M. Trabucchi

Hippocampal and entorhinal cortex atrophy in frontotemporal dementia and Alzheimer’s disease

Objective: To describe atrophic changes of the hippocampus and entorhinal cortex in frontotemporal dementia (FTD) and compare them with those of AD. Background: The medial temporal lobe shows atrophic changes early in the course of AD, but whether these changes are specific to AD or occur in other degenerative dementias, and to what extent, is unclear. Methods: The authors measured the volumes of the left and right hippocampus and entorhinal cortex from MR images (1.5 T, 2-mm–thick slices) in 12 patients with FTD, 30 with AD, and 30 elderly control subjects. Results: In FTD patients, the left and right hippocampus (16% and 21% tissue loss) and the entorhinal cortex (28% and 27% loss) were more atrophic than the control subjects. Atrophy of the hippocampus in FTD was less severe than in AD, but atrophy of the entorhinal cortex was equally severe. Greater hippocampal and entorhinal cortex atrophy was present in the most severe patients in both groups (as high as a 49% tissue loss). The sensitivity of the hippocampus and the entorhinal cortex to discriminate FTD patients from control subjects was low (49% and 52%, respectively; specificity set at 90%), whereas hippocampal volumes could better differentiate AD patients from control subjects (80% sensitivity). Conclusions: At variance with AD, detectable in vivo atrophy of the hippocampus might not be an early event in FTD. Differential patterns of atrophy might help in the diagnostic process of the degenerative dementias.

Dopamine receptors: Pharmacological and anatomical evidences indicate that two distinct dopamine receptor populations are present in rat striatum

(3H)-haloperidol and (3H)-spiroperidol binding studies after kainate injection into the striatum indicate the presence of dopamine receptive sites not located on post-synaptic membranes. The majority of these dopamine “receptors” which are not associated to an adenylate cyclase appear to be localized on terminals of cortico-striatal neurons. On the other hand sulpiride, an antipsychotic drug which increases striatal dopamine synthesis, does not inhibit dopamine-stimulated adenylate cyclase either in vitro or in vivo. However sulpiride stereospecifically displaces (3H)-haloperidol from striatal binding sites.

Procedural memory stimulation in Alzheimer's disease: impact of a training programme

The study evaluates the efficacy of a procedural memory stimulation programme in mild and mild‐moderate Alzheimers disease (AD). Twenty basic and instrumental activities of daily living have been selected, and divided into two groups, comparable for difficulty. Ten normal elderly subjects (age 68.0±4.8 years; MMSE score: 28.7±0.9; education: 7.6±3.5 years) were asked to perform the two groups of daily activities and the time required to perform the tasks of each group was recorded and used as a reference. Ten mild and mild‐moderate AD patients (age 77.2±5.3 years; MMSE score: 19.8±3.5; education: 7.3±4.7 years) without major behavioural disturbances constituted the experimental group. Patients were evaluated in all 20 daily activities and the time employed was recorded at baseline and after a 3‐week training (1 h/d, 5 d/week) period. Five patients were trained during the 3 weeks on half of the 20 daily activities and the other five patients were trained on the remainder. This procedure was adopted in order to detect separately the improvement in “trained” and “not trained” activities, allowing to control better the effects of the intervention. The assessment of the functional impact of the training was directly measured, through the variation of time employed to perform tasks before and after training. After 3 weeks of training a significant improvement was observed for the trained activities, from 3.6 to 1.9 standard deviations below the performance of the normal elderly controls (P<0.05). AD patients improved also in not‐trained activities from 3.5 to 2.7 standard deviations below the controls’performance (P<0.05). The rehabilitation of activities of daily living through developing procedural memory strategies may be effective in mild and mild‐moderate AD patients.

Cytosol protein kinase C downregulation in fibroblasts from Alzheimer's disease patients

We attempted to determine whether changes in protein kinase C (PKC) activity in Alzheimers disease (AD) brains are also present in cultured skin fibroblasts from living patients. Biopsies collected from shoulder skin were transferred to culture plates with an appropriate growth medium, and histone-directed PKC activity as well as phorbol ester binding were individually determined in soluble and particulate fractions prepared from AD and non-AD fibroblast cell lines. Binding experiments indicated that PKC was unevenly distributed between cytosol (78%) and particulate (22%). The Bmax values for phorbol ester binding in soluble and particulate fractions were similar in AD and non-AD patients. Kd values in the cytosol were 94% higher in AD patients, indicating lower affinity of the enzyme for the ligand. Accordingly, the soluble PKC activity was 30% lower in AD patients. The data suggest that the changes in PKC phosphorylating activity represent a diffuse cellular defect in AD and are not confined to the brain. The alterations of the enzyme may participate in the disregulation in processing of β-amyloid precursor protein in AD.

Chronic lead treatment differentially affects dopamine synthesis in various rat brain areas

The effect of chronic dietary lead exposure on brain nigrostriatal, mesolimbic and mesocortial systems was studied. The results show no modification of the dopamine receptors measured either as dopamine sensitive adenylate cyclase or as [3H]spiroperidol binding. On the other hand, dopamine synthesis seems to be reduced in striatum, unaffected in substantia nigra and increased in nucleus accumbens and in the frontal cortex. The increase of DA synthesis observed in some brain areas might be involved in determining the hyperactive behaviour that follows lead intoxication.

Age-related reduced affinity in [3H]nitrendipine labeling of brain voltage-dependent calcium channels

Literature data indicate a reduced calcium uptake in synaptosomes prepared from old rat brains. On this line, the present paper investigates the binding of ([3H]NDP) to brain synaptic membranes prepared from rats at different ages from birth up to 24 months of age. The binding is undetectable at birth but reaches within 9-18 day the values observed in adults [3H]NDP binding affinity and sensitivity to calcium were decreased in old rats (24 months). Tritiated dihydropyridines are believed to label voltage-dependent calcium channels (VDC). The observed age-related reduction in binding suggests that the characteristics of VDC in the aged brain may change.

Effect of chronic ethanol treatment on dopamine receptor subtypes in rat striatum.

Chronic exposure to ethanol (6% in the drinking water, 25 days) reduces the responsiveness of both the dopamine-stimulated and of the dopamine-inhibited adenylate cyclase in rat striatum. The changes in the adenylate cyclase activity are paralleled by alterations in dopamine recognition sites, in fact binding studies using selective ligands indicate that the number of both D1- and D2-receptors is reduced in striatal membranes of treated rats.

The aging brain: Protein phosphorylation as a target of changes in neuronal function

There is evidence that senescence affects neurotransmission at different levels. In particular, this review summarizes the studies on age-dependent modifications in protein phosphorylation, which represents the final pathway in the action of transmitters and hormones at neuronal level. Cyclic AMP-dependent protein kinase and protein kinase C have been reported to be modified during aging in various cerebral areas; the changes may involve either enzyme activity or substrate availability. These findings can be related to the alterations in neurotransmitter function and synaptic efficiency observed in the senescent brain. The activity of the other types of protein kinases (tyrosine-, cGMP-, calcium/calmodulin-dependent) during aging needs to be explored. An emerging point is the role of protein phosphorylation in the transfer of membrane signals to the nucleus, for the activation or disactivation of specific genes responsible for long-term neuronal events. Along this view, alterations in protein kinase pathway during senescence would ultimately affect gene expression, resulting in long term modifications of cell function. The reviewed literature opens the perspective of restoring some of the deficits associated with senescence by modulating protein phosphorylation pathway.

Ethanol metabolism and striatal dopamine turnover

In recent reports it has been indicated that acute and chronic ethanol treatments affect the central dopaminergic system. In particular, after acute ethanol administration it has been detected an increase of dopamine (DA) turnover measured as dihydroxyphenylacetic acid (DOPAC) content in rat corpus striatum. In order to verify the correlation between these neuronal events and the metabolism of ethanol, we measured striatal DA activity after different experimental manipulations of liver function. Ethanol metabolic rate has been stimulated by administering phenobarbital sodium, while liver ethanol metabolism was decreased with a subtotal hepatectomy. In these conditions we found a shift to the left of the time curve for DOPAC levels and a significant reduction of the peak of DOPAC increase respectively. In this paper we report that acetaldehyde induces modifications of the striatal DOPAC content, which become significant after a shorter latency period in comparison with the acute ethanol injection. Our data suggest the hypothesis that the neurochemical effects of ethanol may be mediated by the formation of specific metabolic products.

Chronic lead treatment induces in rat a specific and differential effect on dopamine receptors in different brain areas

There is now evidence that two classes of dopaminergic receptors are present in CNS of the rat: D1, associated, and D2, not associated with adenylate cyclase activity. Drugs which interact specifically with D2 receptor are more capable of antagonizing the hyperkinetic behavior induced by lead exposure in rat. They also have a beneficial effect in children with hyperkinetic disorders. We found that the dose (-)sulpiride which causes sedation is lower in lead intoxicated animals than in controls. On the contrary, haloperidol produces sedation with the same potency in lead-treated and in control rats. The reported behavioral effects were found to be correlated with biochemical changes. In fact, in lead exposed rats D2 receptors, measured by (-)-[3H]sulpiride stereospecific binding, are altered, while D1 receptors seem not to be affected. The alterations are different according to the area examined: D2 receptor function is increased in the striatum and decreased in the nucleus accumbens. The impairment of D2 receptor might explain the better capacity of substituted benzamides to improve the hyperkinetic behavior observed in lead exposed rats.