David W Anderson

Thomas Jefferson University, Philadelphia, Pennsylvania, United States

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Publications (9)28.53 Total impact

  • Lorenz Neuwirth, David W. Anderson, Jay S. Schneider
    Society of Toxicology, San Diego, CA; 03/2015
  • Lorenz Neuwirth, David W. Anderson, Jay S. Schneider
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    ABSTRACT: Exposure to low levels of lead (Pb) impairs a variety of cognitive processes. Although children exposed to lead developmentally present with a variety of cognitive impairments that include deficits in learning, memory, language, and executive functioning, experimental work on Pb toxicity in rats has focused mostly on learning and memory deficits and less on executive functions. However, detrimental effects on executive functioning could lead to or even underlie a variety of other cognitive problems attributed to Pb exposure. In this study, we examined the ability of Long Evans rats (control and Pb-exposed: 150ppm Pb-acetate in food given perinatally (gestation through weaning) or early postnatally (EPN, birth through weaning)) to acquire and perform an attention set shifting test (ASST) that requires animals to locate a food reward based on discriminating between digging materials and odors. The task consisted of simple (SD) and compound (CD) discriminations and reversals and intra-dimensional (ID) and extra-dimensional (ED) shifts followed by reversals. Pb-exposed animals performed the task different than controls. Rats with EPN Pb exposure were unable to learn an odor-based SD. Perinatally exposed rats learned the odor SD but had significant numbers of errors at most task levels with particular difficulty in performing the ID shift. Perinatally exposed rats also exhibited very short response latencies suggesting impulsive responding. Additionally, the more complex the stimuli presented during testing the greater the number of trials needed to reach criterion and the greater the numbers of errors made, suggesting that Pb exposure disrupted cognitive information processing when animals attempted to associate reinforcement with odor and/or digging material. These data suggest that low level Pb exposure results in significant executive dysfunction and in particular, may impair the ability to form, maintain, and shift response sets and may result in impulsivity and problems with cognitive flexibility.
    2014 Society for Neuroscience, Washington DC; 11/2014
  • Jay S. Schneider, Mark E. Ault, David W. Anderson
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    ABSTRACT: Background Optical coherence tomography (OCT) is a noninvasive procedure for analysis of retinal morphology. Significant changes in the thickness of the peripapillary retinal nerve fiber layer (RNFL) in Parkinson's disease (PD) have been reported, and the current study was performed to examine whether such changes can also be detected in an animal model of PD.Methods Optical coherence tomography measurements of peripapillary RNFL thickness, macula volume, and foveal thickness were obtained from 10 normal and five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with stable Parkinsonian signs.ResultsAverage RNFL thickness was significantly decreased in Parkinsonian monkeys compared with controls, with statistically significant RNFL thinning found in nasal and inferior quadrants. Macula volume and foveal thickness were also significantly reduced in Parkinsonian animals compared with controls.Conclusions As described in PD, RNFL thinning, reduced macula volume, and reduced foveal thickness also occurs in monkeys with MPTP-induced Parkinsonism. These findings pave the way for additional studies in which OCT may be used to track changes in the retina that might be present very early in the PD pathological process, perhaps preceding the onset of motor signs. © 2014 International Parkinson and Movement Disorder Society © 2014 International Parkinson and Movement Disorder Society
    Movement Disorders 10/2014; 29(12). DOI:10.1002/mds.25974 · 5.63 Impact Factor
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    ABSTRACT: While extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the role that genetic variation may play in influencing outcomes from developmental Pb exposure. Male and female animals received either perinatal (gestation through lactation) or postnatal (birth through weaning) exposure to Pb in food (0 ppm, 250 ppm, or 750ppm). RNA was extracted from the hippocampus at day 55 and hybridized to Affymetrix Rat Gene 1.0 ST Arrays. There were significant strain-specific effects of Pb on the hippocampal transcriptome with 978 transcripts differentially expressed in LE rats across all experimental groups, 269 transcripts differentially expressed in F344 rats, and only 179 transcripts differentially expressed in SD rats. These results were not due to strain-related differences in brain accumulation of Pb. Further, no genes were consistently differentially regulated in all experimental conditions. There was no set of "Pb toxicity" genes that are a molecular signature for Pb neurotoxicity that transcended sex, exposure condition, and strain. These results demonstrate the influence that strain and genetic background play in modifying the brain's response to developmental Pb exposure and may have relevance for better understanding the molecular underpinnings of the lack of a neurobehavioral signature in childhood Pb poisoning.
    Toxicological Sciences 06/2014; 141(1). DOI:10.1093/toxsci/kfu101 · 4.48 Impact Factor
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    ABSTRACT: Developmental lead (Pb) exposure has profound effects on cognition and behavior. Much is known about effects of Pb on hippocampal-mediated behaviors, but little is known about the molecular consequences of Pb exposure and the influences of developmental timing of exposure, level of exposure, and sex as effect modifiers of Pb exposure on the brain. The aim of this study was to examine the effects of different levels of Pb exposure (250 and 750 ppm Pb acetate) during perinatal (gestation/lactation) and postnatal (through postnatal day 45) periods on the hippocampal transcriptome in male and female Long Evans rats. Total RNA was extracted from hippocampus from four animals per experimental condition. RNA was hybridized to Affymetrix Rat Gene RNA Arrays using standard methods. Pb exposure per se influenced the expression of 717 transcripts (328 unique annotated genes), with many influenced in a sex-independent manner. Significant differences in gene expression patterns were also influenced by timing and level of exposure, with generally larger effects at the lower level of exposure across all groups. Statistically enriched biological functions included ion binding, regulation of RNA metabolic processes, and positive regulation of macromolecule biosynthetic processes. Processes of regulation of transcription and regulation of gene expression were preferentially enriched in males, regardless of timing or amount of Pb exposure. The effect on transcription factors and the diverse pathways or networks affected by Pb suggest a substantial effect of developmental Pb exposure on plasticity and adaptability, with these effects significantly modified by sex, developmental window of exposure, and level of Pb exposure.
    Toxicological Sciences 05/2012; 129(1):108-25. DOI:10.1093/toxsci/kfs189 · 4.48 Impact Factor
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    ABSTRACT: Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of a superfamily of detoxification enzymes found in various tissues that participate in the oxidation of both aliphatic and aromatic aldehydes. In the brain, ALDH1A1 participates in the metabolism of catecholamines including dopamine (DA) and norepinephrine, but is uniquely expressed in a subset of dopaminergic (DAergic) neurons in the ventral mesencephalon where it converts 3,4-dihydroxyphenylacetaldehyde, a potentially toxic aldehyde, to 3,4-dihydroxyphenylacetic acid, a non toxic metabolite. Therefore, loss of ALDH1A1 expression could be predicted to alter DA metabolism and potentially increase neurotoxicity in ventral mesencephalic DA neurons. Recent reports of reduced levels of expression of both Aldh1a1 mRNA and protein in the substantia nigra (SN) of Parkinson's disease patients suggest possible involvement of ALDH1A1 in this progressive neurodegenerative disease. The present study used an Aldh1a1 null mouse to assess the influence of ALDH1A1 on the function and maintenance of the DAergic system. Results indicate that the absence of Aldh1a1 did not negatively affect growth and development of SN DA neurons nor alter protein expression levels of tyrosine hydroxylase, the DA transporter or vesicular monoamine transporter 2. However, absence of Aldh1a1 significantly increased basal extracellular DA levels, decreased KCl and amphetamine stimulated DA release and decreased DA re-uptake and resulted in more tyrosine hydroxylase expressing neurons in the SN than in wildtype animals. These data suggest that in young adult animals with deletion of the Aldh1a1 gene there is altered DA metabolism and dysfunction of the DA transporter and DA release mechanisms.
    Brain research 08/2011; 1408:81-7. DOI:10.1016/j.brainres.2011.06.051 · 2.83 Impact Factor
  • David W Anderson, Kristin A Bradbury, Jay S Schneider
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    ABSTRACT: Numerous factors contribute to substantia nigra pars compacta (SNc) dopamine (DA) neuron death in Parkinson's disease (PD), thus complicating the search for effective neuroprotective agents for this disease. Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse has been widely used for assessing neuroprotective agents for PD, the pathological processes resulting from MPTP exposure can vary greatly depending upon the MPTP administration protocol. This study assessed the degree to which the neuroprotective efficacy of particular agents may depend upon the MPTP administration protocol (i.e. acute vs. subacute toxin administration). Endpoints analysed were changes in tyrosine hydroxylase (TH) and NeuN cell numbers in the SNc, striatal DA and metabolite levels, and striatal TH+ fiber density. The efficacy of putative neuroprotective agents [i.e. LIGA 20, nicotinamide and pramipexole (PPX)] varied depending upon the MPTP administration protocol. LIGA 20 spared striatal DA levels in both MPTP models, while nicotinamide was only effective in the acute toxin administration model and PPX was only effective in the subacute model. In both MPTP models, LIGA 20 and nicotinamide significantly spared DAergic neurons; PPX only spared DAergic neurons in the subacute model. Only acute MPTP-treated mice that received nicotinamide had a significant sparing of striatal DAergic fibers. These results underscore the need to assess putative neuroprotective agents for PD in multiple animal models using multiple endpoints. This strategy may better identify compounds with broad neuroprotective/neurorestorative profiles that may be more likely to be clinically effective.
    European Journal of Neuroscience 01/2007; 24(11):3174-82. DOI:10.1111/j.1460-9568.2006.05192.x · 3.67 Impact Factor
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    ABSTRACT: We tested the hypothesis that movement abnormalities induced by chronic manganese (Mn) exposure are mediated by dysfunction of the nigrostriatal dopamine system in the non-human primate striatum. Motor function and general activity of animals was monitored in parallel with chronic exposure to Mn and Positron Emission Tomography (PET) studies of in vivo dopamine release, dopamine transporters and dopamine receptors in the striatum. Analysis of metal concentrations in whole blood and brain was obtained and post-mortem analysis of brain tissue was used to confirm the in vivo PET findings. Chronic Mn exposure resulted in subtle motor function deficits that were associated with a marked decrease of in vivo dopamine release in the absence of a change in markers of dopamine (DA) terminal integrity or dopamine receptors in the striatum. These alterations in nigrostriatal DA system function were observed at blood Mn concentrations within the upper range of environmental, medical and occupational exposures in humans. These findings show that Mn-exposed non-human primates that exhibit subtle motor function deficits have an apparently intact but dysfunctional nigrostriatal DA system and provide a novel mechanism of Mn effects on the dopaminergic system.
    Experimental Neurology 01/2007; 202(2):381-90. DOI:10.1016/j.expneurol.2006.06.015 · 4.62 Impact Factor
  • David W Anderson, T Neavin, JA Smith, J S Schneider
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    ABSTRACT: This study examined the effect of pramipexole (PPX), a selective dopamine (DA) D(3)/D(2) agonist, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to the nigrostriatal dopamine system in young (8-week-old) and aged (12-month-old) mice. Co-administration of PPX and MPTP to young or aged mice, followed by 2 or 14 days of additional PPX treatment, significantly attenuated MPTP-induced striatal DA loss. Pramipexole treatment also significantly attenuated the loss of tyrosine hydroxylase immunoreactive neurons (TH-IR) within the substantia nigra pars compacta (SNc) in both young and aged animals. Effects of PPX administration on dopaminergic cell survival were confirmed in Nissl-stained sections and by quantitation of retrogradely labeled Fluorogold-positive SNc neurons. Protective effects of PPX on striatal DA levels and SNc DA neuron survival were similar in young and aged animals, although the magnitude of these effects was significantly less in aged animals. These findings support the early initiation of PPX therapy in Parkinson's disease patients.
    Brain Research 07/2001; 905(1-2):44-53. DOI:10.1016/S0006-8993(01)02466-0 · 2.83 Impact Factor