Pharmacologically modulated fMRI--cortical responsiveness to levodopa in drug-naive hemiparkinsonian patients.

According to the basal ganglia-thalamocortical circuit model, dopamine depletion in the nigrostriatal system leads to hypoactivation in the supplementary motor area (SMA) and the primary motor cortex (M1) in Parkinson's disease. This functional cortical deafferentation and its reversibility by levodopa (L-dopa) treatment has been established in previous studies for SMA but remains controversial for M1. We used functional MRI (fMRI) and a simple finger opposition task to correlate blood oxygenation level-dependent (BOLD) signal changes with motor performance, assessed separately for each hand between fMRI scanning sessions. Eight drug-naive patients with an akinetic idiopathic hemiparkinsonian syndrome (Hoehn and Yahr stage 1-1.5) and 10 healthy controls were studied. Patients performed a simple, auditory-paced random finger- opposition task every 3 s before and repeatedly every 20 min after intake of 300 mg of fast-release L-dopa. M1 contralateral to the affected hand and SMA, predominantly of the contralateral side, showed a BOLD signal increase after L-dopa intake. Furthermore, comparing BOLD responses of M1 and SMA between the patients and controls revealed that these areas were hypoactive before L-dopa treatment. Signal changes in M1 and SMA were highly correlated with motor performance, which increased after L-dopa intake. This result is not confounded by a performance effect because the motor task employed during scanning was identical throughout all sessions. In contrast to previous imaging studies in which cortical reorganization in Parkinson's disease was thought to have caused M1 hyperactivation, our data are in accordance with the hypothesis that, in de novo idiopathic hemiparkinsonian syndrome, motor cortex hypoactivation in contralateral M1 and bilateral SMA is caused by a decreased input from the subcortical motor loop, which is reversible by L-dopa.

Increased lipoprotein oxidation in Alzheimer's disease.

Oxidation has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and amyloid beta is considered to induce oxidation. In biological fluids, including cerebrospinal fluid (CSF), amyloid beta is found complexed to lipoproteins. On the basis of these observations, we investigated the potential role of lipoprotein oxidation in the pathology of AD. Lipoprotein oxidizability was measured in vitro in CSF and plasma from 29 AD patients and found to be significantly increased in comparison to 29 nondemented controls. The levels of the hydrophilic antioxidant ascorbate were significantly lower in CSF and plasma from AD patients. In plasma, alpha-carotene was significantly lower in AD patients compared to controls while alpha-tocopherol levels were indistinguishable between patients and controls. In CSF, a nonsignificant trend to lower alpha-tocopherol levels among AD patients was found. Polyunsaturated fatty acids, the lipid substrate for oxidation, were significantly lower in the CSF of AD patients. Our findings suggest that (i) lipoprotein oxidation may be important in the development of AD and (ii) the in vitro measurement of lipid peroxidation in CSF might become a useful additional marker for diagnosis of AD.

Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency is an X linked disorder and the most common inherited cause of hyperammonaemia. Fluctuating concentrations of ammonia, glutamine, and other excitotoxic amino acids result in a chronic or episodically recurring encephalopathy. A heterozygous female patient first presented with protein intolerance, attacks of vomiting, and signs of mental retardation in early childhood. At the age of 16 complex partial seizures occurred which were treated with sodium valproate. Seven days after initiation of valproate therapy, she developed severe hyperammonaemic encephalopathy with deep somnolence. The maximum concentration of ammonia was 480 micromol/l. After withdrawal of valproate, three cycles of plasma dialysis, and initiation of a specific therapy for the inborn metabolic disease, ammonia concentrations fell to normal values. The patient remitted, returning to her premorbid state. Valproate can cause high concentrations of ammonia in serum in patients with normal urea cycle enzymes and may worsen a pre-existing hyperammonaemia caused by an enzymatic defect of the urea cycle. Sufficient diagnostic tests for the detection of metabolic disorders must be performed before prescribing valproate for patients with a history of encephalopathy.

Clinical changes and EEG patterns preceding the onset of periodic sharp wave complexes in Creutzfeldt-Jakob disease.

The conversion of EEG findings and the evolution of clinical signs was investigated in 7 CJD patients who underwent serial EEG recordings along the course. At the onset of PSWC (mean 8.7 weeks), 5 patients had already progressed to akinetic mutism (characterized by loss of verbal contact and directed responses); and a CJD-typical-movement disorder (myoclonia, exaggerated startle reaction or focal dyskinesia) had started in 5 patients. When akinetic mutism commenced (on average at 7.5 weeks), runs of frontal intermittent non-peaked rhythmical delta activity (FIRDA) were found in all cases. These were later replaced by PSWC in 6 patients (interval 1 to 3 weeks). Occurrence of PSWC was often negatively related to external stimuli (2 of 6 cases), and sedative medication (all patients tested). We conclude that the selection of EEG recording dates to detect PSWC in CJD-candidates should be guided by detailed information about movement disorders and conscious level. Regarding the short survival time after their onset (average 8 weeks), PSWC usually mark the terminal stage of CJD. To detect PSWC, especially, EEG registrations in advanced stages are often necessary. In earlier disease stages, FIRDA-like EEG activities should be regarded as compatible with this diagnosis, and encourage further EEG studies for the demonstration of PSWC in a more advanced stage of CJD.

Glucocorticoids and anabolic/androgenic steroids inhibit the synthesis of GABAergic steroids in rat cortex.

Cerebral side effects of therapy with glucocorticoids include mental alterations and behavioral disturbances such as nervousness, insomnia, changes in mood or psychological state and psychopathies of manic-depressive or schizophrenic type. We have investigated the effects of glucocorticoids, anabolic/androgenic steroids and the 5-alpha-reductase inhibitor N,N-bis (1-methyl)-3-oxo-4-aza-5-alpha-androstane-17-beta-carboxamide (1-MAC) on the synthesis of the GABAergic steroids 5-alpha-pregnane-3.20-dione (5-alpha-dihydroprogesterone) and 5-alpha-pregnane-3-alpha-ol-20-one (5-alpha-tetrahydroprogesterone) in rat cortex in vitro. We found potent inhibition of progesterone-3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSDH) by prednisone, prednisolone, dexamethasone and fluocortolone. Inhibition of progesterone 5-alpha-reductase by glucocorticoids was not found. In addition, inhibition of 3-alpha-HSDH and 5-alpha-reductase by androgenic/anabolic steroids and inhibition of 5-alpha-reductase by 1-MAC could be demonstrated. The inhibition of progesterone metabolism in the cerebral cortex by exogenous steroids might lead to altered neuronal activity. We conclude that this mechanism could induce the cerebral side effects, such as mental modifications and behavioral disturbances, of the drugs investigated.

[Acute reversible encephalopathy with brain edema and serial seizures in pseudohypoparathyroidism]. / Akute reversible Enzephalopathie mit Hirnödem und Anfallserie bei Pseudohypoparathyreoidismus.

A 16 year old patient with the typical clinical signs of Albright's hereditary dystrophia developed series of epileptic seizures with loss of consciousness, tonic muscle contractions and bite of the tongue. After termination of the seizures there was coma without focal neurological signs. CT scan revealed diffuse brain edema. Electroencephalographic studies showed generalized slowing. In laboratory tests the only abnormalities were marked hypocalcemia (1.15 mmol/l) and hyperphosphatemia. Blood parathyroid hormone (PTH) was elevated. PTH-Test confirmed the diagnosis of pseudohypoparathyroidism. The patient was treated with calcium and 1,25-dihydroxy-cholecalciferol. After few days the severe encephalopathy, CT and electroencephalographic changes were completely reversible. Hereditary disturbances of the parathyroid hormone metabolism are rare diseases. Hypocalcemia must be included into the differential diagnosis of seizures and brain edema to avoid invasive diagnostic and irrational treatment.

Inhibition of human placental aromatase in a perfusion model. Comparison with kinetic, cell-free experiments.

In vitro perfusion of human placenta was evaluated for characterization of aromatase inhibitors. The results were compared with those in kinetic experiments in cell-free system. Inhibition constants (Ki) were determined by measuring the release of tritiated water during coincubation of human placenta microsomes with varying amounts of [1 beta,2 beta 3H]androstenedione and inhibitor in the presence of NADPH-generating system. Irreversible inactivation constants (Kinact) were determined in a similar manner following preincubation of the microsomes with different amounts of inhibitor for varying times. Lineweaver-Burk plots indicated a competitive type of inhibition with Ki values of 37 nM for 4-hydroxy-androstenedione, 3,700 nM for testolactone, 15 nM for 1-methyl-androsta-1,4-diene-3,17-dione, and 7.5 nM for 19-azido-androstenedione. Additionally, irreversible enzyme inactivation by all four substances could be demonstrated with Kinact values of 3.64 x 10(-3), 0.57 x 10(-3), 0.34 x 10(-3), and 0.69 x 10(-3)sec-1, respectively. Perfusion of a single cotyledon of human term placenta was performed by infusing medium through catheters placed in a fetal artery and in the maternal intervillous space. Perfused medium was collected from a cannulated fetal vein and from the maternal basal plate. The medium was supplemented with [3H]androstenedione (4.2 nM) and inhibitor. The perfusates were analyzed for their [3H]estrone and estradiol content following phenolic partition and Sephadex-LH 20 chromatography. The main results were, (1) the recovery of labelled steroids increased rapidly after perfusion started and reached a plateau within 60 min, when 55 and 30% (mean values) of the infused radioactivity were recovered in the fetal and maternal perfusates, respectively, (2) similar amounts of estrone and estradiol were found in both effluates, whereas androgens (mainly androstenedione and lower amounts of 5 alpha-androstane-3,17-dione) were found nearly exclusively in the fetal perfusate, (3) formation of estrogens (estrone + estradiol) reached a plateau within 20 min of perfusion. (4) The percentage of estrogens formed was not changed by increasing androstenedione concentration in the perfusion medium unless this concentration exceeded 3.5 microM indicating limited capacity of aromatase. (5) The four aromatase inhibitors reduced estrogen formation by 50% at concentrations about 100-fold of their Ki determined in the cell-free system, (6) irreversible aromatase inhibition could not be demonstrated in the perfusion model. It was concluded that the human placenta perfusion model can be successfully used to evaluate aromatase inhibitors.

Metabolism of androgens in human benign prostatic hyperplasia: aromatase and its inhibition.

As an extension of our studies on androgen metabolism in epithelium and stroma of human benign prostatic hyperplasia (BPH) tissue our attempts to demonstrate the presence of aromatase are described. Additionally, the question is raised whether the aromatase inhibitor 17 alpha-oxa-D-homoandrosta-1.4-diene-3.17-dione (testolactone) might also act by inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSDH). In vitro metabolism and inhibition were analyzed by TLC. The main results were: (1) Two aromatase assays (estrone formation and tritium release) were tested with placenta microsomes. Identical results were obtained (Km = 43 +/- 7 nmol/l n = 5; Vmax = 100 resulted in recovery of the aromatase activity added. (3) In BPH tissue alone, formation of estrone from androstenedione could not be detected (less than 7 x 10(-17) mol/min per mg protein, n = 8). (4) 4-Hydroxyandrostenedione inhibited placental aromatase (Ki = 37 nmol/l) distinctly better than 17 beta-HSDH from human BPH (Ki = 18 mumol/l), whereas the Ki values for testolactone (3.7 and 29 mumol/l, respectively) were more similar. It is concluded that aromatization of androgens is not an important pathway in BPH tissue. An alternative mode of action of testolactone by inhibition of 17 beta-HSDH is discussed.