Journal of Neural Transmission - Parkinson's Disease and Dementia Section最新文献

Parkinsonians with predominantly unilateral signs provide an interesting experimental means to evaluate if asymmetric nigro-striatal degeneration may affect neuropsychological functions. The aim of our study was to establish if the side of onset of idiopathic Parkinson's disease, right (PDR) or left (PDL), determines a selective pattern of cognitive performances. Furthermore, we verified if PDR and PDL groups show a different frequency of dementia. PDR and PDL patients with at least seven years of disease duration, matched for age, schooling, severity of extrapyramidal symptomatology and index of lateralization, were evaluated by using an extensive neuropsychological battery aimed at assessing hemispheric cognitive asymmetries. Current side of greater motor impairment was the same as the one affected at the onset of the disease. Only subtle differences in the profile of neuropsychological dysfunction emerged from the comparison of PDR and PDL subjects. Moreover, the number of parkinsonians showing dementia syndrome was the same in both groups. Our results suggest that the side of onset of motor impairment does not significantly influence the cognitive performances in PD. Subcortical anatomic and/or functional asymmetries seem to play a less important role in the intellectual functions than in motor activities.

Seven patients with idiopathic Parkinson's disease were enrolled in a ten week study to evaluate the efficacy of famotidine, an histamine H2-antagonist, in the treatment of bradyphrenia. Patients received famotidine 80 mg/day for a period of six weeks and were evaluated with neuropsychological tests. Overall, patients demonstrated improvement in variables measured. Some patients also reported an improvement in their motor symptoms.

We investigated the effect of neurotrophic factors on dopamine (DA) cells in vitro. At concentrations of nanograms/c.c. basic fibroblast growth factor (bFGF) is a more potent DA-trophic agent than brain derived neurotrophic factor (BDNF) or epidermal growth factor (EGF) in fetal mid brain neurons. In these cells, bFGF produces a greater increase of DA levels and percentage of cells positive for tyrosine hydroxylase (TH+) than BDNF and EGF. Acidic fibroblast growth factor (aFGF) was not tested in fetal DA cells since aFGF requires heparin for its effect and fetal mid brain cultures do not grow well in the presence of a high concentration of heparin. We further investigated the effect of bFGF and aFGF, and two of their analogs, in catecholamine rich human neuroblastoma cells NB69. In these cells aFGF, at concentrations of picograms/c.c., increases DA levels, while its analogs, E118 and super short, have no effect. Acidic FGF also increases norepinephrine levels, the number of TH+ cells, and the percentage of TH+ with respect to the total number of nuclei. Basic fibroblast growth factor (bFGF) produced similar, but less potent effects. Acidic FGF was active only in the presence of heparin; the effect of bFGF was independent of heparin. FGFs are promising drugs for the treatment of PD, though further investigations with these compounds should be performed before their use in clinical trials.

Though depletion of CSF homovanillic acid (HVA) concentration has often been regarded as a direct indicator of dopamine (DA) deficiency in Parkinson's Disease (PD), CSF HVA is normal in mildly affected patients. To explore why, we measured DA and its metabolites in striatum and CSF in rabbits receiving reserpine for 5 days. Reserpine, which depletes striatal DA by disrupting vesicular storage of the neurotransmitter, results in a compensatory increase of DA turnover. In response to a 96% depletion of striatal DA, its catabolic intermediates 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) decreased 64% and 92% in striatum, although the endproduct, HVA, was unchanged. In contrast, CSF concentrations of HVA and DOPAC increased significantly, though 3-MT and levodopa (LD) were unaltered. A 5-fold rise in striatal LD concentration after reserpine-induced DA depletion provided evidence for enhanced DA synthesis. As in PD, the compensatory increase of DA synthesis after reserpine administration confounds the ability of CSF HVA to reflect DA depletion.

We have characterised the muscarinic receptor subtypes found in human skin fibroblasts and compared binding levels in cell lines from members of the Alzheimer's disease family with the Swedish amyloid precursor protein (APP) 670/671 mutation. Binding studies with [3H] quinuclidinyl benzilate ([3H]QNB) and the M2/M4 selective antagonist [3H] (+/-)-5,11-dihydro-11-([(2-[(di-propylamino)methyl]-1- piperidinyl]ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)benzodiazepine-6- one ([3H]AF-DX 384) revealed the presence of a single population of muscarinic receptors on lysed fibroblast membranes. [3H]QNB binding was displaced by a number of selective muscarinic ligands with a rank order of potency: atropine > himbacine > methoctramine > (+/-)-p-fluoro-hexahydro-sila-difenidol hydrochloride > pirenzepine > muscarinic-toxin-3. APP 670/671 mutation carrying cell lines showed 25-35% lower levels of muscarinic receptors labelled with [3H]QNB, [3H]N-methyl scopolamine and [3H]AF-DX 384, compared to controls. This difference was not statistically significant due to large individual variation. It is concluded that muscarinic receptors on adult skin fibroblasts are predominantly of the M2 subtype. Since these cells do not possess M1 and M3 receptor subtypes, they are unlikely to provide a good model for studying muscarinic receptor regulation of APP processing.

We studied changes in the concentrations of serotonin (5-HT), kynurenine, and other indoleamines in the cerebrospinal fluid of patients with Alzheimer type dementia (ATD) and those with Binswanger type vascular dementia (VDBT), and changes in these indoleamine concentrations 2 weeks after administration of citalopram, a 5-HT uptake inhibitor. The concentrations of total 5-HT (p < 0.005) and kynurenine (p < 0.005) were significantly decreased in ATD patients in comparison to those of the controls. After citalopram administration, there was a remarkable increase in 5-HT concentration (249%, p < 0.0001) and a significant decrease in 5-HIAA concentration (22%, p < 0.02). In the VDBT patients, only 5-HT showed a significant decrease (p < 0.005) in comparison to the control values. It also increased significantly (214%) after citalopram administration. The 5-HT/tryptophan and kynurenine/tryptophan ratios were not correlated for the controls, but did significantly for the ATD and VDBT patients; after citalopram treatment, the increase in 5-HT/tryptophan was correlated significantly with that of kynurenine/tryptophan for ATD, but not for VDBT. These results suggest that both the serotonin and kynurenine pathways are impaired in ATD; whereas, the serotonin pathway alone is in VDBT, and that these impairments are ameliorated by the administration of citalopram.

Alzheimer's disease (AD) is a heterogeneous entity. Identifying AD subtypes might have impact in patients' response to different treatment strategies. We designed a study to examine regional cerebral blood flow (rCBF) in AD subtypes. To identify AD subtypes, we performed a cluster analysis including performance on memory, language, visuospatial, praxic, and executive functions. The rCBF measured by 99mTc-HMPAO SPECT was referred to the cerebellum. We examined 35 patients fulfilling the NINCDS-ADRDA criteria of probable AD and 13 age and sex-matched healthy cognitively intact controls. AD patients were at the early stage of the disease, their mean Mini-Mental Status (MMS) score (S.D.) was 22.5 (3.6). The cluster analysis revealed two AD subgroups: AD1 (N = 12) and AD2 (N = 23). The subgroups did not differ in age, sex, or global clinical severity as assessed by MMS and Brief Cognitive Rating Scale (BCRS). Both subgroups had equally impaired memory. The AD2 group was inferior to the AD1 group on verbal, visuospatial, praxic, and executive functions. The AD1 group showed reduced rCBF ratios in the temporal and parietal cortices and the amygdala compared to controls. The AD2 group differed from controls in the rCBF ratios of frontal, temporal, parietal, occipital, basal ganglia, and amygdaloid regions bilateral and from AD1 in the rCBF ratios of frontal and temporal cortices. In AD patients, the rCBF ratios did not correlate with MMS or BCRS scores. In contrast, several significant correlations were found between decreases rCBF ratios and impairment of memory and other cognitive functions. In conclusion, a cluster analysis on neuropsychological test performance identified two AD subgroups that differed on the neuropsychological profile and on the rCBF in spite of similar global clinical severity.

The present study shows that low amounts of applied iron have a potent effect on the ventrolateral striatum. This is reflected by an influence on spontaneous night activity, cognitive behaviour during the water maze navigation task, exploratory activity and in response to postsynaptic apomorphine stimulation. Such functional disturbances could be observed up to months after a single application of either 0.3 microgram or 1.5 micrograms FeCl3. The low dose of iron stimulates while 1.5 micrograms inhibits the spontaneous dopaminedependent locomotor night and explorative activity. The low concentration of ionic iron injected intrastriatally also increases lipid peroxidation in striatal and hippocampal tissues. These results suggest that the functional integrity of the ventral striatum and the regulation of the iron metabolism are critical for the sensorimotor performance.

Amantadine has been shown to displace [3H]MK 801 from its binding site on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24 h reserpine-treated mice to determine whether the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amantadine (5-40 mg/kg IP) produced a modest dose-dependent sedation in dopamine-intact mice, with a reduction in locomotion and other species-typical behaviours (e.g. rearing and grooming), but with no signs of the hyperactivity, stereotypy, ataxia or loss of muscle tone commonly seen with MK 801. Amantadine (5-80 mg/kg IP) effected a small increase in motility in akinetic reserpine-treated mice by itself, but this response was highly variable and not statistically significant. As with MK 801, amantadine significantly inhibited the locomotion induced by the selective D2 agonist RU 24213 (5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.5 mg/kg SC) in monomine-depleted mice, without altering the animals' responsiveness to threshold doses of these drugs. However, amantadine did not facilitate the locomotion induced by threshold (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D1 agonist SKF 38393, which distinguishes amantadine from other NMDA receptor blockers. Since the potentiation of dopamine D1-dependent locomotion may be a major factor in the antiparkinson activity of MK 801 and other glutamate receptor antagonists, the inability of amantadine to potentiate SKF 38393 in this study suggests the mechanism of its anti-akinetic activity differs from that of conventional glutamate blocking drugs.

Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nevertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism under basal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the "cheese effect" such as Ro 41-1049 are comparable to the irreversible MAO-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.