Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson's disease on L-dopa monotherapy.

The aim of the study was to investigate the relationship between dyskinesias and motor fluctuations in patients with Parkinson's disease on l-dopa monotherapy. We identified 116 patients on l-dopa monotherapy treated between 1965 and 1992 and followed until death. Dyskinesias occurred in 102 patients. Of these, 48 only developed dyskinesias while 54 had both dyskinesias and motor fluctuations. Among patients with both complications, 49 developed dyskinesias before fluctuations, and only five had dyskinesias after the onset of fluctuations. Our findings suggest that dyskinesias predict the onset of motor fluctuations, and may share a common pathophysiological mechanism.

Novel dopamine releasing response of an anti-convulsant agent with possible anti-Parkinson's activity.

We used cerebral microdialysis to assess the ability of the anticonvulsant drug Zonisamide (ZNS) to release striatal dopamine in 6-hydroxydopamine nigrotomized rats. Following exogeneously administered ZNS we measured dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in striatal dialysates obtained from the ipsilateral side of the nigrotomy. ZNS administration alone had no effect on levels of DA and its metabolites or rotational behavior. Administration of carbidopa-levodopa alone led to small but insignificant increases in rotational behavior contralateral to the side of the nigrotomy but no corresponding increases in indices of striatal catecholamine release. In contrast, if animals were preloaded with carbidopa and ZNS was co-administered with levodopa 30 minutes later significant increases in contralateral rotational behavior occurred within 20 minutes of ZNS-levodopa injection that lasted for at least 90 minutes. In contrast to the uniform rotational behavioral responses observed in all our nigrotomized animals, less than half demonstrated neurochemical evidence of DA release. In these "responder" animals DOPAC levels increased 300% following carbidopa-levodopa-ZNS administration. We conclude that these results support previously reported findings and provide additional evidence that the anticonvulsant ZNS appears to possess anti-Parkinson's properties. ZNS could therefore be a novel agent for the treatment of PD that could delay the use of or reduce the amount of levodopa needed to treat patients with PD.

Selegiline in the treatment of Parkinson's disease: its impact on orthostatic hypotension.

Less than a consensus exists as to whether chronic treatment with selegiline in combination with levodopa/carbidopa in patients with Parkinson's disease, is associated with more pronounced orthostatic hypotension than treatment with levodopa/carbidopa alone. To resolve this issue, we compared orthostatic tolerance and autonomic reflexes in 95 patients with Parkinson's disease treated chronically with either selegiline alone (n = 10), levodopa/carbidopa alone (n = 49) or both agents combined (n = 36). Supine heart rate and blood pressure, autonomic cardiovascular reflexes and the frequency and magnitude of orthostatic hypotension were similar in all three treatment groups.

Co-occurrence of essential tremor and Parkinson's disease: clinical study of a large kindred with autopsy findings.

A multigenerational family complex with an admixture of essential tremor (ET) and PD is presented. Medical information obtained either by historic documentation and/or examination was available for five generations and included 36 members. Of these, 11 family members had tremor of the limbs and/or head. In all these instances ET made its first appearance at an early age, usually prior to the second decade of life. In one case focal dystonia of the hand, a possible prelude to PD occurred, while in three brothers of the third generation, two of them identical twins, classical Parkinson's disease (PD) developed. They had ET develop at an early age, which persisted and in their 50s began showing evidence of PD. Two decades later the twin brothers succumbed to cancer of the colon and at autopsy typical findings of PD with cell loss in the substantia nigra and Lewy-body formation positive for alpha-synuclein by immunohistochemistry was found. Additionally, more than the usual number of senile plaques and neurofibrillatory tangles were present without clinical evidence of dementia or significant decline in cognitive function. This unusual set of clinical and pathological circumstances can hardly be attributed to chance occurrence and raise the question of a specific genetic mutation and/or clustering, which may link ET with PD.

Intrastriatal iron perfusion releases dopamine: an in-vivo microdialysis study.

We perfused iron as FeCl(3) directly into the striatum of normal rats and used the in vivo microdialysis technique to monitor striatal levels of dopamine (DA). KCl was perfused to assess the functional integrity of the DA receptors at the end of each dialysis experiment. Cu(+2) (as CuSO(4)) and Cl(-) (as NaCl) were perfused to compare the effects of Fe(+3) to that of other heavy metal and donors of Cl(-) anion. Perfusion of FeCl(3) (1 mM for 15 min) produced a 250% increase in striatal levels of DA. Perfusion of CuSO(4) (1 mM for 15 min) or NaCl (10 mM for 15 min) did not affect striatal DA levels. There was a significant increase in DA levels with KCl stimulation (56 mM for 15 min) after perfusion with FeCl(3). We conclude that iron releases DA from striatal nerve endings without the immediate destruction of the DA terminals. The implications of chronic release of dopamine as a cause of dopaminergic cell death are discussed.

COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against L-dopa toxicity in vitro.

L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.

Comparative effects of repeated administration of dopamine agonists on circling behavior in rats.

A paucity of studies are available concerning the comparative therapeutic effectiveness of presently available dopamine agonist agents in the control of Parkinson symptoms. To provide a basis for resolving this issue, we measured the circling response in unilaterally nigrotomized (6-OHDA) rats following the administration of ropinirole, pramipexole, pergolide, bromocriptine, and cabergoline. Cabergoline, and to a lesser extent pergolide, produced the most vigorous and longest lasting circling response. This response was sustained with administration of these agents over a nine day period. Bromocriptine, pramipexole and ropinirole were all less effective. These results suggest that dopamine agonists whose effect is primarily on D1 and D2 receptors are more effective than those whose actions do not include D1 activation.

Postencephalitic parkinsonism--a review.

The pandemic of von Economo's disease which began in January 1917 preceded that of influenza of 1918-1919 by more than a year. Though it has been customary to link the two it seems unlikely that the latter was responsible for the former as has been proposed. It has been assumed that von Economo's disease (ED) was caused by a virus; but in fact the etiology is in question as no virus has yet been transmitted to experimental animals or cells in culture. However, the presence of oligoclonal IgG bands in the CSF of suspected cases and the finding of chronic active lesions in the brain tissue at autopsy suggests a viral etiology. Occasional, sporadic presumed cases of the disease have been reported within the last 25 years. Encephalitides due to established neurotropic viruses or to other viruses that may on occasion invade the CNS only rarely produce parkinsonism, and when they do it differs from that seen in ED. The present report reviews the overall concept of a viral etiology of Parkinson's disease with particular reference to von Economo's disease.

Sertraline induced parkinsonism. A case report and an in-vivo study of the effect of sertraline on dopamine metabolism.

We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, i.p.) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome.

Effects of repeated administration of l-DOPA and apomorphine on circling behavior and striatal dopamine formation.

We tested the circling response to l-DOPA and apomorphine administration in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Rats demonstrated a progressively diminished circling response when l-DOPA-carbidopa was repeatedly administered at 120 min intervals. This decreasing response was not present when apomorphine was administered under the same conditions. We also perfused l-DOPA directly into the striatum in vivo of rats with an ipsilateral 6-OHDA nigrotomy at 60 min intervals and monitored striatal dopamine levels with the technique of brain microdialysis. Dopamine formation increased from the first to the fifth trial. This may be secondary to the decrease in uptake sites which accompanies the loss of striatal dopamine nerve terminals. We postulate that the continued presence of dopamine at striatal receptor sites conditions a short-term loss of dopamine receptor sensitivity and a consequent decreased circling response. The observation that desensitization (as measured by decreasing circling) was not present following repeated apomorphine administration may be attributable to its shorter duration of action. We also perfused l-DOPA into the striatum of normal rats and noted a progressive decrease in striatal dopamine levels from the first to the fifth trial. Since this occurred following direct administration of l-DOPA into the striatum, the decrease could not be accounted for by peripheral pharmacodynamics or bioavailability of l-DOPA in the striatum. Since this decrease in dopamine formation was seen only in the normal striatum, its relevance to the diminished behavioral response is unclear.

Peripheral and central inhibitors of catechol-O-methyl transferase: effects on liver and brain COMT activity and L-DOPA metabolism.

Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be useful adjuncts to L-DOPA in the treatment of Parkinson's disease as they offer the possibility of increasing the availability of the amino acid. It is unknown whether a COMT inhibitor which penetrates the blood-brain barrier is preferable to one restricted to extra-cerebral inhibition. We measured liver and brain COMT activity two hours following administration of two COMT inhibitors: entacapone (ENT), mainly peripherally acting, and dinitrocatechol (DNC), peripheral and central acting. As expected, the full spectrum inhibitor DNC (30 mg/kg) induced a near total inhibition of liver and brain COMT activity. Unexpectedly, however, ENT, at 30 mg/kg, produced the same degree of liver and brain COMT inhibition as DNC; using 10mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5 mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10-30% inhibition) COMT activity. In a second series of experiments, we administered ENT (2.5, 10, and 30 mg/kg) and DNC (30 mg/kg) to rats and monitored extracellular striatal dopamine and dopamine metabolite levels with cerebral microdialysis both under basal conditions and following L-DOPA/carbidopa administration. No compound modified basal striatal levels of dopamine. ENT at 30 mg/kg (but not 2.5 or 10 mg), as well as DNC, decreased striatal levels of the methylated dopamine metabolite homovanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated with DNC and 30 mg/kg ENT (but not 2.5 or 10 mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to the 20% residual liver COMT activity present when the inhibitor was used at less than full doses. Our data indicate that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA. The dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.

Elevated striatal dopamine levels following administration of D-DOPA and its alpha-keto acid metabolite DHPPA: behavioral and physiological studies in vivo in the rat.

The D stereoisomer of dihydroxyphenylalanine (D-DOPA) and its alpha-keto acid metabolite 3,4-dihydroxyphenylpyruvic acid (DHPPA) when infused into the striatum, significantly increased in vivo extracellular dopamine levels. Following D-DOPA administration, the cumulative increase in dopamine levels was 30% of the increase following L-DOPA: following DHPPA it was 11% that of L-DOPA. Rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra demonstrated brisk contralateral turning following each compound. The turning, however, was delayed by 10-20 min and total turning was 40% less following D-DOPA and 57% less following DHPPA than it was following L-DOPA. These data indicate that exogenously administered D-DOPA can be metabolized in vivo within the brain to dopamine and suggest this may occur via a transamination pathway in which DHPPA is an intermediary metabolite. The possible relevance of these findings to the treatment of Parkinson's disease is discussed.

The pattern electroretinogram in Parkinson's disease reveals lack of retinal spatial tuning.

Spatio-temporal visual abnormalities, involving processing of medium coarse stimuli, are known to occur in Parkinson's disease (PD). While these deficits have been related to retinal dopaminergic deficiency, previous ERG studies in PD patients have provided conflicting results, probably due to differences in stimulus conditions. The influence of pattern element size (spatial frequency, SF) on the pattern electroretinogram (PERG) in PD has not been systematically studied. We recorded steady-state PERG to sinusoidal gratings of 50% contrast, counterphase modulated at 7.5 Hz with a series of SFs ranging from 0.5 to 6.9 c/deg in 20 PD patients and 20 healthy volunteers, subdivided in 10 "young" and 10 "age-matched" (AM) subjects. The PERG was analyzed by means of Fast Fourier Transform and the amplitude and the phase of the second harmonic response (15 Hz) were taken into account. We evaluated the medium-to-low SF amplitude ratio and termed it "PERG tuning ratio" (TR). The results indicate that aging affects all the studied SF, but the pattern of age-related loss differs from that observed in PD. Compared to AM subjects, PD patients show a specific deficit at medium SF, with a distorted PERG SF response function. Consequently, all PD patients show an attenuated PERG TR and 17 of them (85%) have an inverted TR. A significant TR decrease is correlated with the clinical stage of PD. There is a marked TR difference between patients receiving and not receiving L-DOPA. We conclude that stimulus SF is a crucial variable of the PERG in PD. PERG measurements and the derived PERG TR may provide a simple tool to evaluate retinal dopaminergic mechanisms and could contribute to the clinical assessment and monitoring of dopaminergic therapy in PD.

An in vivo comparison of the capacity of striatal versus extrastriatal brain regions to form dopamine from exogenously administered L-dopa.

We used the technique of cerebral microdialysis to monitor the metabolism of exogenously administered L-dopa and compared dopamine and dopamine metabolite formation in the striatum (a site containing abundant dopamine nerve terminals and dopa-decarboxylase (DDC) activity) versus the cerebellum and occipital cortex (sites with limited dopaminergic innervation and DDC activity). The concentrations of dopamine and the major dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in each brain region following L-dopa perfusion; however, dopamine formation was 90% less in the occipital cortex as compared to the striatum and 95% less in the cerebellum. DOPAC formation was 57% less in the occipital cortex and 74% less in the cerebellum. HVA formation was 42% less in the occipital cortex and 70% less in the cerebellum. The levels of the L-dopa metabolite 3-O-methyldopa and the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) were identical in the striatum, occipital cortex, and cerebellum both before and after L-dopa administration. We conclude that brain areas with marked reductions in dopamine nerve terminals and DDC activity have a diminished capacity to synthesize dopamine and also lack storage mechanisms to protect the newly synthesized dopamine from degradative metabolism. The relevance of these findings to the use of L-dopa in treating Parkinson's disease is discussed.