Aneurysmal SAH: cognitive outcome and structural damage after clipping or coiling.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) and surgical clipping of intracranial aneurysms are associated with substantial morbidity and mortality. OBJECTIVE: To compare cognitive outcome and structural damage in patients with aneurysmal SAH treated with surgical clipping or endovascular coiling. METHODS: Forty case-matched pairs of patients with aneurysmal SAH treated by surgical clipping or endovascular coiling were prospectively assessed by use of a battery of cognitive tests. Twenty-three case-matched pairs underwent MRI 1 year after the procedure. Matching was based on grade of SAH on admission, location of aneurysm, age, and premorbid IQ. RESULTS: Both groups were impaired in all cognitive domains when compared with age-matched healthy control subjects. Comparison of cognitive outcome between the two groups indicated an overall trend toward a poorer cognitive outcome in the surgical group, which achieved significance in four tests. MRI showed focal encephalomalacia exclusively in the surgical group. This group also had a significantly higher incidence of single or multiple small infarcts within the vascular territory of the aneurysm, but both groups had similar incidence of large infarcts and global ischemic damage. CONCLUSION: Endovascular treatment may cause less structural brain damage than surgery and have a more favorable cognitive outcome. However, cognitive outcome appears to be dictated primarily by the complications of SAH.

Abnormal perception of the tonic vibration reflex in idiopathic focal dystonia.

Although the pathophysiological basis of idiopathic focal dystonia (IFD) remains unclear, we recently reported abnormal perception of the tonic vibration reflex (TVR) in the biceps brachii in IFD. In this study we examined whether the abnormality affects muscles other than the biceps brachii. A 100-Hz vibration stimulating predominantly the muscle spindle afferent was transcutaneously applied to one muscle tendon of the triceps brachii, the wrist extensor and flexor muscles in 29 subjects with IFD (18 with torticollis, 9 with writer's cramp, 2 with blepharospasm) and 15 control subjects. The blindfolded subjects were instructed to copy any perceived movement with the opposite tracking arm. The elbow or wrist angle changes were quantified electronically. The TVR and subjects' perception of the TVR were evaluated by angle movements of the vibrated joint and of the tracking joint, respectively. Perception of the TVR was significantly reduced in dystonic subjects at both elbow and wrist joints, while magnitude of the TVR did not differ between the two groups. Abnormal central perception of the TVR is a feature of IFD, suggesting a widespread involvement of abnormal muscle spindle afferent processing in IFD.

Parkinson's disease and CYP1A2 activity.

UNLABELLED: AIMS MPTP, a neurotoxin which induces parkinsonism is partially metabolized by the enzyme CYP1A2. Smoking appears to protect against Parkinson's disease (PD) and cigarette smoke induces CYP1A2 activity. Thus, we investigated the hypothesis that idiopathic PD is associated with lower CYP1A2 activity using caffeine as a probe compound. METHODS CYP1A2 activity was assessed using saliva paraxanthine (PX) to caffeine (CA) ratios. Caffeine half-life was also estimated from salivary concentrations of caffeine at 2 and 5 h post dose. 117 treated and 40 untreated patients with PD and 105 healthy control subjects were studied. RESULTS PX/CA ratios were 0. 57, 0.93 and 0.77 in treated patients, untreated patients and healthy control subjects, respectively, with no significant differences between study groups (95% CI: treated patients vs controls -0.24, 0.57; untreated patients vs controls -0.75, 0.35). However, patients with PD (treated or untreated) had caffeine half-lives shorter than that in controls (treated patients: 262 min, untreated patients: 244 min, controls: 345 min; 95% CI: controls vs treated patients 23, 143 (P = 0.003); controls vs untreated patients 19, 184 (P = 0.011)). Amongst the patients with PD, caffeine half-life was also inversely related to the age of onset of disease (P = 0.012); gender and concomitant drugs did not influence this significantly. CONCLUSIONS: Based on PX/CA ratio, there was no evidence of decreased CYP1A2 activity in patients compared with control subjects. The observed decrease in the elimination half-life of caffeine in PD may be caused by increased CYP2E1 activity, an enzyme that also contributes to the metabolism of caffeine. The latter warrants further investigation.

Subcortical hypoperfusion following surgery for aneurysmal subarachnoid haemorrhage: implications for cognitive performance?

The incidence and severity of cognitive deficits after surgery for aneurysmal subarachnoid haemorrhage and their relationship to aneurysm site remains controversial. The aim of this study was to investigate the pattern of regional cerebral blood flow which exists in patients one year post-surgery and to identify whether different patterns exist which may be related to the type of cognitive deficit or the location of the aneurysm. 62 patients underwent cognitive assessment and HMPAO SPECT imaging at a mean time of 12 months following surgery. Results were compared to those from healthy control subjects (n = 55 for neuropsychological testing; n = 14 for SPECT imaging). In the patient group, significant stable cognitive deficits occurred in all cognitive domains but no cognitive measure differentiated aneurysm site. On SPECT images, statistical parametric mapping identified a large common area of subcortical hypoperfusion in the patient group as a whole. The findings of this study suggest a possible link between reduced subcortical function and the extent and severity of cognitive deficits.

Slowing of reaction time in Parkinson's disease: the involvement of the frontal lobes.

This study investigated the possibility that the previously mixed findings relating to cognitive deficits in Parkinson's disease might be attributable to inhomogeneity within the patients sampled, with attentional deficits occurring only for those Parkinson's patients who also have additional frontal lobe impairment. Twenty-five patients with idiopathic Parkinson's disease were classified as showing frontal dysfunction, or not, on the basis of their performance on the Wisconsin Card Sorting Test and the picture arrangement subtest of the WAIS. The two groups, and a control group of normal elderly subjects matched for age and IQ, undertook tests of visual attention designed to dissociate baseline response speed from central information processing speed. Error rates did not differ between the groups. Performance of the non-frontally impaired Parkinson's group was indistinguishable from that of the controls. By contrast, the 'frontally impaired' Parkinson's group responded significantly more slowly than the controls. Further analyses indicated that for the frontally-impaired Parkinson's group, information processing and automatic functions were unimpaired but there was a generalised slowing (as reflected by increased baseline response time) which may represent a non-specific global cognitive impairment. These findings suggest that the frontal lobes may be implicated in slowed response speed in Parkinson's disease.

A data-driven approach to the study of heterogeneity in idiopathic Parkinson's disease: identification of three distinct subtypes.

Idiopathic Parkinson's disease (IPD) has been subclassified on the basis of predominant motor symptomatology, age at disease onset, depressive affect, and cognitive performance. However, subgroups are usually arbitrarily defined and not reliably based on qualitatively distinct neuropathology. We explored heterogeneity in IPD in a data-driven manner using comprehensive demographic, motor, mood, and cognitive information collected from 176 patients with IPD. Cluster analysis revealed three subgroups of patients at a disease duration of 5.6 years and two subgroups at 13.4 years. The subgroups may represent the clinical progression of three distinct subtypes of IPD. The "motor only" subtype was characterized by motor symptom progression in the absence of intellectual impairment. Equivalent motor symptom progression was shown by the "motor and cognitive" subtype which was accompanied by executive function deficits progressing to global cognitive impairment. The "rapid progression" subtype was characterized by an older age at disease onset and rapidly progressive motor and cognitive disability. There was no relationship between the motor and cognitive symptoms in any subtype of IPD. We conclude that the clinical heterogeneity of IPD is governed by distinct neuropathologic processes with independent etiologic influences.

Olanzapine in the treatment of hallucinosis in idiopathic Parkinson's disease: a cautionary note.

BACKGROUND: Hallucinosis is a dopaminergic dose limiting complication of the treatment of idiopathic Parkinson's disease. Typical neuroleptic medications cannot be used for suppressing hallucinosis because the extrapyramidal side effects worsen parkinsonian motor control. Olanzapine is a novel atypical antipsychotic drug with few reported extrapyramidal side effects which may be more suitable for controlling hallucinosis in these patients. METHODS: Olanzapine was given to five patients with idiopathic Parkinson's disease and the dosage was titrated until a clinically meaningful reduction in hallucinosis was achieved. The commercially available 5 mg, 7.5 mg and 10 mg tablets were used. RESULTS: After an initial 9 days of treatment, hallucinosis frequency was significantly reduced, an effect which was maintained with continued treatment. However, during this early phase of treatment, parkinsonian motor disability increased, which resulted in two of the patients discontinuing medication. CONCLUSIONS: Olanzapine is effective in the suppression of hallucinosis in patients with idiopathic Parkinson's disease but the currently available dose increments may result in an unacceptable exacerbation of motor disability.

A placebo-controlled evaluation of ropinirole, a novel D2 agonist, as sole dopaminergic therapy in Parkinson's disease.

The efficacy and safety of ropinirole, a novel nonergot dopamine D2-like receptor agonist, was assessed as monotherapy for the treatment of patients with early-stage Parkinson's disease. In this double-blind, multicenter trial, patients were randomly allocated in a ratio of 2:1 to receive, over a 12-week period, either ropinirole or placebo. Clinical status was assessed using the Unified Parkinson's Disease Rating Scale (UP-DRS), Clinician's Global Evaluation (CGE), and a finger-tapping score. In all, 41 patients received ropinirole and 22 received placebo. The end-point analysis, on an intention-to-treat basis, revealed a significant difference (p = 0.018) in improvement in UP-DRS motor score from baseline between treatment groups (ropinirole, 43.4%; and placebo, 21.0%). Other parameters, including the number of responders and improvement in CGE, showed similar results. Three patients in the ropinirole group and one patient in the placebo group discontinued the study because of adverse events. There was no significant difference between the treatment groups in the overall incidence of adverse events. Although the dopaminergic side effects were reported significantly more frequently in the ropinirole group than in the placebo group (dizziness, p = 0.0326; nausea, p = 0.001; and somnolence, p = 0.005), none necessitated study withdrawal. There was no evidence of any chronic effect of the study medication on vital signs. In conclusion, ropinirole is a safe and well-tolerated drug and, as monotherapy, provided significant therapeutic benefit compared with placebo to patients in the early stages of Parkinson's disease.

Hallucinosis in idiopathic Parkinson's disease.

BACKGROUND: Hallucinosis is a complication of the treatment of idiopathic Parkinson's disease commonly thought to afflict older, chronically medicated, cognitively impaired patients. However, patients with idiopathic Parkinson's disease of short duration experiencing hallucinosis on relatively low doses of dopaminergic medication have been found. The aim, therefore, was to investigate the homogeneity of a population of patients with idiopathic Parkinson's disease and hallucinosis. METHODS: The clinical, demographic, and cognitive correlates of hallucinosis were investigated in a sample of 129 patients with idiopathic Parkinson's disease. RESULTS: There were two subgroups of patients with idiopathic Parkinson's disease experiencing hallucinosis. In patients with a disease duration of five years or less, hallucinosis was associated with rapid progression of the motor component of the disease but not cognitive impairment. In patients with idiopathic Parkinson's disease of longer than five years duration, hallucinosis was associated with postural instability, global cognitive impairment, and lack of depressive affect. In all patients with idiopathic Parkinson's disease, hallucinosis was more prevalent when they were treated with a direct acting dopamine receptor agonist. Hallucinosis was not associated with age at onset of idiopathic Parkinson's disease or dosage of dopaminergic medication. CONCLUSION: Hallucinosis in idiopathic Parkinson's disease is heterogeneous, falling into two groups. The difference in the pathophysiological basis of hallucinosis in these two groups of patients is discussed.

Patterns of content, contextual, and working memory impairments in schizophrenia and nonamnesic alcoholism.

This study used tests of content memory (item recognition of words and abstract designs), context memory (order recognition of verbal and nonverbal items), and working memory (recognition at a short retention interval) to examine patterns of performance in 27 schizophrenic patients, 52 chronic alcoholic patients, and 66 healthy control participants. When performance was age- and IQ-adjusted the schizophrenia group was significantly impaired in item and order recognition of verbal and nonverbal material; the alcoholic group was impaired only in order recognition for both material types. Item- and order-recognition deficits in the schizophrenia group were greatest at the shortest retention intervals, a pattern previously observed in patients with Parkinson's disease, suggesting a prominence of a working memory deficit in schizophrenia.

Asymmetric central processing of sensory stimuli in idiopathic focal dystonia.

Idiopathic torsion dystonia is characterized by persistent abnormalities of posture. We tested the hypothesis that abnormal sensorimotor processing is involved pathophysioiogically by looking for asymmetry of sensory processing in patients with asymmetric symptoms. Sixteen patients with torticollis (ten with head turning to the right and six to the left), seven with simple writer's cramp and 19 healthy control subjects were tested. The tasks involved matching one of five lengths of stick or weights presented to one hand with sticks and weights chosen by the other hand. All experiments were performed with the subject blindfolded. Patients with torticollis tended to underestimate weights presented to the hand away from which the head tended to turn. Control subjects showed no significant tendency to overestimate or underestimate lengths or weights with either hand, and dystonic patients showed no tendency to overestimate or underestimate lengths. Those with writer's cramp underestimated weights when the stimulus was presented to the affected hand. An asymmetry can thus be detected in muscles remote from the site of dystonia, indicating a generalized abnormality of sensorimotor processing.

Idiopathic focal dystonia: a disorder of muscle spindle afferent processing?

As muscle spindles are involved in the sensation of position and movement of the body, we tested their involvement in the pathophysiology of idiopathic focal dystonia. Twenty patients with torticollis, nine with writer's cramp, two with blepharospasm and 16 healthy control subjects participated. In the first task, the blindfolded subject matched the position of the passively moved forearm with the opposite forearm when the elbow joint was slowly flexed. In a second matching task, passive movement was replaced by stimulation of one biceps tendon with a 50-Hz vibratory stimulus (a selective stimulus for muscle spindle Ia afferents). In normal individuals, this stimulus produces flexion of the vibrated arm around the elbow joint. Movement in both arms was recorded electronically. In experiments without vibratory stimuli, dystonic subjects showed normal movement of the tracking arm during attempts to match the position of the passively moved arm and no difference between the arms in the initial and final steady state positions. In experiments using vibratory stimuli, vibration of biceps tendons in normal subjects elicited flexion of the stimulated arm at the elbow and a matching movement of the opposite arm. In patients with dystonia, there was a similar flexion response to the vibratory stimulus in the stimulated arm but movement of the tracking arm was reduced. Taken together, these experiments suggest that there is abnormal perception of motion, but not position, in dystonic subjects. Dystonic subjects showed bilateral abnormalities of perception of the tonic vibration reflex which were remote from the clinically affected site. These findings are discussed in relationship to the role of muscle spindle Ia afferents in focal dystonia.

Stem-completion priming in Alzheimer's disease: the importance of target word articulation.

Stem-completion priming performance in patients with Alzheimer's type dementia (DAT) was explored in three experiments in which both the standard repetition priming effect and a novel indirect form of priming, cohort priming, were measured. In the first experiment, in which study stimuli were words, both priming effects were found to be markedly attenuated in the DAT group. In the second experiment, the study stimuli were specially constructed nonwords, and it was found that cohort priming was present at normal levels in the DAT group. In a third experiment we tested the specific hypothesis that the requirement to overtly articulate target stimuli during the study phase was critical for the appearance of normal cohort priming in the DAT group in Experiment 2, and also for the normal levels of repetition priming which have been reported in some published studies. Two encoding conditions were compared, one in which subjects simply had to read aloud the target words and a second in which subjects were required to make evaluative (pleasantness) ratings for each of the target words (identical to that used in Experiment 1). Stem-completion priming performance following the latter condition was significantly attenuated in the DAT group relative to a healthy control group, but following the "read aloud" encoding condition, normal levels of repetition and cohort priming were observed. It is suggested that the most fruitful approach to understanding the performance of DAT subjects on lexical repetition priming tasks will involve a detailed analysis of language functions and how they interact with other, possibly mnemonic, processes in the generation of primed responses.

Cognitive outcome after aneurysm rupture: relationship to aneurysm site and perioperative complications.

We evaluated cognitive outcome in a group of 37 patients who had undergone surgery for rupture and repair of a single intracranial aneurysm at least 6 months previously. We compared outcome--assessed by tests of intelligence, attention, executive functions sensitive to frontal lobe lesions, memory, neglect, and mood, as well as by a specially devised questionnaire--between a group of 20 patients who had aneurysms of the anterior communicating artery and 17 patients who had aneurysms located on other branches of the internal carotid artery. There were no differences in cognitive outcome between patients with anterior communicating artery aneurysms and those with aneurysms on other branches of the internal carotid artery. The patient group as a whole, however, showed impairment in executive functions and some aspects of memory in comparison with normative data. Overall, 65% of the patients were impaired in at least one cognitive domain, with 19% showing executive impairments alone, 14% showing memory impairments alone, and 32% showing deficits in both domains. Cognitive outcome was most strongly predicted by postoperative neurologic events, although clipping of an anterior cerebral artery was associated with a higher impairment rating on a symptom profile completed by patients' relatives, and although preoperative rebleeding of aneurysms predicted impairment of executive function.

Automatic registration of SPECT images as an alternative to immobilization in neuroactivation studies.

Subtraction of the two components (baseline and stimulation) of a neuroactivation study using 99Tcm HMPAO SPECT requires accurate registration of the two images. Immobilization of the subject during and between the two components of the study can prove difficult and degrades signal to noise ratio. The use of an automated image registration technique for registering the two components of the test can, even in the case where the subject is removed from the scanner, produce significantly better registration than immobilization.

A deficit profile of executive, memory, and motor functions in schizophrenia.

This study examined the neuropsychological deficits associated with schizophrenia and the interrelationships among multiple dissociable cognitive and motor functions. The tests were selected for their previously demonstrated sensitivity to circumscribed brain pathology and included four functional domains: executive functions, short-term memory and production, motor ability, and declarative memory. Each test composite was divided according to verbal versus nonverbal material or left- versus right-hand performance; this distinction permitted functions principally subserved by the left or right cerebral hemispheres to be tested separately. Data reduction was theoretically driven by the test selection and was achieved first by standardizing the scores of each test for age-related differences observed in the normal control group, and then by calculating test composite scores as an average of the age-corrected Z-scores of the tests comprising a functional composite. The schizophrenic group was impaired equivalently on all composites for both cerebral hemispheres; on average, the Z-scores of the patients were 1 standard deviation below those of the control group. The cognitive test composite scores were highly intercorrelated but showed only weak associations with motor ability. Multiple regression analyses suggested that symptom severity was a significant predictor of the Declarative Memory and Short-Term Memory/Production composite scores after accounting for disease duration, whereas disease duration uniquely contributed to the Executive Functions composite scores after controlling for symptom severity. Even though the schizophrenics as a group showed an equivalent level of deficit across all test composites, 1) the deficits were associated with different aspects of psychiatric symptomatology, 2) the motor deficit was independent of the cognitive deficits, and 3) each neuropsychological domain contributed independently to the deficit pattern. Thus, what appears to be a generalized functional deficit in schizophrenia may actually be, at least in part, combinations of multiple specific deficits.

The role of the striatum in motor learning: dissociations between isometric motor control processes in Parkinson's disease.

Studies of Parkinson's disease (PD) have been used to support the hypothesis that the striatum serves procedural learning but interpretation of the results is confounded by extra-striate pathology and coincidental non-procedural cognitive deficits. The motor deficit of PD involves particularly internally cued movement, without visual feedback, because of disruption to frontostriatal circuits. Thus, we used a non-visual isometric task as a sensitive measure of motor learning in early non-demented patients with PD and examined the effects of dopamine replacement. The PD group showed disproportionate under-shooting of the target but normal motor learning. Learning correlated with some cognitive measures but not clinical motor disability or depression. Treatment had no effect on performance, despite clinical improvement. The results indicate dissociations between motor control processes resulting from striatal pathology. Putaminal circuits are involved in force generation and prediction but not critically in motor learning.

Two tests for assessing remote public knowledge: a tool for assessing retrograde amnesia.

Guidelines for the construction and development of tests of remote memory are provided. These guidelines follow from methodological considerations and from certain theoretical issues we believe that remote memory tests should address if they are to further our understanding of amnesia. These include: the pattern of temporal gradient; memory for different broad classes of information such as famous names and famous events; and recall and recognition of different types of detail such as contextual and non-contextual information associated with remote memory. With respect to the first of these, we argue that it is impossible to fully evaluate competing hypotheses about temporally graded retrograde amnesia unless items are selected from at least two difficulty levels, and from at least two time periods. The construction of two equivalent tests of remote memory, one for famous people, the other for famous events, is described, and the theoretical issues listed earlier were addressed using these tests in a study comparing the remote memory of 13 organic amnesics and 13 age- and IQ-matched controls. The principal findings were as follows. There was only weak evidence that amnesics' remote memory for famous people and events was temporally graded over a 20 year period, and recognition memory and memory for non-contextual detail were equally impaired. Mayes, Meudell, and Pickering's (1985) context memory deficit hypothesis was supported, however, because amnesics were more impaired in their ability to date recognised items. In addition, although there was little support for a temporally graded retrograde impairment on the recognition question, there was much clearer evidence for the temporal dating question. Also, one patient, SR, showed a selective deficit in dating recognised names and events from the 1980s. Finally, the correlations between measures of anterograde and retrograde amnesia were all non-significant. Suitable items for the construction of remote memory tests probing the four decades 1950s to 1980s are presented. A subset of these, from the 1970s and 1980s, were shown to have satisfactory psychometric qualities, and can therefore be recommended for more widespread clinical use, although more extensive normative data than that provided here will be necessary.