Sources of Disability in Tourette Syndrome: Children vs. Adults

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by tics and neuropsychiatric co-morbidities like Obsessive Compulsive Disorder (OCD) and Attention Deficit Disorder (ADHD), among others. In many instances tics get better with age but this is not always true regarding the psychiatric co-morbidities. Methods: This manuscript reviews the disease-specific Quality of Life (QOL) instruments used to measure disability in TS and the existing literature on sources of functional impairment in children and adults with TS. Results: Traditionally, disability in TS has been recorded using objective measures. In recent years there has been a development of disease-specific instruments to measure subjectively the impact of the different aspects of TS on the patient's daily function. The differential impact of tics vs. the psychiatric co-morbidities in children with TS is an issue of debate in the existing literature. In adults with TS, the literature is scant, therefore the sources of disability in this group are even less defined compared to children. Discussion: As clinicians, we need to focus on determining the sources of disability in children and adults with TS so we can target our interventions successfully

Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra

Nuclear receptor-related factor 1 (Nurr1), a member of the nuclear receptor superfamily, is associated with the induction of dopaminergic (DA) phenotypes in developing and mature midbrain neurons. It is well established that dopaminergic nigrostriatal function decreases with age. Whether age-related deficits in DA phenotypic markers are associated with alterations in Nurr1 expression is unknown. The present study found that virtually all of tyrosine hydroxylase-immunoreactive (TH-ir) neurons within the young adult human substantia nigra were Nurr1-immunoreactive (Nurr1-ir) positive. Stereologic counts revealed a significant reduction in the number of Nurr1-ir nigral neurons in middle-aged (23.13%) and aged (46.33%) individuals relative to young subjects. The loss of Nurr1-ir neurons was associated with a similar decline in TH-ir neuron number. In this regard, TH-ir neuronal number was decreased in middle-aged (11.10%) and in aged (45.97%) subjects, and this loss of TH-ir neurons was highly correlated (r = 0.92) with the loss of Nurr1-ir neurons. In contrast, the number of melanin-containing nigral neuron number was generally stable across age groups, indicating that changes in Nurr1 and TH reflect phenotypic age-related changes and not frank neuronal degeneration. In support of this concept, confocal microscopic analyses of Nurr1-ir and TH-ir fluorescence intensity revealed parallel decreases in Nurr1- and TH-immunofluorescence as a function of age. These data demonstrate that age-related decline of DA phenotypic markers is associated with down-regulation of Nurr1 expression in the SN. © 2002 Wiley-Liss, Inc

Nurr1 in Parkinson\u27s disease and related disorders

In mammals, the transcription factor Nurr1 is expressed early in development and continues to be detectable throughout the organism\u27s lifetime. Nurr1 is involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system. This protein is reduced over the course of normal aging, which is a major risk factor for Parkinson\u27s disease (PD). However, whether Nurr1 expression is affected by PD has not been documented. The present study examined the role of Nurr1 in the maintenance of the dopaminergic phenotype within neurons in substantia nigra in PD compared with patients with diagnoses of progressive supranuclear palsy (PSP) or Alzheimer\u27s disease (AD) or age-matched-matched controls. In PD, the optical density (OD) of Nurr1 immunofluorescence was significantly decreased in nigral neurons containing α-synuclein-immunoreactive inclusions. Similarly, the OD of Nurr1 immunofluorescence intensity in the nigra of AD cases was decreased in neurons with neurofibrillary tangles (NFTs). In contrast to PD and AD, the OD of Nurr1 immunofluorescence intensity was severely decreased in the neurons with or without NFTs in PSP cases. Decline of Nurr1-ir neuronal number and OD was observed within substantia nigra (SN) neurons in PD but not within hippocampal neurons. The decline in Nurr1-ir expression was correlated with loss of tyrosine hydroxylase immunofluorescence across the four groups. These data demonstrate that Nurr1 deficiency in dopaminergic neurons is associated with the intracellular pathology in both synucleinopathies and tauopathies. © 2005 Wiley-Liss, Inc

Chronic ischemic stroke model in cynomolgus monkeys: Behavioral, neuroimaging and anatomical study

Previous nonhuman primate stroke models have employed temporary occlusion of arteries, had limited behavioral testing and imaging, and focused on the short-term outcome. Our goals were 1. to develop a stable model of chronic stroke in the nonhuman primate, 2. to study in vivo the long-term biochemical changes in the area adjacent to the infarct, using proton magnetic resonance spectroscopy ( 1 H MRS), and 3. evaluate these changes in relation to the histopathological effects of stroke. Four adult cynomologous monkeys had an occlusion of the M1 segment of the right MCA. Behavioral tests included a clinical rating scale, motor planning task, fine motor task, and activity monitoring. Eight months afterwards, MRI and 1 H MRS were performed. Following the imaging studies the monkeys were perfused transcardially, their brains extracted and processed. Nissl staining and immunohistochemistry for neuronal markers (NeuN) were performed and used to measure the lesion volume and neuronal optical density (OD). All animals developed a left hemiparesis and were unable to perform a fine motor task with the left hand. There was a significant (31%) decline in the motor planning ability with the nonparetic extremity. Monkeys displayed a stooped posture, episodes of rotation to the side of the lesion, partial left hemianopsia, and transient changes in activity. The clinical signs improved over the first 6-8 weeks but the deficits remained stable for the remaining six months of follow up. MRI demonstrated a subcortical and cortical infarction in the right MCA distribution. 1 H MRS data detected a significant decrease in the N-acetyl-aspartate (NAA)/creatine (Cr) ratio in the area adjacent to the infarction (VOI-St) compared to a mirror area in the contralateral hemisphere (VOI-Co). Histopathological measurements revealed a significant decline in neuronal crosssectional area and neuronal optical density in the region of the VOI-St. We established a stable and reproducible model of chronic stroke in the MCA distribution, in the macaque monkey. Our data indicate that NAA detected by 1 H MRS can be used to measure neuronal loss in vivo and help target this area for intervention. Our model may be particularly suitable for studies testing the effects of therapeutic strategies involving neural or stem cell transplantation, trophic factors or gene therapy

Effects of Estrogen Replacement Therapy on Cholinergic Basal Forebrain Neurons and Cortical Cholinergic Innervation in Young and Aged Ovariectomized Rhesus Monkeys

Estrogen modulates the function of cholinergic basal forebrain neurons in aged female rats. The present study tested the hypothesis that estrogen enhances the phenotype of cholinergic basal forebrain neurons and their cortical cholinergic innervation in young adult and aged ovariectomized rhesus monkeys. Sixteen monkeys (9 young and 7 aged) received two injections of estradiol cypionate or vehicle separated by 3 weeks. All monkeys were killed 1 day after the last injection. Quantitative immunofluorescence in the vertical limb of the diagonal band (VLDB) revealed enhanced optical density for choline acetyltransferase (ChAT) in both young and aged monkeys treated with estrogen. In contrast, optical density for low-affinity p75 neurotrophin receptor immunoreactivity in the VLDB did not change after estrogen treatment in either aged or young animals. Quantitative immunofluorescence for either ChAT or the low-affinity p75 neurotrophin receptor in the nucleus basalis Meynert failed to reveal differences between vehicle and estrogen treatment in either age group. Quantitative estimates of acetylcholinesterase (AChE) fiber density revealed that estrogen-treated aged monkeys but not their younger counterparts had decreased numbers of AChE-positive fibers in layer II of frontal, insular, and cingulate cortices. These data indicate that estrogen administered in a manner simulating natural hormonal cyclicity produces modest age-specific chemical phenotypic and regional changes in select neuronal subfields of the cholinergic basal forebrain and their cortical projection sites in nonhuman primates. © 2004 Wiley-Liss, Inc

Association of Tic Disorders with Poor Academic Performance in Central Spain: A Population-Based Study

Objective: To analyze the association between tic disorders and poor academic performance in school-aged children. Study design: This was a cross-sectional, observational study conducted in a randomly selected sample of mainstream school-aged children (aged 6-16 years). The sampling frame included different types of schools and educational levels. Children with poor academic performance (eg, repeating a grade, special needs), and tic disorders (defined based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criteria) were identified. Children with and without tics and children with and without poor academic performance were compared in terms of clinical features (ie, medical history and neurologic and psychiatric comorbidities), school, and environmental characteristics. Logistic regression analyses were performed using school performance (dependent variable) and tic disorders (independent variable), after adjusting for confounding variables. Results: The study cohort comprised 1867 children (mean age, 10.9 + 2.9 years; 1007 males [53.9%]). Tics were present in 162 children (8.6%), and poor academic performance was noted in 223 (11.9%). Overall poor academic performance was associated with age (OR, 1.71; P < .0001), television viewing (OR, 5.33; P = .04), attention deficit hyperactivity disorder (OR, 1.38; P < .0001), and family history of school dysfunction (OR, 2.43; P = .02) and was negatively associated with higher IQ score (OR, 0.90; P < .0001) and tic disorders (OR, 0.29; P = .01). Conclusion: After adjusting for other covariates, the presence of tic disorders was not associated with poor academic performance in our cohort. Early academic support and modification of environmental characteristics are needed for children at higher risk for school dysfunction, to enhance academic performance.Supported by SACYL, Biomedicine project GRS 157-A, Health Research Grant PI 070846, and the European General Development Co-funding