Acta neurologica Scandinavica. Supplementum最新文献

Intracerebral transplantation of immature neural tissue is a promising therapeutical approach that has the potential of restoring damaged neuronal circuitries and reversing functional deficits. The development of the technique as a human application has progressed the furthest in Parkinson's disease (PD), with the demonstration of significant longlasting functional improvements, in combination with evidence of surviving grafted tissue, using a fluorodopa positron emission tomography (PET) scanning technique in a few patients. Although the technique is promising, and the effects observed are significant and of clinical importance for the grafted patients in the best cases so far, there are still incomplete effects and no transplantation treatment is suggested since there are still several technical aspects that might further improve the outcome. The progress of the development in the field is briefly reviewed.

This review describes the neuropathology and pathophysiology of interneurons in dorsal hippocampus of the adult rat subjected to transient global cerebral ischemia. The object is to verify if the interneurons die or survive after an ischemic insult, and study if ischemia changes GABA inhibition in the period preceding delayed CA1 pyramidal cell death. The findings are discussed from the point of the hypothesis that loss of GABA inhibition may result in excitatory hyperactivity (possibly epilepsy) and excitotoxic glutamate release. Thereby, early ischemic damage to interneurons may exacerbate the ischemic process resulting in the major and delayed CA1 cell death in hippocampus. Interneurons, located in dentate hilus, and a small number of interneurons located in the mossy fiber layer are selectively lost after ischemia. These interneurons contain somatostatin and neuropeptide Y, but the inhibitory or excitatory nature of them is unknown. However, counts of all hippocampal cells immunoreactive for glutamic acid decarboxylase showed that the GABA interneurons survive ischemia. It is therefore suggested that the vulnerable interneurons in hilus and the mossy fiber layer do not contain GABA. As the GABA interneurons, other hippocampal interneurons also survive ischemia. Among these, the CA1 and CA3 interneurons containing neuropeptide Y demonstrate permanently reduced immunoreactivity for neuropeptide Y, evident 1-2 days after ischemia. Another subpopulation transiently shows a decrease in immunoreactivity for parvalbumin approximately 4 days after ischemia. These results are in contrast to the finding that protein synthesis in hippocampal interneurons returns to preischemic levels 9 hours after ischemia. The integrity between excitation and inhibition in CA1 is unchanged in hippocampal slices taken from animals 1-2 days after ischemia. Furthermore, GABA can readily be released upon potassium stimulation in the period preceding CA1 pyramidal cell death. Binding to hippocampal benzodiazepine sites, however, declines prior to ischemic CA1 pyramidal cell death. It is demonstrated that administration of diazepam and GABA uptake inhibitors during this period offers postischemic neuron protection in CA1. There is no conclusive evidence of excitatory hyperactivity preceding ischemic CA1 pyramidal cell death. On the contrary, results from Chang et al. (1) suggest that ischemic loss of interneurons in the dentate hilus is associated with an increase in inhibition. However, it is suggested that GABA inhibition is insufficient to counterbalance the detrimental process during normal or even reduced postischemic excitation, since drugs believed to increase GABA inhibition reduce ischemic cell death. The early and permanent reduction in neuropeptide Y immunoreactivity may reflect a reduced capacity of these interneurons to release neuropeptide Y and thereby reduce presynaptic glutamate release.(ABSTRACT TRUNCATED AT 400 WORDS)

This thesis concerns the epidemiology of Alzheimer's disease (AD) and some aspects of the validity of such studies. AD is a common and chronic dementing disorder among elderly people. Due to the lack of treatment and to the invalidating nature, the social impact of this disease is high in all the societies in which the proportion of elderly is increasing. Three studies on AD etiology have been performed. The first is a case-control study on early-onset AD and a wide range of putative risk factors. The cases were gathered from a clinical study on AD carried out in Italy. The information on the exposure obtained from a next-of-kin of 116 cases was compared with the information similarly collected from the next-of-kin of 116 hospital and 97 population controls. The other two etiological studies deal with late-onset AD and are a prevalence study on sociodemographic variables and a case-control study on selected putative risk factors. These two studies were performed within a population-based study on ageing and dementia that is ongoing in Stockholm, Sweden. The study on sociodemographic variables included 116 AD cases among 1810 people. The case-control study compared the information obtained by the informants of 98 AD cases and 266 controls. The main results of these three investigations are: (1) The prevalence of AD increases with age, even in advanced ages. (2) The prevalence of AD does not vary by gender and education. (3) The main risk factor for both early- and late-onset AD is the familial aggregation of dementia (relative risk of 2.6 and 3.2, respectively). (4) A second risk factor for early-onset AD may be the advanced age of the mother at index delivery, but this result needs confirmation. No other risk factors reported by others emerged in our study. (5) High relative risks were found for alcohol consumption and manual work in late-onset AD. Manual work could be an indicator of occupational exposures as well as life conditions or life habits. Although both these results may be affected by bias, the results are provocative for future research. Three validation studies were carried out on three different aspects: diagnosis, case ascertainment, and exposure assessment. The first study investigated the reproducibility of AD diagnosis according to the DSM-III-R diagnostic criteria. The diagnoses made by the examining physicians were compared with the diagnosis made independently by another clinician on the subjects' clinical records.(ABSTRACT TRUNCATED AT 400 WORDS)

In order to supplement the deficient catecholamine neurotransmitters, dopamine and noradrenaline, in parkinsonian brains, the following strategies have been tried: (1) the precursor amino acids, L-DOPA and L-threo-dihydroxyphenylserine (DOPS), (2) 6R-L-erythro-tetrahydrobiopterin (BPH4) as tyrosine hydroxylase (TH) cofactor and nicotinamide adenine dinucleotide (NADH) as cofactor of dihydropteridine reductase to stimulate TH, (3) brain transplant of TH-containing cells, (4) inhibitors of monoamine oxidase (MAO) and/or catechol O-methyltransferase (COMT) with or without L-DOPA or L-DOPS, and (5) dopamine receptor agonists. Among these strategies, the precursor, L-DOPA, L-DOPS, MAO and COMT inhibitors, and dopamine receptor agonists have proved to be clinically effective. As a new strategy, increase in deficient TH activity has been tried experimentally and clinically either by stimulation of residual TH activity by the cofactors, BPH4 or NADH, or by brain transplant of natural TH-containing cells (fetal substantia nigra) or genetically engineered TH-containing cells.

The findings three decades ago that the symptoms of Parkinson's disease were related to a deficiency of striatal dopamine and that they were reversible by the administration of levodopa heralded a new era of investigative interest in this disorder. Since then, there has been steady progress towards a better understanding of the nature of Parkinson's disease. The breadth of the clinical entity as regards its phenomenology and natural history have been more fully defined, new concepts regarding its etiology and early detection have been suggested and numerous approaches to treatment developed. In the main, therapy has been directed towards control of symptoms, but recent attempts at halting the inevitable progression have been developed. This presentation critically reviews these various aspects of Parkinson's disease.

A short period of cerebral ischemia leads to necrosis of the hippocampal CA1 pyramidal cells. Until recently no mechanisms contributing to this selective vulnerability were known. During the last decade an increasing amount of research has been concentrated on identifying signs of disturbed signal transduction in these neurons after ischemia. The present thesis is a review of these studies with some emphasis on my own contributions to the field. Gerbil and rat models of transient global ischemia are the most frequently employed. In order to produce the selective necrosis the main arteries to the brain are occluded for 5-20 minutes. In the rat it is often also necessary to lower the blood pressure. It takes 2-7 days of recirculation before the CA1 pyramidal cells become necrotic. The studies show that the necrosis can be attenuated or aggravated by drugs acting as inhibitors or enhancers of signal transduction--also if administered shortly after ischemia. The necrosis can be similarly influenced by lesions of excitatory or inhibitory afferent neurons. The protective effect of the lesion however, can be due to the lesion-induced decrease in metabolism. During ischemia there is an increase in the extracellular concentration of several excitatory and inhibitory neurotransmitters as well as in intracellular second messengers. Some of the latter also show an increase during recirculation. In vitro autoradiographic studies of receptor proteins show either unchanged or diffusely distributed downregulation of the ligand binding to the various extra- and intracellular receptor proteins following ischemia and early recirculation. A second decrease is seen in the CA1 at the time of and probably secondary to the necrosis. The IP3 receptor decrease appears during the first minutes of recirculation and lasts for up to 14 days. The protective lesion of the excitatory afferents from CA3 also leads to a decrease in IP3 binding. The changes in receptor regulation are not accompanied by increased postischemic electrophysiological activity in the CA1. In vivo autoradiographic mapping of the regional cerebral metabolic rate of glucose show increased metabolism in the CA1 during the first hour of recirculation compared to the rest of the brain were it is depressed. This relative hypermetabolism is not seen if the CA1 has been deprived of its primary source of excitatory afferents. A later secondary increase seen in the more or less necrotic CA1 pyramidal cell layer is probably due to macrophage activity. In situ hybridization and immunohistochemical studies on the expression of c-fos mRNA and protein respectively has been used to depict neurons with increased activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Normal function of the central nervous system (CNS) requires intact morphology as well as neurotransmission. Diseases of the CNS can become manifest as a sensorimotor deficit or psychic alteration, or both. When observing neuropsychiatric diseases, interaction of different transmitter systems is obvious. Thus, an increase or a decrease of transmitter systems affect each other. Mechanisms of compensation can also lead to alterations in transmitter systems not involved in the pathological process. Parkinson's disease, hyperkinetic movement disorders like ballism and Huntington's chorea, epilepsy and anxiety will be used in this paper as examples of the synergistic action of dopaminergic, peptidergic, glutamatergic, GABAergic and cholinergic neurotransmission. With our knowledge of the functional balance of transmitter systems in the CNS, various pharmacological strategies have been available to intervene in the pathophysiological process. The excitatory or inhibitory quality of the transmitter systems must be considered if such strategies are to be employed. On the other hand, a functional balance between two or more transmitter systems may cause a contrary therapeutic intervention on the opposite side of the balance.

The last decades have been characterized by impressive research activity in connection with Parkinson's disease (PD). A wealth of new results have enriched our knowledge of the pathophysiology of the disorder and led to new approaches for its therapy. Whereas anticholinergic drugs remained the main, though unsatisfactory, treatment of PD for almost 100 years, the situation has changed since the 1960s. An impetus for this turning-point was given by the finding that the striatum of rats contained a high concentration of dopamine (DA) which until then had been considered to be a mere intermediate of the biosynthesis of noradrenaline and adrenaline, without a physiological role in its own right. Subsequently, the role of dopamine as neurotransmitter and the importance of dopaminergic pathways for the control of extrapyramidal motricity were firmly established. As a consequence, new therapeutic possibilities emerged and the anticholinergic drugs, although still in use, lost their supremacy. The present minireview will be restricted to new treatments which have been developed and introduced since 1960 and to recent pharmacotherapeutic approaches with potential future usefulness.