Brain morphology in children with 47, XYY syndrome: a voxel- and surface-based morphometric study.

The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y-chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y-chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age-matched healthy controls by combining voxel-based morphometry (VBM) and surface-based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y-chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.

Transition to young adulthood in Ullrich-Turner syndrome: neurodevelopmental changes.

Studies describing the neurocognitive profile of Ullrich-Turner syndrome (UTS) have focused primarily on neurodevelopmental changes in childhood and adolescence or in adults with UTS. The objective of the present study was to describe neurodevelopmental changes that occur in UTS females during the transition from adolescence to young-adulthood. The subjects included 99 females with UTS and 89 normal female controls matched for age and socioeconomic status. Subjects were between the ages of 13 and 21 years. All subjects received a battery of neurocognitive tests designed to assess general cognitive ability, academic achievement, memory, language, executive function, visual-spatial/perceptual and motor skills, affect recognition, attention, and motor skills. Results from our study indicated that females with UTS performed significantly less well than controls on measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attentional abilities, and executive function, consistent with previous reports of cognitive abilities in adolescent UTS females. Moreover, our results indicate that decreased performance in some of these areas persists through late adolescence and into early adulthood while improvement occurs in other areas. It is possible that catch-up in certain cognitive deficiencies in UTS females represents a maturational/developmental lag. Alternatively, the neurodevelopmental changes that were observed in UTS females may result from the cumulative effects of estrogen replacement therapy during adolescence. Therapeutic interventions specific to the demands of young-adulthood are also discussed.

Parkinson's disease: improved function with GM1 ganglioside treatment in a randomized placebo-controlled study.

BACKGROUND/OBJECTIVE: Studies in animal models of Parkinson's disease (PD) suggest that GM1 ganglioside treatment can restore neurologic and dopaminergic function. In view of positive preclinical findings and the results of a previous open-label study demonstrating efficacy of GM1 in PD patients, this study compared effects of GM1 ganglioside and placebo on motor functions in PD patients. METHODS: Forty-five patients with mild to moderate PD were studied. The primary efficacy measure was change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. After three independent baseline assessments, patients received IV infusion of the test drug (1,000 mg GM1 or placebo) and then self-administered either GM1 or placebo twice daily (200 mg/day, subcutaneously) for 16 weeks. Patients were examined during monthly follow-up visits. RESULTS: There was a significant difference between groups in UPDRS motor scores at 16 weeks (p=0.0001). The activities of daily living portion of the UPDRS (off-period assessment) also showed a significant effect in favor of the GM1-treated patients (p=0.04). GM1-treated patients also had significantly greater mean improvements than placebo-treated patients in performance of timed motor tests including tests of arm, hand, and foot movements, and walking. GM1 was well tolerated and no serious adverse events were reported. CONCLUSIONS: This study demonstrates that GM1 ganglioside treatment enhances neurologic function significantly in PD patients. Further study is warranted to evaluate long-term effects of GM1 in PD patients and to elucidate further the mechanisms underlying patient improvements.

Developmental changes in motor function in girls with Turner syndrome.

The Turner syndrome phenotype is characterized by a particular neurocognitive profile of normal verbal skills, impaired visuospatial and/or visuoperceptual abilities, and difficulty with motor function. We investigated motor function in non-estrogen-treated girls (ages 7-9 and 10-12 years) with Turner syndrome and age-matched female controls. Our goal was to delineate the differences in motor performance between girls with Turner syndrome (n = 78) and control girls (n = 145). Cognitive and motor tasks were administered, as well as nonspatial, repetitive motor tasks, and spatially mediated motor tasks. Questionnaires were also administered. Turner subjects performed less well than the controls on the motor tasks with the greatest spatial demands, particularly in the older age group (age 10-12.9 years). The older control group, unlike the older Turner syndrome group, had significantly increased speed on most of the motor tasks, suggesting a Turner syndrome-associated deficiency in motoric development. The superior performance of the dominant (right) versus the nondominant (left) hand was similar for the Turner syndrome and control groups. In general, the girls with Turner syndrome had evidence of a decreased sense of athletic ability and physical self-image. A likely explanation for motoric deficiency in the older Turner syndrome group relates to their gonadal dysgenesis and estrogen deficiency. In addition to the obvious physical benefits of estrogen replacement, estrogen treatment may have a positive impact on motor function; this will be the subject of future investigations.

GM1 ganglioside treatment of Parkinson's disease: an open pilot study of safety and efficacy.

We performed an open-label study testing the effects of GM1 ganglioside on 10 Parkinson's disease (PD) patients. Patients received 1,000 mg of GM1 by IV infusion after the last of three baseline functional assessments. Patients then self-administered GM1 at a dose of 200 mg/d, by subcutaneous injection, for 18 weeks. Under these conditions, GM1 ganglioside proved to be safe and well tolerated. There were no serious adverse events and none of the patients developed elevated anti-GM1 antibody titers. Improvements on at least some functional measures were present in most patients, beginning after 4 to 8 weeks of GM1 treatment. When functional improvements occurred, they lasted for the duration of the study. These results suggest that GM1 ganglioside is well tolerated and may be a useful adjunct to the treatment of PD, and that a double-blind, placebo-controlled study is now warranted.

Spelling and attention in early Alzheimer's disease: evidence for impairment of the graphemic buffer.

The present study was conducted to investigate the spelling ability of persons affected by mild Alzheimer's disease (AD). AD subjects produced more phonemically implausible (PI) spelling errors (e.g. enough-->enougigh) than normal subjects; in addition, AD subjects produced a higher percentage of PI spelling errors than normal AD subjects. We found that two clinical visual attention tests were better predictors of the number of PI spelling errors than a language measure. Moreover, we also found that AD subjects performed more poorly when they copied words that were viewed and removed from sight than when the same words were copied directly. In contrast, there was no significant difference in the performance of the normal elderly on direct and delayed copying tasks. AD subjects produced more errors when spelling long words than when spelling short words. Although the spelling performance of the normal elderly was also affected by the length of the words spelled, AD subjects showed a significantly greater drop in performance than normal subjects when the length of the words increased. The vocabulary of the short and long word lists did not differ in frequency of occurrence or imagability (i.e. abstractness). The results suggest that visual attention impairment and not language impairment accounts for the PI spelling errors of mild AD subjects. The results are discussed with reference to graphemic buffer deficits identified in case studies of stroke patients with dysgraphia.

Decline in homophone spelling associated with loss of semantic influence on spelling in Alzheimer's disease.

The homophone spellings of 20 subjects with Alzheimer's disease (AD) and mild dementia were compared to those of matched normal controls. Both groups were tested once (Time 1) and then again 9 months to 1 year later (Time 2). At Time 1, AD subjects misspelled more homophones than the control group and the discrepancy between the two groups' performances significantly increased by Time 2. Two types of errors were tabulated: homophone confusions (i.e. an inappropriate yet correctly spelled homophone given the context, such as spelling doe, given the context "bake the bread dough") and other spelling errors (e.g. doue, dogh). The relationship between homophone confusions and confrontation naming increased from Time 1 to Time 2. In contrast, the relationship between the number of spelling errors (that were not homophone confusions) and confrontation naming performance was not significant at Time 2. One subgroup of 3 subjects showed an increase in homophone confusions and confrontational naming errors and not more spelling errors. Another subgroup of 4 subjects showed neither an increase in homophone confusions nor in confrontational naming errors, but did show an increase in spelling errors. Based on these results, we suggest that homophone confusions are primarily due to impairment of semantic access to a functional orthographic output lexicon. Other spelling errors may reflect post-linguistic spelling deficits without a significant change in the use of semantic input for spelling homophones.

Effects of dihydrexidine, a full dopamine D-1 receptor agonist, on delayed response performance in chronic low dose MPTP-treated monkeys.

Monkeys exposed to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over long periods of time develop cognitive deficits without severe parkinsonian motor signs. In the present study we assessed the effects of the selective and full dopamine D-1 receptor agonist dihydrexidine on delayed response deficits in chronic low dose (CLD) MPTP-treated monkeys. Dihydrexidine caused a dose-dependent improvement in task performance, that could be blocked by the D-1 receptor antagonist SCH-23390. In addition to reducing the number of mistakes made during delayed response performance, dihydrexidine also improved task persistence. These data suggest that dihydrexidine may be useful in treating cognitive as well as motor deficits of parkinsonism.

Apraxia due to a pathologically documented thalamic infarction.

We report a pathologically documented case of infarction of the dominant thalamus with extensive involvement of the ventral lateral, ventral posterolateral, and lateral posterior nuclei and some involvement of the pulvinar. This patient exhibited linguistic impairment with features fairly typical for thalamic lesions. He also demonstrated a severe ideomotor apraxia. The preservation of repetition, syntax, and implicit memory despite severe naming deficits in patients with thalamic lesions suggests the possibility that thalamic involvement in cognitive function involves processes underlying declarative as opposed to nondeclarative (eg, implicit or procedural) memory. The occurrence of apraxia with thalamic lesions may be consistent with this hypothesis if it is accepted that only actual tool use approaches a pure skill that involves only nondeclarative memory, while other aspects of praxis implicate declarative memories.

Effects of dopamine agonists on delayed response performance in chronic low-dose MPTP-treated monkeys.

Monkeys exposed to low doses of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) develop difficulty in performing a previously learned delayed response (DR) task. In the present group of animals, performance deficits were manifested as a combination of mistakes or incorrect responses and no response errors, trials on which the animals failed to respond. Methylphenidate and the dopamine D2 receptor agonist LY-171555, at low doses, decreased the number of no-response errors but not mistakes. The partial D1 agonist SKF-38393 had no effects on no-response errors or mistakes. Thus, behavioral deficits associated with decreased task persistence may be amenable to treatment with dopamine agonists, and particularly D2 agonists, while cognitive performance per se may not be improved by such drugs. The similarities between this primate model and the cognitive/behavioral deficits associated with early Parkinson's disease and attention deficit hyperactivity disorder suggest that this may be a useful model for testing hypotheses concerning the pharmacological treatment of these disorders.

Task persistence and learning ability in normal and chronic low dose MPTP-treated monkeys.

Monkeys exposed to low doses of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) develop cognitive deficits in the absence of gross motor dysfunction. Attentional deficits and task impersistence are now also described in these animals. The task impersistence correlated with no-response errors (i.e. errors of omission) on a delayed response task and improved with dopamine agonist therapy. In parallel studies, it was observed that there were significant differences in the ability of normal monkeys to learn to perform cognitive tasks. We found that monkeys classified as poor learners had similar deficits in task persistence as did MPTP-exposed monkeys, suggesting a relationship between poor cognitive performance and task impersistence in untreated as well as MPTP-treated monkeys. The possible significance of these results for two clinical disorders, early Parkinson's disease and attention deficit hyperactivity disorder is discussed. Cognitive and behavioral similarities between chronic low dose MPTP-treated monkeys, early Parkinson's disease patients and people with attention deficit hyperactivity disorder may suggest the existence of related pathophysiological mechanisms in these disorders.

Delayed matching-to-sample, object retrieval, and discrimination reversal deficits in chronic low dose MPTP-treated monkeys.

Cognitive deficits following chronic exposure to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in monkeys asymptomatic for a gross parkinsonian motor disorder. Monkeys developed deficits in performance of delayed matching-to-sample, visual pattern discrimination reversal, and object retrieval tasks, all tasks that rely upon the integrity of the frontal-striatal axis. Performance on a visual pattern discrimination task, that relies primarily on inferotemporal cortex function, remained intact. These results extend previous findings of frontal-like cognitive deficits in MPTP-treated monkeys and further support the use of this model for studying the pathophysiology of the cognitive deficits associated with parkinsonism.

Phonological error analysis, development and empirical evaluation.

A method of error analysis, designed to examine phonological and nonphonological reading and spelling processes, was developed from preliminary studies and theoretical background, including a linguistic model and the relationships between articulatory features of phonemes. The usefulness of this method as an assessment tool for phonological ability was tested on a group of normal subjects. The results from the error analysis helped clarify similarities and differences in phonological performance among the subjects and helped delineate differences between phonological performance in spelling (oral and written) and reading within the group of subjects. These results support the usefulness of this method of error analysis in assessing phonological ability. Also, these results support the position that phonological approximation of responses is an important diagnostic feature and merely cataloging errors as phonologically accurate or inaccurate is inadequate for assessing phonological ability.

Motor and nonmotor behavioral deficits in monkeys made hemiparkinsonian by intracarotid MPTP infusion.

We tested five monkeys (three Macaca mulatta, two Macaca nemistrina) made hemiparkinsonian by internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) for lateralized motor function using a bar press task and a reaction time/movement time task and for hemispatial neglect or hemi-inattention using a double simultaneous stimulation (DSS) task, a lateralized reward retrieval task, and a task that assessed response to lateralized moving stimuli. All monkeys had impaired bar press performance and prolonged reaction and movement times with the limb contralateral to the lesion. However, using the limb ipsilateral to the lesion, all animals showed extinction to DSS, that is, they responded to single stimuli presented on the impaired side (contralateral to the MPTP lesion) more often than to stimuli presented on the impaired side that were presented simultaneously with stimuli on the unimpaired side (ipsilateral to the lesion). There was a response bias toward the side ipsilateral to the lesion in the lateralized retrieval task and a deficit in the ability to direct attention toward the side contralateral to the lesion when moving stimuli were employed. These latter results could not be explained by primary motor or sensory impairments. We conclude that unilateral MPTP-induced dopamine depletion in monkeys causes a complex syndrome characterized by overt motor disturbances contralateral to the side of lesion and less overtly apparent sensorimotor integration deficits.

Denial of visual perception.

An adult with the diagnosis of cortical blindness, complaining of a complete visual loss of 2 years in duration, was found to have a small preserved visual field and remarkably preserved visual abilities. Although denying visual perception, he correctly named objects, colors, and famous faces, recognized facial emotions, and read various types of single words with greater than 50% accuracy when presented in the upper right visual field. Upon confrontation regarding his apparent visual abilities, the patient continued to deny visual perceptual awareness, typically stating "I feel it." CT indicated bioccipital lesions sparing the left inferior occipital area but involving the left parietal lobe. The denial of visual perception evidenced by this patient may be explained by a disconnection of parietal lobe attentional systems from visual perception. The clinical presentation is described as representing "inverse Anton's syndrome."

Chronic low-dose MPTP in nonhuman primates: a possible model for attention deficit disorder.

Schneider and Kovelowski (1990) showed that chronic low-dose N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration to monkeys caused cognitive dysfunction without significant motor impairment on tasks thought to be related to the caudate-frontal axis. The cognitive difficulties were similar to those seen in monkeys with frontal lesions, normal young monkeys, and normal young children. The caudate-frontal dysfunction is consistent with the cognitive difficulties that are thought to exist in children with attention deficit disorder (ADD). The caudate-frontal dysfunction is also consistent with the distribution of decreased cerebral blood flow and, presumably, decreased metabolism that has recently been found in children with ADD. In monkeys given chronic low-dose MPTP, pilot neurochemical studies have suggested abnormalities in dopamine and norepinephrine metabolism, the two neurotransmitters most frequently linked with ADD. We suggest that chronic low-dose MPTP induced cognitive dysfunction in primates may not only be a model for the cognitive disturbances that accompany Parkinson's disease but may also aid in understanding the cognitive dysfunction seen in children with ADD.

Developmental phonological and lexical agraphia in adults.

Many cases of agraphia from acquired cerebral lesions may be divided into two groups, phonological and lexical, suggesting two dissociable spelling systems. Studies of developmental agraphia have described some children who have spelling patterns similar to acquired phonological or lexical agraphia. This study analyzed spelling results from 22 adolescent and adult subjects with developmental agraphia (DA) and compared them to those from control subjects and subjects with acquired agraphia (AA). On the basis of spelling ability, subjects with DA could be divided into two groups. Analysis of the profile of spelling abilities indicated that the two groups of subjects with DA were almost indistinguishable from the two groups of subjects with AA, phonological and lexical. This supports the contention that DA in adults may be divided into phonological and lexical groups and further supports the two-system hypothesis for linguistic agraphia.

Memory dysfunction following unilateral transection of the fornix: a hippocampal disconnection syndrome.

This study presents a case with a discrete nondischarging lesion of the left fornix that resulted in a marked anterograde memory deficit that was defined by the same material, modality and methodologically specific features characteristic of unilateral lesions of the hippocampus. Since the fornix is the major efferent pathway of the hippocampus to the mamillary bodies, septal nuclei and anterior thalamic nuclei, this patient could be considered to have a hippocampal disconnection syndrome.

Memory dysfunction in myasthenia gravis: evidence for central cholinergic effects.

Two studies are presented that investigate the possible central cholinergic effects of myasthenia gravis as measured by cognitive dysfunction. In the first study, performance on a battery of cognitive tasks by 12 subjects with myasthenia gravis is compared with that of ten healthy control subjects and ten medical control subjects with chronic disease of a nonneurologic nature. The tests used were the Boston Naming Test, Rey Auditory Verbal Learning Test (AVLT), and the Logical Memory and Design Reproduction portions of the Wechsler Memory Scale (WMS). Results indicate that the myasthenic group was significantly impaired relative to both the medical and healthy control groups for performance on the Boston Naming Test, WMS Logical Memory, and WMS Design Reproduction. Both the myasthenic and the medical control groups were impaired relative to the healthy controls on the AVLT. In the second study, a myasthenic patient had plasmapheresis for treatment of her myasthenia on two separate occasions. Her memory was examined prior to as well as following each series of plasma exchanges with a variation of the Peterson-Peterson consonant trigram task. Results showed that this patient had significantly fewer interference effects and less rapid forgetting following plasmapheresis. The results of these two studies support the hypothesis that myasthenia gravis has central cholinergic effects manifested by cognitive dysfunction.