Oxidative stress related markers in the "VITA" and the centenarian projects.

Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.

Human post-mortem striatal alpha4beta2 nicotinic acetylcholine receptor density in schizophrenia and Parkinson's syndrome.

The density of nicotinic alpha4beta2 receptors, which are believed to largely mediate nicotine's effects, has been reported to be decreased in post-mortem hippocampus of patients with schizophrenia. In the present study, using [(3)H]cytisine as a radioligand, we observed a significant 30% decrease in post-mortem striatum of patients with schizophrenia (n=12) as compared to controls (n=12). A 25% decrease of striatal alpha4beta2 receptor density in patients with Parkinson's syndrome (n=12) was not significant. As an upregulation of alpha4beta2 receptors has been observed due to nicotine consumption, the beneficial effects of nicotine described in patients with schizophrenia may be partly due to a compensation for a decrease in alpha4beta2 nicotinic acetylcholine receptors.

Platelet monoamine oxidase B activity in dementia. A 4-year follow-up.

Platelet monoamine oxidase B (MAO-B) activity has been found to increase significantly in demented patients. For the first time, a 4-year follow-up of platelet MAO-B activity and Mini-Mental State (MMS) was performed in patients with probable dementia of the Alzheimer type (DAT) and age-matched controls. MAO-B activity of DAT patients increased significantly 2 years after the beginning of the study as compared with controls and remained significantly higher for the entire period of the examinations (p < 0.0001). The decrease of the MMS scores did not correlate with the time course of the increase of platelet MAO-B activity (Spearman rank correlation test). The decline of the MMS scores of DAT patients preceded the elevation of MAO-B activity. Since degenerative processes in brain areas which are responsible for cognitive function and are reflected by the MMS scores rather affect cerebral cholinergic than monoaminergic neurotransmitter systems, degeneration of the latter at late stages of DAT might be reflected by increased platelet MAO-B activity.

Blood transferrin and ferritin in Alzheimer's disease.

In the present study we found a significant correlation between severity of dementia of Alzheimer's type (DAT) and both transferrin and ferritin serum levels. Levels of transferrin in serum of 41 DAT patients tended to be lower than those of 19 age-matched controls, while levels of ferritin were not significantly different in DAT patients compared to controls. These results are interpreted in line with previous findings of higher brain ferritin and lower brain transferrin levels in DAT and are a circumstantial support for the oxygen radical hypothesis of degenerative brain disease.

Calculation abilities in dementia of Alzheimer's type and in vascular dementia.

Calculation abilities tested by 12 additive and 12 multiplicative tasks were investigated in 19 patients suffering from vascular dementia and in 23 patients suffering from dementia of Alzheimer's type as well as in 17 age-matched controls. Arithmetic impairment expressed by the number of correct results showed a significant correlation with the degree of dementia, measured by the Mini-Mental State Examination. An error type analysis was performed, but was of no help in the differential diagnosis of dementia. Calculation abilities are similarly impaired in both vascular dementia and dementia of Alzheimer's type.

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

Long-term levodopa treatment in Parkinson's disease is typically associated with "motor side effects" consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p = 0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p = 0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with > 50% substitution by bromocriptine exhibited half the risk observed in those with < 30% (p = 0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p = 0.046). In conclusion, partial substitution of levodopa by bromocriptine (> 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.

Therapeutic brain concentration of the NMDA receptor antagonist amantadine.

Amantadine (1-amino-adamantane) is clinically used for the management of Parkinson's disease and drug-induced extrapyramidal symptoms. It has previously been shown that amantadine is a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with rapid blocking and unblocking channel kinetics (Ki-value at the PCP binding site = 10 microM). The aim of the present studies was to estimate concentrations of amantadine in the central nervous system under therapeutic conditions. In homogenates of postmortem human brain tissue the amantadine concentration appeared to be homogeneously distributed over a wide range of brain areas. Amantadine concentration increased with duration of treatment and decreased wit drug-free time. When the duration of treatment was > or = 10 days and drug-free time < or = 3 days, mean amantadine concentrations in postmortem brain tissue ranged from 48.2 to 386 microM. In contrast to brain tissue, amantadine concentration in cerebrospinal fluid (CSF) and serum was in the low micromolar range ( < 17 microM). CSF and serum total values were highly correlated to each other and were always lower in CSF. The mean CSF/serum ratio for total amantadine was 0.76. To further estimate the extracellular concentration, amantadine was determined in microdialysates in the rat striatum. At behaviorally active doses, amantadine concentration in striatal microdialysates ranged between 6 and 21 microM. These results indicate that extracellular concentrations of amantadine (CSF and serum values in patients, striatal microdialysates in the rat) are in the range of its Ki-value at the PCP binding site. Amantadine concentrations in brain tissue are much higher, probably due to intralysosomal accumulation.

Twenty-five years of amantadine therapy in Parkinson's disease.

Until a few years ago, the anti-parkinsonian effect of amantadine hydrochloride (AHCl) and amantadine sulfate (AS) could not be explained. The beneficial effect of amantadine, which has been observed for a long time, may be connected with its site of action at the glutamatergic excitatory transmitter system, i.e. the N-methyl-D-aspartate receptor. A clear distinction can be made between AHCl and AS with regard to this pharmacokinetic profile. Therefore, AS can be administered in higher doses than AHCl and is thus more effective. A major advantage of AS is that it can also be given intravenously. Yet so far it is marketed only in twelve countries of the world. Intravenous infusions of AS permit the treatment of patients with aphagia during akinetic crises and when L-dopa and dopaminergic agonists are not tolerated in the akinetic terminal stage. Amantadine has the best ratio of therapeutic effects to side effects when compared with the other anti-parkinsonian drugs currently used. Long-term treatment with amantadine may have a considerable L-dopa saving effect. Given in higher doses, amantadine may permit a drastic reduction of L-dopa dosis and dopaminergic agonists so that the well known side effects of such drugs disappear. In addition, some authors assume a neuroprotective action of amantadine. Unlike L-dopa and dopaminergic agonists, AS does not produce hemiballism or dystonia.

Platelet monoamine oxidase B activity and vitamin B12 in dementia.

The activity of platelet monoamine oxidase B (MAO-B) was highly correlated with the severity of dementia in 39 patients suffering from probable dementia of the Alzheimer type and in 18 age-matched controls. There was no association between a low vitamin B12 level and high MAO-B activity in our sample of patients, who are living in a geriatric hospital where the balanced nutrition of inpatients is controlled by diet assistants.

Ideomotor apraxia in Alzheimer's disease.

Ideomotor apraxia, tested on verbal command and by imitation, was checked in 23 patients suffering from dementia of Alzheimer's type of different severity and in 17 age-matched controls. A significant deterioration of ideomotor praxis could be shown even in mild dementia. Correlations of ideomotor apraxia and aphasia, tested by the Token test were found to be significant.

Glutamatergic-dopaminergic balance in the brain. Its importance in motor disorders and schizophrenia.

Dopamine appears to be of less importance in the regulation of psychomotor functions than was previously thought. A central dopaminergic-glutamatergic balance may be important for both akinetic motor disorders and psychosis. In Parkinson's disease glutamate antagonists may counteract central glutamatergic hyperactivity and may be of value as anti-parkinsonian drugs. An increase of dopaminergic activity and/or a reduction of glutamatergic activity may contribute to the development of paranoid hallucinatory psychosis in schizophrenic patients and of pharmacotoxic psychosis in Parkinson's disease. Because of possibly severe side-effects of glutamatergic antagonists and agonists in the treatment of akinesia and psychosis, the development of partial glutamate agonists/antagonists could be an alternative strategy capable of producing antipsychotic or anti-kinetic effects with only mild adverse reaction.

Mental disorders in Parkinson's disease.

Certain psychiatric complications are associated with various stages of PD. The possible causes known to date are analysed. Depression, isolated cognitive impairments, pharmacotoxic psychosis and dementia-related changes are the predominant mental disorders in PD. PD and depression syndrome occur very frequently in old age. Behaviour and mimicry of patients with progressive PD and of patients with depression syndrome are sometimes so similar that the two conditions can be differentiated only by long-term monitoring. In addition, PD and depression may occur simultaneously. However, frequency and intensity of depressive phases do not differ in PD patients and aged-matched depressed patients without PD. About one third of patients hospitalized at the neurological department of the Geriatric Hospital Lainz require antidepressant drug treatment. Similar percentages were found for other chronic cerebral and extracerebral diseases in the aged. Major depressions are independent of the parkinsonian disability and can be successfully managed only by antidepressant medication. Pharmacotoxic psychoses are not only serious conditions, they also reveal the limitations of therapeutic options. The unusual frequency of such acute psychoses, i.e. 30 to 60% in the terminal stages of the disease, indicates a special relation between antiparkinson medication and increasing neurotransmitter disturbances. Permanent pronounced depression in the sense of DSM III is not one of the symptoms of typical PD. States of dementia occur only in connection with a second or third cerebral pathology, mostly in combination with SDAT and MID.

Synaptic pathology in Alzheimer's disease: immunological data for markers of synaptic and large dense-core vesicles.

We have analysed several markers for small synaptic vesicles (synaptin-synaptophysin, p65 and SV2) and large dense-core vesicles (chromogranin A, secretogranin II/chromogranin C) in the brains of patients with Alzheimer's disease, and normal controls by immunoblotting and immunohistochemistry. In comparison to age-matched controls the levels of all three synaptic vesicle markers were decreased in temporal cortex of Alzheimer patients. On the other hand, the levels of chromogranin A were increased, and those of secretogranin II lowered. This resulted in a significant increase of the ratios of chromogranin A to synaptophysin, p65 or SV2 and of that for chromogranin A to secretogranin II. These increases were significantly correlated to clinical severity of dementia and extent of neuropathological changes. By immunohistochemistry a high percentage of senile plaques was found to contain chromogranin A-reactive dystrophic neurites, whereas synaptophysin reactivity within plaques was rare. These results indicate that the number of synaptic vesicles is lowered in Alzheimer's disease, and that one component of large dense-core vesicles, i.e. chromogranin A, is elevated. We, thus, suggest that in Alzheimer's brain distinct changes occur for both types of synaptic organelles.

Release signs in Parkinson's disease with and without dementia.

Release signs have been described in both age-associated diseases and in the healthy elderly. We investigated the palmomental, snout, grasp, corneomandibular and glabellar reflexes in demented and non-demented Parkinson-patients compared to Alzheimer's disease and age-matched controls. The palmomental reflex and a persisting glabellar reflex were linked to parkinsonism irrespective of dementia and were found also in Alzheimer's disease. A corneomandibular reflex was observed more frequently in demented than non-demented Parkinson-patients and in Alzheimer's disease. The snout-reflex was present in nearly all individuals irrespective of diagnosis. Thus, various release signs react quite differentially to degenerative brain disease and dementia.

Bromocriptine lessens the incidence of mortality in L-dopa-treated parkinsonian patients: prado-study discontinued.

L-Dopa supplemented by a peripheral decarboxylase inhibitor is considered the most potent therapeutic regimen prolonging active life in Parkinsonian patients. The long-term benefit of therapy is limited by adverse effects, such as dyskinesia and on-off phenomena, which can be mitigated by the concomitant administration of dopamine agonists, such as bromocriptine. In order to quantify the beneficial impact of early combination therapy, a controlled clinical trial (PRADO: PRA videl1 + DO pa) in patients with early Parkinson's disease was carried out, whereby L-Dopa monotherapy (in a fixed combination with benserazide (DoBe) was being compared with the same combination plus bromocriptine (DoBeBro). Patients were recruited and treated by 101 practising neurologists in the Federal Republic of Germany and in Hungary. Twenty seven clinical university centers cross-checked the patients at regular intervals. The trial started with 3 months of DoBe monotherapy (median dose of 375 mg L-Dopa for both randomized groups) followed by gradual substitution of DoBe by bromocriptine over 3 months in one of the groups (250 mg L-Dopa/10 mg bromocriptine). The target medication was maintained from study months 6 to 54. Parkinsonian symptoms were classified according to the Webster rating scale, the Hoehn and Yahr scale and the Zung Self-Rating Depression Scale. Adverse events and life status were checked at regular intervals. Special emphasis was given to motor performance tests. 587 patients (302 in the DoBe group and 285 in the DoBeBro group) were available for intention-to-treat analysis. Both groups were homogeneous at baseline in all observed parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

[Differential diagnosis of dementia diseases. A prospective clinical study with neuropathologic diagnostic verification]. / Die Differentialdiagnose der Demenzerkrankungen. Eine prospektive klinische Untersuchung mit neuropathologischer Diagnosestellung.

We present clinico-pathological correlations for a consecutive series of 44 demented patients in the Vienna longitudinal study on dementia. Prospective clinical diagnosis used the DSM-III-R and the NINCDS-ADRDA criteria. Not only the clinical, but also the neuropathological diagnosis of DAT is based on exclusion criteria, and depends on the interpretation of minimal vascular lesions. Although we did not exclude atypical cases from the study, 80% of diagnoses could be validated at autopsy. Nevertheless, our set of clinical criteria needs further validation in patients in the earliest stages of dementia.

Prospective neuropathological validation of Hachinski's Ischaemic Score in dementias.

The sensitivity and specificity of Hachinski's Ischaemic Score (IS) in the diagnosis of the vascular aetiology of dementia was studied in a series of 32 demented patients, dementia of the Alzheimer type (16), multi-infarct dementia (7), mixed dementia (6), Pick's disease (3), with neuropathological diagnosis as the point of reference. The IS distinguished between primary degenerative dementia and multi-infarct or mixed dementia. As single features of the IS "a positive history of stroke" and "a fluctuating course" showed differing prevalences in the latter two diagnostic categories. The IS labelled 21% of patients with primary degenerative dementia as having a vascular aetiology. The uncritical application of the IS to large samples in epidemiological studies may cause incorrect labelling of a significant proportion of patients with primary degenerative dementia as vascular dementia. These results are based on observations of long-term inpatients and depend on neuropathological criteria. While the definite diagnosis of DAT by threshold criteria concerning plaque and tangle counts is well established, neither clinical nor pathological evidence of stroke necessarily means that cerebrovascular disease has anything to do with a patient's dementia.

[Alzheimer dementia. A clinical long-term study with quantitative neuropathology]. / Die Demenz vom Alzheimer-Typ. Eine klinische Längsschnittstudie mit quantitativer Neuropathologie.

Alzheimer's disease causes about 80% of dementias in old age. The pathological hallmarks of Alzheimer's disease are senile plaques (SP) and neurofibrillary tangles (NFT), which to a lesser degree can also be found in the brains of mentally intact elderly. The question whether SP or NFT or any other process are primarily correlated to severity of dementia can only be answered in prospective longitudinal clinical and neuropsychological studies with quantitative neuropathological investigation. We report the correlations between mini-mental-state scores and lesion counts in 3 isocortical and 3 hippocampal areas in a consecutive series of 19 Alzheimer's patients studied prospectively in the Vienna Longitudinal Study on Dementia. Lesion counts increased at very late stages of dementia and were rather low in mild to moderate severity of dementia. Mildly demented patients with very slow progression of dementia also had rather high lesion counts. Neurofibrillary changes in NFT and neuritic plaques were correlated with severity of dementia, but diffuse plaques, i.e. SP without neuritic degeneration, were not at all correlated with severity of dementia. We speculate that NFT and SP do not represent the primary process which leads to dementia.

Depression in dementia of the Alzheimer type and in multi-infarct dementia.

The authors used the Hamilton Rating Scale for Depression and a rating of depressed mood to investigate the prevalence of depression in 55 patients with Alzheimer's disease, 37 patients with multi-infarct dementia, and 30 nondemented comparison subjects. The prevalence of depressed mood depended on the severity of dementia as measured by the Mini-Mental State examination and was significantly lower among patients in more severe stages of Alzheimer's disease but not among patients with severe multi-infarct dementia.