy (step 5). There are major differences with other algorithms regarding timing of augmentation step, best agents for augmentation and role of MAOI. Conclusion:, Algorithms for AD treatment vary according to national and local preferences. Although the evidence for most of the treatment strategies is rather meagre, an AD algorithm appears to be an useful instrument in clinical practice. [source]

    Impulsive aggression in adults with attention-deficit/hyperactivity disorder

    J. H. Dowson
    Dowson JH, Blackwell AD. Impulsive aggression in adults with attention-deficit/hyperactivity disorder. Objective:, DSM-IV criteria for attention-deficit/hyperactivity disorder (ADHD) include examples of ,impulsivity'. This term can refer to various dysfunctional behaviours, including some examples of aggressive behaviour. However, impulsive aggression is not included in the DSM-IV criteria for ADHD. The associations of impulsive aggression with ADHD were investigated. Method:, Seventy-three male adults with DSM-IV ADHD, and their informants, completed questionnaires. Impulsive aggression was assessed by ratings of two criteria for borderline personality disorder (BPD), involving hot temper and/or self-harm. Results:, Logistic regression indicated that features of DSM-IV ADHD were predictors of comorbid impulsive aggression. However, compared with ADHD features, verbal IQ and comorbid psychopathology were more strongly associated with impulsive aggression. Conclusion:, The findings support the inclusion of features of impulsive aggression, such as hot temper/short fuse, in the ADHD syndrome in adults. These overlap with features of BPD. The findings inform the selection of research samples. [source]

    The differential diagnosis of atopic dermatitis in childhood

    Alfons Krol
    ABSTRACT:, Atopic is the most common of the dermatitides seen in infancy and childhood, but there are numerous other diseases that can mimic the skin findings. These include seborrheic dermatitis, immunodeficiency, and psoriasis in infancy; scabies, tinea corporis infection, perioral, nummular, contact, and molluscum dermatitis in childhood. It is sometimes extremely difficult to differentiate between ichthyosis and AD, and it is also important to differentiate AD from erythrodermic conditions including acrodermatitis enteropathica, biotin deficiency, and Netherton syndrome. A rare condition in children that may mimic AD is mycosis fungoides. [source]

    Patterns of care and referral in children with atopic dermatitis and concern for food allergy

    Michele M. Thompson
    ABSTRACT:, Although many providers believe that up to 30% of atopic dermatitis (AD) is food induced, food challenge studies show that food-induced eczematous reactions are rare. When food allergy is suggested to cause AD, it often leads to allergy testing with a high false-positivity rate, in turn further focusing parents on food allergy. Study subjects were children less than 11 years old with AD and food allergy suspicion. Prior diagnoses, provider, and testing patterns were assessed by questionnaire given to the parents. Thirty-eight patients with AD were enrolled. Most subject's parents suspected food allergy induced AD. Initial skin diagnoses were made by pediatricians (79%) and family practitioners (18%) as eczema. Allergy was suggested by providers as cause for AD in 63% of the present study's patients. Seventy-nine percent had allergy testing. Greater than 90% of parents claimed their children had food allergy and food-induced AD. Sixty-six percent had positive food allergy tests and 37% had definite history of immediate IgE reactions to food. The majority of this population had allergy suggested as causative for eczema by their primary care provider and were subsequently evaluated by allergist and allergy testing. Consensus about the role of food allergy between the different providers of AD in children would result in more effective, efficient, and less costly health care. [source]

    Does food allergy cause atopic dermatitis?

    Food challenge testing to dissociate eczematous from immediate reactions
    ABSTRACT:, The objective is to evaluate and diagnose, in a controlled setting, suspected food allergy causation in patients hospitalized for management of severe, unremitting atopic dermatitis (AD). Nineteen children were hospitalized at Oregon Health and Science University with atopic dermatitis from 1986 to 2003 for food restriction, then challenge, following standard recommendations. Challenges were prioritized by categories of (a) critical foods (e.g., milk, wheat, egg, soy); (b) important foods; and (c) other suspected foods. Patients were closely observed for evidence of pruritus, eczematous responses, or IgE-mediated reactions. If results were inconsistent, double-blind, placebo-controlled food challenge was performed. A total of 17 children with atopic dermatitis were assessed. Two could not be fully evaluated, thus were excluded from data tabulations. Only one positive eczematous food response was observed of 58 challenges. Three children had well-documented histories of food-induced IgE-mediated anaphylactoid or urticaria reactions to seafood and/or nuts and were not challenged with those foods. Atopic dermatitis, even in the highest-risk patients, is rarely induced by foods. Undocumented assumptions of food causation detract from proper anti-inflammatory management and should be discouraged. Immediate IgE-mediated food reactions are common in atopic dermatitis patients; such reactions are rapid onset, typically detected outside the clinic, and must be distinguished from eczematous reactions. Diagnosis of food-induced eczema cannot be made without food challenge testing. Such tests can be practical and useful for dispelling unrealistic assumptions about food allergy causation of atopic dermatitis. [source]

    Topical tacrolimus in the management of atopic dermatitis in Japan

    Masutaka Furue
    ABSTRACT:, Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Topical calcineurin inhibitors, such as tacrolimus, not only complement existing treatment options but also overcome some of the drawbacks of topical steroid therapy and fulfill the long-term needs of patients in preventing disease progression. Short- and long-term efficacy and safety of topical tacrolimus has been widely recognized and it is also accepted as a first-line treatment for the inflammation of AD. In order to reduce the possible long-term adverse effects, it is important to monitor the clinical dose in daily clinics. [source]

    Rate of progression of mild cognitive impairment to dementia , meta-analysis of 41 robust inception cohort studies

    A. J. Mitchell
    Objective:, To quantify the risk of developing dementia in those with mild cognitive impairment (MCI). Method:, Meta-analysis of inception cohort studies. Results:, Forty-one robust cohort studies were identified. To avoid heterogeneity clinical studies, population studies and clinical trials were analysed separately. Using Mayo defined MCI at baseline and adjusting for sample size, the cumulative proportion who progressed to dementia, to Alzheimer's disease (AD) and to vascular dementia (VaD) was 39.2%, 33.6% and 6.2%, respectively in specialist settings and 21.9%, 28.9% and 5.2%, respectively in population studies. The adjusted annual conversion rate (ACR) from Mayo defined MCI to dementia, AD and VaD was 9.6%, 8.1% and 1.9%, respectively in specialist clinical settings and 4.9%, 6.8% and 1.6% in community studies. Figures from non-Mayo defined MCI and clinical trials are also reported. Conclusion:, The ACR is approximately 5,10% and most people with MCI will not progress to dementia even after 10 years of follow-up. [source]

    Is the dementia rate increasing in Beijing?

    Prevalence, incidence of dementia 10 years later in an urban elderly population
    Objective:, To examine the time trend of dementia morbidity over the past decade in Beijing, China. Method:, In 1997, 1593 community-dwelling elderly aged 60+ years were examined and followed-up over 2-years to identify incident dementia. A similar cohort study of dementia conducted in the same district 10 years prior was used as historical comparison to examine the time trend of dementia incidence. Results:, Forty prevalent dementia cases were identified at the initial examination for a prevalence of 2.51% (95% CI: 1.74,3.28) and 25 incident cases were identified at the follow-up visit for an incidence of 0.90% (0.55,1.25) among residents aged 60+ years. Alzheimer's dementia (AD) was the most common type of dementia in both prevalent and incident cases. Conclusion:, The prevalence and incidence rates of dementia in Beijing were slightly higher than those 10 years ago, which was partly because of population aging. AD became the most common subtype of dementia. [source]

    Cognitive training in Alzheimer's disease: a meta-analysis of the literature

    D. I. Sitzer
    Objective:, To systematically review the literature and summarize the effect of cognitive training (CT) for Alzheimer's disease (AD) patients on multiple functional domains. Method:, Effect sizes (Cohen's d) were calculated for 17 controlled studies identified through a comprehensive literature review. Results:, An overall effect size of 0.47 was observed for all CT strategies across all measured outcomes. Mean effect sizes were higher for restorative (0.54) than for compensatory (0.36) strategies. Domain-specific effect sizes ranged from 2.16 (verbal and visual learning) to ,0.38 (visuospatial functioning). Data are also presented on the relative impact of restorative and compensatory strategies for each domain of functioning. Conclusion:, CT evidenced promise in the treatment of AD, with primarily medium effect sizes for learning, memory, executive functioning, activities of daily living, general cognitive problems, depression, and self-rated general functioning. Restorative strategies demonstrated the greatest overall effect on functioning. Several limitations of the published literature are discussed. [source]

    Complex visual hallucination and mirror sign in posterior cortical atrophy

    T. Yoshida
    Objective:, In posterior cortical atrophy (PCA), visual hallucinations are rare symptoms and mirror sign has not been described. Method:, Single case report. Results:, We reported a 60-year-old woman with PCA who reported complex visual hallucinations, such as a man walking in her room, and mirror sign, which was the perception of a stranger staring at her when she looked into a mirror. She could not recognize images of herself in the mirror correctly, although she could recognize that a person standing next to her and the images of that person reflected in the mirror were the same person. Conclusion:, Early complex visual hallucinations in this patient appeared to be more characteristic of dementia with Lewy body than Alzheimer's disease (AD). It is hard to explain mirror sign in this patient as being because of either prosopagnosia, Balint's syndrome or advanced AD. This patient may have other underlying cognitive dysfunction. [source]

    Differential physiologic responses of ,7 nicotinic acetylcholine receptors to ,-amyloid1,40 and ,-amyloid1,42

    Daniel H.S. Lee
    Abstract The ,-amyloid peptides (A,), A,1,40 and A,1,42, have been implicated in Alzheimer's disease (AD) pathology. Although A,1,42 is generally considered to be the pathological peptide in AD, both A,1,40 and A,1,42 have been used in a variety of experimental models without discrimination. Here we show that monomeric or oligomeric forms of the two A, peptides, when interact with the neuronal cation channel, ,7 nicotinic acetylcholine receptors (,7nAChR), would result in distinct physiologic responses as measured by acetylcholine release and calcium influx experiments. While A,1,42 effectively attenuated these ,7nAChR-dependent physiology to an extent that was apparently irreversible, A,1,40 showed a lower inhibitory activity that could be restored upon washings with physiologic buffers or treatment with ,7nAChR antagonists. Our data suggest a clear pharmacological distinction between A,1,40 and A,1,42. © 2003 Wiley Periodicals, Inc. J Neurobiol 55: 25,30, 2003 [source]

    Association between apolipoprotein E ,4 allele and apathy in probable Alzheimer's disease

    R. Monastero
    Objective:, There have been inconclusive results to date on the association between the Apolipoprotein E (ApoE) genotype and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We investigated whether ApoE ,4 allele is associated with NPS in probable AD. Method:, Data for 197 subjects with probable AD were analysed. The Neuropsychiatric Inventory was used to evaluate the frequency and severity of NPS. Multiple logistic regression models were used to test the association between ApoE genotype and NPS in AD. Results:, The ApoE ,3/3 genotype was present in 52.3%, ,3/4 in 44.1%, and ,4/4 in 3.6% of patients. ApoE ,4 carriers showed a higher frequency of apathy than non-carriers. After multiple adjustments, the ApoE ,4 allele was significantly associated with apathy. Conclusion:, Our results suggest a relationship between the ApoE ,4 allele and apathy in patients with AD. [source]

    Searching for schizophrenia in ancient Greek and Roman literature: a systematic review

    K. Evans
    Objective:, The aim of this study was to systematically examine ancient Roman and Greek texts to identify descriptions of schizophrenia and related disorders. Method:, Material from Greek and Roman literature dating from the 5th Century BC to the beginning of the 2nd Century AD was systematically reviewed for symptoms of mental illness. DSM IV criteria were applied in order to identify material related to schizophrenia and related disorders. Results:, The general public had an awareness of psychotic disorders, because the symptoms were described in works of fiction and in historical accounts of malingering. There were isolated instances of text related to psychotic symptoms in the residents of ancient Rome and Greece, but no written material describing a condition that would meet modern diagnostic criteria for schizophrenia. Conclusion:, In contrast to many other psychiatric disorders that are represented in ancient Greek and Roman literature, there were no descriptions of individuals with schizophrenia in the material assessed in this review. [source]

    Prediction of transition from cognitive impairment to senile dementia: a prospective, longitudinal study

    S. Artero
    Objective: The purpose of this investigation was to replicate the statistical approach used in a previous investigation (Toronto study) within a French population to determine the best predictive model for Alzheimer's disease (AD). Method: Data from neuropsychological tests from two prospective studies were entered into a regression model. Results: Replication of the statistical approach in the Montpellier sample produced a three-test model with a specificity of 99% and sensitivity of 73%. This model consisted of a delayed auditory verbal recall test, a construction test, a category fluency test and provides probability estimates for the transition to dementia in individual cases. Conclusion: The models derived from these two longitudinal studies provide an empirical basis for the selection of tests for the definition of mild cognitive impairment of the Alzheimer type (MCI-A). The small set of tests derived are suitable for use in general practice. [source]

    A review of the epidemiological transition in dementia , cross-national comparisons of the indices related to Alzheimer's disease and vascular dementia

    Guk-Hee Suh
    Objective: To examine temporal changes in the prevalence of dementia and associated factors. Method: All publications on the epidemiology of dementia were identified using a medline search for the years 1966,1999. Results: Alzheimer's disease (AD) has become nearly twice as prevalent as vascular dementia (VaD) in Korea, Japan, and China since transition in early 1990s. Prior to this, in the 1980s, VaD was more prevalent than AD in these countries. In Nigeria, the prevalence of dementia was low. Indian studies were contradictory, with both AD and VaD being more prevalent in different studies. American and European studies consistently reported AD to be more prevalent than VaD. Conclusion: A theoretical model of transition from low incidence,high mortality society to high incidence,high mortality society to low incidence,low mortality society may explain these findings. Rigorous testing in prospective, longitudinal and population-based cross-national studies using culture-fair diagnostic instruments is required. [source]

    Are commonly used self-report inventories suitable for screening postpartum depression and anxiety disorders?

    M. Muzik
    Objective: The utility of several self-report symptom inventories were examined for detecting postpartum depression (MDD) and anxiety disorders (AD). Method: Fifty women (3 or 6 months postpartum), at heightened risk for MDD, completed several depression and anxiety symptom checklists. Psychiatric diagnoses were obtained via SCID interview. Results: Rates of MDD (n=9) and AD (n=9) were equivalent in this sample, with minimal diagnostic overlap. While all the self-report depression inventories screened accurately for MDD, none discriminated AD sensitively and reliably. Conclusion: The frequent occurrence of AD emphasizes the need to identify appropriate screening instruments for postpartum anxiety disorders. [source]

    Neophyte species richness at the landscape scale under urban sprawl and climate warming

    Michael P. Nobis
    Abstract Aim, Land use and climate are two major components of global environmental change but our understanding of their simultaneous and interactive effects upon biodiversity is still limited. Here, we investigated the relationship between the species richness of neophytes, i.e. non-native vascular plants introduced after 1500 AD, and environmental covariates to draw implications for future dynamics under land-use and climate change. Location, Switzerland, Central Europe. Methods, The distribution of vascular plants was derived from a systematic national grid of 1 km2 quadrates (n = 456; Swiss Biodiversity Monitoring programme) including 1761 species, 122 of which were neophytes. Generalized linear models (GLMs) were used to correlate neophyte species richness with environmental covariates. The impact of land-use and climate change was thereafter evaluated by projections for the years 2020 and 2050 using scenarios of moderate and strong changes for climate warming (IPCC) and urban sprawl (NRP 54). Results, Mean annual temperature and the amount of urban areas explained neophyte species richness best, with a high predictive power of the corresponding model (cross-validated D2 = 0.816). Climate warming had a stronger impact on the potential increase in the mean neophyte species richness (up to 191% increase by 2050) than ongoing urban sprawl (up to 10% increase) independently from variable interactions and model extrapolations to non-analogue environments. Main conclusions, In contrast to other vascular plants, the prediction of neophyte species richness at the landscape scale in Switzerland requires few variables only, and regions of highest species richness of the two groups do not coincide. The neophyte species richness is basically driven by climatic (temperature) conditions, and urban areas additionally modulate small-scale differences upon this coarse-scale pattern. According to the projections climate warming will contribute to the future increase in neophyte species richness much more than ongoing urbanization, but the gain in new neophyte species will be highest in urban regions. [source]

    Translational medicine perspective in development of disease modifying therapies for Alzheimer's disease: biomarkers to buy down the risk

    Hong I. Wan
    Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of age-related dementia. Currently available pharmacologic therapies, including acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, only treat symptoms and do not address the underlying neurodegeneration. In addition to potentially improve the accuracy of diagnosis, biomarkers serve important roles for the development of putative disease-modifying drugs for AD. In this article, we review the existing and emerging areas of biomarker research and development for AD. Biochemical biomarkers in cerebrospinal fluid have been used to provide a link to disease pathology and may provide important proof of concept data for several classes of emerging therapeutics. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or radioligands binding to amyloid plaque are discussed. Appropriate uses of these biomarkers in the context of the development of disease-modifying therapies are discussed. Drug Dev Res 70, 2009. © 2009 Wiley-Liss, Inc. [source]

    In vitro and in vivo characterization of TC-1827, a novel brain ,4,2 nicotinic receptor agonist with pro-cognitive activity

    Georg Andrees Bohme
    Abstract Nicotine activates specific receptors that are cation-permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC-1827, a novel metanicotine derivative that activates brain ,4,2 nicotinic receptors is described. TC-1827 has high affinity for nicotine-labeled receptors in the cortex (Ki=34 nM), full-agonist intrinsic activity in ,4,2 -mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long-term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC-1827 dose-dependently occupies thalamic nicotinic receptors labeled with [3H]-cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC-1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13,65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC-1827 is a selective and potent activator of brain ,4,2 nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev. Res. 62:26,40, 2004. © 2004 Wiley-Liss, Inc. [source]

    Role of meta-analysis of clinical trials for Alzheimer's disease

    Jesús M. López Arrieta
    Abstract Alzheimer's disease (AD) is a growing worldwide medical, social, and economic problem. In all countries, both prevalence and incidence of this disorder increase with age. The task of translating scientific clinical research into effective interventions for dementia has proved to be a difficult challenge. Data about the effects of therapeutic interventions come from several sources of evidence, ranging from studies with little potential for systematic bias and minimal random error, such as well-designed randomized controlled trials, through controlled but nonrandomized cohort and case-control studies, all the way to opinions based on laboratory evidence or theory. Although clinical trials are widespread in AD, there is increasing recognition that the results of studies do not necessarily apply to the type of patients that are seen by clinicians because of differences in patient characteristics, comorbidities, cotherapies, severity of disease, compliance, local circumstances, and patients preferences, which may differ sufficiently from those in the trial situation to attenuate or change the benefit-to-risk ratio. There are several methods to address those issues, like pragmatic trials and n-of-1 trials. When data from randomized clinical trials do not provide clear answers from sufficiently similar studies in the magnitude of effect sizes, lack of statistical significance, or identification of subgroups, systematic reviews and meta-analysis may help to provide a better summary of the data. A major difference between a traditional review and a systematic is the systematic nature in which studies are chosen and appraised. Traditional reviews are written by experts in the field who use differing and often subjective criteria to decide what studies to include and what weight to give them, and hence the conclusions are often very diverse, depending on the reviewer. Publication and selection bias is a major concern of traditional reviews. Systematic reviews and meta-analysis are being increasingly used in dementia, propelled by the Cochrane Dementia and Cognitive Improvement Group, to make decisions about treatment, management, and care and to guide future research. This narrative review describes the rationale for randomized clinical trials and systematic reviews in dementia, particularly AD. Drug Dev. Res. 56:401,411, 2002. © 2002 Wiley-Liss, Inc. [source]

    Nonsteroidal antiinflammatory drugs as therapeutic agents for Alzheimer's disease

    Todd E. Golde
    One feature of the end-stage pathology of Alzheimer's disease (AD) is the presence of numerous inflammatory markers associated with the amyloid , protein (A,) deposits in the brain. Experimental data strongly suggests that A, aggregates can incite an inflammatory response, but there are also data suggesting that inflammation can promote A, production and deposition. Thus, antiinflammatory drugs may have some role in AD therapy. This idea is supported by epidemiologic data, which shows that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) confers protection from the development of AD. Significantly, oral salicylates have not been consistently shown to confer protection. Such studies have raised questions regarding the target or targets of NSAIDs that account for their apparent protection from AD. We have recently found that some NSAIDs have a novel mechanism of action, namely, selective lowering of the pathogenic A,42 peptide, that could contribute to their efficacy in AD. Further study will be needed to determine if the classic antiinflammatory properties of NSAIDs, the A,42-lowering property, another known or unknown property, or a combination of these contributes to NSAIDs apparent ability to protect individuals from the development of AD. Drug Dev. Res. 56:415,420, 2002. © Wiley-Liss, Inc. [source]

    Development of antiinflammatory therapy for Alzheimer's disease

    Paul S. Aisen
    Abstract Inflammatory mechanisms are active in the Alzheimer's disease (AD) brain. Studies that range from epidemiological surveys to therapeutic trials in transgenic mice provide growing support for the theory that antiinflammatory drugs may be useful in the prevention and/or treatment of the disease. Randomized controlled trials in humans have not yet confirmed this theory. However, prevention and treatment trials continue to test specific antiinflammatory strategies for AD. Drug Dev. Res. 56:421,427, 2002. © 2002 Wiley-Liss, Inc. [source]

    Targeting Alzheimer's disease: Is there a light at the end of the tunnel?

    David Gurwitz
    Abstract The prevalence of Alzheimer's disease (AD) is on the rise in developed nations as a consequence of longer human lifespan. Current costs to society are alarming, and are projected to become even more demanding on future health budgets. Considering the relative success of Parkinson's disease pharmacotherapy, the success of AD therapy has been disappointing. Quite a few novel and promising AD drug targets are presented in this special issue of Drug Development Research. These are built on countless research studies, by many bright minds, carried out over the last several decades. However, the answer to the growing AD threat must include reliable and accurate tools, presently lacking, for its early diagnosis in at-risk individuals. Drug Dev. Res. 56:45,48, 2002. © 2002 Wiley-Liss, Inc. [source]

    ,-Amyloid immunization approaches for Alzheimer's disease

    Bruno P. Imbimbo
    Abstract Alzheimer's disease (AD) represents the third leading cause of death in the U.S. and the leading cause of dementia in the elderly population. Until recently, there was little hope of efficiently combating this devastating disease. The deposition of ,-amyloid (A,) is the major pathological hallmark of AD brains. Genetic, biochemical, and pharmacological evidence support the hypothesis that A, plays a key role in the development of the disease. Thus, in the last 5 years a number of pharmacological strategies have been developed to interfere with the A, cascade. The most revolutionary of these approaches was proposed in 1999 by scientists at Elan Pharmaceuticals, which immunized against A, transgenic mice with spontaneously developing A, pathology. The immunization was achieved by subcutaneous injections of a preaggregated form of the synthetic human 42-amino acid A, emulsified with Freund's adjuvant, an immune stimulant. The vaccination caused a near complete inhibition of A, plaque formation in younger animals and a marked reduction of the A, burden in older animals. The effects on A, plaques were accompanied by a reduction of A,-associated astrogliosis and neuritic dystrophy. These results were later confirmed by other groups with similar vaccination protocols, which also demonstrated that the A, immunization of transgenic animals normalize or reduce the cognitive impairment associated with A, pathology. Interestingly, effective removal of brain A, plaques was also obtained by peripherally administering A, antibodies. The mechanism with which the vaccine increases A, clearance is not fully understood. Centrally, the vaccine appears to activate A, phagocytosis by microglial monocytes. Peripherally, serum A, antibodies bind and sequester A,, thus altering its equilibrium between CNS and plasma. The dramatic results obtained in animal models of AD raised unprecedented hopes for both a preventive and a curative intervention for this devastating disorder. A vaccine preparation for human use (AN-1792) composed of preaggregated human A,42 peptide and a highly purified saponin derivative (QS-21) was developed by Elan Pharmaceuticals and Wyeth Ayerst and tested in AD patients. Unfortunately, a Phase IIa study aimed at evaluating the safety and immunological activity of AN-1792 in 360 AD patients was discontinued because 15 subjects receiving the vaccine developed serious signs of CNS inflammation. Both central activation of cytotoxic T cells and autoimmune reactions were proposed as potential mechanisms of toxicity. Other therapeutic A, vaccination strategies are being pursued, including immuno-conjugates and monoclonal antibodies. The future of these and other A, immunization approaches depend on a clear understanding of the mechanism of A, clearance and additional insight into the role of inflammation in the AD brain. Drug Dev. Res. 56:150,162, 2002. © 2002 Wiley-Liss, Inc. [source]

    Cytosolic protein-protein interactions that regulate the amyloid precursor protein

    Shasta L. Sabo
    Abstract Alzheimer disease (AD), a progressive neurodegenerative disease, is the most common cause of dementia in the elderly and is among the leading causes of death in adults. AD is characterized by two major pathological hallmarks, amyloid plaques and neurofibrillary tangles. For a number of reasons, amyloid plaque accumulation is widely thought to be the probable cause of AD. The amyloid plaque core is largely composed of an approximately 4-kDa peptide referred to as A,. A, is derived from its precursor, the Alzheimer amyloid protein precursor (APP), by endoproteolytic processing. APP is a type I integral membrane protein, with a long extracellular domain, one transmembrane domain, and a short (,50 amino acid) cytoplasmic tail. Despite intense efforts to decipher the function of APP, its normal physiological role has remained elusive. The carboxy-terminus of APP contains the sequence YENPTY, which is absolutely conserved across APP homologues and across species. The YENPTY sequence is important for regulation of APP processing and trafficking. Given the importance of the cytoplasmic domain in APP physiology, a number of laboratories have hypothesized that proteins that bind to the YENPTY sequence in the cytoplasmic domain of APP might regulate APP processing, trafficking, and/or function. In this article, we will discuss data revealing which proteins bind to the cytoplasmic domain of APP, how these binding-proteins regulate APP metabolism and function, and why such protein-protein interactions provide an exciting new target for therapeutic intervention in AD. Drug Dev. Res. 56:228,241, 2002. © 2002 Wiley-Liss, Inc. [source]