Biomedical subjects

Harvey S Singer

Publications and source records attributed to Harvey S Singer.

32 records · Page 2Linked to original sources

PubMed2004

Increased prefrontal D2 protein in Tourette syndrome: a postmortem analysis of frontal cortex and striatum.

The precise neuropathological mechanism underlying Tourette syndrome (TS) is unknown. In order to evaluate a variety of proposed dopaminergic abnormalities, postmortem tissue samples were obtained from three individuals with TS (two typical males with childhood onset, ages 29 and 77, and a 62-year-old female with adult-onset) and three age- and sex-matched controls. Samples from caudate, putamen, ventral striatum, and prefrontal cortex (Brodmann's area 9, BA9) were analyzed by semiquantitative immunoblotting for relative densities of dopamine receptors (D1, D2), transporter (DAT), monoamine terminals (vesicular monoamine transporter type 2), vesicular docking and release proteins (VAMP-2, synaptotagmin, SNAP-25, syntaxin, synaptophysin), and receptors inhibiting dopamine release (alpha 2-adrenergic receptors, alpha-2A). Concentrations of monoamine neurotransmitters and their metabolites were assessed by high performance liquid chromatography. Data from each TS sample was calculated as a percent value of its control. Results showed that prefrontal cortex, rather than striatum, had the greatest number of changes in the two typical TS cases, including increases for D2, DAT, VAMP-2, and alpha-2A. All three TS subjects had increased densities of prefrontal D2 receptor protein, greater than 140% of their matched control. These results suggest the presence of a prefrontal-dopaminergic abnormality in TS and emphasize the need for a more specific focus on the frontal lobe.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Striatal microinfusion of Tourette syndrome and PANDAS sera: failure to induce behavioral changes.

Rodent striatal microinfusions have been suggested as a model for assessing the behavioral effects induced by antineuronal antibodies. We used this approach to evaluate the proposed autoimmune etiology for Tourette syndrome (TS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Sera were assessed from patients with TS (n = 9) preselected based on the presence of elevated enzyme-linked immunosorbent assay optical densities against putamen homogenate and sera from patients with PANDAS (n = 8), selected from a larger group assayed for antibodies against a putamen synaptosomal preparation. The effect of antibodies against the streptococcal M5 protein were also studied. A total of 44 Fischer rats received bilateral infusion of sera: 23 ventral striatum (5 PANDAS, 5 TS, 5 anti-M5 protein, and 8 control); 21 ventrolateral striatum (5 PANDAS, 5 TS, 5 anti-M5 protein, and 6 controls). Cannulas were placed bilaterally and symmetrically by stereotactic techniques. After animals were allowed to recover for 1 week, sera were microinfused for 3 days. Animal behavior was then simultaneously quantified by daily observation and monitoring using automated activity boxes for 10 days after infusion. No significant alterations in stereotypic behavior or movement were observed between the PANDAS, TS, or anti-M5 protein and control groups. Our findings are in contrast to previous reports, and suggest the need for further investigations to determine the validity of the model and of autoimmune-mediated hypotheses for pediatric movement disorders.

Animals↗

PubMed2004

Anti-basal ganglia antibodies in PANDAS.

An autoimmune-mediated mechanism involving molecular mimicry has been proposed for a variety of pediatric movement disorders that occur after a streptococcal infection. In this study, anti-basal ganglia antibodies (ABGA) were measured in 15 children with the diagnosis of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and compared with those in 15 controls. ELISA and Western immunoblotting (WB) methods were used to detect ABGA against supernatant (S1), pellet (P2), and synaptosomal preparations from adult postmortem caudate, putamen, and globus pallidus. ELISA optical density values did not differ between PANDAS patients and controls across all preparations. Immunoblotting identified multiple bands in all subjects with no differences in the number of bands or their total density. Discriminant analysis, used to assess mean binding patterns, showed that PANDAS patients differed from controls only for the caudate S1 fraction (Wilks' lambda = 0.0236, P < 0.0002), with PANDAS-primarily tic subjects providing the greatest discrimination. Among the epitopes contributing to differences between PANDAS and control in the caudate S1 fraction, mean binding to the epitope at 183 kDa was the most different between groups. In conclusion, ELISA measurements do not differentiate between PANDAS and controls, suggesting a lack of major antibody changes in this disorder. Further immunoblot analyses using a caudate supernatant fraction are required to completely exclude the possibility of minor antibody repertoire differences in PANDAS subjects, especially in those who primarily have tics.

Adolescent↗

PubMed2004

Repetitive arm and hand movements (complex motor stereotypies) in children.

OBJECTIVE: To characterize clinical features, associated problems, and outcomes for children with complex motor stereotypies who do not have mental retardation or pervasive developmental disorders. STUDY DESIGN: We performed a record review for 40 children (63% male) aged 9 months to 17 years with complex motor stereotypies between 1993 and 2003. RESULTS: Age at onset was at or before 3 years in 90% of the sample. Symptoms occurred at least once daily in 90%. Excitement was identified as a trigger in 70%. Movements stopped when cued in 98%, and none had stereotypies during sleep. A total of 25% had comorbid attention deficit hyperactivity disorder (ADHD), and 20% had a learning disability. Family history of stereotypies was identified in 25%, tics in 33%, ADHD in 10%, and mood-anxiety disorder in 38%. Pharmacotherapy to target associated conditions was used in 40%, and behavioral therapy was used in 23%. A total of 53% identified symptoms for more than 5 years. Movements resolved in 5% of the children, improved in 33%, were unchanged in 50%, and worsened in 13%. CONCLUSIONS: The clinical course of complex motor stereotypies appears chronic. Better understanding of the clinical features of complex stereotypies in primary care settings is essential for early diagnosis and management.

Adolescent↗

PubMed2004

Restless legs syndrome: association with streptococcal or mycoplasma infection.

Group A beta-hemolytic streptococcal infections have been reported to cause neuropsychiatric symptoms, such as chorea, tics, and obsessive-compulsive disorder, presumably through autoimmune damage to basal ganglia. Mycoplasma pneumoniae infections have also been reported to cause damage to the basal ganglia. Restless legs syndrome is a movement disorder with focal restlessness, an irresistible desire to move, and exacerbation by long periods of sitting or lying. We present three children with transient restless legs syndrome-like symptoms possibly associated with group A beta-hemolytic streptococcal infection or Mycoplasma pneumoniae infection. One of three patients had persistently elevated enzyme-linked immunosorbent optical density values against human caudate and putamen.

Adolescent↗

PubMed2003

PANDAS: a commentary.

PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection. As defined, the criteria include prepubertal children with either a tic or obsessive-compulsive disorder in whom a Group A beta-hemolytic streptococcal infection (GABHS) triggers the abrupt onset or exacerbation of tics/obsessive-compulsive behaviors. Pathophysiologically, it is proposed that antibodies produced against GABHS cross-react with neuronal cells, in a process involving molecular mimicry. Although PANDAS has received widespread notoriety, the existence of this condition has been questioned. This commentary reviews clinical and laboratory issues pertinent to the diagnosis of this entity. We conclude that PANDAS is an intriguing hypothesis that requires further confirmation.

Antibodies, Bacterial↗

PubMed2003

Anti-basal ganglia antibody abnormalities in Sydenham chorea.

Anti-basal ganglia antibodies (ABGA) were measured in nine children with Sydenham chorea (SC) and compared to nine controls. Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) methods were used to detect ABGA against supernatant (S1), pellet, and synaptosomal preparations from adult and pediatric postmortem caudate, putamen, and globus pallidus. ELISA optical density (OD) values were higher in SC patients than controls across all preparations, but did not reach a level of significance. Although WB identified multiple bands in all subjects, discriminant analysis showed that the mean binding patterns of SC patients were significantly different from control, most notably in the caudate S1 fraction (Wilks' lambda=0.011, p<0.0001). Numerous antigens contributed to differences between groups; the two most defining molecular masses were at 126 and 113 kDa. In contrast to WB with discriminant analysis, ELISA measurements did not significantly differentiate between the SC group and controls.

Adolescent↗

PubMed2003

Neurobiology of Tourette's syndrome: concepts of neuroanatomic localization and neurochemical abnormalities.

Despite a preponderance of evidence suggesting an organic rather than psychogenic origin for Tourette syndrome, the precise neurobiological abnormality remains speculative. Neuroanatomically, there is expanding confirmation that cortico-striato-thalamo-cortical pathways represent the site of origin for tics and accompanying neuropsychiatric problems. Pathophysiological hypothesis are generally defined based on involvement of (1) a specific anatomical site (striato-thalamic circuits, striatal compartments), (2) physiologic abnormality (excess thalamic excitation, impaired intracortical inhibition), or (3) involvement of a specific neurotransmitter or synaptic component. This review provides information essential for understanding current and future proposals pertaining to the neurobiology of this intriguing disorder.

Brain↗

PubMed2003

Antistreptococcal, neuronal, and nuclear antibodies in Tourette syndrome.

Previous studies have suggested associations between Tourette syndrome and attention-deficit-hyperactivity disorder and antistreptococcal antibodies and between Tourette syndrome and antinuclear antibodies. In this study, antistreptolysin O, antideoxyribonuclease B, antinuclear, and antineuronal antibodies were measured in 41 children with Tourette syndrome and 38 controls, selected without regard to history of streptococcal infection. Results revealed that mean antistreptococcal titers did not differ between diagnostic groups. In addition, multiple regression analysis was unable to predict antistreptococcal antibody titers according to age and diagnosis. The frequency of elevated antistreptolysin O titers, based on a cutoff of 1:240, was significantly higher (P = 0.04) in patients with attention-deficit-hyperactivity disorder (64%) than in the group without attention-deficit-hyperactivity disorder (34%) but not when dichotomized according to age-matched normal values. No analysis of antideoxyribonuclease B titers identified any differences between groups. Antinuclear antibody titers were at least 1:160 in three of 33 Tourette syndrome patients; only one subject manifested a homogeneous staining pattern. Multiple regression analyses were unable to predict antinuclear, antineuronal, or anti-HTB-10 antibody titers according to the combination of age, diagnosis, and antistreptococcal titer. We suggest that longitudinal rather than single-point-in-time laboratory measurements be evaluated before definitive conclusions are drawn on associations between the diagnosis of Tourette syndrome, attention-deficit-hyperactivity disorder, or obsessive-compulsive disorders and antistreptococcal or antinuclear antibody titers.

Adolescent↗

PubMed2002

MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome.

Dysfunction of frontal-striatal-thalamic-frontal circuitry has been hypothesized to underlie both attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). Several research groups have therefore used anatomic magnetic resonance imaging (aMRI) to obtain volumetric measurements of subregions of the frontal lobe in these disorders. Most previous studies have relied on subparcellation methods that utilize callosal landmarks to derive subregions of the frontal lobe. In contrast, we present here an investigation of frontal lobe morphometry in ADHD and TS based on a reliable frontal subparcellation protocol that combines contiguous sulcal/gyral boundaries to derive frontal lobe modules based on prior functional studies. This highly reliable procedure subdivides the frontal lobe into five major modules: prefrontal, premotor, motor (precentral gyrus), anterior cingulate, and deep white matter. The first four modules are also segmented into gray and gyral white matter compartments. The protocol was applied to T1-weighted, SPGR coronal MRI images of 13 school-aged boys with ADHD, 13 boys with TS, and 13 age- and gender-matched controls. In ADHD, we found volumetric reductions in both the gray and white matter of the prefrontal cortex. These findings, in conjunction with previous reports on basal ganglia abnormalities, suggest that prefrontal-striatal pathways may be anomalous in ADHD. In TS, we found volumetric decreases in the left deep frontal white matter. Decreases in deep white matter suggest the presence of abnormalities in long associational and projection fiber bundles in TS. The findings of this study both confirm and extend our knowledge of the neurobiology of ADHD and TS, indicating that the reliable parcellation method presented has the potential of increasing our understanding of the role of the frontal lobe in developmental and psychiatric disorders.

Adult↗

PubMed2002

Effects of IQ on executive function measures in children with ADHD.

The present study compared children with Attention-Deficit Hyperactivity Disorder (ADHD) and controls on a selected set of clinical measures of executive function (EF). A total of 92 children (51 ADHD, 41 control), ages 6-16, completed measures chosen from a larger neuropsychological battery to illustrate diverse components of the EF construct (planning, inhibitory control, response preparation, memory search). The selected measures were moderately correlated with one another, and moderately correlated with IQ. After controlling for age, sex, presence of learning disability (LD), ADHD, and IQ test version, Full Scale IQ was significantly related to four of the five selected EF measures. A second analysis showed group differences on the EF measures at different IQ levels. After covarying for age, there was a significant multivariate effect for IQ level (average, high average, superior) and a significant multivariate interaction between group (ADHD vs. control) and IQ level. Three of the five selected EF measures showed significant univariate group effects (controls performing better than ADHD) at the average IQ level; however, there were no significant group differences between children with ADHD and controls at high average or superior IQ levels. These results suggest that clinical measures of EF may differ among children with ADHD and controls at average IQ levels, but there is poorer discriminatory power for these measures among children with above average IQ.

Adolescent↗

PubMed2002

Elevated intrasynaptic dopamine release in Tourette's syndrome measured by PET.

OBJECTIVE: Dopaminergic abnormalities in frontal-subcortical circuits have been hypothesized as the underlying pathophysiologic mechanism in Tourette's syndrome. The objective of this study was to test the hypothesis that presynaptic dopamine release from the striatum is abnormal in adults with Tourette's syndrome. METHOD: Seven adults with Tourette's syndrome and five age-matched comparison subjects each received two positron emission tomography (PET) scans with high specific activity [11C]raclopride. The first scan followed an intravenous injection of saline; the second followed an intravenous injection of amphetamine. The relative dopamine release was estimated as the percentage difference in binding potential between the postsaline and postamphetamine scans. RESULTS: Binding potential determined after the initial [11C]raclopride scan did not significantly differ between Tourette's syndrome and comparison subjects. After amphetamine challenge, the mean value of intrasynaptic dopamine in the putamen (as determined by true equilibrium bolus estimation) increased by 21% in the subjects with Tourette's syndrome and did not change in the comparison subjects; the mean values increased by 16.9% and decreased by 1.8%, respectively, when measured by the constrained method. Dopamine release in the caudate region was not significantly different in the Tourette's syndrome and comparison subjects. CONCLUSIONS: Greater putamen dopamine release was seen in adults with Tourette's syndrome than in comparison subjects after a pharmacologic challenge with amphetamine. These results suggest that the underlying pathobiology in Tourette's syndrome is a phasic dysfunction of dopamine transmission.

Adult↗

PubMed2002

Validity of the behavior rating inventory of executive function in children with ADHD and/or Tourette syndrome.

The dynamic, multidimensional nature of executive function (EF), thought to be characteristically impaired in those with attention deficit hyperactivity disorder (ADHD), has been challenging to operationalize and assess in a clinical setting [Barkley, R. A. (1997). ADHD and the nature of self-control. New York: Guilford Press.]. Gioia, Isquith, Guy, and Kenworthy [Gioia, G. A., Isquith, P. K., Guy, S. C., & Kenworthy, L. (2000) Behavior Rating Inventory of Executive Function. Odessa, FL: Psychological Assessment Resources.] developed the Behavior Rating Inventory of Executive Function (BRIEF) to address these concerns. In order to provide concurrent validity information on the BRIEF, parents of 76 children (ADHD=18; Tourette syndrome (TS)=21; TS+ADHD=17; controls=20) completed the BRIEF, additional behavior rating scales and interviews, measures of psychoeducational (PE) competence, and performance-based measures of EF. Both ADHD and TS+ADHD groups were rated as more impaired (P<.0001) than the other groups on the five primary BRIEF indices. BRIEF index scores showed no significant correlation with performance-based EF or PE measures, with the exception of math achievement; however, the BRIEF showed a strong relationship with interviews and other parent rating measures of behaviors seen in ADHD. Future attempts to validate the BRIEF should focus on differences within subtypes of ADHD (e.g., inattentive, combined subtypes), and separating ADHD from other clinical groups in which EF is reported to be a problem.

Journal Article↗

PubMedDate not supplied

Neuropsychiatric effects of guanfacine in children with mild tourette syndrome: a pilot study.

The objective of this study was to evaluate the neuropsychiatric effects of the alpha-2a adrenergic agonist guanfacine in children with Tourette syndrome (TS). Twenty-four children with TS participated in a 4-week, double-blind, placebo-controlled study of guanfacine. Tic severity, neuropsychologic functioning, and parent ratings of behavior were evaluated pre- and post-treatment. The sample had mild tic severity and subtle neuropsychologic dysfunction pretreatment. Post-treatment, patients receiving guanfacine were rated by parents as significantly improved (compared to placebo) on one measure of executive function (parent-rated metacognition). Improvement on tic severity, performance-based neuropsychologic measures, and all other parent ratings were not significantly better than placebo. At a moderate dose and short-term treatment duration, guanfacine did not provide significant neuropsychiatric benefits in this group of children with mild TS.

Adolescent↗