compiled by Teresa Binstock for
Generation Rescue
June 2008

Etiologic Models in ADHD

Introduction: As presented on other urls in this collection, numerous studies describe associations among environmental pollutants, AD, and ADHD. Some studies focus on subtle genetic factors such as less common alleles of genes for dopamine receptors. Some studies and some abstracts suggest that a "mostly genetic model" has the greatest relevance, even as associations with pollutants are increasingly described in peer-reviewed medical literature. The model wherein environmental factors are etiologically significant, particularly if predisposing alleles are present, has merit. Overall, the data suggest that that environmental pollutants which become intra-body pollutants may be etiologically significant in many and perhaps most individuals with AD and ADHD and also that some among these pollutants may be relevant to therapeutic protocols.

Richard Deth and colleagues are documenting important aspects of attention related to methylation of D4 dopamine receptors, eg, "dopamine-stimulated methylation of membrane phospholipids may be an important mechanism for modulating [neuronal] firing activity, while impaired methylation can contribute to disorders of attention." (30)
       A folate pathway merits special attention (eg, 32) and, whereas its relevance is being studied in autistic children (34-37), findings may have significance for subgroups of individuals with AD or ADHD.
       Importantly, thimerosal at molarities present after vaccinations can affect methionine synthase, an enzyme which participates in normal methylation (38). Furthermore, aluminum is present in some vaccines (39) and is associated with hyperactivity and learning disorders in children (40).

1. The Etiology of ADHD

By National Health and Medical Research Council Government of Austrailia
and The National Health and Medical Research Council of Austrailia
http://www.mental-health-matters.com/articles/article.php?artID=648

2. Practitioner review: early adversity and developmental disorders

Taylor E, Rogers JW.
J Child Psychol Psychiatry. 2005 May;46(5):451-67.

BACKGROUND: Knowledge of genetic influences, on developmental disorders such as autism spectrum, attention deficit/hyperactivity disorder and learning disabilities, has increased the opportunities for understanding the influences of the early environment. METHODS: This paper provides a selective, narrative review for clinicians of the effects of factors such as exposure to toxins and stresses in utero and in postnatal life; brain injuries and perinatal compromise; neglect, malnutrition and selective food deficiencies. It also considers what is known about the mechanisms through which early adversities operate. RESULTS: Gaps in the research are identified and suggestions made about clinical investigations. Several types of environmental adversity have associations with later disorders that suggest a causal role. The effects are often on a broad range of psychological processes, and are not always quickly reversible. Several adversities often coexist, calling for skilled judgement about priorities in treatment. CONCLUSIONS: Individuals vary considerably in their exposure to adversity and their vulnerability to its effects, and genetic inheritance can influence both.
PMID: 15845126

3. Attention-deficit disorder (attention-deficit/ hyperactivity disorder without hyperactivity): a neurobiologically and behaviorally distinct disorder from attention-deficit/hyperactivity disorder (with hyperactivity)

Diamond A.
Dev Psychopathol. 2005 Summer;17(3):807-25.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1474811&blobtype=pdf

Most studies of attention-deficit/hyperactivity disorder (ADHD) have focused on the combined type and emphasized a core problem in response inhibition. It is proposed here that the core problem in the truly inattentive type of ADHD (not simply the subthreshold combined type) is in working memory. It is further proposed that laboratory measures, such as complex-span and dual-task dichotic listening tasks, can detect this. Children with the truly inattentive type of ADHD, rather than being distractible, may instead be easily bored, their problem being more in motivation (underarousal) than in inhibitory control. Much converging evidence points to a primary disturbance in the striatum (a frontal-striatal loop) in the combined type of ADHD. It is proposed here that the primary disturbance in truly inattentive-type ADHD (ADD) is in the cortex (a frontal-parietal loop). Finally, it is posited that these are not two different types of ADHD, but two different disorders with different cognitive and behavioral profiles, different patterns of comorbidities, different responses to medication, and different underlying neurobiologies.
PMID: 16262993

4. Synaptic gating and ADHD: a biological theory of comorbidity of ADHD and anxiety

Levy F.
Neuropsychopharmacology. 2004 Sep;29(9):1589-96.
http://www.nature.com/npp/journal/v29/n9/pdf/1300469a.pdf

To derive a biologically based theory of comorbidity in Attention Deficit Hyperactivity Disorder (ADHD). Theoretical concepts and empirical studies were reviewed to determine whether the behavioral inhibition concept provided an understanding of biological processes involved in comorbidity in ADHD. Empirical studies of ADHD have shown comorbidity of ADHD and anxiety, while studies of behavioral inhibition tend to suggest independent disruptive and anxiety traits. This paradox can be resolved by an understanding of the dynamics of mesolimbic dopamine (DA) systems, where reward and delay of reinforcement are determined by tonic/phasic DA relationships, resulting in impulsive 'fearless' responses when impaired. On the other hand, comorbid anxiety is related to impaired synaptic processes, which selectively gate fear (or aggressive) responses from the amygdala at the accumbens. Monosynaptic convergence between prefrontal, hippocampal, and amygdala projection neurons at the accumbens allows the operation of a synaptic gating mechanism between prefrontal cortex (PFC), hippocampus, and amygdala. Impairment of this mechanism by lowered PFC inhibition allows greater amygdala input, and anxiety-related processes more impact, over the accumbens. In conclusion, a dual theory incorporating long-term tonic/phasic mesolimbic DA relationships and secondly impairment of PFC and hippocampal inputs to synaptic gating of anxiety at the accumbens has implications for comorbidity in ADHD, as well as for possible pharmacological interventions, utilizing either stimulant or axiolytic interventions. The use of DA partial agonists may also be of interest.
PMID: 15114344

5. Deficits in attention, motor control, and perception: a brief review

Gillberg C.
Arch Dis Child. 2003 Oct;88(10):904-10.
http://adc.bmj.com/cgi/content/full/88/10/904

The concept of DAMP (deficits in attention, motor control, and perception) has been in clinical use in Scandinavia for about 20 years. DAMP is diagnosed on the basis of concomitant attention deficit/hyperactivity disorder and developmental coordination disorder in children who do not have severe learning disability or cerebral palsy. In clinically severe form it affects about 1.5% of the general population of school age children; another few per cent are affected by more moderate variants. Boys are overrepresented; girls are currently probably underdiagnosed. There are many comorbid problems/overlapping conditions, including conduct disorder, depression/anxiety, and academic failure. There is a strong link with autism spectrum disorders in severe DAMP. Familial factors and pre- and perinatal risk factors account for much of the variance. Psychosocial risk factors appear to increase the risk of marked psychiatric abnormality in DAMP. Outcome in early adult age was psychosocially poor in one study in almost 60% of unmedicated cases. There are effective interventions available for many of the problems encountered in DAMP.
PMID: 14500312

6. Etiologic classification of attention-deficit/hyperactivity disorder

Millichap JG.
Pediatrics. 2008 Feb;121(2):e358-65.
http://pediatrics.aappublications.org/cgi/content/full/121/2/e358

Attention-deficit/hyperactivity disorder is a neurobiological syndrome with an estimated prevalence among children and adolescents of 5%. It is a highly heritable disorder, but acquired factors in etiology are sometimes uncovered that may be amenable to preventive measures or specific therapy. Early reports have described symptoms similar to attention-deficit/hyperactivity disorder that followed brain trauma or viral encephalitis, and recent MRI studies have demonstrated brain volumetric changes that may be involved in the pathophysiology of the syndrome. The American Psychiatric Association's Diagnostic Statistical Manual, introduced in 1968, emphasizes symptomatic criteria in diagnosis. Here, an overview of environmental factors in the etiology of attention-deficit/hyperactivity disorder is presented to encourage more emphasis and research on organic causal factors, preventive intervention, and specific therapies. An organic theory and the genetic and biochemical basis of attention-deficit/hyperactivity disorder are briefly reviewed, and an etiologic classification is suggested. Environmental factors are prenatal, perinatal, and postnatal in origin. Pregnancy- and birth-related risk factors include maternal smoking and alcohol ingestion, prematurity, hypoxic-ischemic encephalopathy, and thyroid deficiency. Childhood illnesses associated with attention-deficit/hyperactivity disorder include virus infections, meningitis, encephalitis, head injury, epilepsy, toxins, and drugs. More controversial factors discussed are diet-related sensitivities and iron deficiency. Early prenatal recognition, prevention, and treatment of environmental etiologies of attention-deficit/hyperactivity disorder may reduce physician reliance on symptomatic modification with medication, a frequent reason for parental concern.
PMID: 18245408

7. Sex differences in child-onset, life-course-persistent conduct disorder. A review of biological influences

Eme RF.
Clin Psychol Rev. 2007 Jun;27(5):607-27.

Sex is widely acknowledged to be an important factor in understanding many aspects of behavior, not the least of which is antisocial behavior. When antisocial behavior manifests itself in the domain of juvenile psychopathology, it often takes the form of a type of conduct disorder (CD) that begins in childhood and is life-course-persistent. There is an overwhelming consensus that there is a massive male preponderance in this type of CD and that biological variables are major influences on this difference. This review built on this consensual scaffolding in an attempt to provide some useful leads for identifying the biological contributions to the predominantly male complexion of life-course-persistent CD by linking it to three different levels of biological mechanisms.
PMID: 17331630

8. Etiology of sex differences in the prevalence of ADHD: an examination of inattention and hyperactivity-impulsivity

Rhee SH, Waldman ID.
Am J Med Genet B Neuropsychiatr Genet. 2004 May 15;127B(1):60-4.

Several studies have examined the predictions of two models (i.e., the polygenic multiple threshold (PMT) model and the constitutional variability (CV) model) developed to explain sex differences in the prevalence of attention-deficit/hyperactivity disorder (ADHD), and the results of these studies are conflicting. Although there is substantial evidence that two distinct, moderately correlated symptom dimensions (inattention and hyperactivity-impulsivity) underlie ADHD symptoms, all of these studies have examined ADHD as a unidimensional construct. Therefore, we tested the PMT and CV models for the two ADHD symptom dimensions separately. Dizygotic twins or siblings of girls with ADHD had a higher number of ADHD symptoms than twins or siblings of boys with ADHD. This evidence for the PMT model and against the CV model was found for both inattention and hyperactivity-impulsivity, but became weaker for hyperactivity-impulsivity as symptom severity increased. Copyright 2003 Wiley-Liss, Inc.
PMID: 15108181

9. Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity

Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L.
Biol Psychiatry. 2005 Feb 1;57(3):229-38.

BACKGROUND: The hypothesis that altered dopamine transmission underlies hyperactive-inattentive behavior in children with attention-deficit/hyperactivity disorder (ADHD) is based on genetic studies and the efficacy of psychostimulants. Most of previous positron emission tomography (PET) and single photon emission tomography (SPET) studies have shown altered binding of dopamine markers in the basal ganglia. Yet, the functional role of the neurochemical disturbances are poorly understood. The purpose of our study was to examine dopamine transporter (DAT) and dopamine D2 receptor (D2R) binding in adolescents with ADHD and to search for its relationship with cognitive functions as well as locomotor hyperactivity. METHODS: Twelve adolescents with ADHD and 10 young adults were examined with PET using the selective radioligands [11C]PE2I and [11C]raclopride, indexing DAT and D2R density. The simplified reference tissue model was used to calculate binding potential (BP) values. Attention and motor behavior were investigated with a continuous performance task (CPT) and motion measurements. RESULTS: The BP value for [11C]PE2I and [11C]raclopride in the striatum of children with ADHD did not differ from that of the young adult control subjects. In the midbrain, however, the BP values for DAT were significantly lower (16%; p = .03) in children with ADHD. Dopamine D2 receptor binding in the right caudate nucleus correlated significantly with increased motor activity (r = .70, p = .01). CONCLUSIONS: The lower BP values for DAT in the midbrain suggest that dopamine signaling in subjects with ADHD is altered. Altered dopamine signaling might have a causal relationship to motor hyperactivity and might be considered as a potential endophenotype of ADHD.
PMID: 15691523

10. Prenatal and perinatal striatal injury: a hypothetical cause of attention-deficit-hyperactivity disorder?

Toft PB.
Pediatr Neurol. 1999 Sep;21(3):602-10.

Experimental data indicate a particular vulnerability of striatal neurons in the developing brain, and together with the idea that the striatum is important for context recognition and behavior, these data have led the author to search for subtle striatal lesions, in the form of biochemical changes, in children who have suffered perinatal adverse events. Evidence is presented to demonstrate that the composition of metabolites in the striatum is altered, primarily in the form of an elevated level of lactate, in human neonates who have suffered various perinatal disorders, such as germinal matrix hemorrhage, intrauterine growth retardation, and asphyxia. An elevated level of lactate suggests tissue hypoxia, which may interfere with the formation of frontostriatal circuits and may play a role in the pathogenesis of the behavioral disturbances observed in a proportion of children with a history of perinatal adverse events.
PMID: 10513685

11. Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy

Lou HC.
Acta Paediatr. 1996 Nov;85(11):1266-71.

Attention-deficit Hyperactivity Disorder (ADHD), defined as a disorder of awareness with impulsivity, has lately been characterized as a dysfunction of the striatum (neostriatum = globus pallidus + putamen). This structure is in a unique position of contextual analysis and samples information samples information from almost the entire cortex through its spiny neurons. The etiology is heterogeneous, with genetic as well as lesional factors. Among the latter, pre- and perinatal events are prominent. Advances in the understanding of the role of fetal circulatory insufficiency with loss of autoregulation and systemic hypotension have drawn attention to the vulnerability of watershed regions, including the striatum. Not only circulatory facts are important for this selectivity, however. The anatomical characteristics, with convergent glutaminergic afferent synaptic transmission from almost the entire cortex contribute to the vulnerability in ischemia-induced liberation of glutamate: The striatum becomes the victim of its virtue. Repeated hypoxic-ischemic events are particularly common in prematurity, a fact which seems to explain the high incidence of ADHD in this patient group. The magnitude, of the problem is increasing with the increased survival rate among premature infants.
PMID: 8955450

12. Striatal neuronal loss or dysfunction and choline rise in children with attention-deficit hyperactivity disorder: a 1H-magnetic resonance spectroscopy study

Jin Z, Zang YF, Zeng YW, Zhang L, Wang YF.
Neurosci Lett. 2001 Nov 23;315(1-2):45-8.

Twelve previously untreated boys suffering from attention-deficit hyperactivity disorder (ADHD) were investigated by using proton magnetic resonance spectroscopy (1H MRS) before and after one dose (10 mg) of methylphenidate. Pre- and post-methylphenidate spectra were acquired bilaterally in the globus pallidus. Peaks of N-acetylaspartate (NAA), choline (Cho), myo-inositol, glutamate and creatine (Cr) were measured and the ratios of the peaks were calculated and compared with data from ten matched controls. In children having ADHD, NAA/Cr ratio decreased significantly in the bilateral striatum while Cho/Cr ratio showed a mild unilateral increase. One oral dose of methylphenidate did not affect the ratios significantly. These findings suggest that the striatum was bilaterally involved in pediatric ADHD patients. Approximately 20-25% of neurons may have died or may be severely dysfunctional. There seems to be a mild hyperactivity of the cholinergic system.
PMID: 11711211

13. Pre-, peri-, and postnatal trauma in subjects with attention-deficit hyperactivity disorder

Zappitelli M, Pinto T, Grizenko N.
Can J Psychiatry. 2001 Aug;46(6):542-8.

OBJECTIVE: To review research on pre-, peri-, and postnatal stress and their potential relation to attention-deficit hyperactivity disorder (ADHD). METHOD: We selected and critically reviewed 51 research reports from the medical and psychology literature, between January 1, 1976 and May 1, 2001, based on the subjects of pre-, peri-, or postnatal stress and ADHD. RESULTS: Children with ADHD show higher percentages of pre-, peri-, or postnatal insult, compared with unaffected children; however, the relative influence of various factors is still controversial. CONCLUSIONS: The etiology of ADHD encompasses genetic and environmental factors. Pre-, peri-, and postnatal stressors are environmental factors that may play a role in its etiology. Future research should carefully examine interactions between genetic predisposition and environmental factors as etiologies of ADHD.
PMID: 11526811

14. The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence

Bass JL, Corwin M, Gozal D, Moore C, Nishida H, Parker S, Schonwald A, Wilker RE, Stehle S, Kinane TB.
Pediatrics. 2004 Sep;114(3):805-16.
http://pediatrics.aappublications.org/cgi/content/full/114/3/805

OBJECTIVE: A review of the evidence concerning the effect of chronic or intermittent hypoxia on cognition in childhood was performed by using both a systematic review of the literature and critical appraisal criteria of causality. Because of the significant impact of behavioral disorders such as attention-deficit/hyperactivity disorder on certain cognitive functions as well as academic achievement, the review also included articles that addressed behavioral outcomes. METHODS: Both direct and indirect evidence were collected. A structured Medline search was conducted from the years 1966-2000 by using the OVID interface. Both English- and non-English-language citations were included. Significant articles identified by the reviewers up to 2003 were also included. To be included as direct evidence, an article needed to be an original report in a peer-reviewed journal with data on cognitive, behavioral, or academic outcomes in children up to 14 years old, with clinical conditions likely to be associated with exposure to chronic or intermittent hypoxia. Indirect evidence from other reviews and publications in closely related fields, including experimental studies in adults, was used to help formulate conclusions. Two reviewers screened abstracts and titles. Each article included as direct evidence received a structured evaluation by 2 reviewers. Adjudication of differences was performed by a group of 2 reviewers and a research consultant. After this review, tables of evidence were constructed that were used as the basis for group discussion and consensus development. Indirect evidence assigned by topic to specific reviewers was also presented as part of this process. A formal procedure was used to rank the studies by design strength. The critical appraisal criteria for causation described in Evidence Based Pediatrics and Child Health (Moyer V, Elliott E, Davis R, et al, eds. London, United Kingdom: BMJ Books; 2000:46-55) were used to develop consensus on causality. RESULTS: A total of 788 literature citations were screened. For the final analysis, 55 articles met the criteria for inclusion in the direct evidence. Of these, 43 (78.2%) reported an adverse effect. Of the 37 controlled studies, 31 (83.8%) reported an adverse effect. Adverse effects were noted at every level of arterial oxygen saturation and for exposure at every age level except for premature newborns. The studies were classified into 5 clinical categories: congenital heart disease (CHD), sleep-disordered breathing (SDB), asthma, chronic ventilatory impairment, and respiratory instability in infants. Two of these categories, CHD and SDB, which accounted for 42 (76.4%) of the included articles, fulfilled the Evidence Based Pediatrics and Child Health criteria for causation. The indirect evidence included 8 reviews, 1 meta-analysis, and 10 original reports covering the fields of adult anoxia, animal research, SDB in adults, natural and experimental high-altitude studies, perinatal hypoxic-ischemic encephalopathy, anemia, and carbon-monoxide poisoning. The studies of high-altitude and carbon-monoxide poisoning provided evidence for causality. CONCLUSIONS: Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children with CHD and SDB as well as in a variety of experimental studies in adults. This should be taken into account in any situation that may expose children to hypoxia. Because adverse effects have been noted at even mild levels of oxygen desaturation, future research should include precisely defined data on exposure to all levels of desaturation.
PMID: 15342857

15. Update on perinatal hypoxic insult: mechanism, diagnosis and interventions

Amato M, Donati F.
Eur J Paediatr Neurol. 2000;4(5):203-9.

Cerebral hypoxia-ischaemia in the neonate can produce irreversible tissue injury and is always associated with major perturbations in the energy status of the brain. The major neurological manifestations of brain injury in these babies are spastic motor deficits. Different pathogenetic mechanisms may underlie hypoxic-ischaemic injury of the brain such as decreased blood flow autoregulation, altered cerebral metabolism, thrombosis, haemorrhage, accumulation of toxic metabolites such as glutamate, impaired intracellular calcium turnover, release of interleukins and prostaglandins, iron accumulation and overproduction of free-radicals. In summary, hypoxia-ischaemia in neonates triggers a cascade of biological processes culminating in cell death. Important advances in the assessment of cerebral injuries in neonates have been made in the area of neuroimaging, especially in magnetic resonance imaging which may provide useful prognostic information when obtained in the course of brain injury. Future studies may focus on new therapeutic pharmacological and non-pharmacological strategies aimed at the reversal of the pathophysiological mechanisms activated by perinatal hypoxia-ischaemia.
PMID: 11030066

16. Symptoms of attention-deficit/hyperactivity disorder following traumatic brain injury in children

Levin H et al.
J Dev Behav Pediatr. 2007 Apr;28(2):108-18.

METHODS: We investigated changes in inattentive and hyperactive symptoms over 2 years following traumatic brain injury (TBI) in relation to preinjury attention-deficit/hyperactivity disorder (ADHD), injury, and socioeconomic status (SES) variables. Postinjury stimulant medication treatment was also documented. Of 175 consecutive patients of ages 5 to 15 years with acute TBI, 148 consented, including 114 without preinjury ADHD (mean age, 10.0 years, SD = 2.76) and 34 with preinjury ADHD (mean age 10.36 years, SD = 2.75). The Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version, was administered at baseline and at 6, 12, and 24 months post-injury to assess the presence of nine core inattentive and nine hyperactive symptoms and associated impairment. The baseline assessment was performed within 1 month post-injury to establish preinjury diagnosis. RESULTS: Nonlinear change in inattentive symptoms in patients without preinjury ADHD contrasted with higher and more stable symptom levels in children with preinjury diagnosis, including the cubic trend (chi2(1) = 6.23, p = .0126). There was also a significant interaction of group x gender effect (chi2(1) = 4.08, p = .0435) as males had higher numbers of inattentive symptoms than females in the preinjury ADHD group. Change in hyperactive symptoms over time also differed by group, including both linear (chi2(1) = 5.42, p = .0199) and cubic trends (chi2(1) = 8.91, p = .0029), reflecting greater and more frequent fluctuations in children without preinjury ADHD. Socioeconomic level also contributed to change in hyperactive symptoms as reflected by the interaction of SES and linear time (chi2(1) = 6.91, p = .009), as well as quadratic time (chi2(1) = 4.90, p = .027). Occurrence of ADHD diagnosed post-injury ranged from 14.5% (12 months) to 18.3% (24 months) in the group without preinjury ADHD compared with a range from 86.4% (12 months) to 96.2% (6 months) in children with preinjury ADHD. In children without preinjury ADHD, SES was the only patient variable that predicted onset of ADHD, t(110) = -2.85, p = .0052. Treatment with stimulant medication post-injury was more frequently associated with preinjury ADHD (39% vs 7% of children without preinjury ADHD), p< .0001 (Fisher exact test). Children with preinjury ADHD who were treated pre-injury with stimulant medication had fewer total symptoms at 24 months post-injury relative to untreated patients with preinjury ADHD (F[1,14] = 3.93, p = 0.069, Cohen's d = 1.28). CONCLUSION: Change in ADHD symptoms after TBI varies with preinjury diagnosis, reflects injury severity in children without preinjury ADHD, and is treated with stimulant medication mainly in those patients with preinjury ADHD.
PMID: 17435461

17. Predictors of attention-deficit/hyperactivity disorder within 6 months after pediatric traumatic brain injury

Max JE et al.
J Am Acad Child Adolesc Psychiatry. 2005 Oct;44(10):1032-40.

OBJECTIVE: To assess the phenomenology and predictive factors of attention-deficit/hyperactivity disorder (ADHD) after traumatic brain injury (TBI), also called secondary ADHD (SADHD). METHOD: Children without preinjury ADHD 5-14 years old with TBI from consecutive admissions (n = 143) to five trauma centers were observed prospectively for 6 months (baseline and 6 months), with semistructured psychiatric interviews. Injury severity, lesion characteristics, and preinjury variables including psychiatric disorder, family psychiatric history, family psychiatric history of ADHD, family function, socioeconomic status, psychosocial adversity, and adaptive function were assessed with standardized instruments. RESULTS: SADHD in the first 6 months after injury occurred in 18 of 115 (16%) of returning participants. All subtypes of ADHD occurred. Socioeconomic status (p = .041) and orbitofrontal gyrus lesions (p = .005) independently significantly predicted SADHD. CONCLUSIONS: These findings are consistent with research on developmental ADHD that implicate psychosocial factors and prefrontal structural and functional differences between those with and without the disorder.
PMID: 16175108

18. Evidence of brain dysfunction in attention deficit-hyperactivity disorder: a controlled study with proton magnetic resonance spectroscopy

Fayed N, Modrego PJ, Castillo J, Dávila J.
Acad Radiol. 2007 Sep;14(9):1029-35.

RATIONALE AND OBJECTIVES: Attention deficit-hyperactivity disorder (ADHD) is a socially disabling condition whose pathophysiology is mostly unknown. Previous magnetic resonance imaging (MRI)-based reports have shown structural abnormalities in the prefrontal region and the striatum, but with inconsistencies across the studies with regard to right/left specificity of changes. Our study is aimed at finding evidence of dysfunction with more refined MRI techniques such as diffusion-weighted MRI and spectroscopy. MATERIALS AND METHODS: We enrolled 22 ADHD children (mean age 9; SD 2.91) and 8 healthy children (mean age 7.5; SD 3). All of them underwent diffusion-weighted MRI in several areas of the brain bilaterally: prefrontal, lentiform nucleus, posterior cingulate, and centrum semiovale; and single-voxel proton magnetic resonance spectroscopy in the left centrum semiovale and right prefrontal region. RESULTS: We did not see either apparent structural abnormalities of the brain in conventional MRI or differences in the apparent-diffusion coefficients in any of the areas studied. However, we observed significant differences in the N-acetyl-aspartate/creatine ratios in relation to controls in the right prefrontal corticosubcortical region: 1.58 (SD 0.09) versus 1.47 (0.08), P = .01); and in the left centrum semiovale: 2.02 (0.13) versus 1.79 (0.13), P = .0003. This finding is consistent with a published report on eight ADHD children in whom N-acetyl-aspartate/creatine ratios were also elevated. CONCLUSIONS: Given these results, we hypothesize that a biochemical dysfunction might underlie in the brain of ADHD children. The N-acetyl-aspartate/creatine ratio may be regarded as a potential marker of the disease.
PMID: 17707309

19. Mechanisms of perinatal brain injury

Inder TE, Volpe JJ.
Semin Neonatol. 2000 Feb;5(1):3-16.

This article is focused on the mechanisms underlying primarily ischaemic/reperfusion brain injury in both the term and premature infant. Although the mechanisms involved include similar initiating events, principally ischaemia-reperfusion, and similar final common pathways to cell death, particularly free radical-mediated events, there are certain unique maturational factors influencing the type and pattern of cellular injury. We will therefore initially describe the physiological and cellular/molecular mechanisms of brain injury in the term infant, followed by the mechanisms in the premature infant. Copyright 2000 Harcourt Publishers Ltd.
PMID: 10802746

20. Perinatal complications and abnormal proton metabolite concentrations in frontal cortex of adolescents seen on magnetic resonance spectroscopy

Kinney DK, Steingard RJ, Renshaw PF, Yurgelun-Todd DA.
Neuropsychiatry Neuropsychol Behav Neurol. 2000 Jan;13(1):8-12.

OBJECTIVE: The relation of perinatal complications to metabolism of orbitofrontal cortex was studied in 12 normal adolescents aged 13 to 17 years. BACKGROUND: Perinatal complications are associated with both (a) behavioral signs of frontal lobe dysfunction and (b) increased risk for mood disorders and schizophrenia. Perinatal complications are not usually sufficient to produce these disorders, however, suggesting an etiologic model in which perinatal complications interact with a second, familial, liability factor. The present study tested a key prediction of this "two-factor" model, namely, that perinatal complications will be associated with physiologic signs of frontal dysfunction, even in persons who have no personal or family history of these psychiatric disorders. METHODS: Subjects were screened by structured interviews with the Kiddie Schedule for Affective Disorders and Schizophrenia and had no personal or family history of psychiatric disorder. Ratios of choline and N-acetyl aspartate to creatine in orbitofrontal cortex were measured using proton magnetic resonance spectroscopy. Perinatal complications were scored with the examiners blinded to magnetic resonance spectroscopy data, applying published scales to hospital records on subjects' gestations and births. RESULTS: Perinatal complications were significantly correlated with reduced concentrations of choline and N-acetyl aspartate. CONCLUSIONS: Our results complement earlier findings of significant relations between perinatal complications and signs of frontal lobe dysfunction, as well as elevated rates of these two types of variables in mood disorders and schizophrenia.
PMID: 10645731

21. Tourette's and comorbid syndromes: obsessive compulsive and attention deficit hyperactivity disorder. A common etiology?

Sheppard DM, Bradshaw JL, Purcell R, Pantelis C.
Clin Psychol Rev. 1999 Aug;19(5):531-52.

Tourette's syndrome (TS), a neuropsychiatric movement disorder that manifests itself in childhood, is often associated with comorbid symptomatology, such as obsessions, compulsions, hyperactivity, distractibility, and impulsivity. Epidemiological studies suggest that a substantial number of TS patients develop clinical levels of obsessive-compulsive disorder (OCD) and/or attention deficit hyperactivity disorder (ADHD). This review aims to provide an integrated account of the three disorders in terms of their comorbidity. Neuroimaging studies suggest that all three disorders involve neuropathology of the basal-ganglia thalamocortical (BGTC) pathways: TS in the sensorimotor and limbic BGTC circuits; OCD in the prefrontal and limbic BGTC pathways; and ADHD in the sensorimotor, orbitofrontal, and limbic BGTC circuits. The pattern of comorbidity and other evidence indicates that the TS gene(s) may be responsible for a spectrum of disorders, including OCD and ADHD, but also that the disorders OCD and ADHD can exist in their own right with their own etiologies.
PMID: 10467490

22. Foods and additives are common causes of the attention deficit hyperactive disorder in children

Boris M, Mandel FS.
Ann Allergy. 1994 May;72(5):462-8.

The attention deficit hyperactive disorder (ADHD) is a neurophysiologic problem that is detrimental to children and their parents. Despite previous studies on the role of foods, preservatives and artificial colorings in ADHD this issue remains controversial. This investigation evaluated 26 children who meet the criteria for ADHD. Treatment with a multiple item elimination diet showed 19 children (73%) responded favorably, P < .001. On open challenge, all 19 children reacted to many foods, dyes, and/or preservatives. A double-blind placebo controlled food challenge (DBPCFC) was completed in 16 children. There was a significant improvement on placebo days compared with challenge days (P = .003). Atopic children with ADHD had a significantly higher response rate than the nonatopic group. This study demonstrates a beneficial effect of eliminating reactive foods and artificial colors in children with ADHD. Dietary factors may play a significant role in the etiology of the majority of children with ADHD.
PMID: 8179235

23. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial

McCann D et al.
Lancet. 2007 Nov 3;370(9598):1560-7.

BACKGROUND: We undertook a randomised, double-blinded, placebo-controlled, crossover trial to test whether intake of artificial food colour and additives (AFCA) affected childhood behaviour. METHODS: 153 3-year-old and 144 8/9-year-old children were included in the study. The challenge drink contained sodium benzoate and one of two AFCA mixes (A or B) or a placebo mix. The main outcome measure was a global hyperactivity aggregate (GHA), based on aggregated z-scores of observed behaviours and ratings by teachers and parents, plus, for 8/9-year-old children, a computerised test of attention. This clinical trial is registered with Current Controlled Trials (registration number ISRCTN74481308). Analysis was per protocol. FINDINGS: 16 3-year-old children and 14 8/9-year-old children did not complete the study, for reasons unrelated to childhood behaviour. Mix A had a significantly adverse effect compared with placebo in GHA for all 3-year-old children (effect size 0.20 [95% CI 0.01-0.39], p=0.044) but not mix B versus placebo. This result persisted when analysis was restricted to 3-year-old children who consumed more than 85% of juice and had no missing data (0.32 [0.05-0.60], p=0.02). 8/9-year-old children showed a significantly adverse effect when given mix A (0.12 [0.02-0.23], p=0.023) or mix B (0.17 [0.07-0.28], p=0.001) when analysis was restricted to those children consuming at least 85% of drinks with no missing data. INTERPRETATION: Artificial colours or a sodium benzoate preservative (or both) in the diet result in increased hyperactivity in 3-year-old and 8/9-year-old children in the general population.
PMID: 17825405

24. Synergistic interactions between commonly used food additives in a developmental neurotoxicity test

Lau K, McLean WG, Williams DP, Howard CV.
Toxicol Sci. 2006 Mar;90(1):178-87.
http://toxsci.oxfordjournals.org/cgi/content/full/90/1/178

Exposure to non-nutritional food additives during the critical development window has been implicated in the induction and severity of behavioral disorders such as attention deficit hyperactivity disorder (ADHD). Although the use of single food additives at their regulated concentrations is believed to be relatively safe in terms of neuronal development, their combined effects remain unclear. We therefore examined the neurotoxic effects of four common food additives in combinations of two (Brilliant Blue and L-glutamic acid, Quinoline Yellow and aspartame) to assess potential interactions. Mouse NB2a neuroblastoma cells were induced to differentiate and grow neurites in the presence of additives. After 24 h, cells were fixed and stained and neurite length measured by light microscopy with computerized image analysis. Neurotoxicity was measured as an inhibition of neurite outgrowth. Two independent models were used to analyze combination effects: effect additivity and dose additivity. Significant synergy was observed between combinations of Brilliant Blue with L-glutamic acid, and Quinoline Yellow with aspartame, in both models. Involvement of N-methyl-D-aspartate (NMDA) receptors in food additive-induced neurite inhibition was assessed with a NMDA antagonist, CNS-1102. L-glutamic acid- and aspartame-induced neurotoxicity was reduced in the presence of CNS-1102; however, the antagonist did not prevent food color-induced neurotoxicity. Theoretical exposure to additives was calculated based on analysis of content in foodstuff, and estimated percentage absorption from the gut. Inhibition of neurite outgrowth was found at concentrations of additives theoretically achievable in plasma by ingestion of a typical snack and drink. In addition, Trypan Blue dye exclusion was used to evaluate the cellular toxicity of food additives on cell viability of NB2a cells; both combinations had a straightforward additive effect on cytotoxicity. These data have implications for the cellular effects of common chemical entities ingested individually and in combination.
PMID: 16352620

25. Consequences of variations in genes that affect dopamine in prefrontal cortex

Diamond A.
Cereb Cortex. 2007 Sep;17 Suppl 1:i161-70.
http://www.pubmedcentral.nih.go/picrender.fcgi?artid=2238775&blobtype=pdf

Patricia Goldman-Rakic played a groundbreaking role in investigating the cognitive functions subsevred by dorsolateral prefrontal cortex and the key role of dopamine in that. The work discussed here builds on that including: 1) Studies of children predicted to have lower levels of prefrontal dopamine but otherwise basically normal brains (children treated for phenylketonuria [PKU]). Those studies changed medical guidelines, improing the children's lives. 2) Studies of visual impairments (in contrast sensitivity and motion perception) in PKU children due to reduced retinal dopamine and due to excessive phenylalanine during the first postnatal weeks. Those studies, too, changed medical guidelines. 3) Studies of working memory and inhibitory control differences in typically developing children due to differences in catechol-O-methyltransferase (COMT) genotype, which selectiely affect prefrontal dopamine leels. 4) Studies of gender differences in the effect of COMT genotype on cognitive performance in older adults. 5) A hypothesis about fundamental differences between attention deficit hyperactiity disorder (ADHD) that includes hyperactivity and ADHD of the inattentive type. Those disorders are hypothesized to differ in the affected neural system, underlying genetics, responsiveness to medication, comorbidities, and cognitive and behavioral profiles. These sound quite disparate but they all grew systematically out the base laid down by Patricia Goldman-Rakic.
PMID: 17725999

26. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis

Swanson JM et al.
Neuropsychol Rev. 2007 Mar;17(1):39-59.

Multiple theories of Attention-Deficit/Hyper-activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.
PMID: 17318414

27. Gene-environment interactions reexamined: does mother's marital stability interact with the dopamine receptor D2 gene in the etiology of childhood attention-deficit/hyperactivity disorder?

Waldman ID.
Dev Psychopathol. 2007 Fall;19(4):1117-28.

Potential candidate Gene x Environment interactions in the etiology of childhood attention-deficit/hyperactivity disorder (ADHD) are examined between the dopamine receptor D2 gene (DRD2) and putative family environmental risk factors that reflect mothers' marital stability. Specifically, interactions were tested between DRD2 and mothers' marital status, number of marriages or cohabiting relationships, and age at first marriage. Moderate relations were found among the marital stability measures, and mother's marital status and number of marriages or cohabiting relationships (but not age at first marriage) were risk factors for their children's ADHD. All three mother's marital stability variables were associated with either the child's or mother's DRD2 genotypes. Gene x Environment interactions were found for children's ADHD diagnoses between children's DRD2 genotypes and mother's marital status and number of marriages or cohabiting relationships. It is of interest that these interactions were strengthened with the progressive addition of sets of covariates intended to control for alternative causal pathways that represent background genetic and environmental context confounds. The present findings highlight the importance of considering both the nexus of putative environmental risk factors and whether their etiology and effects are truly environmental in future Gene x Environment interaction research.
PMID: 17931438

28. Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype.

Neuman RJ, Lobos E, Reich W, Henderson CA, Sun LW, Todd RD.
Biol Psychiatry. 2007 Jun 15;61(12):1320-8.

BACKGROUND: In utero exposure to smoking and alcohol are common risk factors that have been associated with attention-deficit/hyperactivity disorder (ADHD) in human beings and animal models. Furthermore, molecular studies have focused on the association between ADHD and DNA polymorphisms in dopamine pathway-related genes. We examined the joint effects of genetic and prenatal substance exposures on DSM-IV and population-defined subtypes of ADHD. METHODS: Logistic regression was used to assess the relationship between ADHD subtypes, DAT1 and DRD4 polymorphisms, and prenatal substance exposures in a birth-record sample of male and female twin pairs, aged 7-19 years. RESULTS: Interactions between prenatal exposure to smoking and variations in the DAT1 and DRD4 loci were observed in children with either the DSM-IV or population-defined ADHD combined subtypes. The odds of a diagnosis of DSM-IV combined subtype was 2.9 times greater in twins who had inherited the DAT1 440 allele and who were exposed, than in unexposed twins without the risk allele. The OR was 2.6 in the population-defined subtype. Odds ratios for the DRD4 seven-repeat allele were 3.0 (2.8) in the population-defined (DSM-IV) combined ADHD subtypes. The OR for exposed children with both alleles was 9.0 (95% confidence interval=2.0-41.5) for the population-defined combined subtypes. CONCLUSIONS: Results indicate that smoking during pregnancy is associated with specific subtypes of ADHD in genetically susceptible children.
PMID: 17157268

29. Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children

Konofal E, Cortese S, Marchand M, Mouren MC, Arnulf I, Lecendreux M.
Sleep Med. 2007 Nov;8(7-8):711-5.

OBJECTIVE: Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). To date, the impact of iron deficiency, RLS and familial history of RLS on ADHD severity has been scarcely examined in children. These issues are addressed in the present study. METHODS: Serum ferritin levels, familial history of RLS (diagnosed using National Institutes of Health (NIH) criteria) and previous iron supplementation in infancy were assessed in 12 ADHD+RLS children, 10 ADHD children and 10 controls. RLS was diagnosed using NIH-specific pediatric criteria, and ADHD severity was assessed using the Conners' Parent Rating scale. RESULTS: ADHD symptom severity was higher, although not significantly, in children with ADHD+RLS compared to ADHD. The mean serum ferritin levels were significantly lower in children with ADHD than in the control group (p<0.0005). There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores. CONCLUSIONS: Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.
PMID: 17644481

30. A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation

Kuznetsova AY, Deth RC.
J Comput Neurosci. 2008 Jun;24(3):314-29.

We describe a new molecular mechanism of dopamine-induced membrane protein modulation that can tune neuronal oscillation frequency to attention-related gamma rhythm. This mechanism is based on the unique ability of D4 dopamine receptors (D4R) to carry out phospholipid methylation (PLM) that may affect the kinetics of ion channels. We show that by deceasing the inertia of the delayed rectifier potassium channel, a transition to 40 Hz oscillations can be achieved. Decreased potassium channel inertia shortens spike duration and decreases the interspike interval via its influence on the calcium-dependent potassium current. This mechanism leads to a transition to attention-related gamma oscillations in a pyramidal cell-interneuron network. The higher frequency and better synchronization is observed with PLM affecting pyramidal neurons only, and recurrent excitation between pyramidal neurons is important for synchronization. Thus dopamine-stimulated methylation of membrane phospholipids may be an important mechanism for modulating firing activity, while impaired methylation can contribute to disorders of attention.
PMID: 17929154

31. Protein kinase C regulates dopamine D4 receptor-mediated phospholipid methylation

Sharma A, Waly M, Deth RC.
Eur J Pharmacol. 2001 Sep 14;427(2):83-90.

Dopamine D4 receptors (D4 receptors) mediate dopamine-stimulated, folate-dependent phospholipid methylation. To investigate possible regulation of this multi-step D4 receptor-mediated phospholipid methylation cycle by protein kinases, specific kinase activators and inhibitors were studied in SK-N-MC human neuroblastoma cells, using [14C] formate to label folate-derived single-carbon groups. Phorbol dibutyrate (PDB), an activator of protein kinase C, stimulated basal phospholipid methylation and also shifted the dose-response curve for dopamine-stimulated phospholipid methylation to the right by more than an order of magnitude. Calphostin C, an inhibitor of protein kinase C, had little effect on basal phospholipid methylation but significantly inhibited dopamine-stimulated phospholipid methylation and also blocked the stimulatory response to PDB. Chelerythrine, which inhibits protein kinase C and other kinases, strongly inhibited both basal and dopamine-stimulated phospholipid methylation. Forskolin, an activator of protein kinase A, inhibited basal and dopamine-stimulated phospholipid methylation, but only at high concentrations while Rp-cAMP, an inhibitor of protein kinase A, did not block this effect. Inhibition of protein kinase G produced a modest decrease in dopamine-stimulated phospholipid methylation, but neither sodium nitroprusside, which increases nitric oxide (NO) production and activates protein kinase G, nor the NO synthase inhibitor N-nitro-L-arginine had any effect on basal or dopamine-stimulated phospholipid methylation. These observations indicate that protein kinase C is an important regulator of basal and D4 receptor-mediated folate-dependent phospholipid methylation, whereas protein kinase A and protein kinase G have a lesser or minimal role.
PMID: 11557258

32. Relationship between dopamine-stimulated phospholipid methylation and the single-carbon folate pathway

Zhao R et al.
J Neurochem. 2001 Aug;78(4):788-96.

In a previous study we demonstrated the ability of dopamine (DA) to stimulate phospholipid methylation (PLM) via a novel mechanism involving the D4 dopamine receptor (D4R) in which single-carbon folates appeared to be the primary source of methyl groups. To further understand the relationship between D4R-mediated PLM and folate metabolism, we examined the effect of several folate pathway interventions on the level of basal and DA-stimulated incorporation of [14C]-labeled formate into phospholipids in cultured SH-SY5Y neuroblastoma cells. These interventions included: (i) Overexpression of methenyltetrahydrofolate synthetase (MTHFS). (ii) Treatment with 5-formylTHF. (iii) Treatment with the MTHFS inhibitor 5-formyltetrahydrohomofolic acid (5-formylTHHF). (iv) Growth in nucleoside-free media. 31P-NMR was also used to follow DA-induced changes in cell phospholipid composition. MTHFS overexpression and 5-formylTHHF treatment, both of which lower 5-methylTHF levels, each reduced basal PLM and its stimulation by DA. In contrast, 5-formylTHF, which increases 5-methylTHF, caused a dose-dependent increase in both basal and DA-stimulated PLM. Growth in nucleoside-free media caused time-dependent changes in PLM, which were due to the absence of purine nucleosides. While basal PLM was maintained at a reduced level, DA-stimulated PLM was initially increased followed by a later decrease. Together, these findings indicate a close functional relationship between single-carbon folate metabolism and DA-stimulated PLM, consistent with a role for 5-methylTHF as the methyl donor for the D4R-mediated process.
PMID: 11520899

33. A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation

Kuznetsova AY, Deth RC.
J Comput Neurosci. 2008 Jun;24(3):314-29.

We describe a new molecular mechanism of dopamine-induced membrane protein modulation that can tune neuronal oscillation frequency to attention-related gamma rhythm. This mechanism is based on the unique ability of D4 dopamine receptors (D4R) to carry out phospholipid methylation (PLM) that may affect the kinetics of ion channels. We show that by deceasing the inertia of the delayed rectifier potassium channel, a transition to 40 Hz oscillations can be achieved. Decreased potassium channel inertia shortens spike duration and decreases the interspike interval via its influence on the calcium-dependent potassium current. This mechanism leads to a transition to attention-related gamma oscillations in a pyramidal cell-interneuron network. The higher frequency and better synchronization is observed with PLM affecting pyramidal neurons only, and recurrent excitation between pyramidal neurons is important for synchronization. Thus dopamine-stimulated methylation of membrane phospholipids may be an important mechanism for modulating firing activity, while impaired methylation can contribute to disorders of attention.
PMID: 17929154

34. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis

Deth R et al.
Neurotoxicology. 2008 Jan;29(1):190-201.
http://tinyurl.com/65f8jb

Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.
PMID: 18031821

35. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism

James SJ et al.
Am J Clin Nutr. 2004 Dec;80(6):1611-7.
http://www.ajcn.org/cgi/content/full/80/6/1611

BACKGROUND: Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated with other neurologic diseases, these pathways have not been evaluated in persons with autism. OBJECTIVE: The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. DESIGN: Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. RESULTS: Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. CONCLUSIONS: An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
PMID: 15585776

36. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

James SJ et al.
Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56.

Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism. (c) 2006 Wiley-Liss, Inc.
PMID: 16917939

37. Abnormal Transmethylation/transsulfuration Metabolism and DNA Hypomethylation Among Parents of Children with Autism

S. Jill James et al.
May 30, 2008
Journal of Autism and Developmental Disorders

38. Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

Waly M et al.
Mol Psychiatry. 2004 Apr;9(4):358-70.

Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.
PMID: 14745455

39. The health effects of aluminium--a review

Cooke K, Gould MH.
J R Soc Health. 1991 Oct;111(5):163-8.

This review covers the occurrence of aluminium in soil, air, water and food. In addition, aluminium levels in body tissues and its movement within the body have been considered. The adverse effects of aluminium that have been reported in recent years include Alzheimer's disease, dementia and hyperactivity and learning disorders in children.
PMID: 1795349

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