Alzheimer Disease: Davis S

Davis S, Laroche S. · Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, CNRS UMR 8620, Université Paris-Sud, 91405 Orsay, France. · Mol Neurobiol. · Pubmed #12845151 No free full text.

Abstract: The prolongation of life and the rapidly increasing incidence of Alzheimer's disease have brought to the foreground the need for greater understanding of the etiology of the disease and the means to prevent or at least slow down the process. Out of this need the transgenic mouse and the production of synthetic amyloid peptides have been developed in an attempt to create experimental models of Alzheimer's disease that will help our understanding of the cellular and molecular mechanisms by which the pathology leads to memory dysfunction and to test potential therapeutic strategies. Despite 10 or so years of reasonably intensive research with these models, both fall short of producing a viable and faithful model of the complete pathology of Alzheimer's disease and the behavioral consequences are far from modelling the progressive decline in cognitive function. Here we review the advantages and the caveats associated with the two models in terms of the pathology, the associated memory dysfunction, and the effect on synaptic plasticity. Given the more recent advances that have been made in the understanding of the neurobiological changes that occur with the disease and with the consideration of other environmental effects, which have been clearly shown to have an impact on the progression of the disease in humans, we emphasis the advantage of pharmacological or environmental in transgenic mice or rodents injected with synthetic peptides that may prove to be more fruitful in our understanding of the memory deficits associated with the disease.

Vaillend C, Rampon C, Davis S, Laroche S. · Laboratoire de Neurobiologie de I'Apprentissage, de la Mémoire et de la Communication, CNRS UMR 8620, University of Paris-Sud, Orsay, France. · Curr Mol Med. · Pubmed #12420801 No free full text.

Abstract: There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections between neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular and molecular bases of learning and memory. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. Here we briefly review these mechanisms and illustrate with a few examples of animal models of neurological disorders how new knowledge about these mechanisms can provide valuable insights into identifying the mechanisms that go awry when memory is deficient, and how, in turn, characterisation of the dysfunctional mechanisms offers prospects to design and evaluate molecular and biobehavioural strategies for therapeutic prevention and rescue.

Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL. · Departments of Pathology, The University of Melbourne, The Mental Health Research Institute of Victoria, Parkville, Victoria, Australia. · Arch Neurol. · Pubmed #14676042 links to  free full text

Abstract: BACKGROUND: Alzheimer disease (AD) may be caused by the toxic accumulation of beta-amyloid (Abeta). OBJECTIVE: To test this theory, we developed a clinical intervention using clioquinol, a metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Abeta, thereby promoting Abeta dissolution and diminishing its toxic properties. METHODS: A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease. RESULTS: Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, >/=25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma Abeta42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated. CONCLUSION: Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein-attenuating compound.

Schneider LS, Tariot PN, Lyketsos CG, Dagerman KS, Davis KL, Davis S, Hsiao JK, Jeste DV, Katz IR, Olin JT, Pollock BG, Rabins PV, Rosenheck RA, Small GW, Lebowitz B, Lieberman JA. · Clinical Antipsychotic Trials of Intervention Effectiveness Program of the National Institute of Mental Health at the University of North Carolina, Chapel Hill, NC, USA. · Am J Geriatr Psychiatry. · Pubmed #11739062 No free full text.

Abstract: The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.

Davis S. · Brown Medical School, Department of Family Medicine, Memorial Hospital of Rhode Island, Pawatucket 02860, USA. · Med Health R I. · Pubmed #15779549 No free full text.

This publication has no abstract.

Schneider LS, Ismail MS, Dagerman K, Davis S, Olin J, McManus D, Pfeiffer E, Ryan JM, Sultzer DL, Tariot PN. · Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles 90033, USA. · Schizophr Bull. · Pubmed #12908661 links to  free full text

Abstract: This article describes the development of the protocol for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer's disease trial, which was developed in collaboration with the National Institute of Mental Health to assess the effectiveness of atypical antipsychotics for psychosis and/or agitation occurring in outpatients with Alzheimer's disease. The article provides a detailed description of the methodology used in the trial as well as the clinical outcomes and effectiveness measures incorporated into it, discussing the most salient issues encountered in developing the design of the trial, as well as the unique features of the trial.

O'Brien JT, Ames D, Desmond P, Lichtenstein M, Binns D, Schweitzer I, Davis S, Tress B. · University of Newcastle upon Tyne, UK. J.T.O' · Int Psychogeriatr. · Pubmed #11495391 No free full text.

Abstract: OBJECTIVE: To compare the utility of temporal lobe magnetic resonance imaging (MRI) and single-photon emission tomography (SPET) scanning in discriminating between subjects with Alzheimer's disease (AD) and age-matched controls. METHODS: Thirty subjects with NINCDS-ADRDA AD (23 probable AD, 5 possible AD, 2 definite AD) and 22 age- and sex-matched controls underwent T1-weighted coronal MRI scanning (0.3 T) and technetium 99m-HMPAO SPET scanning. MRI scans were analyzed using a digitizer system with volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and whole cerebral cortex calculated. From SPET scans, regional cerebral blood flow (rCBF) was assessed in anterior and posterior frontal, parietal, occipital, and mesial temporal cortex using a region of interest analysis with the cerebellum as a reference area. RESULTS: Using MRI, the areas that best separated groups were left hippocampal and left amygdala volume, resulting in correct classification (patient vs. control) in 79% of cases (sensitivity 77%, specificity 82%). Exactly the same proportion of subjects were correctly classified by SPET, with the most discriminating rCBF changes being left parietal and right posterior frontal. Combining information from both scans improved the proportion of correctly classified subjects in a discriminant function to 90% (sensitivity 93%, specificity 86%; only 2 AD and 3 controls misclassified). All AD subjects had abnormalities on MRI and/or SPET (sensitivity for combined examinations 100%), while abnormalities on both MRI and SPET had a positive predictive value of 100% for dementia (including the detection of one control subject who later had dementia). Significant correlations between MRI and SPET measures were seen in control subjects but not in patients. CONCLUSION: Both 0.3 T MRI and single rotating gamma camera SPET were equally useful in separating AD subjects from age-matched controls, although the combination of both significantly enhanced discrimination. In particular, all AD subjects had abnormalities on either MRI or SPET and both techniques may have an important role in assisting with clinical diagnosis, though replication in other centers and examination of differentiation of AD from other causes of dementia need to be examined.

Stéphan A, Laroche S, Davis S. · Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8620, Université Paris Sud, 91405 Orsay, France. · J Neurosci. · Pubmed #11466442 links to  free full text

Abstract: We injected a combination of the beta-amyloids (Abetas) Abeta40 and Abeta43 to "seed" formation of amyloid deposits in the dorsal dentate gyrus of rats in vivo, on the basis of a theory of Jarrett and Landsbury (1993). Rats were tested on several different learning tasks, and synaptic transmission and plasticity were assessed in vivo. Between 7 and 16 weeks after injection, we found aggregated amyloid material, reactive astrocytosis, microgliosis, and cell loss around the sites of injection. Rats were impaired specifically in working memory type tasks in accordance with the type of memory deficit observed in the early stages of Alzheimer's disease. Synaptic transmission and long-term potentiation, a candidate cellular mechanism for memory, were severely impaired in vivo. Injections of the same dose of fragments individually did not induce these effects. These findings suggest that aggregated amyloid material induces cognitive deficits similar to those observed in the early phases of Alzheimer's disease via an alteration in neuronal transmission and plasticity.