Neuropsychological correlates of L-deprenyl therapy in idiopathic parkinsonism.

1. Monoaminergic neurotransmitter systems are known to play an important role in neuropsychological functions and they are impaired in dementia of DAT and PD. 2. L-deprenyl is a monoamine-enhancing drug which at low doses selectively inhibits MAO-B, an enzyme whose brain activity has been reported to increase in normal aging and neurodegenerative dementing disorders. 3. The authors studied the effects of L-deprenyl, 10 mg/day, on several cognitive domains in idiopathic parkinsonians without dementia. Ten out-patients, treated with levodopa plus DDI, were tested before receiving L-deprenyl and retested six months after they had been treated with the drug. A control group of ten parkinsonian out-patients treated with only levodopa plus DDI, matched for age, educational level, severity and duration of extrapyramidal disease, was tested by the same neuropsychological battery and retested after a comparable time interval. 4. Statistically significant changes were noted in the verbal and visuospatial learning performances of PD patients treated with the combination of L-deprenyl and levodopa.

Neuropsychological follow-up of parkinsonian patients with and without cognitive impairment.

In order to evaluate possible progression in the severity of their cognitive impairment, 34 parkinsonians with intellectual impairment were followed longitudinally for 7 years. Each patient was matched for age, sex, severity and duration of illness, and pharmacological treatment, with a parkinsonian patient without cognitive impairment. Results suggest that cognitive deficits are not static but rather there is a progression in the severity. Furthermore, patients suffering from severe dementia are more likely to die during the follow-up period. The prognosis of Parkinson's disease seems to be changed substantially by the occurrence of dementia. The natural history of parkinsonian dementia does not seem to differ from the history of other forms of dementia with a progressively disabling course leading to a complete loss of autonomy.

Alzheimer-type dementia and verbal memory performances: influence of selegiline therapy.

In a double blind randomized crossover trial lasting 6 months selegiline, a selective MAO-B inhibitor, was tested against placebo for activity on verbal memory performances in Alzheimer-type dementia (DAT). Verbal memory was assessed with the Rey-Auditory-Verbal Learning Test at the start of treatment, at the time scheduled for crossover (90 days) and at the end of the trial (180 days). The results suggest that selegiline possesses significant activity on some memory parameters, which seems to depend on an improvement both in information processing abilities and in learning strategies at the moment of acquisition.

L-deprenyl therapy improves verbal memory in amnesic Alzheimer patients.

Altered monoaminergic neurotransmission could play an important role in the cognitive dysfunctions typical of dementia of the Alzheimer type (DAT). DAT is not, however, a homogenous phenomenon inasmuch as two forms are distinguishable: early onset (EO) and late onset (LO). Moreover, focal patterns of neuropsychological deterioration fall into various subgroups. According to our hypothesis, DAT patients, who at the onset of the disease mainly manifest memory disorders, also represent a specific subgroup characterized by impaired cortically projecting catecholaminergic pathways. In a 6-month randomized, double-blind, cross-over study versus placebo we analysed the influence of L-deprenyl on the verbal memory of 19 amnesic EO-DAT patients. Verbal memory was assessed by means of the Rey Auditory Verbal Learning Test. The results obtained show significantly better performances for L-deprenyl treated patients in learning and long-term memory skills. We suggest that L-deprenyl, through selective inhibition of MAO-B and by increasing the activity of the catecholaminergic systems, positively influences cognitive functions and behaviour founded on memory efficiency.

[The verbal fluency test for the diagnosis of dementia]. / Il test di fluenza verbale nella diagnosi di demenza.

Two forms of verbal fluency test, phonological (FF) and semantic (FS) sets, have been administered to four groups of demented patients: 11 with Alzheimer-type dementia (DAT), 13 with multi-infarct dementia (MID), 8 with Parkinson-Dementia (P-D) and 11 with adult chronic hydrocephalus (ICA). Patients were matched for age, educational level and neuropsychological impairment pattern. Further, ten neurologically healty subjects were selected as control group. Control subjects result to be different from all other groups in both FF and FS; moreover, FF test results to be more impaired in ICA than in DAT. Furthermore, FF is more impaired than FS in P-D and ICA patients. On the basis of our results, verbal fluency tests might represent an useful instrument to differentiate demented subjects from non-demented ones and within demented groups to characterize the different neuropsychological pattern of the cortical and subcortical type of cognitive deterioration.

Neuropsychological effects of L-deprenyl in Alzheimer's type dementia.

The monoaminergic neurotransmission defect seen in dementia of the Alzheimer type (DAT) is linked to a known increased activity of type B cerebral monoamine oxidases (MAO-Bs). The use of drugs that are able to block this abnormal activity could therefore be useful in the treatment of some cognitive deficits that characterize DAT. Twenty patients with a clinical diagnosis of DAT and with a slight-moderate mental deterioration were treated with 10 mg/day of L-deprenyl, a selective MAO-B inhibitor, according to a double-blind crossover design vs. placebo. Initial treatment (drug or placebo) was randomly assigned. The patients' cognitive functions were evaluated at baseline and then after 3 and 6 months of treatment with drug or placebo. The patients crossed over treatment after 3 months, without a washout interval. The results of the study show the higher and statistically significant effects of L-deprenyl on memory and attention that seem to be due to an improved function of the monoaminergic systems involved in the process of neuronal degeneration.

[Treatment of progressive supranuclear palsy]. / La terapia della paralisi sopranucleare progressiva.

The neuropharmacological and neurochemical features of Progressive Supranuclear Palsy (PSP) are reviewed, together with the results obtained by various therapeutic trials. PSP is a neurodegenerative disease which often causes Parkinsonian symptoms but dopaminomimetic drugs have given rise to poor improvement, in spite of dopamine decrease observed in PSP patients' nigrostriatal region. The uselessness of L-DOPA therapy in PSP patients may explain the numerous failures encountered in PSP patients misdiagnosed as Parkinsonian. On the basis of the recent discovery of striatal dopaminergic receptor abnormalities and of interaction between various neurotransmitters, the authors suggest some possible therapeutic substances that might improve the outcome of the disease.

Effect of subconvulsive doses of bicuculline on the incorporation of radioactive precursors into glycerolipids in rat brain areas.

Bicuculline (either 25 mumol or 12.5 mumol/kg body wt) was administered to rats by intraperitoneal route. Animals treated with 25 mumol/kg experienced convulsions, whereas those receiving 12.5 mumol/kg did not. Controls received saline instead of the drug. Radioactive precursors [2-3H] glycerol and/or [1,2 14C] ethanolamine were injected into cerebral ventriculi simultaneously with bicuculline and the rats were killed 12 min afterwards. Their brains were dissected by hand into four parts (cerebellum, brain stem, hippocampus, cerebral cortex) and the labeling of lipid classes determined after extraction and separation. Although glycerol was incorporated into lipid better than ethanolamine in all areas, the fate of the injected radioactive precursors varied according both to area and treatment. The lowest uptake of radioactivity was in the cerebral cortex and the highest in the brain stem and hippocampus. Moreover, the administration of bicuculline influenced the distribution of radioactivity among lipid classes; these variations, however, were not dependent on the administered doses of bicuculline. We conclude that the effects on glycerolipid metabolism observed in convulsing animals are due to several causes including alterations of systemic parameters (hypertension, hypoxia, etc.). The distribution of glycerol label between phospholipid and neutral lipid is proposed as a biochemical model for the study of convulsive and subconvulsive states.

[MPTP: a new chapter in the history of Parkinson's disease]. / MPTP: un nuovo capitolo della storia del Parkinson.

Great interest has been recently raised by the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a meperidine analogue capable of producing an irreversible Parkinson's disease. On the basis of papers published during the last years, we examined the structural features and the specific mechanism of action of this substance at the level of dopaminergic neurons. Furthermore, the clinical features of the experimental Parkinson model, obtained by means of MPTP inoculation in various animals and their similarities to the analogous human disease are described. We can conclude that the MPTP discovery enhances the hypothesis that Parkinson's disease can be also attributed to toxic factors.

[Therapy of insomnia]. / La terapia dell'insonnia.

The authors review the neurochemical and electrophysiological features of insomnia, together with the results obtained by various substances. The literature data show that the benzodiazepines (BZ) should be administered for short periods of time, in order to avoid addiction and withdrawal symptoms. For this reason, the authors suggest that, before starting a therapy with such substances, an accurate clinical evaluation should be made and a good knowledge of the pharmacokinetics of the various BZ is essential.

Frontal lobe dysfunction in Parkinson's disease: prognostic value for dementia?

The purpose of this longitudinal study was to investigate if the presence of frontal motor deficits in parkinsonians without signs of global intellectual impairment may have a predictive value for the development of a progressive dementing process during the course of the illness. An examination of the higher level of motor organization, using skills thought to depend upon the integrity of the frontal regions, was performed by 30 parkinsonian patients who did not present any signs of general intellectual impairment. According to their performance, as compared with controls, they were divided into two subgroups: those with and those without frontal dysfunctions. After a mean period of 4 years, a second neuropsychological examination was carried out to assess any eventual change of mental status. The results suggest that frontal dysfunctions may be observed several years before the appearance of generalized intellectual impairment and may be considered one of the predictive factors for development of dementia in Parkinson's disease. Careful consideration of these defects during examination of motor abilities may be of value in the clinical management of parkinsonian patients.

Valproic acid and bicuculline affect the formation of glycerolipid in rat brain.

To ascertain the effects of bicuculline and of sodium valproate on the incorporation of glycerol into rat brain lipid, rats were divided into 5 groups: (a) controls; (b) treated with sodium valproate (400 mg/kg body wt); (c) treated with bicuculline (12.5 ?mol/kg body wt); (d) treated with sodium valproate as in (b) + bicuculline as in (c); and (e) treated with bicuculline (25 ?mol/kg body wt). Only rats of group (c) had seizures, which lasted until the end of the experiment. Each animal received 20 ?Ci of [2-(3)H]glycerol by intraventricular route and was sacrificed 12 min afterwards. Hippocampi and cerebella were taken and lipid extracted and separated by chromatography. The type of treatment influenced very much the fate of injected, labeled glycerol. Indeed, total recovered radioactivity increased following either convulsions or the administration of valproate, whereas both treatments decreased the amount of radioactivity incorporated into lipid. These effects were more evident in cerebella than in hippocampi. The distribution of radioactivity among lipid classes (diglyceride, triglyceride and total phospholipid) was also affected by seizures, which decreased the labeling ratio phospholipid/neutral lipid. The distribution of radioactivity among phospholipid classes was influenced by bicuculline (both at convulsant and non-convulsant doses) and these effects were sometimes antagonized by valproate. We conclude that some effects of bicuculline are exerted through the systemic modifications due to seizures and that other effects are probably connected to neuronal hyperfiring. The data reported in this paper are consistent with both mechanisms of action proposed for valproate, i.e. increased membrane permeability and modifications of GABAergic systems.

Individual differences in cerebral organization: influence of sex and familial sinistrality in the language lateralization of strongly right-handed subjects.

Sixty right-handed subjects, divided into four groups of 15 according to sex and familial sinistrality (FS), performed a test of language lateralization. A verbal-manual dual-task paradigm was employed. Results suggest that the pattern of cerebral organization may differ among right-handers in relation to both sex and FS. However, it is not merely the separate influence of these two factors, but rather their interaction which determines the pattern. It is stressed that identification of individual predictors of language laterality may provide some information on prognosis and management of aphasic patients.

[2 cases of Binswanger's disease not associated with arterial hypertension: clinical-instrumental and neuropsychological evaluation]. / Su due casi di malattia di Binswanger non associata ad ipertensione arteriosa: valutazione clinico-strumentale e neuropsicologica.

Two cases of subcortical arteriosclerotic encephalopathy (Binswanger's disease) are reported. The two patients lacked a clinical history of hypertension, relevant pathogenetic factor in the development of the small and medium size cerebral arteries atherosclerosis, which is the main pathologic finding of the disease. The two subjects clinically showed a marked intellectual deterioration, together with mood depression and focal neurological signs, that were an expression of the multifocal neurologic involvement. In both cases CT scans evidentiated a mainly periventricular leucoencephalopathy associated, in the first patient, with small multiple ischemic lesions and, in the second, with a unique hypodense area in the centrum semiovale. A review of the literature on the subjects is proposed, together with an attempt of pathogenetic interpretation of our two cases.

Incorporation of glycerol and ethanolamine into glycerophospholipid in rat brain areas during bicuculline-induced convulsive seizures.

The effect of bicuculline-induced convulsive seizures on lipid metabolism has been studied in four brain areas (cerebellum, cerebral cortex, hippocampus, and brainstem) using [2-3H]glycerol and [1,2-14C]ethanolamine as radioactive lipid precursors administered simultaneously with bicuculline. Twelve minutes after the administration, the uptake of radioactivity depended both on brain area and treatment, being generally higher in convulsing rats. The uptake of glycerol was influenced to a larger extent than that of ethanolamine and increased during convulsions, but its incorporation into lipids did not. In contrast, the amount of ethanolamine incorporated into lipids increased during bicuculline-induced seizures. The difference in behavior of glycerol and of ethanolamine is also indicated by the decrease of the 3H/14C ratio of phosphatidyl-ethanolamine in various brain areas during convulsions. It is, therefore, evident that the metabolism of the two precursors is affected differently by seizures.

Cerebellar metabolism of phosphatidylethanolamine and its water-soluble precursors during bicuculline-induced convulsive seizures.

The incorporation of labeled ethanolamine into phosphatidylethanolamine (PE) and its water-soluble precursors, phosphoethanolamine and CDP-ethanolamine, is measured in rat cerebella during the course of bicuculline-induced convulsive seizures. The labeling of CDP-ethanolamine and phosphoethanolamine diminishes 6 min after the administration of both bicuculline and radioactive ethanolamine whereas that of PE is unaffected in these conditions. Time is very important to this effect; indeed, no differences of the labeling of PE water-soluble precursors can be found in rat cerebellum of normal and convulsing animals 12 min after the administration. The cerebellar pool of CDP-ethanolamine doubles after 6 min of convulsions, which means that unlabeled CDP-ethanolamine forms from a non-radioactive source, such as lipid, may be through the reversal of the ethanolamine phosphotransferase reaction. This effect disappears 12 min after the injection of the convulsant.

Effect of cytidine on the modification of phospholipid metabolism induced by ischemia.

[1-14C-]Arachidonic acid was injected into the lateral ventricle of the gerbils (meriones unguiculatus) two hours before producing brain ischemia by the bilateral ligation of the carotid arteries. Ten minutes before the carotid ligation a group of animals received an additional intraventricular injection of cold cytidine (2.5 mumol/brain). Control animals with and without cytidine, together with the ischemic group, were decapitated directly into liquid nitrogen ten minutes after carotid ligation or sham surgery. Cytidine is able to both stimulate arachidonic acid incorporation into lipids and noticeably correct the release of this acid from polar lipids induced by ischemia. Based on these findings, it is possible to assume that cytidine exerts an effect on the biosynthesis of phosphoglycerides as well as on their catabolic activities.