Cluster analysis of risk factor genetic polymorphisms in Alzheimer's disease.

Multiple genetic variants may contribute to the risk of developing Alzheimer's disease. We have analyzed polymorphisms in 9 genes to determine whether particular combinations would contribute to this risk. The genes were APOE, LDLr, CST3, CTSD, TNF, BACE1, MAPT, STH, eNOS, and TFCP2. Three risk groups for the disease were identified. Risk group I was younger, was heterozygous for the CST3 (GA), CTSD2936 (AG), TNF -308 (AG) genetic variants. Risk group II was older, was homozygous for the -427 APOE promoter polymorphism (TT), and heterozygous for the MAPT deletion and for the STH variant (QR). Group III had both the youngest and oldest subjects, were heterozygous for the -863 (AC) and -1031 (CT) TNF promoter polymorphisms. All three groups carried the APOE 4 allele and were heterozygous for both BACE1 polymorphisms. The control groups were carriers of the APOE 3 allele and were homozygous for the BACE1 genetic variants.

Contributions of the left intralaminar and medial thalamic nuclei to memory. Comparisons and report of a case.

A patient complained of memory disturbance after a small left thalamic infarction. Neuropsychological testing revealed her memory to be normal provided that she was allowed to rehearse or use semantic encoding strategies. When these strategies were prevented, her performance was impaired. Mapping of the lesion demonstrated involvement of the caudal intralaminar nuclei (centre médian and parafascicular nuclei), and portions of the medial nuclei (medioventral [reuniens], centromedial, and the most inferior aspect of the mediodorsal nucleus). The majority of mediodorsal nucleus, the mammillary bodies, the mammillothalamic tract, and the anterior thalamic nuclei, were spared. A comparison among our patient's performances and those of alcoholic Korsakoff patients, patient NA, and amnestic patients with circumscribed diencephalic lesions suggests that there are two distinct behavioral and anatomic types of memory impairment associated with diencephalic lesions. The severe amnesia associated with damage to the mammillary bodies, midline nuclei, mammillothalamic tract, and/or dorsomedial nucleus of the thalamus (eg, Korsakoff and NA) is characterized by encoding deficits that never approximate normal performance. The memory disturbance associated with damage to the intralaminar and medial nuclei of the thalamus is milder and is characterized by severe distractibility.

Electroencephalographic, volumetric, and neuropsychological indicators of seizure focus lateralization in temporal lobe epilepsy.

CONTEXT: Anterior temporal lobectomy is an effective treatment for medically intractable temporal lobe seizures. Identification of seizure focus is essential to surgical success. OBJECTIVE: To examine the usefulness of presurgical electroencephalography (EEG), magnetic resonance imaging (MRI), and neuropsychological data in the lateralization of seizure focus. DESIGN: Presurgical EEG, MRI, and neuropsychological data were entered, independently and in combination, as indicators of seizure focus lateralization in discriminant function analyses, yielding correct seizure lateralization rates for each set of indicators. SETTING: Comprehensive Epilepsy Program, Shands Teaching Hospital, University of Florida, Gainesville. PATIENTS: Forty-four right-handed adult patients who ultimately underwent successful anterior temporal lobectomy. Left-handed patients, those with less-than-optimal surgical outcome, and any patients with a history of neurological insult unrelated to seizure disorder were excluded from this study. MAIN OUTCOME MEASURES: For each patient presurgical EEG was represented as a seizure lateralization index reflecting the numbers of seizures originating in the left hemisphere, right hemisphere, and those unable to be lateralized. Magnetic resonance imaging data were represented as left-right difference in hippocampal volume. Neuropsychological data consisted of mean scores in each of 5 cognitive domains. RESULTS: The EEG was a better indicator of lateralization (89% correct) than MRI (86%), although not significantly. The EEG and MRI were significantly superior to neuropsychological data (66%) (P=.02 and .04, respectively). Combining EEG and MRI yielded a significantly higher lateralization rate (93%) than EEG alone (P<.01). Adding neuropsychological data improved this slightly (95%). CONCLUSIONS: The EEG and MRI were of high lateralization value, while neuropsychological data were of limited use in this regard. Combining EEG, MRI, and neuropsychological improved focus lateralization relative to using these data independently.

Anosognosia during intracarotid barbiturate anesthesia: unawareness or amnesia for weakness.

Previous studies have demonstrated asymmetric hemispheric contributions to deficit awareness during hemisphere inactivation with intracarotid barbiturate infusion (Wada studies). These observations provide insight into the neuropsychological basis of anosognosia for hemiparesis (AHP), arguing against earlier explanations based upon psychological denial, global cognitive disturbance, or emotional indifference. Although prior Wada studies equated AHP after the procedure with AHP during the period of deficit, a selective memory failure could also account for these findings. We, therefore, assessed the occurrence of AHP during and after right-hemisphere inactivation in a group of epilepsy patients undergoing preoperative Wada testing. Because aphasia obscures assessment of deficit awareness during left carotid studies, we compared the frequency of AHP between right- and left-hemisphere inactivation only after recovery. As noted in earlier reports, AHP was present significantly more often after right- than left-hemisphere inactivation. The proportions of subjects with AHP during right-hemisphere anesthesia compared with the proportion of subjects with AHP after the procedure were statistically equivalent, suggesting that the AHP observed after right-hemisphere anesthesia results from true failure of deficit awareness rather than inability to recall the deficit.

Apraxia during Wada testing.

Apraxia is the loss of the ability to perform learned skilled movements correctly. In right-handers, apraxia and aphasia are most frequently associated with left-hemisphere lesions. When they are dissociated, however, aphasia is more common in the absence of apraxia than vice versa. There are two hypotheses that can account for this discrepancy: (1) in right-handers, praxis is more likely than language to be mediated by the right hemisphere, or (2) the left-hemisphere network that mediates language is either more widely distributed than the network that mediates praxis or is more likely to be in the middle cerebral artery distribution. We studied apraxia in a group of right-handers undergoing selective hemispheric anesthesia, or Wada testing. All nine subjects had language lateralized to the left hemisphere, and seven of the nine had praxis lateralized to the left hemisphere. Two of the subjects had praxis bilaterally represented. Although our data suggest that speech and praxis functions tend to be lateralized to the left hemisphere in most right-handers, praxis appears to be more distributed between the hemispheres than speech-language functions. Furthermore, an analysis of the types of errors made during praxis testing suggests differential roles of the hemispheres in praxis functions.

Anosognosia during Wada testing.

Anosognosia, the verbally explicit denial of hemiplegia, is more often reported after right- than left-hemisphere lesions. However, this asymmetric incidence of anosognosia may be artifactual and related to the aphasia that often accompanies left-hemisphere lesions. Anosognosia has been attributed to psychological denial and the emotional changes associated with hemispheric dysfunction. Eight consecutive patients undergoing intracarotid barbiturate (methohexital) injections as part of their presurgical evaluations for intractable epilepsy were assessed for anosognosia after their hemiplegia and aphasia had cleared. After their left-hemisphere anesthesia, all subjects recalled both their motor and language deficits. However, after right-hemisphere anesthesia, none of the eight patients recalled their hemiplegia. These results suggest that anosognosia is more often associated with right- rather than left-hemisphere dysfunction and that it cannot be attributed to either psychological denial or the emotional changes associated with hemispheric dysfunction.

Dissociation of anosognosia for hemiplegia and aphasia during left-hemisphere anesthesia.

The stroke literature indicates that the explicit denial of hemiplegia, a form of anosognosia, is associated more commonly with right- than left-hemisphere lesions. Some investigators have suggested that this asymmetry may be an artifact and that the aphasia that often accompanies left-hemisphere dysfunction may mask some instances of anosognosia. Mechanisms suggested for anosognosia have been either "global" or "modular" in nature. Mechanisms posited in global explanations include psychological denial and general mental deterioration; modular explanations include feedback and feedforward theories. Videotapes of 54 patients with medically intractable seizures who had selective barbiturate anesthesia (Wada test) as part of their evaluation for seizure surgery were assessed for anosognosia of hemiplegia and aphasia after hemispheric anesthesia had worn off. The results suggest that, although aphasia may confound the reported rate of anosognosia for hemiplegia following left-hemisphere dysfunction, the frequency of anosognosia for hemiplegia is still higher with right- than left-side dysfunction. Anosognosia for hemiplegia and aphasia were dissociable, providing support for the postulate that awareness of dysfunction is mediated by a modular system.

Anosognosia for hemiplegia: test of the personal neglect hypothesis.

OBJECTIVE: To test the personal neglect hypothesis of anosognosia for hemiplegia (AHP) using selective anesthesia of the right hemisphere. BACKGROUND: Although AHP most commonly follows right-hemisphere injury, the mechanism responsible for this hemispheric asymmetry has not been entirely elucidated. Because denial of ownership of parts on the contralesional side of one's body (personal neglect) also more commonly follows right-hemisphere damage, personal neglect might account for AHP. DESIGN/METHODS: AHP and personal neglect were assessed in 20 patients during right intracarotid barbiturate infusion. With vision restricted to the central field, patients were randomly presented with either their own hands or those of examiners matched for size, gender, and race. Patients were asked to read numbers placed on the hands to establish that hemianopia did not confound hand recognition. RESULTS: All subjects correctly read the numbers on all trials. Only 4 of 20 subjects misidentified their hands and denied awareness of left hemiplegia. All errors occurred for the left hand, indicating personal neglect. However, the 16 subjects without personal neglect also demonstrated AHP. CONCLUSION: Because AHP and personal neglect are dissociable, personal neglect cannot completely account for AHP.

Planum temporale asymmetry and language dominance.

Language is lateralized to the left hemisphere in most individuals, and leftward asymmetry of the planum temporale has been reported in postmortem and imaging studies. In this study we measured the planum temporale on magnetic resonance imaging (MR) scans of patients (11 right-handers, 1 non-right-hander) who had selective hemispheric anesthesia or Wada testing performed for language lateralization. All subjects who had language lateralized to the left hemisphere (11 right-handers) had a leftward asymmetry of the planum temporale. One subject who had language lateralized to the right hemisphere (non-right-hander) had a strong rightward asymmetry of the planum temporale. These data suggest that planum temporale asymmetries determined by MR are associated with language dominance and may predict language laterality.

Basal ganglia dysfunction, working memory, and sentence comprehension in patients with Parkinson's disease.

To investigate the role of the basal ganglia in working memory and sentence comprehension, 14 patients with Parkinson's disease (PD) were administered experimental measures of semantic and phonological working memory, and a measure of sentence comprehension, while receiving dopaminergic medications and after a period of withdrawal from these medications. An age- and education- matched control group (N=14) received the same measures. Comparison with control subjects revealed deficits in patients with PD in sentence processing regardless of medication status, but no deficits in working memory. In contrast to previous studies, withdrawal of dopaminergic medications had no significant impact on task- related working memory functions or on sentence comprehension. Results suggest that basal ganglia dysfunction does not solely account for sentence comprehension deficits seen in PD.

Tapping, talking and the thalamus: possible influence of the intralaminar nuclei on basal ganglia function.

A patient with a discrete lesion of the left, intralaminar thalamic, nuclei exhibited a paradoxical finding with regard to finger-tapping. Normal subjects typically reduce their tapping rate when performing simultaneous verbal activity. Tapping was impaired in our patient's contralesional hand on baseline trials; however, performing the controlled oral word association (COWA) task, while finger-tapping, normalized her deficit. Subsequent experiments showed that motoric tasks rather than cognitive aspects of the COWA task were critical in potentiating finger-tapping performance. A SPECT study performed at rest revealed focal perfusion asymmetries in motor and premotor cortices. Because the caudal intralaminar nuclei project heavily to the striatum, striatal deafferentiation may account for these asymmetries. These observations provide some insight into the influences of the caudal intralaminar thalamic nuclei on basal ganglia function and the basal ganglia's influence on motor gating.

Radiotherapy for pituitary adenoma: long-term outcome and sequelae.

PURPOSE: To review outcome and treatment sequelae in patients treated with external beam radiotherapy for pituitary adenomas. METHODS AND MATERIALS: One hundred forty-one patients with pituitary adenomas received radiotherapy at the University of Florida and had 2-year minimum potential follow-up. One hundred twenty-one had newly diagnosed adenomas, and 20 had recurrent tumors. Newly diagnosed tumors were treated with surgery and radiotherapy (n = 98) or radiotherapy alone (n = 23). Patients with recurrent tumors received salvage treatment with surgery and radiotherapy (n = 10) or radiotherapy alone (n = 10). The impact of age, sex, presenting symptoms, tumor extent, surgery type, degree of resection, hormonal activity, primary or salvage therapy, and radiotherapy dose on tumor control was analyzed. Tumor control is defined by the absence of radiographic progression and stable or decreased hormone level (in hormonally active tumors) after treatment. Effect of therapy on vision, hormonal function, neurocognitive function, life satisfaction, and affective symptoms were examined. A Likert categorical scale survey was used for assessment of neurocognitive, life satisfaction, and affective symptom status. Survey results from the radiotherapy patients were compared with a control group treated with transsphenoidal surgery alone. Multivariate analysis used the forward step-wise sequence of chi squares for the log rank test. RESULTS: At 10 years, tumor control for the surgery and radiotherapy group (S + RT) was 95% and not statistically different (p = 0.58) than for patients treated with radiotherapy alone (RT) (90%). Patients with prolactin- and ACTH-secreting tumors had significantly worse tumor control, as did patients treated for recurrent tumors. Multivariate analysis for tumor control revealed that only young age was predictive of worse outcome (p = 0.0354). Visual function was either unaffected or improved in most patients, although four patients developed visual loss due to treatment. Hormonal function was affected adversely in 46 of the 93 patients for whom detailed hormonal information was available. Neurocognitive function evaluation revealed that patients in the S + RT group were more likely (p = 0.005) to report difficulty with memory than those in the RT-alone or S-alone groups. No significant difference in life satisfaction or affective symptoms was evident. CONCLUSIONS: Pituitary adenomas are well controlled by external beam radiotherapy, either alone or in combination with surgery. Visual symptoms often improve after treatment. Hormonal sequelae require medical intervention in many patients. Neurocognitive sequelae may be different among treatment groups.

Effects of kidney transplantation on cognitive performance in a pediatric population.

The cognitive functioning of 20 children and adolescents with end-stage renal disease was assessed 1 to 3 weeks prior to the onset of hemodialysis, and at 1 month and 1 year after successful kidney transplantation, and results were compared with those of a matched control group. A battery of intelligence, achievement, problem solving, learning, memory, and attention tasks were administered. Both groups had significantly improved scores over time on most measures. The group with renal disease exhibited significantly greater improvement than the control group from initial testing to 1 month after transplantation on the performance IQ and full-scale IQ as well as in mathematics achievement. This significant difference was not maintained, however, at 1 year after transplantation. Cognitive performance was less impaired the later the onset of renal failure or the fewer the years in end-stage renal disease. BUN nitrogen, serum creatinine levels, and BP did not consistently correlate with any of the cognitive or academic achievement measures.

XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28.

We report on a family with severe X-linked mental retardation (XLMR) and progressive, severe central nervous system deterioration. Three of the five affected males died of secondary complications before the age of 10 years and none have survived past the age of 10. These complications included swallowing dysfunction and gastroesophageal reflux with secondary recurrent respiratory infections. In addition, hypotonia and a mild myopathy were also present. All had a characteristic facies, including downslanting palpebral fissures, hypertelorism, and a short nose with a low nasal bridge. The two older boys showed cerebral atrophy by CT. No metabolic abnormalities were identified. Three obligate carriers had an IQ less than 80. The causal gene has been localized distal to DXS8103 in Xq28, a region spanning 5cM. No other XLMR disorder with these manifestations have been localized to this region and this appears to be a new disorder.

Assessing neurobehavioral changes in HIV+ infants and children. A methodological approach.

The rationale and development of a developmental approach to assessing neurobehavioral changes in infants and children exposed to or infected with the HIV-1 virus is presented. Methodological problems in earlier approaches to assessment are reviewed. Among these are measures employed, impact of different treatments on measures of outcome, multicultural differences between samples, and analytic approaches to developmental data. The assessment protocol developed by the Pediatric Neurobehavioral Study Group of NIMH/NICHD/NIAID is described.

Cognitive and neuropsychological functioning in children with cerebral palsy.

This article reviews the extant literature on intellectual functioning in different subtypes of cerebral palsy. Following a definition of the characteristics of each of three major cerebral palsy groups, typical neurologic and magnetic resonance imaging findings are reported. More recent studies that examine the intellectual and neuropsychological functioning of children within these classification groups are also reviewed. This review concludes that there remains a significant lack of precise information about the impact of cerebral palsy on the intellectual, motor, and neuropsychological functioning of children and that neuropsychological assessment can provide the necessary tools for such studies.

Neurobehavioral development in Joubert syndrome.

Research on children with Joubert syndrome has focused on brain structural abnormalities and associated clinical symptoms. The degree of developmental delay has not been objectively reported. We investigated the neurobehavioral development of children with Joubert syndrome through neurobehavioral assessment in the largest sample to date. Thirty-two parents of children with Joubert syndrome completed the Child Development Inventory and magnetic resonance imaging (MRI) data was gathered on 17 of these children. Results indicate that 94% were severely impaired according to the Child Development Inventory, with age being positively correlated with degree of neurobehavioral impairment. The average developmental age of our sample was 19 months (63% below chronological age). Severity of illness as measured by the General Development scale of the Child Development Inventory and severity of illness as measured by MRI (overall severity rating) did not yield consistent data regarding severity of the midbrain and cerebellar malformations. Similarly, markers of abnormal cerebral development such as cortical atrophy and delayed myelination were independent of severity of illness ratings on the Child Development Inventory. The degree of developmental delay in Joubert syndrome and the severity of gross central nervous system malformations appear independent.

Altered cognitive functioning in children with idiopathic epilepsy receiving valproate monotherapy.

Once a child is diagnosed with epilepsy, a primary concern is whether or not the child's behavior and cognitive abilities will be affected by the disease, by the drug prescribed for seizure control, or both. Direct cognitive effects by the epileptic condition have been described. On the other hand, cognitive effects in epilepsy have been attributed to antiepileptic drug therapy. Valproate is an antiepileptic drug of choice in managing the commonest childhood epilepsy syndromes. Although frequently prescribed in pediatric neurology practice, there have been relatively few studies investigating the cognitive effects of valproate therapy in children. Cognitive effects of valproate reported in normal adult volunteers and in adults with epilepsy cannot be generalized to the pediatric population. The results of investigations on children are less conclusive. Guidelines for antiepileptic drug trials in children have recently been formulated. Carefully designed studies are required in determining the cognitive effects of valproate in the pediatric population. Neuropsychological measures that are likely to assess subtle changes in higher brain functions crucial to learning in children should be employed. We propose a test battery to assess for cognitive changes associated with anticonvulsant therapy in children.

Parental burden, coping, and family functioning in primary caregivers of children with Joubert syndrome.

Children with Joubert syndrome have physical and intellectual disabilities. The purpose of this study was to assess the impact of Joubert syndrome on parental burden, coping, and family functioning. Forty-nine primary caregivers were surveyed. Forty-three primary caregivers were mothers and six were fathers; their mean age was 34 years. The following measures were used: Beck Depression Inventory, Child Development Inventory, Caregiver Strain Index, Family Assessment Device, and Ways of Coping Checklist-Revised. The data show that caregiver burden is not related to the severity of the child's illness, but that caregivers report significant burden. Higher burden was associated with the use of palliative coping methods, and family functioning was problematic. The results of this study suggest that for parents of children with Joubert syndrome, degree of parental burden depends more on the parents' coping skills and the level of family functioning rather than on the degree of the child's impairment. These findings highlight the importance of assessing caregiver burden, as well as decreased family functioning or coping abilities, since these problems often can be managed with psychologic intervention.

Cognition, behavior, and development in Joubert syndrome.

This article reports on a series of studies of children with Joubert syndrome who were examined in three investigations from 1994 through 1998. Neuropsychologic screening of 10 of 40 children showed a variety of deficits in cognition, verbal memory, visuomotor, motor, and language-related tasks. Parent report of developmental attainments revealed only 3 of 40 children functioning in the borderline range, with the rest scoring in the severely impaired range. Parent reports of behaviors revealed problems in temperament, hyperactivity, aggressiveness, and dependency, as well as problems in physical development and care that were felt to be related to their neurologic handicaps. Future directions of research with this rare disorder are suggested.