Treatment of Parkinson's disease.
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Amino Acid Sequence↗
Biomedical subjects
D B Calne
Publications and source records attributed to D B Calne.
Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels.
Postmortem counts of dopaminergic cell densities in the substantia nigra (5 subjects) and striatal levels of dopamine (DA) and its metabolites (6 subjects) were determined on 1 parkinsonian (PD), 3 progressive supranuclear palsy (PSP), 1 amyotrophic lateral sclerosis, and 1 Alzheimer's case who had been positron emission tomography scanned with 6-[18F]fluorodopa during life. [18F]Fluorodopa uptake rate constants, which presumably depend on the number of functioning striatal DA terminals, were strictly proportional to cell densities (significant correlation with zero intercept) and also correlated significantly with striatal DA levels but with an intercept indicating greater losses of DA than of terminals in PSP and PD. Postmortem data on 6 PD, 1 PSP, and 9 neuronally normal controls substantiated the significant correlation between cell counts and DA levels, with the latter being the more depressed in pathological cases.
Adult↗
Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices.
Striatal 18F-6-fluorodopa (FD) uptake constants were measured by positron emission tomography in (1) normal cynomolgus monkeys and (2) a series of cynomolgus and rhesus monkeys that had received intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After the animals were killed, the number and average size of dopaminergic neurons in the substantia nigra pars compacta were measured. Striatal levels of dopamine and its metabolites, and the striatal activities of the dopaminergic synthetic enzymes, were also determined. The striatal FD uptake constants showed highly significant positive correlations with both number and size of dopaminergic neurons, indicating atrophy of surviving neurons in MPTP-treated animals. The uptake constants also showed significant positive correlations with striatal levels of dopamine, total catecholamines, and the activities of the synthetic enzymes. Both histochemical and biochemical data on tyrosine hydroxylase suggested some contralateral enzyme loss in these MPTP-treated monkeys, as well as decreased enzyme activity in surviving neurons on the lesioned side. However, residual enzyme activities were apparently not rate limiting to striatal FD uptake. It is concluded that PET-FD measurements by positron emission tomography provide a good index of the integrity of the nigrostriatal pathway.
Animals↗
The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.
The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain.
Amino Acids↗
Positron emission tomographic studies of dopa-responsive dystonia and early-onset idiopathic parkinsonism.
There are two major syndromes presenting in the early decades of life with dystonia and parkinsonism: dopa-responsive dystonia (DRD) and early-onset idiopathic parkinsonism (EOIP). DRD presents predominantly in childhood with prominent dystonia and lesser degrees of parkinsonism. EOIP presents before age 40 with parkinsonism (often with associated dystonia). Both disorders are exquisitely sensitive to levodopa, although the long-term prognosis in each appears to be different. Some have suggested, however, that DRD is a form of EOIP. We performed positron emission tomography with 6-fluoro-dopa in 10 patients with DRD and 18 patients with EOIP to study the integrity of their nigrostriatal dopaminergic systems. In DRD, we found normal striatal FD uptake. In contrast, patients with EOIP had reduced striatal FD uptake. We conclude that the patho-physiologies of DRD and EOIP are distinct. Although both disorders presumably represent a deficiency of striatal dopamine, the results suggest that in DRD dopa uptake, decarboxylation, and storage mechanisms are intact. This may explain the sustained response of DRD to low doses of levodopa. 6-Fluoro-dopa positron emission tomography distinguishes DRD from EOIP.
Adolescent↗
Further observations on Tau-positive glia in the brains with progressive supranuclear palsy.
The previously reported unusual, Tau-positive glia with astrocytic morphology seen in brain tissues from cases of progressive supranuclear palsy (PSP) were re-examined immunohistochemically using antibodies to CD44 and vimentin, as well as Alz-50. Four brains of PSP cases, one of whom had atypical clinical features, were examined. All four cases showed the unusual glia which were positive to Alz-50 and anti-CD44 antibodies, but negative to anti-vimentin antibody. Ultrastructurally, they had either paired nucleated or lobulated nuclei and the cytoplasm frequently contained lipofuscin pigment. The CD44 was located on the surface of the cell bodies and their processes. Such glia were most numerous in the striatum in all cases. They also appeared in the cortex and some subcortical nuclei in the three typical cases. They were not seen in the lower brain stem or cerebellum. In their morphological characteristics and regionally specific appearance, these unusual glia seemed similar to the Alzheimer type I glia which are commonly seen in hepatic encephalopathy or Wilson's disease.
Aged↗
Parametric imaging of the rate constant Ki using [18Fluoro]-L-dopa positron emission tomography in progressive supranuclear palsy.
Positron emission tomography (PET) studies using [18F]-L-dopa were carried out in 9 patients with supranuclear palsy and 13 controls. For quantification of PET data a rate constant Ki was calculated for the radiotracer using a graphical method. Corrections for nonspecific activity were performed in both arterial plasma and brain tissue. The purpose of this study was to test the hypothesis that parametric images of the rate constant K mapping can be obtained on a pixel-by-pixel basis using an appropriate mathematical algorithm. Ki values from these parametric images and the graphical approach were compared. Both correlated closely, with y = 0.013 + 0.947*x, r = 0.992 and y = -0.052 + 1.018*x, r = 0.965 in patients and controls, respectively. Contrast measurements were also performed and showed a striking increase in contrast on parametric images. K mapping offers several advantages over the graphical approach, since parametric images are time-independent, i.e. one image represents the quantitative result of the study. In addition, parametric images of the rate constant are normalized to arterial plasma radioactivity and corrected for tissue metabolites. Thus, parametric images of Ki in different individuals can be compared directly without further processing in order to assess the nigrostriatal integrity.
Aged↗
Cross-cultural cognitive examination: validation of a dementia screening instrument for neuroepidemiological research.
OBJECTIVE: Validation of a new instrument for screening dementia, the Cross Cultural Cognitive Examination (CCCE), is described. DESIGN: Criterion and concurrent validation and cross-cultural comparison of a new instrument. PARTICIPANTS: All individuals over the age of 40 in a village in southern Guam participated in a door-to-door survey. Alzheimer's and Parkinson's Disease patients and healthy controls aged 40-90 participated in the US mainland study. MEASUREMENTS: The CCCE was administered to all subjects. Effects of age, language, education, and gender on test performances and social-cultural differences were assessed. Concurrent validation of the test with respect to other well accepted screening instruments was determined. RESULTS: High specificity (> 94%) and sensitivity (> 99%) for detecting dementia were found in Guam and US mainland samples, and these were not biased by differences in gender, linguistic preference, education, or cultural background. Sensitivity and specificity of the CCCE matched or exceeded that of already accepted dementia screening instruments. CONCLUSIONS: These validation studies support the usefulness of the CCCE for identifying patients with generalized dementia, rather than focal types of cognitive impairment, quickly and reliably in cross-cultural neuroepidemiological research.
Adult↗
Pathogenesis of idiopathic parkinsonism.
Idiopathic parkinsonism (Parkinson's disease) makes up the largest diagnostic subgroup of patients with parkinsonism. Various hypotheses exist regarding the pathogenesis of idiopathic parkinsonism: these include genetic predilection aging, environmental factors, oxidative stress, excitotoxicity, autoimmunity, and trauma. We suggest that the pathogenesis of idiopathic parkinsonism is likely to be multifactorial, deriving from environmental factor(s) acting upon a genetically predisposed individual. Because of the compelling evidence indicating common clinical and pathological findings in idiopathic parkinsonism, Alzheimer's disease, and amyotrophic lateral sclerosis, we believe that these conditions result from pathological processes with more similarity than diversity. A primary glutamatergic cell neocortical abnormality provides an attractive unifying explanation which may explain the overlapping abnormalities found in idiopathic parkinsonism, Alzheimer's disease, and amyotrophic lateral sclerosis.
Alzheimer Disease↗
A scoring error in the Mini-Mental State test.
A scoring error is identified in the Mini-Mental and the Modified Mini-Mental State test. The major effect of this error is to produce a gap in the total score distribution of the test, resulting in a potential spurious underestimation of the score. Two possible remedies are suggested to resolve this problem.
Attention↗
Botulinum toxin in the treatment of writer's cramp: a double-blind study.
We treated 20 patients with writer's cramp in a double-blind, placebo-controlled study. Each patient received two treatments in tandem, one with botulinum-A toxin (BTX-A) injections and another with normal saline, separated by 3 months. Treatment order was randomized and unknown to the patient and physician. Patients were assessed before each treatment and 2 and 6 weeks after each treatment by objective measurements of pen control. Twelve patients had improvement in pen control after treatment with BTX-A, but only four had significant improvement in writing. BTX-A injections are effective in relieving symptoms in selected cases of writer's cramp, particularly in those with significant wrist-joint deviation.
Adult↗
Progression after chronic manganese exposure.
We report a longitudinal follow-up study on six patients with chronic manganese-induced parkinsonism following cessation of manganese exposure. Compared with the 1987 study, their parkinsonian symptoms showed a slow progression, particularly in gait disturbances such as freezing during turning and walking backward with retropulsion. The mean disability scores on the King's College Hospital Rating Scale were 15.0 +/- 4.2 in 1987 and 28.3 +/- 6.7 in 1991 (p = 0.003, paired t test). Review of the video records also confirmed a worsening of parkinsonism, especially in difficulty turning. Three of six patients receiving levodopa treatment had an initial improvement. The response decreased after 2 to 3 years. During the therapy, they did not develop on-off fluctuation or dyskinesia. We conclude that patients with manganese-induced parkinsonism may develop increasing neurologic dysfunction long after cessation of exposure and that their responses to levodopa are different from those of patients with Parkinson's disease.
Adult↗
Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women.
Lubag (X-linked dystonia-parkinsonism) has been considered a sex-linked recessive trait and has been mapped to the pericentromeric region of the X chromosome. We studied a 54-year-old man with lubag and two of his female first cousins. Genetic typing was carried out using X chromosome markers. Fluorodopa PET was performed on the man and one of the women. The man had moderately severe parkinsonism and dystonia. A 61-year-old female first cousin had mild left-sided dystonia and her 54-year-old sister had mild generalized chorea. Genetic typing data revealed that all three inherited an X chromosome with marker alleles strongly associated with lubag. Cytologic analysis did not reveal evidence of X chromosomal deletion. Fluorodopa PET in both the man and one affected cousin revealed reduced striatal uptake rate constants consistent with nigrostriatal involvement. These observations suggest that lubag may be a codominant disorder and that it is possible for women to be affected.
Alleles↗
[Hereditary Parkinson disease: report of 3 families with dominant autosomal inheritance].
We have studied three families who ancestors immigrated to North America from contiguous regions of northern Germany and southern Denmark. The pedigrees contain 77,206 and 376 individuals spanning 6, 7 and 8 generations with 7,7 and 11 affected members, respectively. Autosomal dominant inheritance pattern is present in two families and probable in the third. Typical L-dopa-responsive parkinsonism with bradykinesia, rigidity, resting tremor, and impaired postural reflexes uniformly develop in affected individuals from all three families. Further research on these three families, including genetic, pathologic and clinical examinations is planned.
Adult↗
Clinical heterogeneity of dopa-responsive dystonia: PET observations.
Parkinsonism without dystonia has been reported in several older members of families with DRD. This raises the question whether such patients represent a variant in the clinical picture of DRD, or a separate disease, IP. We employed 6-FD PET to study the nigrostriatal dopaminergic function in a woman with typical DRD and two of her relatives with late-onset parkinsonism. These two had an excellent and prolonged therapeutic response to small doses of L-DOPA, without complications. We found that the dystonic patient and the women with "benign" parkinsonism had normal striatal 6-FD uptake. In conjunction with other clinical evidence, our PET study indicates that the biochemical lesion in these members may be "proximal" to dopa decarboxylase, as is suggested in DRD patients. We conclude that the adult-onset parkinsonism in DRD families is due to the same pathophysiological mechanism as the childhood-onset dystonia in the disease. DRD may display substantial clinical heterogeneity depending on the age of onset.
Adult↗
PET scan study on the dopaminergic system in a Japanese patient with hereditary progressive dystonia (Segawa's disease). Case report.
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Corpus Striatum↗
Citation of original research.
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Periodicals as Topic↗