Biomedical subjects
Publications and source records attributed to R Mayeux.
Physostigmine caused myoclonus in two patients with Alzheimer's disease during a clinical trial. Neither patient had myoclonus before or after physostigmine treatment. We hypothesize that physostigmine reduced the sensitivity of the remaining muscarinic receptors in these two patients, altering the interaction between cholinergic and either serotoninergic or dopaminergic neurotransmitter systems.
Dementias occurring in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are associated with dysfunction and death of neurons in a variety of cell populations, including cholinergic, monoaminergic, and peptidergic systems. In the present investigation of these three disorders, we demonstrated decreased levels of corticotropin releasing factor (CRF)-like immunoreactivity in the frontal, temporal, and occipital poles of the neocortex. Moreover, reductions in peptidergic immunoreactivity correlated with reductions in the activity of choline acetyltransferase, the enzyme that catalyzes the formation of acetylcholine. The reduction in cortical CRF levels may be due to abnormalities of intrinsic cortical neurons or to dysfunction in neurons that contain CRF and innervate cortex.
Bradyphrenia is considered the mental equivalent of bradykinesia in Parkinson's disease. Patients are described as inattentive and "slow thinking," but not demented. We compared the performance of three groups: parkinsonians age-matched controls, and mildly impaired patients with probable Alzheimer's disease in tests of general intellect, memory reaction time, and in a continuous performance task measuring attention and vigilance. Metabolites of the major biogenic amine in CSF were also measured. The parkinsonians formed two distinct groups. In one, intellectual function and CSF measures were similar to that of controls. The other group of parkinsonians had significantly more omission errors and fewer correct response on the continuous performance task than did controls or patients with Alzheimer's disease. We considered this second group to have bradyphrenia. Their performance on measures of general intellectual and memory function was similar to that of the patients with Alzheimer's disease. CSF-MHPG, the major metabolite of norepinephrine, correlated with the continuous performance task and reaction time in all parkinsonians, and those with bradyphrenia had the highest CSF-MHPG levels. Our data suggest that bradyphrenia is an impairment of attention and vigilance, unique to Parkinson's disease, that may be associated with dementia and with an alteration in norepinephrine metabolism.
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Functional disability in Huntington's disease usually results from a combination of the movement disorder, intellectual decline, and psychopathological changes, but the unique contribution of each element has never been investigated. The Shoulson-Fahn functional capacity rating scale measures independence in such daily activities as eating, dressing, and managing personal finances, and is used to stage the illness and follow its progression. To determine which problems contribute most to reduced functional capacity as the disease evolves, we reviewed the records of 48 consecutive patients who were evaluated for intellectual and emotional status and motor disability. Each patient was staged and rated for functional capacity at the time of the examinations. Thirty-three of these patients were followed over several years with repeat evaluations at 6-month intervals. Intellectual impairment and depression correlated significantly with reduced functional capacity. However, when the somatic symptoms of depression were eliminated from the analysis, its relationship to functional capacity was no longer significant. Duration of illness, motor disability, and age at onset also had little impact. Neuropsychological test performance and functional capacity deteriorated over time. Our data suggest that intellectual impairment is a major factor in reducing functional capacity in the early stages of Huntington's disease.
A patient with Gilles de la Tourette syndrome later developed Parkinson's disease in middle age. This was accompanied by a marked reduction in the frequency of tics but levodopa toxicity exacerbated the tics. The dopamine hypothesis of tic disorders is supported by this observation.
Among 49 consecutive patients with Parkinson's disease, 40% were depressed according to DSM-III; they had major depression or dysthymic disorder accompanied by sleep disturbance, fatigue, psychomotor retardation, loss of self-esteem, and excessive guilt. During a 10-day dopamine-free period, lumbar puncture was performed to measure the metabolites of dopamine, serotonin, and norepinephrine. Patients were given an overnight dexamethasone suppression test, and the effects of thyrotropin-releasing hormone and L-dopa on plasma growth hormone and prolactin were examined. Level of CSF 5-hydroxyindoleacetic acid was lowest in parkinsonian patients with major depression and was related to psychomotor retardation and loss of self-esteem.
Transient withdrawal of therapy has been advocated as a method of dealing with the complications of long-term use of levodopa in the treatment of Parkinson's disease. We retrospectively examined the effect of a 10-day period of levodopa withdrawal, or "drug holiday," in 28 patients. We then compared the subsequent clinical course of these patients over one year with that of 30 other randomly selected, similar patients with Parkinson's disease. In both groups the disease progressed; there was no difference in disease severity, capacity for daily living activities, or total amounts of dopamine agonists eventually used. For some patients, it was possible to reduce dopamine agonists used immediately after the drug holiday without causing deterioration, but a pulmonary embolus and other complications occurred. Subsequent complications related to long-term dopamine-agonist therapy during the follow-up period were similar in the two groups. this investigation indicates that a drug holiday carries some risk and does not improve the efficacy of levodopa therapy or prevent the problems that occur with long-term administration.
We reviewed records of 121 consecutive patients with dementia of the Alzheimer type. Patients with myoclonus or extrapyramidal signs had greater intellectual decline and functional impairment in daily activities. Among patients studied over 4 years, there were four groups: benign--little to no progression; myoclonic--severe intellectual decline and frequent mutism after younger onset; extrapyramidal--severe intellectual and functional decline and frequent psychotic symptoms; typical--a gradual progression of intellectual and functional decline, but without other distinguishing features. Except for the group with myoclonus, no subgroup was segregated by age at onset or other demographic variables. This study suggests that dementia of the Alzheimer type is heterogeneous, and that certain clinical manifestations may be useful in predicting outcome.
Data from three patients and 22 previously reported cases suggest that cerebral microinfarction causes a recognizable clinical syndrome. All cases present with stroke, followed by progressive dementia and often with visual field deficits, peripheral vascular disease, and signs of motor neuron dysfunction. The average age at onset is 45, and most patients have been men. Many patients have had valvular or ischemic heart disease; in one of our cases, mitral stenosis caused embolic microinfarcts.
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Delayed reaction time and diminished vigilance have been observed in Parkinson's disease (PD) but have not been related to biochemical changes in the disease. As norepinephrine is reduced in the brain in PD and this neurotransmitter has been related to attention and learning, we investigated the relationship of neuropsychological measures, including those of reaction time and vigilance, to the norepinephrine metabolite 3-methoxy - 4 - hydroxyphenethyleneglycol (MHPG) in 39 patients with idiopathic PD. The MHPG levels correlated with a measure of general intellectual ability and with performance on reaction time and continuous performance tasks. Our data suggest that altered norepinephrine metabolism may contribute to some aspects of intellectual dysfunction in PD.
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Patients with Parkinson's disease and controls traced patterns of increasing complexity presented on a vertical transparent screen. Some patterns were presented with missing segments which subjects were required to fill in. Digitising equipment quantitated movements for computer analysis. Subjects also completed a brief test of general intellectual function, a construction test and an assessment for depression, and the severity of patients' Parkinsonian signs and symptoms was rated. Patients performed more poorly than controls on complete patterns, and their errors increased more sharply than controls on patterns with missing segments. Patients' errors, but not those of controls, in filling in missing segments were uniquely related to performance on construction tasks. Other aspects of patients' tracing performance correlated with the severity of their Parkinsonian symptoms. These findings suggest that there is an underlying perceptual motor deficit in Parkinson's disease that affects performance on both tracing and construction tasks.
Pergolide mesylate, a long-acting dopamine agonist, is effective in treating Parkinson's disease. Behavioral change is said to be one adverse effect. We therefore studied 19 parkinsonian patients with neuropsychological tests before and after initiating pergolide therapy. Intellectual and behavioral changes were also monitored clinically for up to 2 years. There was no decline in performance on the neuropsychological tests. Six patients had transient psychiatric or intellectual changes that were controlled by reducing drug dosage. These changes were similar to those seen with other dopamine agonists.
We determined the gene frequencies for the alleles of the HLA-linked complement markers C2, properdin factor B (BF), C4A (Rodgers) and C4B (Chido), and the red cell enzyme glyoxalase-I in 38 unrelated patients with senile dementia of the Alzheimer type, 42 patients with idiopathic Parkinson's disease, and 59 unaffected, aged-matched control blood donors. In senile dementia of the Alzheimer type and in Parkinson's disease, no significant difference was found in the gene frequencies of alleles at either the BF, C2, or GLO-I locus compared with those of age-matched controls. In senile dementia of the Alzheimer type, a striking increase in the frequency of the rare C4B locus allele, C4*B2, was apparent, resulting in the high relative risk of RR = 8.8 (p less than 0.0001) for this disorder.
Depression is a common symptom in patients with Parkinson's disease. It is not related to the severity of the motor symptoms or changes in dopamine metabolism and does not improve on treatment with dopamine agonists. Alterations in serotonin metabolism are found in primary (endogenous) depression. The brain content of serotonin in Parkinson's disease is also reduced, but this has not been related to any manifestation of the disorder. We found that the CSF content of the major metabolite of serotonin, 5-hydroxyindoleacetic acid, was lower in depressed than in nondepressed parkinsonians. The data suggest that the alterations in serotonin metabolism in Parkinson's disease identify a subgroup of patients who are prone to depression.