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Biomedical subjects

D B Calne

Publications and source records attributed to D B Calne.

At least 73 records · Page 4Linked to original sources
PubMed1994

Parkinsonism induced by solvent abuse.

We report the first description of a patient with parkinsonism induced by solvent abuse. Our patient developed parkinsonism acutely, following heavy abuse of lacquer thinner. Her clinical deficits were indistinguishable from idiopathic parkinsonism (Parkinson's disease) and she responded to levodopa. Parkinsonism has persisted for more than 3 months. Brain computed tomography was normal. Positron emission tomographic studies showed normal fluorodopa uptake and reduced raclopride binding, indicating an unusual disturbance of striatal dopaminergic function. This patient suggests that organic solvents may cause parkinsonism in susceptible individuals.

Administration, Inhalation↗
PubMed1994

Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes.

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.

Adult↗
PubMed1994

Age-dependent decline of nigrostriatal dopaminergic function: a positron emission tomographic study of grandparents and their grandchildren.

Despite postmortem evidence for an age-related decline in nigrostriatal dopaminergic function, position emission tomography (PET) studies have produced inconsistent results. This may be due to differences in methods or of subject selection. To investigate further the effect of age on dopaminergic function, we performed PET with 6-L-[18F]fluorodopa (FD) on 12 pairs of grandchildren and their grandparents. The FD uptake rate constant (Ki) was calculated using a graphical method for the whole striatum to avoid confounding of the results by striatal atrophy. The mean Ki was significantly lower in grandparents (p = 0.020). These PET observations represent in vivo confirmation of postmortem evidence that nigrostriatal dopaminergic function declines with aging.

Adult↗
PubMed1994

Longitudinal fluorodopa positron emission tomographic studies of the evolution of idiopathic parkinsonism.

Previous estimates of the rate of progression of the nigral pathology underlying idiopathic parkinsonism (IP) have been derived mainly from pathological studies that have an inherent selection bias. Fluorodopa positron emission tomography (PET) is a reliable tool for assessing nigrostriatal dopaminergic function in vivo. We performed fluorodopa PET on two occasions, 7 years apart, on 16 patients with IP (age at the time of the first scan, 51 +/- 14 yr [mean +/- SD]) and 10 normal controls (age, 54 +/- 16 yr). For the patients with IP, the average duration of symptoms from the time of diagnosis to the first scan was 4.5 years (range, 1-12 yr); their PET index (striatal-occipital)/occipital ratio, dropped by 1.7% per year, from 0.49 +/- 0.08 to 0.43 +/- 0.08 (p < 0.001). The normals' ratio decreased by 0.3% per year from 0.77 +/- 0.05 to 0.75 +/- 0.10 (p = 0.33). The ratios in the IP group progressed significantly faster than the controls (p = 0.036). The rate of decline in IP represents 7.8% per decade, expressed as a fraction of the normals' initial mean value at 54 years of age. These results also permit power analysis for the design of future studies assessing the effect of treatment on the underlying pathology in IP.

Adult↗
PubMed1994

Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions.

Transient exposure to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a syndrome resembling idiopathic parkinsonism (IP). While IP inevitably progresses, the long-term evolution of MPTP-parkinsonism is unknown. Fluorodopa positron emission tomography (FD-PET) is a reliable tool for assessing nigrostriatal dopaminergic function. We performed FD-PET and clinical assessments on two occasions, 7 years apart, on 10 human subjects exposed to MPTP (age at the first scan, 32.7 +/- 6.9 yr [mean +/- SD], and on 10 normal individuals (age, 53 +/- 16 yr). At the time of their first scan, 5 of the subjects exposed to MPTP were clinically normal and 5 had limited signs of parkinsonism; 5 had new clinical deficits 7 years later. In the subjects exposed to MPTP, the PET index [(striatal-occipital)/occipital ratio] dropped by 2.3% per year from 0.70 +/- 0.10 (mean +/- SD) to 0.58 +/- 0.10 (p < 0.001). This was significantly faster than normal aging (p < 0.01) and similar to the progression observed in IP (p = 0.06). The findings suggest that short-term exposure to MPTP leads to a protracted decline in nigrostriatal dopaminergic function more rapid than occurs in normal aging and similar to IP progression. This is the first evidence that transient exposure to a toxin can cause progressive nigral pathology. At present, the mechanism leading to this progression is unknown. Our findings support the hypothesis that some neurodegenerative disorders may result from transient exposure to an environmental agent.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Tendon jerks in Parkinson's disease.

Tendon reflexes were examined in 119 patients with idiopathic parkinsonism (IP) and 40 spouse controls to estimate the type and frequency of any alterations in the reflexes. Forty one of 119 patients and 2 of 40 controls had reflex ratings of 3+ at two or more sites (p < 0.001). There was no correlation of reflex score with the severity of disease or with the cardinal signs of IP. In 21 patients with asymmetric tendon jerks the side with the more active reflexes correlated with the side with greater parkinsonian signs. We conclude that an increase in tendon jerks is a feature of IP. The pathophysiology of this change in reflexes should be investigated further to establish if it is a heretofore overlooked manifestation of basal ganglia dysfunction or a link with other neurodegenerative diseases.

Adult↗
PubMed1994

Clinical observations on the rate of progression of idiopathic parkinsonism.

The time course of evolution of clinical deficits has been a traditional guide to the nature of the aetiopathogenesis of neurological disease. We studied the influence of ageing and duration of disease on the natural history of idiopathic parkinsonism (IP). Two hundred and thirty-eight patients with IP were examined while off medication. Bradykinesia scores were analysed against patients' age and duration of disease by multiple regression. There was no significant interaction between the effects of age and of duration (P = 0.923). We conclude that age and duration of symptoms influence the natural history of IP additively and independently. Furthermore, the rate of neuronal death is more rapid in the earlier stages of evolution of the pathology; subsequently, the velocity of progression slows down to approach the rate of attrition produced by normal ageing. This time course has implications for possible models of pathogenesis.

Aged↗
PubMed1994

A mathematical model of pathogenesis in idiopathic parkinsonism.

We used our observations relating clinical deficits in idiopathic parkinsonism (IP) to age and to disease duration (Lee et al, Brain 1994; 117: 501-7), to develop a mathematical model of the temporal profile of neurodegeneration in IP. We also examined other sets of relevant published observations and applied three additional assumptions which permitted the formulation of this model. Our model indicates that accelerating or decelerating processes should be excluded as the driving forces behind neuronal death in IP. Mechanisms in accord with the model include: (i) an event that kills some neurons and damages others in such a way that their life expectation is reduced; or (ii) an event that starts a process which is continuously killing healthy neurons at a constant rate. The model enables us to extrapolate back to estimate when the causal event occurred. It also explains why IP proceeds more rapidly in older patients. The model has potential relevance to other neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis.

Adult↗
PubMed1994

Normal CAG repeat length in the Huntington's disease gene in senile chorea.

There is a widely held belief that most patients presenting with senile chorea have late-onset Huntington's disease (HD) with an unknown family history. We measured CAG trinucleotide repeat expansion in the HD gene in four patients with a clinical presentation of senile chorea and found that CAG repetition lengths were normal. These findings support senile chorea as being a distinct clinical entity that is nosologically separate from late-onset HD.

Aged↗
PubMed1994

Manganism and idiopathic parkinsonism: similarities and differences.

From the comparison we have made between PD and manganism, we draw the following conclusions: 1. There are similarities between PD and manganism, notably the presence of (a) generalized bradykinesia and (b) widespread rigidity. 2. There are also dissimilarities between PD and manganism, notably the following in manganism: (a) less-frequent resting tremor, (b) more frequent dystonia, (c) a particular propensity to fall backward, (d) failure to achieve a sustained therapeutic response to levodopa, and (e) failure to detect a reduction in fluorodopa uptake by PET. Further studies are likely to yield more discriminants between PD and manganism. For example, PET with raclopride may be useful in early cases of manganism, and MRI may be helpful in patients with advanced manganism.

Brain↗
PubMed1994

Levodopa failure in chronic manganism.

We report a placebo-controlled study of levodopa in four patients with extrapyramidal deficits caused by chronic manganese intoxication. Their parkinsonism and dystonia had progressed slowly over a period of 5 years after they left the site of exposure. Initially the patients appeared to respond to levodopa in open observations, but this apparent benefit was not sustained. This short-term, double-blind study indicates that their parkinsonism and dystonia failed to respond to levodopa.

Adult↗
PubMed1994

Initiating treatment for idiopathic parkinsonism.

The initial decision in the management of idiopathic parkinsonism is whether any pharmacotherapy is indicated. There is no conclusive evidence that treatment is helpful before symptoms start to affect the patient's life, although some neurologists believe that deprenyl, also known as selegiline, could be useful. Once functional deficits begin to interfere with the patient's work or social activities, treating symptoms becomes appropriate. Anticholinergics and amantadine can be used, but their limited benefit is often accompanied by unacceptable adverse effects. Dopaminomimetics are the most satisfactory medications, including levodopa and such artificial dopamine agonists as bromocriptine, pergolide, or lisuride.

Antiparkinson Agents↗
PubMed1994

Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects.

UNLABELLED: Fluorine-18-6-fluorodopa (FD) positron emission tomography (PET) is established for measuring nigrostriatal dopaminergic function. This is despite the absence of data on the reproducibility of results. METHODS: With an ECAT 953B/31 tomograph, we performed two or three repeated FD PET scans in 10 normal subjects to measure the scan-to-scan variation in the total striatal uptake rate constant (Ki). RESULTS: We found a scan-to-scan standard deviation (s.d.) of 8.7% of the mean. The between-subject s.d. was 26% of the mean, resulting in a reliability coefficient of 90%. Analysis of the variation in the components contributing to Ki showed a reliability varying from 77% to 86% (depending on the different time points analyzed) for emission data measured by the PET camera. The reliability of the blood radioactivity time course, as reflected by the stretch time, varied from 43% to 81%. The overall reliability for the correction of the blood time course for metabolites of FD was 71%. Variation in the blood radioactivity contributed to the variability of Ki by 50% more than the metabolite correction and by 200% more than the emission data. CONCLUSION: The striatal Ki is a reliable measurement; it has a 95% chance of lying within +/- 18% of its value for an individual normal subject.

Adult↗
PubMed1994

Early idiopathic parkinsonism: initiation and optimization of treatment.

Once a diagnosis of idiopathic parkinsonism has been made, the choice and timing of therapy depend almost entirely on the patient's need for symptomatic relief, as no presently available therapy has any effect on the pathogenesis of the disease. Five categories of drugs are available for the treatment of idiopathic parkinsonism. Anticholinergic agents are effective against tremor but have prominent adverse effects. Amantadine has similar effects but is more active against rigidity and bradykinesia. Selegiline is a monoamine oxidase-B inhibitor; once thought to affect the pathogenesis of idiopathic parkinsonism, it is now known to offer only symptomatic relief. The dopamine agonists (bromocriptine, pergolide, and lisuride) stimulate D2 receptors; they have antiparkinsonian effects and tolerance profiles broadly similar to those of levodopa but are slightly less efficacious. Pleural effusions and pulmonary fibrosis are unusual but important complications of these drugs; chest x-ray examinations are therefore recommended for all patients starting such treatment. Levodopa (combined with an extracerebral decarboxylase inhibitor to prevent nausea, the main adverse effect) has become the standard antiparkinsonism treatment. Patients using this preparation can suffer considerable variations in mobility and dyskinesia, which may be related to rapid, large-scale oscillations in plasma levodopa concentrations. Controlled-release (CR) preparations have been developed in an attempt to minimize these fluctuations and reduce long-term side effects. There is no universally agreed treatment for idiopathic parkinsonism. However, experience shows that a good balance of antiparkinsonian activity and adverse effects can be obtained by initiating treatment with a combination of levodopa and a decarboxylase inhibitor. A dopamine agonist can be added if the disease progresses and increased therapeutic activity is required.

Amantadine↗
PubMed1993

Evidence for a dopaminergic deficit in sporadic amyotrophic lateral sclerosis on positron emission scanning.

Although rare, the chronic neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and idiopathic parkinsonism coexist to a greater degree than expected by chance. This suggests that patients with ALS may have subclinical lesions of the nigrostriatal dopaminergic pathway. To study this hypothesis, we did positron emission tomography with 6-fluorodopa on 16 patients with sporadic ALS and without extrapyramidal disease, and compared the results with age-matched controls. We found a significant progressive fall in 6-fluorodopa uptake with time since diagnosis, and reduced dopaminergic function in 3 patients with ALS of long duration. This supports the hypothesis that ALS and IP may share pathogenesis and, perhaps, aetiology.

Adult↗