Cognitive manifestations of Huntington disease in relation to genetic structure and clinical onset.

OBJECTIVE: To examine the cognitive manifestations of Huntington disease (HD) with respect to age, clinical onset, progression, and genetic analyses. DESIGN: Case series of people with HD or at risk (AR) for HD. SETTING: Movement disorders and medical genetics clinics. PARTICIPANTS: Volunteer sample of 50 patients with HD and 127 AR adults. MEASURES: Neuropsychological evaluation was conducted with multiple measures of cognitive function (intelligence, memory, attention, executive, spatial, language), strength, manual speed/dexterity, somatosensory function, and mood. Quantitative molecular genetic analysis by means of polymerase chain reaction was conducted on 31 patients with HD and 86 AR subjects. RESULTS: In clinical HD, cognitive impairment correlated with number of years affected but not age at onset. The linear regression had a negative intercept, suggesting impaired cognitive function by the time of onset. In AR gene carriers, lower cognitive performance correlated with more trinucleotide repeats. In clinical HD, trinucleotide repeats interacted with disease chronicity such that more repeats were associated with worse performance over time; the overall effect of this was small compared with the effect of disease chronicity alone. Except for one AR subject, mood state was not associated with cognitive performance in either patients with HD or AR subjects. CONCLUSIONS: Cognitive decline appears to start before clinical onset of HD and is correlated with the number of trinucleotide repeats. Subsequent cognitive decline is primarily a function of number of years affected, although there is evidence that the presence of more trinucleotide repeats is associated with faster deterioration.

Acute effects on neuropsychological function and quality of life by high-dose multiple daily fractionated radiotherapy for malignant astrocytomas: assessing the tolerability of a new radiotherapy regimen.

Cognitive and other quality of life measures were assessed in 29 patients with supratentorial malignant astrocytomas before and after high-dose (8000 cGy) multiple daily fractionated radiotherapy. Assessments were done immediately before and after radiotherapy. Patients completed a neuropsychological evaluation and the Functional Living Index: Cancer (FLIC). Spouses completed the Family Environment Scale and the Profile of Mood States. Cognitive abilities generally improved over the course of radiotherapy. Occasionally, deterioration of potential clinical importance was observed on functions associated with the tumour site. Quality of life as assessed by the FLIC was stable in most cases and improved in five, but deteriorated in three patients. Families showed slightly less Conflict and slightly more Cohesion than the norm; this was especially so when patients had greater cognitive deficit. Emotional state of spouses was variable, with increased fatigue or reduced activity most commonly reported, followed by depression and anxiety. Mostly this improved with time or remained stable, but two spouses reported worsening emotional state. Results are generally encouraging for tolerance of this radiotherapy protocol, although they demonstrate that limited adverse effects may occur in some cases.

Postischemic therapy with MK-801 (dizocilpine) in a primate model of transient focal brain ischemia.

The purpose of this study was to develop a primate model for assessing EEG, behavior and histology, and to test the effect of NMDA receptor blockade in transient focal ischemia. Squirrel monkeys (Saimiri sciureus) under halothane anesthesia were subjected to 110 min of transient focal ischemia (n = 15) by temporary clip occlusion of the MCA. An eight-lead EEG was recorded. Neurobehavioral testing was done in a subgroup of animals (n = 6). Brain temperature (37.5 degrees C) was monitored and controlled to avoid hypothermia or intergroup temperature differences, and blood pressure was regulated to 60 mmHg. The entire brain was subserially sectioned, and 52 standardized coronal sections encompassing the infarct were examined histologically 2 wk after the ischemia. Animals were randomized to receive either (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) 1 mg/kg of maleate salt or carrier solution, 20 min and again at 12 h after the onset of ischemia. Cingulate and retrosplenial cortex were examined for NMDA-antagonist-induced neuronal necrosis. No reduction, or trend toward reduction of neurobehavioral deficit was seen with MK-801. MCA occulsion reduced EEG power over the ischemic hemisphere. MK-801 appeared to cause brain activation, and globally increased power at several frequencies. MK-801 did not reduce infarction in either neocortex (p > 0.05) or striatum (p > 0.05). No selective neuronal necrosis was seen in the cingulate or retrosplenial cortex. We conclude that MK-801 given 20 min after the onset of transient ischemia offers no significant neuroprotective effect against either neurobehavioral deficit or ischemic infarction in this model of transient focal ischemia. Further experiments in unanesthetized animals are necessary to determine if MK-801-induced necrosis exists in the gyrencephalic brain, but the enhancement of primate brain electrical activity by MK-801 suggests that brain activation occurs in primates as it does in rodents.

Failure of metacontrol: breakdown in behavioural unity after lesion of the corpus callosum and inferomedial frontal lobes.

A right-handed man suffered aneurysmal haemorrhage with lesions of the genu and body of the corpus callosum and the inferomedial frontal lobes bilaterally (right more than left). He exhibited remarkable breakdown in behavioural unity characterized by conflict between the two sides of the body, actions inconsistent with verbalizations, and internal conflict over control of the left hand. A major feature of the deficit was its temporal variability. This is interpreted as reflecting intermittent failure of metacontrol processes, which are neural mechanisms for maintaining behavioural unity. Medial frontal structures and their interconnections through the corpus callosum appear particularly important in the maintenance of metacontrol.

Psychiatric morbidity in patients with HIV infection.

A psychiatric examination was conducted on 144 patients at various stages of HIV infection and on 29 controls found to be seronegative. One-half of the control group had at least one DSM-III-R Axis I diagnosis, most commonly cannabis abuse, alcohol abuse, or adjustment disorder. Compared to this baseline, HIV-infected subjects had higher rates of adjustment disorder. AIDS patients were also more likely to suffer from organic mental disorder. The rate of unemployment increased as the disease progressed. Major depression was seen in only ten patients, and there were no differences between controls and HIV-infected subjects. Formal assessment of mood state and feelings of pessimism also showed no differences among the groups. The importance of helping improve the patient's lifestyle through the control of alcohol and drug abuse is underscored.

High-altitude mountaineering and brain function: neuropsychological testing of members of a Mount Everest expedition.

Concern has been raised regarding the possibility that hypoxic conditions encountered during high-altitude mountaineering may have lasting harmful effects on the human brain. Members of an expedition to Mount Everest completed a series of neuropsychological tests before and after the expedition. Exposure to altitudes above 7,200 m was limited to a maximum of four consecutive nights, separated by rest periods at lower altitudes. No significant decline in performance was observed on any test. The subjects also completed a short series of tests at different altitudes during the expedition. No significant deterioration was observed at altitudes up to 7,500 m. There do not appear to be lasting harmful effects on brain function under these conditions.

Presymptomatic neuropsychological impairment in Huntington's disease.

Ten asymptomatic individuals at risk for Huntington's disease (HD) were determined by the use of linked DNA probes to have a high (HD+ group) or low (HD- group) probability of having inherited the mutant gene. Neuropsychological examination, performed without knowledge of DNA results, revealed impairments in five of seven subjects in the HD+ group. Abnormalities were related to visuospatial abilities or to functions associated with the frontal lobes. All three subjects in the HD- group showed no neuropsychological impairment. Statistical analyses confirmed differences between the HD+ and HD- groups. Affected parents of subjects were at least 12 years older at symptom onset. These results demonstrate that clear neuropsychological impairment may be present in HD even when overt signs and symptoms are not expected for a number of years.

Is octopamine a 'false transmitter'? Regional distribution and serial changes in octopamine and noradrenaline following locus coeruleus lesions.

The effects of electrolytic lesions of the locus coeruleus (LC) on endogenous octopamine and noradrenaline levels were observed at various temporal intervals. Noradrenaline was assayed from halved tissue samples by high-performance liquid chromatography (HPLC) while octopamine was determined from the other halves of the brain samples by radioenzymatic assay methods accompanied by chromatographic separation. Brains were dissected into 8 regions: cerebellum, anterior and posterior cortex, hippocampus, hypothalamus, medulla/pons, midbrain and striatum. Assays were performed at postlesion intervals of 4, 8, 13 and 18 days. The rates of depletion of noradrenaline at the tested intervals roughly matched those of octopamine in the anterior cortex, posterior cortex and striatum. In the cerebellum, hypothalamus, hippocampus and pons/medulla, levels of octopamine diminished later than those of noradrenaline, at times showing an initial increase within the first week after the LC lesion. In the midbrain however, this pattern was reversed, octopamine levels initially decreasing in parallel with noradrenaline but subsequently recovering to significantly higher values. The results do not unequivocally support the hypothesis that octopamine is present in the brain solely as a 'false transmitter' in noradrenergic neurones. Neither, however, do they provide clear support for earlier contentions that octopamine is likely to play a role in central neurones as a synaptic transmitter, independent of the noradrenergic system.

Performance of manual copying tasks after focal cortical lesions.

Patients with unilateral frontal or temporal excisions and normal control subjects were required (1) to copy single, difficult positions of the arm, fingers, or both, and (2) to copy the experimenter as three hand positions were presented one after the other at an increasing rate. All patient groups were impaired relative to the control group on both tasks, but on the second task patients with frontal lesions were also impaired relative to those with temporal lesions. Results suggested a role of the left-and right-frontal lobes in rapid execution of multiple manual responses.

Gesture fluency after focal cortical lesions.

Patients with unilateral cortical excisions and normal control subjects were given two 'gesture fluency' tasks: one assessed their ability to generate novel finger positions, and the other their ability to produce meaningful gestures. Patients with left-frontal lesions were impaired on both tasks, and patients with right-frontal lesions were impaired on the latter. The deficit after right-frontal lesions appeared to be associated with involvement of ventro-lateral or orbital cortex, whereas there was no evidence for localization within the left frontal lobe. The results extend previous findings of deficits after frontal lesions on tests of word and design fluency.

Manual sequence learning after focal cortical lesions.

Patients with unilateral frontal or temporal excisions and normal control subjects learned sequences of hand positions. Left-frontal and left-temporal lesions impaired learning these sequences. No group had particular trouble when order of response was restricted to the original order, compared to when it was not restricted; nor were group differences seen when subjects learned new orders of already-familiar positions. Delayed recall of the positions (which had been learned to a common criterion), was not impaired in any group. Results suggested a role of the left-frontal and left-temporal lobes in learning series of manual responses.

Hemispheric asymmetry for a visuo-spatial task in monkeys.

The hypothesis that hemispheric asymmetries for visuo-spatial ability exist in rhesus monkeys was tested using a task for which the right hemisphere is specialized in man. The task required discrimination between two squares, one containing a central dot and the other a dot displaced upwards from centre. The animals' thresholds were determined before and after left-sided (LH-lesion) or right-sided (RH-lesion) unilateral occipital lobectomy combined with splenial transection, and the percentage change in threshold calculated. The LH-lesion monkeys were all worse than the RH-lesion monkeys on this measure, indicating the existence of a functional asymmetry.

Misreaching in monkeys after combined unilateral occipital lobectomy and splenial transection.

Studies of the effects of lesions of the parietal cortex suggest that this region plays a critical role in visuomotor guidance, whereas experiments on the effects of disconnecting this region from visual input have been inconsistent in supporting this hypothesis. In the present experiment, monkeys with a unilateral occipital lobectomy and splenial transection initially showed marked misreaching by the hand contralateral to the lobectomy when tested informally with peanuts presented by hand. Although this severe misreaching recovered within a few weeks, there was a persistent deficit in the contralateral hand on two, more difficult, reaching tasks. One task allowed full vision of the reaching hand; the other limited vision by requiring the monkeys to reach under an opaque shelf. Misreaching persisted on these tasks for at least 200 days after surgery. Monkeys with only an occipital lobectomy did not show contralateral-hand misreaching on informal testing or on the limited-vision task, and only very minor misreaching in two of three animals on the full-vision task. Results indicate that geniculostriate visual information must reach posterior cortical regions for visually guided reaching by the contralateral limb to be fully accurate.

Hemispheric asymmetries in motor function: I. Left-hemisphere specialization for memory but not performance.

Patients with unilateral brain lesions of vascular origin were administered tests designed to determine if left-hemisphere specialization in manual-sequence tasks involves memory for these sequences, or performance of them, or both. Patients with left-sided lesions were worse than patients with right-sided lesions on two tasks requiring the recall of hand positions. Whereas patients with left-sided lesions showed a trend towards being worse on speeded performance of an already learned manual sequence, in both groups on this task there were a large number of failures to remember the sequence. When memory demands were better controlled by providing a model during the speeded performance task, there were no group differences. It is proposed that there is left-hemisphere specialization for memory but not performance of such motor tasks.

Hemispheric asymmetries in motor function: II. Ordering does not contribute to left-hemisphere specialization.

Patients with unilateral brain lesions of vascular origin were administered tests designed to determine if the left hemisphere is specialized for the ordering of motor acts. Patients with left- and right-sided lesions responded similarly to manipulations of ordering demands in two motor tasks, one a test of manual sequence learning and the other a test of speeded performance. A detailed analysis of performance on an Ideational Apraxia task indicated that the deficit of patients with left-sided lesions was best characterized as a deficit in generating appropriate acts rather than ordering them. It was concluded that there is no evidence for left-hemisphere specialization for the ordering of motor acts. It was hypothesized that there are two broad stages of motor function: generation of motor "target" acts (which is lateralized to the left hemisphere) and the ordering and execution of these acts (which are not lateralized).

Fimbria-fornix lesions and sexual-social behavior of the guinea pig.

Male and female guinea pigs were given fimbria-fornix lesions and their sexual-social activity was compared to lesioned control animals. The lesions reduced the sexual and aggressive behavior of the male guinea pig. In the female, on the other hand, aggression towards the male increased during attempted copulation. Both experimental and control animals were given an open-field activity test. It was found that fimbria-fornix lesioned animals displayed less activity than did their control counterparts. These results were consistent with earlier findings and were related to previous observations of decorticate rats. It was suggested that the hippocampal output via the fimbria-fornix during sexual-social behavior plays a role in selecting motor patterns appropriate for the motivational state of the animal.