Biomedical subjects

Andrew W Zimmerman

Publications and source records attributed to Andrew W Zimmerman.

11 recordsLinked to original sources

PubMed2006

Maternal antibrain antibodies in autism.

Autism is a neurodevelopmental disorder of prenatal onset that is behaviorally defined. There is increasing evidence for systemic and neuroimmune mechanisms in children with autism. Although genetic factors are important, atypical prenatal maternal immune responses may also be linked to the pathogenesis of autism. We tested serum reactivity in 11 mothers and their autistic children, maternal controls, and several groups of control children, to prenatal, postnatal, and adult rat brain proteins, by immunoblotting. Similar patterns of reactivity to prenatal (gestational day 18), but not postnatal (day 8) or adult rat brain proteins were identified in autistic children, their mothers, and children with other neurodevelopmental disorders, and differed from mothers of normal children, normal siblings of children with autism and normal child controls. Specific patterns of antibody reactivity were present in sera from the autism mothers, from 2 to 18 years after the birth of their affected children and were unrelated to birth order. Immunoblotting using specific antigens for myelin basic protein (MBP) and glial acidic fibrillary protein (GFAP) suggests that these proteins were not targets of the maternal antibodies. The identification of specific serum antibodies in mothers of children with autism that recognize prenatally expressed brain antigens suggests that these autoantibodies could cross the placenta and alter fetal brain development.

Adolescent↗

PubMed2006

Antibrain antibodies in children with autism and their unaffected siblings.

Serum autoantibodies to human brain, identified by ELISA and Western immunoblotting, were evaluated in 29 children with autism spectrum disorder (22 with autistic disorder), 9 non-autistic siblings and 13 controls. More autistic subjects than controls had bands at 100 kDa in caudate, putamen and prefrontal cortex (p<0.01) as well as larger peak heights of bands at 73 kDa in the cerebellum and cingulate gyrus. Both autistic disorder subjects and their matched non-autistic siblings had denser bands (peak height and/or area under the curve) at 73 kDa in the cerebellum and cingulate gyrus than did controls (p<0.01). Results suggest that children with autistic disorder and their siblings exhibit differences compared to controls in autoimmune reactivity to specific epitopes located in distinct brain regions.

Autistic Disorder↗

PubMed2006

Plasma serotonin in autism.

Serotonin is necessary for normal fetal brain development. Administration of serotonin inhibitors to pregnant rats results in offspring with abnormal behaviors, brain morphology, and serotonin receptor numbers. Low maternal plasma serotonin may contribute to abnormal brain development in autism. In this study, plasma serotonin levels in autism mothers and control mothers of typically developing children were compared, and plasma serotonin levels in children with autism (n = 17) and their family members were measured. Plasma serotonin levels in autism mothers were significantly lower than in mothers of normal children (P = 0.002). Plasma serotonin levels correlated between autism mothers and their children, but differed between autistic children and their fathers (P = 0.028) and siblings (P = 0.063). Low maternal plasma serotonin may be a risk factor for autism through effects on fetal brain development.

Adolescent↗

PubMed2006

HLA-DR4 in families with autism.

Autoimmune disorders are observed with increased frequency among parents of individuals with autism, particularly mothers. Because there is evidence supporting an association between autoimmune disorders and specific alleles of the human leukocyte antigen (HLA) system, we examined HLA types and subtypes in families with autism. Two groups were studied: 16 families selected from a geographically defined area in eastern Tennessee have males with a diagnosis of autism; and 33 families selected across all regions in the United States have multiple males having autism diagnosis. The HLA-DR4 frequencies of mothers, fathers, and children in these two groups were compared with a reference series of 475 normal, unrelated Caucasians. Results of HLA typing indicated that mothers and their sons in the geographically defined group had a significantly higher frequency of DR4 than normal control subjects (odds ratio = 5.54, 95% confidence interval = 1.74-18.67 and odds ratio = 4.20, 95% confidence interval = 1.37-13.27, respectively). No significant difference in the distribution of HLA alleles was evident between the United States-all region group and control subjects. Findings of this study are consistent with a hypothesis that prenatal maternal-fetal immune interaction can affect fetal brain development in a population residing in a geographically defined region. Such immune interactions may involve HLA and related genes in both genetic and epigenetic mechanisms during pregnancy.

Adult↗

PubMed2006

Developmental regression and mitochondrial dysfunction in a child with autism.

Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative phosphorylation disorder in a 19-month-old girl. Subtle abnormalities in the serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate led us to perform a muscle biopsy, which showed type I myofiber atrophy, increased lipid content, and reduced cytochrome c oxidase activity. There were marked reductions in enzymatic activities for complex I and III. Complex IV (cytochrome c oxidase) activity was near the 5% confidence level. To determine the frequency of routine laboratory abnormalities in similar patients, we performed a retrospective study including 159 patients with autism (Diagnostic and Statistical Manual of Mental Disorders-IV and Childhood Autism Rating Scale) not previously diagnosed with metabolic disorders and 94 age-matched controls with other neurologic disorders. Aspartate aminotransferase was elevated in 38% of patients with autism compared with 15% of controls (P <.0001). The serum creatine kinase level also was abnormally elevated in 22 (47%) of 47 patients with autism. These data suggest that further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent.

Aspartate Aminotransferases↗

PubMed2005

Neuroglial activation and neuroinflammation in the brain of patients with autism.

Autism is a neurodevelopmental disorder characterized by impaired communication and social interaction and may be accompanied by mental retardation and epilepsy. Its cause remains unknown, despite evidence that genetic, environmental, and immunological factors may play a role in its pathogenesis. To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Fresh-frozen tissues available from seven patients and CSF from six living autistic patients were used for cytokine protein profiling. We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1. Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain.

Adolescent↗

PubMed2005

Cerebrospinal fluid and serum markers of inflammation in autism.

Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P = 0.037) and neopterin (P = 0.003) were decreased, and biopterin (P = 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated compared with controls (P < 0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid.

Adolescent↗

PubMed2005

Immunity, neuroglia and neuroinflammation in autism.

Autism is a complex neurodevelopmental disorder of early onset that is highly variable in its clinical presentation. Although the causes of autism in most patients remain unknown, several lines of research support the view that both genetic and environmental factors influence the development of abnormal cortical circuitry that underlies autistic cognitive processes and behaviors. The role of the immune system in the development of autism is controversial. Several studies showing peripheral immune abnormalities support immune hypotheses, however until recently there have been no immune findings in the CNS. We recently demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism, findings that support the view that neuroimmune abnormalities occur in the brain of autistic patients and may contribute to the diversity of the autistic phenotypes. The role of neuroglial activation and neuroinflammation are still uncertain but could be critical in maintaining, if not also in initiating, some of the CNS abnormalities present in autism. A better understanding of the role of neuroinflammation in the pathogenesis of autism may have important clinical and therapeutic implications.

Animals↗

PubMed2005

beta2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins.

Gestational and genetic factors can contribute to autism during infancy and early childhood through their effects on fetal brain development. Previous twin studies have shown strong genetic components for the development of autism, a disorder that can have multiple causes. We investigated the effects of prenatal overstimulation of the beta2-adrenergic receptor in dizygotic twins who were exposed to terbutaline, a selective beta2-adrenergic receptor agonist used to treat premature labor, as a gestational factor. As a possible genetic mechanism, we studied two beta2-adrenergic receptor polymorphisms in twins from whom DNA was available: glycine substitution at codon 16 (16G) and glutamic acid substitution at codon 27 (27E), which show diminished desensitization in vivo compared with the wild-type receptor. Continuous terbutaline exposure for 2 weeks or longer was associated with increased concordance for autism spectrum disorders in dizygotic twins (relative risk = 2.0), with a further increase in the risk for male twins with no other affected siblings (relative risk = 4.4). A significant association was found between the presence of 16G and 27E polymorphisms in autistic patients compared with population controls (P = .006). Prenatal overstimulation of the beta2-adrenergic receptor by terbutaline or by increased signaling of genetic polymorphisms of the beta2-adrenergic receptor that have diminished desensitization can affect cellular responses and developmental programs in the fetal brain, leading to autism.

Autistic Disorder↗

PubMed2004

Autism clinical trials: biological and medical issues in patient selection and treatment response.

Biomedical measures are critical in the initial patient-screening and -selection phases of a clinical trial in autism and related disorders. These measures can also play an important role in the assessment and characterization of response and can provide an opportunity to study underlying etiologic and pathophysiologic processes. Thus, biomedical measures, including clinical laboratory analyses, metabolic screening, and chromosomal analysis, are used to screen for potential safety-related problems, to decrease biological and genetic heterogeneity, and to define subgroups. Neurobiological measures can be examined as possible predictors, modifiers or surrogates of therapeutic response, and adverse effects. Neurobiological research measures can also be used to study mechanisms and extent of drug action and to perform baseline and longitudinal investigations of possible pathophysiologic alterations. The potential utility and desirability of specific measures are considered and the general approach to choosing measures for incorporation is discussed.

Autistic Disorder↗

PubMed2003

Proton MR spectroscopic imaging in Pelizaeus-Merzbacher disease.

BACKGROUND AND PURPOSE: Pelizeaus-Merzbacher disease (PMD) is a clinically and molecularly heterogeneous disorder linked to deletion, mutations, or duplication of the proteolipid protein (PLP1) gene locus at Xq22. The current study was conducted to characterize the results of proton MR spectroscopic (MRS) imaging in PMD. METHODS: Three boys with PMD (one with the severe connatal form and two with a more mild clinical phenotype [spastic paraplegia type 2]). and three age-matched healthy control subjects (age range, 2-7 years) underwent MR and MRS imaging. All imaging was performed at 1.5 T. For MRS imaging, oblique-axial sections (thickness, 15 mm; intersection gap, 2.5 mm) were recorded parallel to the anterior commissure-posterior commissure line (TR/TE/NEX, 2300/272/1) with lipid and water suppression. Ratios of metabolite peak areas were calculated, and spectra were bilaterally evaluated. RESULTS: Diffuse or focal reductions in N-acetylaspartate were observed in the affected white matter in all three cases. These reductions seemed to be consistent with axonal damage. In addition, mild increases in choline and creatine levels were observed; these may have been due to astrocytic changes. CONCLUSION: Proton MRS imaging may be helpful in evaluating regional pathophysiologic abnormalities in PMD and in distinguishing PMD from other leukodystrophies, which exhibit different metabolic profiles.

Aspartic Acid↗