V. Sonninen

Hereditary Multi-Infarct Dementia

This paper summarizes the clinical and genetic features of a disease occurring in 16 patients from the same extended family, which resembles the multi-infarct dementia described by Sourander and Wålinder [Acta neuropath. 39: 247-254, 1977]. This family has relapsing strokes with neuropsychiatric symptoms, and they affect relatively young adult individuals of both sexes. The entity of the disease is characterized by autosomal dominant transmission with late onset and by association with occlusive cerebrovascular infarcts in the white matter, which was also generally reduced. Both of these features can be seen in the CT scan. In 13 members of this family the diagnosis can be regarded as certain and in a further 3 cases as more or less probable.

Mortality of patients with parkinson's disease treated with levodopa

SummaryThe effect of levodopa on the mortality of patients with Parkinsons disease was investigated in 349 patients treated with levodopa or levodopa combined with a decarboxylase inhibitor during 1969–1975 inclusive. During the study period, 61 patients died. The expected mortality was 32.99 resulting in a ratio of actual to expected deaths of 1.85. The excess mortality was accounted for by patients with a severe disease at entry and especially, by the less favorable effect of levodopa treatment than in the living patients. In comparison with the prelevodopa era, the reduction of mortality and the increase of life expectancy of patients with Parkinsons disease during levodopa treatment possibly reflect the decrease of the early mortality due to Parkinsons disease.ZusammenfassungDie Auswirkung der Levodopa-Behandlung auf die Mortalität von Parkinson-Patienten wurde anhand einer Serie von 349 Fällen untersucht, welche in den Jahren 1969–1975 einerseits mit L-Dopa, andererseits mit L-Dopa zusammen mit Decarboxylasehemmern behandelt wurden. Während der Beobachtungsperiode verstarben 61 Patienten. Die erwartete Mortalität hätte 32,99 betragen müssen, was eine Relation von tatsächlicher zu erwarteter Mortalität von 1,85 ergibt. Für die höhere Mortalität waren Fälle verantwortlich mit schweren Krankheitserscheinungen bei Beginn der Therapie und im besondern auch mit einem geringeren Effekt der L-Dopa-Therapie als bei den überlebenden Patienten. Verglichen mit den Beobachtungen vor Einführung der L-Dopa-Therapie beruht wohl die Verminderung der Mortalität und die erhöhte Lebenserwartung von Parkinson-Patienten unter L-Dopa auf der Abnahme der Frühtodesfälle durch die Parkinsonsche Krankheit.

THE ACTIVATING EFFECT OF L‐DOPA TREATMENT ON SEXUAL FUNCTIONS AND ITS EXPERIMENTAL BACKGROUND

It is supposed that the centres of sexual behaviour and gonadotrophin release are situated in the hypothalamus (Orthner 1968). The hypothalamus regulates the gonadotrophin secretion from the anterior pituitary, and monoamines play an important role in this process (Fuxe and HGkftlt 1967, Hyyppu 1969, Schneider and McCann 1969). The specific function of dopamine has remained obscure. On the other hand, many monoamines influence the sexual behaviour of laboratory animals. Bearing in mind the role of hypothalamic dopamine on sexual functions, it is of interest to study how L-Dopa treatment acts on the sexual functions of Parkinsonian patients. For the clarification of its background the changes in the content of hypothalamic dopamine after castration were measured quantitatively in rats. A total of 41 Parkinsonian patients, followed for 2-9 months and treated with L-Dopa (approximately 4-5 g daily), were interviewed about their sexual functions. In the experimental study 15 male rats were used in three groups: One (5) castrated, one (5) castrated and testosteronized (testosterone-propionate 0.6 mg daily for 14 days), and one (5) sham-operated. The rats were killed after 1 month, and the dopamine content was determined in the hypothalamus and forebrain by the method of Lauerty and Sharman (1965). Ten out of the 41 patients ( 7 males and 3 females) told of increased libido. Among these, five ( 3 males and 2 females) had strongly increased sexual activity. Two of the patients had sexual dreams; one of them observed decreasing libido when the L-Dopa dose was gradually decreased from 5 to 3 g daily. One of the female patients experienced menstrual bleeding, which she had not had for six months. Results of the experimental studies showed that the hypothalamic dopamine content of control rats was 0.58 * 0.28 pg/g (S.D.); that of castrated was 0.46 k 0.13, and that of castrated and with testosterone compensated was

Brain Glutamic Acid Decarboxylase Activity in Parkinson’s Disease

The activity of glutamic acid decarboxylase (GAD), the enzyme involved in formation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), was studied in autopsy brain samples from six parkinsonian patients and 13 controls. There was relatively good postmortem stability of GAD in deep-frozen brain samples over a 3-week period. The activity of GAD was significantly reduced in brain samples of patients with Parkinson’s disease, being about 50% of that in controls. Moreover, levodopa treatment showed a tendency to increase the activity of GAD. The results suggest the involvement of GABA neurons in Parkinson’s disease.

L-Dopa treatment in Parkinson's Disease.

Double-blind and non-blind therapeutic trials of orally administered L-Dopa in the long-term treatment of Parkinsonism were carried out with 126 patients. For correlative studies the amount of hornova

Plasma Concentration of Levodopa in Patients with Parkinson’s Disease

Responses in plasma concentration of levodopa to administration of levodopa alone or combined with the extracerebral decarboxylase inhibitor, Ro 4-4602, were studied in 173 parkinsonian patients both

GABA receptor binding in the parkinsonian brain

Abstract The binding of GABA to postsynaptic receptors was studied in the cerebral and cerebellar cortex, caudate nucleus, putamen, pallidum and substantia nigra from autopsy brains of 12 parkinsonian patients and 11 controls. GABA receptor binding in the substantia nigra was significantly decreased in the parkinsonian brain. In the other brain regions, however, GABA binding was unchanged. There was no correlation between GABA binding and sex, age, duration or severity of the disease. The results suggest the involvement of nigral GABA receptor in Parkinsons disease.

Treatment of Parkinson's disease with l-DOPA and decarboxylase inhibitor

SummaryClinical trials on the effect of l-DOPA and decarboxylase inhibitor, Ro 4-4602, in the long-term treatment of Parkinsons disease were carried out and compared with l-DOPA alone. Altogether 59 parkinsonian patietns were treated for 3 to 9 months. For correlative studies the plasma level of DOPA and the concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) was analysed.A daily dosage of 800 to 1000 mg of l-DOPA combined with 200 to 250 mg of decarboxylase inhibitor induced during long-term treatment a significant therapeutic response which was equal to that induced by 4 to 5 g of l-DOPA alone. During combined treatment there was a significant reduction of nausea and especially of vomiting. However, in the dosage range used the frequency of abnormal involuntary movements was equal to that with l-DOPA alone.There were only a few transient laboratory abnormalities during l-DOPA and decarboxylase inhibitor treatment. Liver biopsy studies on 10 volunteer parkinsonian patients did not show any light or electron microscopic changes which could be related to the treatment.The maximum plasma level of l-DOPA after 200 mg of l-DOPA and 50 mg of Ro 4-4602 was equal to that of 1000 mg of l-DOPA alone.During l-DOPA and decarboxylase inhibitor treatment the concentration of HVA in the CSF increased significantly and correlated significantly with the dosage but not with the degree of clinical improvement. On the other hand, the concentration of 5-HIAA in the CSF decreased significantly during treatment. l-DOPA and decarboxylase inhibitor seems to be an effective, well-tolerated and safe drug in the treatment of parkinsonian patients. The decrease in gastro-intestinal side-effects affords a considerable advantage over l-DOPA alone.ZusammenfassungEs wurden vergleichende Untersuchungen über den klinischen Effekt von l-DOPA in Kombination mit dem Decarboxylase-Hemmer Ro 4-4602 und von l-DOPA allein bei Langzeitbehandlung von Parkinsonkranken durchgeführt. Insgesamt 59 Parkinsonpatienten wurden über einen Zeitraum von 3–9 Monaten behandelt. Für vergleichende Studien wurde der Gehalt des Plasmas an DOPA und die Konzentration von Homovanillinmandelsäure und 5-Hydroxyindol-Essigsäure im Liquor bestimmt.Eine tägliche Dosis von 800 bis 1000 mg l-DOPA, kombiniert mit 200–250 mg des Decarboxylase-Hemmers, bewirkte in der Langzeittherapie eine signifikante Besserung, welche analog derjenigen von 4–5 g l-Dopa allein war. Während der kombinierten Behandlung war eine signifikante Verminderung von übelkeit und Erbrechen festzustellen. Hingegen war in der verwendeten Dosierung die Häufigkeit abnormer unwillkürlicher Bewegungen gleich wie diejenige bei l-LOPA.Es fanden sich lediglich einige geringfügige und vorübergehende abnorme Laborbefunde während der l-DOPA-Decarboxylase-Hemmer-Behandlung. Leberbiopsien an 10 Parkinsonpatienten, die sich hierfür freiwillig zur Verfügung gestellt hatten, zeigte weder licht- noch elektronenoptisch Veränderungen, die mit der Therapie in Zusammenhang gebracht werden konnten.Die höchsten Plasmawerte von l-DOPA nach 200 mg l-DOPA und 50 mg Ro 4-4602 waren gleich wie diejenigen nach 1000 mg l-DOPA allein. Während l-DOPA und Decarboxylase-Hemmer-Behandlung nahm die Homovanillinmandelsäurekonzentration im Liquor signifikant zu und korrelierte mit der verabreichten Medikamentendosis, jedoch nicht mit dem Ausmaβ der klinischen Besserung. Andererseits nahm die Konzentration der 5-Hydroxyindol-Essigsäure im Liquor während der Behandlung signifikant ab. l-DOPA und Decarboxylase-Hemmer scheinen eine wirksame und gut ertragene, gefahrlose Medikation in der Behandlung von Parkinsonpatienten darzustellen. Die verminderung gastrointestinaler Nebenwirkungen stellt einen nennenswerten Vorteil gegenüber der Verabreichung von l-DOPA allein dar.

Debrisoquine oxidation in Parkinson's disease

Variations in the activities of xenobiotic metabolizing liver enzymes may be involved in the pathophysiology of diseases, including Parkinsons disease. We therefore studied the activity of the debrisoquine metabolizing enzyme in 97 patients with newly diagnosed Parkinsons disease. The urine debrisoquine metabolic ratios (MR) of the patients were compared with a group of 176 healthy subjects. There were 4 poor metabolizers (4.1%) among the parkinsonians. This proportion did not differ from that found in the group of healthy subjects (5.1%). In contrast to earlier finding, the parkinsonian poor metabolizers (PM) had the onset of the disease later than the parkinsonian extensive metabolizers (EM). In the parkinsonian patients, it was observed that the excretion of debrisoquine and 4‐OH‐debrisoquine into urine correlated inversely with the actual age and age at disease onset. Our results indicate that in patients with Parkinsons disease, debrisoquine hydroxylation is comparable with healthy subjects.

BRAIN ACETYLCHOLINESTERASE IN PARKINSON'S DISEASE

The activity of acetylcholinesterase was studied in various autopsy brain samples of nine parkinsonian patients and eight control subjects without extrapyramidal disorders. Putamen and caudate nucleus showed the highest activities of acetylcholinesterase when different brain areas were compared. Acetylcholinesterase values expressed per wet weight or protein were somewhat lower in the extrapyramidal brain regions of parkinsonian patients than in those of controls. When values were calculated per desoxyribonucleic acid (DNA) it was found that extrapyramidal brain regions, especially substantia nigra, showed higher activities in parkinsonian material than in controls. This difference is due to the decrease of DNA which in the substantia nigra mainly reflects the loss of dopaminergic substantia nigra neurons. Furthermore, analyses of dopamine from the same tissue samples showed many times increased acetylcholinesterase‐dopamine ratio in parkinsonian brain than in controls. Levodopa alone or combined with a decarboxylase inhibitor did not have any significant effect on the activity of acetylcholinesterase. It is concluded that the cholinergic mechanisms in the extrapyramidal system of parkinsonian brain are not so severely affected as the dopaminergic ones leading to relative and functional cholinergic dominance.