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Cerebrotendinous xanthomatosis is a familial recessive disorder. Patients with the disorder present with tendon xanthomas, juvenile cataracts, dementia, and pyramidal and cerebellar abnormalities but have normal plasma cholesterol. High plasma cholestanol concentrations and abnormal bile acid metabolism are specific for this disease. The authors describe four patients with cerebrotendinous xanthomatosis and prominent psychiatric symptoms. In three of these patients appropriate diagnosis and treatment were delayed for years because the presence of cerebrotendinous xanthomatosis was not recognized. Early recognition of this potentially lethal disease is important because both the psychiatric and neurological symptoms respond to treatment with chenodeoxycholic acid.

The effect of sedation induced by intravenous diazepam on cerebral glucose metabolic activity was examined with [18F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) in five patients with probable Alzheimer's disease. Each subject was studied on 2 separate days: on one occasion at rest with eyes patched and ears open, and on the second when sedated with intravenous diazepam titrated to maintain stage II sleep by clinical and EEG criteria. Similar patterns of glucose uptake were observed in both the presence and the absence of sedation, but overall glucose utilization was depressed an average of 20% and was closely correlated with the amount of diazepam administered prior to the injection of FDG. The predominant temporoparietal hypometabolism and relative sparing of frontal metabolism observed in this disease are therefore not explained by differences in anxiety or activity level in this patient group. Utilization of diazepam sedation for PET study appears to be safe and may permit the study of patients otherwise unable to cooperate with FDG-PET procedures.

Local cerebral glucose metabolism and psychometric function were compared in 17 patients with Alzheimer's disease and 5 healthy age-matched controls. Performance on tests of global intellectual function averaged 30 to 45% lower in the Alzheimer's group. Mean cortical glucose metabolism, as determined by positron emission tomography following fluorine-18-labeled fluorodeoxyglucose administration, was reduced by 30% in the Alzheimer's group. There was a significant positive correlation between the degree of overall dementia and the amount of metabolic reduction. The distribution of cortical hypometabolism was not uniform: the posterior parietal lobes and contiguous portions of the posterior temporal and anterior occipital lobes were most severely involved. The frontal cortex was relatively spared. These findings are compatible with the major clinical deficits found in patients with Alzheimer's disease and may help focus future biochemical probes into the pathophysiology of this disease.

The ability of adult humans to synthesize taurine was assessed by measurement of the 18 O content of urinary taurine in eight subjects following 60 minutes inhalation of 18 O 2 (97% 18 O). All subjects had at least one 3-hour urine collection in which the mole ratio of 18 O-taurine to taurine was at least three times greater than the standard deviation of the stable isotope measurement. The peak mole ratios of 18 O-taurine/ 16 O-taurine ranged from 0.00075 to 0.015. These data indicated that adult human subjects have a significant ability to synthesize taurine.

Evidence suggesting a reduction of cerebral gamma-aminobutyric acid (GABA) neurons in Alzheimer's disease has been reported. To evaluate the possible contribution of GABA system dysfunction to the intellectual decline associated with this disorder, a controlled therapeutic trial of a potent and specific GABA agonist, THIP [4,5,6,7-tetrahydroisoxazolo(5,4,-c)pyridin-3-ol], was undertaken. Six Alzheimer patients with mild to moderately severe dementia and low spinal-fluid GABA levels received THIP at maximum individually tolerated dosage. No significant change in cognitive function could be discerned, despite attainment of dose levels that produced centrally mediated adverse effects similar to those of other GABA agonists. The results support the views that pharmacologic attempts to stimulate central GABA-mediated synaptic function may not confer therapeutic benefit to patients with Alzheimer's disease and that a GABA system deficit may not serve as a critical determinant of the dementia that characterizes this disorder.

Progressive supranuclear palsy (PSP) is characterized by supranuclear palsy of gaze, axial dystonia, bradykinesia, rigidity, and a progressive dementia. Pathological changes in this disorder are generally restricted to subcortical structures, yet the type and range of cognitive deficits suggest the involvement of many cerebral regions. We examined the extent of functional impairment to cerebral cortical and subcortical structures as measured by the level of glucose metabolic activity at rest. Fourteen patients with PSP were compared to 21 normal volunteers of similar age using 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose metabolism was reduced in the caudate nucleus, putamen, thalamus, pons, and cerebral cortex, but not in the cerebellum in the patients with PSP as compared to the normal subjects. Analysis of individual brain regions revealed significant declines in cerebral glucose utilization in most regions throughout the cerebral cortex, particularly those in the superior half of the frontal lobe. Declines in the most affected regions of cerebral cortex were greater than those in any single subcortical structure. Although using conventional neuropathological techniques the cerebral cortex appears to be unaffected in PSP, significant and pervasive functional impairments in both cortical and subcortical structures are present. These observations help to account for the constellation of cognitive symptoms in individual patients with PSP and the difficulty encountered in identifying a characteristic psychometric profile for this group of patients.

The effect of nadolol, a peripherally acting beta-adrenergic blocker, on resting tremor was examined in eight patients with idiopathic Parkinson's disease. With the use of a double-blind, placebo-controlled study of crossover design, patients received 80 to 320 mg of nadolol for 6 weeks while continuing their previous treatment regimen. Accelerometer readings showed a progressive reduction in tremor amplitude, but no change in tremor frequency, with increasing nadolol dosage. Maximum benefit was achieved at 240 mg, when resting tremor improved 50% (p less than 0.01). Physician ratings confirmed these findings. The results suggest that response to beta-adrenergic blockade may not be limited to postural or intention tremor and that such agents may not reliably differentiate between the tremor of Parkinson's disease and essential tremor.

We administered N-propylnorapomorphine, a potent aporphine-family dopamine (DA) agonist, to schizophrenic patients with active psychotic symptoms. After acute administration a significant antipsychotic action of N-propylnorapomorphine, maximal at an oral dose of 19 mg, was noted. The antipsychotic action predominated in subjects with neuroleptic-responsive symptoms, not in neuroleptic-nonresponders. However, when N-propylnorapomorphine was administered on a subchronic dosage schedule, no antipsychotic effect occurred. These observations suggest a rapid-onset tolerance phenomenon of psychosis to N-propylnorapomorphine and are consistent with results from preclinical experiments. These data support the idea that the acute antipsychotic response of DA agonists is mediated by the DA autoreceptor but fail to provide evidence for the potential clinical usefulness of this treatment approach.

Regional cerebral glucose metabolism, an index of neuronal activity, was compared in 20 patients with Alzheimer's disease and 8 age-matched normal volunteers by positron emission tomography following [18F]2-fluoro-2-deoxy-D-glucose administration. Overall cortical glucose utilization in the Alzheimer's group was 10 to 49% below that of control individuals. The posterior parietal cortex and contiguous portions of posterior temporal and anterior occipital lobes were most severely affected; frontal cortex was relatively spared. This pattern of cortical involvement is consistent with the major clinical features of Alzheimer's disease. Comparison of patients with early and more advanced dementia suggested that a substantial decline in glucose metabolism occurs before cognitive impairment becomes evident; once the patient is symptomatic, however, small additional metabolic decrements are associated with a marked deterioration in intellectual function.

• A patient with hyperkalemic periodic paralysis experienced the gradual onset of additional and unexpected neurologic abnormalities in middle age, suggestive of progressive supranuclear palsy. Although the concurrence of these findings may be coincidental, these features may evade recognition in other patients by being misattributed to chronic myopathy or depression.

The ability to mimic skilled movements or to pantomime them in response to spoken command was compared with psychometric performance and with regional glucose utilization as estimated by [18F]fluorodeoxyglucose positron emission tomography in 17 right-handed patients with Alzheimer's disease and 6 age-matched normal subjects. Apraxia scores, both on tests to command and to imitation, were significantly lower in the Alzheimer patients. Imitation scores correlated best with performance on tests of visual--spatial ability and with cortical metabolism in the right parietal lobe; command scores related most closely with the results of tests reflecting verbal proficiency and with cortical metabolism in the left inferior hemisphere, especially frontally. Apraxia to command and imitation may thus reflect neuronal dysfunction in distinct cerebral regions in patients with Alzheimer's disease.

We studied sleep patterns for three nights in 10 subjects with moderate to severe progressive supranuclear palsy and correlated the findings with disease severity using quantitative measures of motor, cognitive, and eye movement impairment. All subjects had severe insomnia, spending 2 to 6 hours awake per night; the mean time awake per night for the group was more than 4 hours. Sleep latency became shorter and the number of awakenings increased with greater motor impairment, and total sleep time declined as dementia worsened. These findings indicate that in progressive supranuclear palsy insomnia is related to disease severity. Insomnia associated with progressive supranuclear palsy appears to be worse than the insomnia of Parkinson's disease or Alzheimer's disease and may be due to degenerative changes in brain structures responsible for sleep maintenance.

1. Two modifications of the usual method of assay for folic acid in solutions are reported which appear to improve this procedure. These are a reduction of incubation time and dilution with 95% ethanol. 2. Experimental results are reported which indicate that Dilantin (5,5-diphenylhydantoin) does not interfere with the microbiological assay for folic acid.

Choline acetyltransferase (ChAT) activity and neuropeptide Y (NPY) levels in post-mortem tissues from patients with histologically proven Alzheimer's disease were compared with age-matched neurologically normal control individuals. Despite the high NPY concentrations in human cerebral cortex, no significant abnormalities were found. However, ChAT activity was reduced throughout the cortex, without a relationship to areas of functional deficit, as previously identified using fluorodeoxyglucose. These results lend further support to the concept of Alzheimer's disease as a highly selective neurodegenerative disorder.

99mTc-HM-PAO was used to evaluate regional cerebral blood flow in a 26-year-old woman with Moyamoya disease. This patient had an 18-month history of recurrent neurologic deficits and had angiographic evidence of Moyamoya disease. She had used oral contraceptives and cigarettes, but had no other risk factors for stroke. Single photon emission computed tomographic images showed bilateral and asymmetric reductions in blood flow to anterior and lateral brain regions. These findings correlated better with clinical symptomatology and suggested more extensive brain involvement than did computed tomography.

Computed tomography (CT) both with and without contrast agents has been used to diagnose syringomyelia. We report a case in which the diagnosis was made by injection of metrizamide into a ventriculoperitoneal shunt. Continuity of the syringomyelic cavity with the ventricular system was demonstrated. This case supports the hydrodynamic concept of syringomyelia formation and illustrates a potentially useful approach to its diagnosis.

Blink rate, a putative noninvasive marker of central dopamine activity, was assessed in medication-free patients with Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dystonia. The normal control rate of 24 blinks per minute was significantly higher than the rate of 12 and 4 blinks per minute recorded for patients with Parkinson's disease and progressive supranuclear palsy, respectively. The rates for patients with Huntington's disease and dystonia did not differ significantly from those of controls (36 and 26 blinks per minute, respectively).

The central auditory (dichotic) function of 38 patients with Alzheimer's disease was found to be significantly impaired when compared with a control group. Significant relationships were observed between dichotic scores and intelligence quotient, cortical atrophy in the temporal lobes, and cerebral glucose metabolism in the left temporal lobe. Comparing atrophy and glucose metabolism in the temporal lobes, we observed contralateral ear effects in dichotic performance as well as an interaction of asymmetry of atrophy with dichotic performance, consistent with previous models of dichotic listening in other forms of temporal lobe pathology.

Local rates of cortical glucose metabolism were estimated by positron emission tomography in 13 right-handed patients with Alzheimer's disease. Individuals with disproportionate failure of language function had markedly diminished metabolism in the left frontal, temporal, and parietal regions. Patients with predominant visuo-constructive dysfunction evidenced a hypometabolic focus in the right parietal cortex. Patients with memory failure as the most apparent feature had no significant metabolic asymmetry in cortical regions. In all subjects, verbal competency generally correlated with metabolic activity in the left frontal and temporal areas, while visuo-constructive test performance was linked to glucose utilization in the right parietal lobe.

Somatostatin-like immunoreactivity in Alzheimer CSF was significantly lower than in that from age-matched controls. The degree of reduction correlated with indices of intellectual impairment and decline in cortical glucose utilization as determined by PET. There was a close association between reduction in CSF somatostatin and glucose hypometabolism in the parietal lobe. In postmortem cortical tissue from Alzheimer patients, somatostatin levels were lower in posterior parietal but not in anterior frontal cortex. Loss of somatostatin-containing neurons, especially in the parietal association cortex, may be a critical determinant for Alzheimer dementia.

Regional cerebellar perfusion was imaged using technetium Tc 99m hexamethylpropylene amine oxime and single photon emission computed tomography (HM-PAO-SPECT) in a patient with chronic left lateral medullary syndrome with contralateral weakness due to traumatically induced thrombosis of the left vertebral artery. Despite continued neurologic deficits, x-ray transmission computed tomography was normal. However, HM-PAO-SPECT demonstrated that blood flow to the left cerebellar hemisphere was significantly impaired. This abnormality was still apparent after correction for atrophy as estimated by magnetic resonance imaging. Technetium Tc 99m hexamethyl-propyleneamine oxime and single photon emission computed tomography effectively imaged regional blood flow in the vertebrobasilar circulation and appears to more clearly reflect the nature and extent of the neurologic deficit than either x-ray transmission computed tomography or magnetic resonance scanning.

We evaluated the therapeutic efficacy of gamma aminobutyric acid (GABA) system stimulation in four patients with classical Huntington's disease and one with the hypokinetic-rigid form. Orally administered THIP (4,5,6,7-tetrahydroisoxazolo-[5,4,-c] pyridin-3-ol), a novel GABA receptor agonist, failed to improve motor or cognitive function during a 2-week trial. At maximum levels, THIP mimicked another putative GABA agonist, muscimol, in causing unsteadiness of gait, diminished attention to sensory stimuli, and somnolence. These effects suggest that central GABA systems participate in the regulation of some human and behavioral functions. CSF content of homovanillic acid, a major metabolite of dopamine, increased during high-dose THIP therapy, suggesting that augmentation of dopaminergic function may have contributed to the drug's lack of efficacy.

Postmortem studies of patients with progressive supranuclear palsy (PSP) have demonstrated loss of cholinergic neurons in the striatum, nucleus basalis of Meynert, and the pedunculopontine nucleus. These findings suggest that cholinergic drugs might be an effective treatment for this disease. We studied the efficacy of RS-86, a direct cholinergic agonist, upon motor abilities, eye movements, and psychometric performance in 10 patients with PSP during a 9-week placebo-controlled, double-blinded, crossover trial. Glycopyrrolate, a peripheral anticholinergic drug, was given throughout the trial to minimize cholinergic side effects. We used changes in rapid eye movement (REM) sleep to assess the degree of cholinergic activation achieved by treatment. Despite the enhancement of cholinergic activity in the CNS as indicated by increases in REM sleep latency and REM sleep time, RS-86 did not improve motor signs, eye movements, or cognition. Pharmacologic replacement of the cholinergic deficits in PSP does not result in significant clinical benefit.

Twenty-four parkinsonian patients compared pergolide and bromocriptine therapy in a randomized double-blind, two-period crossover study. Both drugs were adjusted to an optimal balance between benefits and side effects. The mean daily dose and dose range for pergolide and bromocriptine were 3.3 mg (0.7 to 7.2) and 42.7 mg (5.8 to 87.5), respectively. Adjunctive medications, which for most patients included levodopa (plus carbidopa), were not altered during the study. A similar spectrum of clinical effects was found with both drugs and with lisuride, which was used to treat 13 of the patients in a previous study. Despite neurochemical differences in the antiparkinsonian ergots, their clinical utility is quite similar. We draw attention to hepatotoxicity and pleural reactions that may occur rarely with these drugs.

Although the most prominent neurochemical change in parkinsonism is nigrostriatal dopamine deficiency, norepinephrine content is also diminished in the CNS. In this study, dopamine-beta-hydroxylase (DBH) activity, a marker of central noradrenergic activity, was measured in the CSF of previously unmedicated parkinsonian patients and normal controls. The parkinsonian patients showed a reduction in CSF DBH levels to 41% of control values (p less than 0.01). Possible explanations for the decrease included a decreased noradrenergic nerve pool or a diminished rate of synthesis of catecholamines.

• We compared local cerebral glucose metabolism, as determined by positron emission tomography following administration of fluorodeoxyglucose F 18, with Wechsler Adult Intelligence Scale (WAIS) scores in 22 right-handed persons. Five study subjects were normal volunteers and the remainder had Alzheimer's disease. Subtest scores within the verbal IQ group or the performance IQ group were generally highly interrelated; there was usually no correlation between the verbal and performance subtests. The cortical distribution of regions in which glucose metabolism was most closely associated with verbal subtest scores generally centered in the left parasylvian area. In contrast, scores on the performance subtests mainly localized to the right posterior parietal region. Most WAIS subtests thus appeared to evaluate primarily either verbal or visuospatial cognitive functions and either left parasylvian or right posteroparietal cortical activity.