Amantadine-induced "vocal" myoclonus.
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Aged↗
Biomedical subjects
R F Pfeiffer
Publications and source records attributed to R F Pfeiffer.
Descriptive epidemiology of Parkinson's disease through proxy measures.
BACKGROUND AND OBJECTIVE: In preparation for analytic study we undertook to describe areas of relative excess and deficit of Parkinson's Disease (PD) in Nebraska and tested two methodologic tools for inexpensive assessment of descriptive epidemiology of PD. METHODS: In lieu of large-scale population screening and diagnosis, we obtained sales information of anti-PD drugs in the state in 1988-1990 as well as listings of all people dying from 1984 to 1993 who had Parkinson's Disease mentioned anywhere on their death certificate. The anti-PD drug sales data are intended as a proxy for prevalence, while the death certificate data are intended as a proxy for incidence. RESULTS: Sales divided by population over age 54 indicates where anti-PD drug sales differ from expected. We found high correlation of drug sales rates with several farming exposures. Age-adjusted death rates, however, showed a low degree of association with sales or farming variables. This may be attributable to differences in death certificate completion or in underlying incidence versus prevalence. CONCLUSIONS: These techniques provide a useful tool for delineating possible differences in incidence and prevalence. While not as accurate as full community survey with expert diagnosis, they are not as expensive, and can be followed by local cluster investigations and individual-level etiologic studies to test hypotheses resulting from the initial study.
Epidemiologic Methods↗
Neurologic dysfunction in gastrointestinal disease.
The various disease processes described in this review by no means exhaust the list of GI diseases in which neurologic dysfunction may occur, but merely serve as a representative sampling. Recognition is often a function of awareness, and the growing knowledge of the rich interaction between GI and neurologic systems on many levels suggests that additional associations will be uncovered in the future.
Acute Disease↗
Localization of the gene for rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration to chromosome 17q21.
Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration (PPND) is a neurodegenerative disorder which begins later in life (> 30 years of age) and is characterized by rapidly progressive parkinsonism, dystonia, dementia, perservative vocalizations and pyramidal tract dysfunction. The disease is observed in a large American family that includes almost 300 members in nine generations with 34 affected individuals. In this kindred evidence for linkage to chromosome 17q21 was obtained with a maximum lod score of 9.08 for the D17S958 locus. Multilocus analysis positions the disease gene in an approximately 10 cM region between D17S250 and D17S943. Notably, the disease locus for a clinically distinct familial neurodegenerative disease named 'disinhibition-dementia-parkinsonism-amyotrophy complex' (DDPAC) was recently mapped to the same region of chromosome 17, suggesting that PPND and DDPAC may possibly originate from mutations in the same gene.
Adult↗
Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson's disease.
Cabergoline is a dopaminergic agonist relatively specific for the D2 receptor and much longer-acting than other dopamine agonists. We conducted a randomized, placebo-controlled, double-blind study of cabergoline in 188 levodopa/carbidopa-treated patients with suboptimally controlled Parkinson's disease (PD). The cabergoline patients had significantly better Activities of Daily Living (p = 0.032) and Motor Examination (p = 0.031) scores at the conclusion of the trial compared with the placebo group. The daily levodopa dose for the cabergoline patients decreased 18% compared with a 3% reduction for the placebo group (p < 0.001). The amount of time in the "on" state increased more in the cabergoline group (p = 0.022). The side-effect was similar to that seen with other dopamine agonists, and cabergoline was generally well tolerated. We conclude that cabergoline is an effective adjunct to levodopa for the treatment of PD.
Activities of Daily Living↗
Antiparkinsonian agents. Drug interactions of clinical significance.
Within the past 3 decades revolutionary changes have taken place in the pharmacological management of Parkinson's disease. Used alone, or often in combination, antiparkinsonian agents can dramatically and meaningfully ameliorate the symptoms of Parkinson's disease. However, with the development of effective therapeutic agents has come the potential for drug interactions; these interactions can produce consequences that range from the inconsequential to incapacitating and even life-threatening. Drug-drug interactions are not a major problem with either the anticholinergic medications or amantadine. However, cumulative anticholinergic toxicity may occur when multiple drugs with anticholinergic properties are utilised concomitantly, and amantadine toxicity can be triggered by drugs that impair its renal clearance. Gastric emptying and levodopa absorption can be significantly altered by medications and dietary contents. A rather extensive array of medications can interfere with dopaminergic function and thus produce clinical parkinsonism or impair the effectiveness of levodopa. The effectiveness of direct dopamine agonists can also be affected by a small group of agents. As a selective monoamine oxidase type B (MAO-B) inhibitor, selegiline (deprenyl) is free of the 'cheese-effect' when employed in recommended dosages. However, potentially life-threatening drug interactions, with both pethidine (meperidine) and with fluoxetine and other antidepressant medications, have been described, presumably occurring via serotonergic mechanisms. Awareness of the potential for drug interactions with antiparkinsonian agents, and prompt recognition of them when they do occur, is vital for the optimum clinical management of Parkinson's disease.
Antiparkinson Agents↗
Simultaneous electromyography and manometry of the anal sphincters in parkinsonian patients: technical considerations.
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Anal Canal↗
Genetic linkage studies in autosomal dominantly inherited L-DOPA responsive parkinsonism. Evaluation of candidate genes.
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Adult↗
6-Hydroxydopamine-mediated induction of rat brain metallothionein I mRNA.
Oxidative stress, resulting either from excess generation or reduced scavenging of free radicals, has been proposed to play a role in damaging striatal neurons in Parkinson's disease. Since metallothionein is able to regulate the intracellular redox potential, we have undertaken a group of experiments to learn whether or not 6-hydroxydopamine, which generates free radicals and is toxic to dopaminergic neurons, could alter the levels of zinc and metallothionein in the brain. The lesioning of the rat striatum with 6-hydroxydopamine (8.0 micrograms in 4 microliter 0.02% ascorbic acid) resulted in a reduction in the levels of zinc and metallothionein in the striatum but not other brain regions tested. However, the intracerebroventricular administration of 6-hydroxydopamine, in a dosage regimen that does not lesion catecholaminergic pathways but causes oxidative stress, enhanced dramatically the level of metallothionein I mRNA in some brain areas such as hippocampus, arcuate nucleus, choroid plexus, and granular layer of cerebellum, but not in the caudate putamen. The results of these studies are interpreted to suggest that zinc or metallothionein are altered in conditions where oxidative stress has taken place. Moreover, it is proposed that areas of brain, such as striatum containing high concentrations of iron, but low levels of inducible metallothionein are particularly vulnerable to oxidative stress.
Animals↗
Selegiline protects dopaminergic neurons in culture from toxic factor(s) present in the cerebrospinal fluid of patients with Parkinson's disease.
The cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) contains substance(s) that inhibit the growth and functions of dopaminergic neurons. Further, selegiline, a monoamine oxidase B (MAO) inhibitor (0.125-0.250 microM) enhanced the number of tyrosine hydroxylase (TH)-positive neurons, augmented the high affinity uptake of dopamine (DA), and averted the neurotoxic effects of CSF of PD patients on rat mesencephalic neurons in culture. The neuroprotective effects of selegiline may be related either to its ability to inhibit MAO B, preventing the generation of free radicals, or to neuronal rescue property due to unknown mechanisms.
Animals↗
A Greek-American kindred with autosomal dominant, levodopa-responsive parkinsonism and anticipation.
Interest is increasing concerning the role of genetic factors in the etiology of Parkinson's disease. We report the analysis of a Greek-American kindred with levodopa-responsive parkinsonism. Of the 98 individuals present in six generations of this pedigree, 16 individuals in three successive generations have developed parkinsonism. Affected members were examined both in Greece and in the United States. The clinical presentation consisted of asymmetric rigidity, resting tremor, bradykinesia, and postural instability, and symptoms were responsive to levodopa. The disease appears to be inherited in an autosomal dominant manner. The inheritance pattern and the development of parkinsonism in successive generations on two continents challenges environmental factors as the primary cause in the pathogenesis of parkinsonism in this kindred. Anticipation is present in this pedigree. The affected members in the third generation developed symptoms at ages 50 to 71, in the fourth at ages 40 to 55, and in the fifth at age 31 years. This is another example of a neurodegenerative disease with autosomal dominant inheritance and anticipation. A molecular genetic analysis of this pedigree is in progress.
Adult↗
Anorectal function in fluctuating (on-off) Parkinson's disease: evaluation by combined anorectal manometry and electromyography.
Anorectal dysfunction and constipation are well recognized in Parkinson's disease and may reflect the direct involvement of the gastrointestinal tract by the primary Parkinson's disease process. We hypothesized, therefore, that anorectal function would alter in parallel with fluctuations in motor function related to on- and off-periods in Parkinson's disease, and employed combined anorectal manometry and electromyography to investigate anorectal function during both on- and off-periods in patients with Parkinson's disease. Manometric recordings revealed a deterioration in voluntary sphincter squeeze during off-periods (squeeze index, on versus off, mean +/- SEM: 46.4 +/- 11.1 versus 29.6 +/- 7.9 mm Hg, p < 0.05); correspondingly, simultaneous electromyographic (EMG) recordings showed poor recruitment of external anal sphincter and puborectalis muscles during off-periods. A hypercontractile ("paradoxical") rectosphincteric reflex response occurred during both on- and off-periods, and was associated with an increase in EMG activity in the external sphincter and/or the puborectalis muscle. These changes in manometric and EMG parameters paralleled changes in overall motor function. These findings provide further support for the involvement of the pelvic floor musculature in the Parkinson's disease process and also provide EMG correlates for some of the manometric abnormalities described in Parkinson's disease.
Age of Onset↗
Expression and regulation of brain metallothionein.
Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminals and release it by a calcium-dependent mechanism. These "vesicular" pools of zinc are viewed as endogenous modulators of ligand- and voltage-gated ion channels. Metallothioneins (MTs) are low molecular weight zinc-binding proteins consisting of 25-30% cysteine, with no aromatic amino acids or disulfide bonds. The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT isoforms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT. A similar nucleotide and amino acid sequence has made it difficult to obtain cDNA probes and antibodies capable of distinguishing indisputably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an additional seven amino acids, is expressed mostly in the brain and to a very minute extent in the intestine and pancreas; whereas MT-IV isoform is found in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic vesicles, the regulation of the expression of MT isoforms is extremely important in terms of maintaining the steady-state level of zinc and controlling redox potentials. The concentration of zinc has been shown to be altered in an extensive number of disorders of the central nervous system, including alcoholism. Alzheimer-type dementia, amyotrophic lateral sclerosis, Down's syndrome, epilepsy, Friedreich's ataxia, Guillaine-Barré syndrome, hepatic encephalopathy, multiple sclerosis, Parkinson's disease, Pick's disease, retinitis pigmentosa, retinal dystrophy, schizophrenia, and Wernicke-Korsakoff syndrome. The status of MT isoforms and other low molecular weight zinc-binding proteins in these conditions, diseases, disorders, or syndromes is being delineated at this time. Since several of these disorders, such as amyotrophic lateral sclerosis, are associated with oxidative stress, and since MT is able to prevent the formation of free radicals, it is believed that cytokine-induced induction of MT provides a long-lasting protection to avert oxidative damage.
Amino Acids↗
Cerebrospinal fluid of Parkinson's disease patients inhibits the growth and function of dopaminergic neurons in culture.
We report the possible existence of an inhibitory factor in the CSF of Parkinson's disease patients that inhibits the function and growth of dopaminergic neurons in rat mesencephalic culture. After 40 hours' exposure to the < 10 kd fraction of CSF from PD patients, the high-affinity dopamine uptake was 66% of that of cultures exposed to CSF from controls. However, the number of dopaminergic neurons remained unchanged at this time. After 90 hours' exposure to the < 10 kd fraction of CSF from PD patients, the number of dopaminergic neurons decreased to 10% of that in cultures exposed to CSF from controls, and the size of the remaining dopaminergic neurons in the culture became smaller. This inhibitory factor did not affect the growth of other types of neurons. The chemical nature of this inhibitory factor is under investigation.
Aged↗
Western Nebraska family (family D) with autosomal dominant parkinsonism.
The etiology of Parkinson's disease (PD) remains uncertain. Environmental influences may have an important role, but genetic factors have been firmly implicated in several recently reported kindreds. We studied a family (family D) whose ancestors probably immigrated to the United States from England. The pedigree contains 188 individuals spanning six generations with 18 affected members. Autosomal dominant inheritance is present. Typical levodopa-responsive PD with bradykinesia, rigidity, resting tremor, and impaired postural reflexes develops. Eye movement abnormalities, pyramidal and cerebellar signs, sensory disturbances, and orthostatic blood pressure changes do not occur. Disease progression is slow. PET with [18F]-6-fluoro-L-dopa (FD) performed on an affected individual revealed decreased uptake of FD in a pattern consistent with PD. Autopsy performed on another affected individual demonstrated neuronal and pigmentary loss, gliosis, and Lewy bodies in the substantia nigra pars compacta. This large kindred appears to represent a neurodegenerative disorder closely resembling, if not identical to, idiopathic PD.
Aged↗
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↗
Anorectal manometry in the assessment of anorectal function in Parkinson's disease: a comparison with chronic idiopathic constipation.
We investigated the role of anorectal manometry in evaluating constipation and anorectal function in 15 patients with Parkinson's disease (PD) and compared results with those of 9 patients with idiopathic constipation (IC) and 8 control (C) subjects. Anal sphincter pressures on voluntary squeeze were lower in the PD patients. Sustained squeeze pressures (mm Hg C versus IC versus PD: 46.8 +/- 5.2 versus 31.2 +/- 3.6 versus 26.6 +/- 3.9; p < 0.05 PD versus C), squeeze duration (seconds: 53.6 +/- 2.5 versus 48.5 +/- 4.1 versus 33.6 +/- 9; p < 0.05 PD versus C) and squeeze index (area under the squeeze curve: 44.0 +/- 2.9 versus 34.5 +/- 3.3 versus 21.4 +/- 2.9; p < 0.001 PD versus C) were significantly lower in the PD group in comparison to the control group. In contrast, none of the parameters of anorectal manometry differed between controls and patients with idiopathic constipation. Some Parkinson's disease patients demonstrated an abnormal, hypercontractile response on testing of the rectoanal inhibitory reflex. Anal sphincter length, basal sphincter pressures, maximal squeeze pressures, extent of relaxation on rectoanal inhibitory reflex and threshold volume for rectal sensation were similar in the three groups. We conclude that an impaired squeeze response is a specific feature of anorectal function in Parkinson's disease. This may indicate direct involvement of the pelvic floor musculature by the parkinsonian disease process.
Aged↗