[Ischemic heart disease and vascular brain diseases viewed from historico-geographical standpoint].
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Cerebral Hemorrhage↗
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How proteomics reveals potential biomarkers in brain diseases.
The brain is complex, and so are the proteomics studies of brain tissue and its diseases, including Alzheimer's Disease, Parkinson's Disease and schizophrenia. In this review, general considerations and strategies of proteomics technologies, the advantages and challenges as well as the special needs for brain tissue are described and summarized. In addition, the results of the first studies are presented including a quality evaluation of the candidate proteins for these diseases. A paragraph is dedicated to the efforts of standardization in this field.
Animals↗
Global gene expression in a type 2 Gaucher disease brain.
Gaucher disease is a member of a family of inherited disorders called sphingolipidoses that among others includes Tay-Sachs and Sandhoff diseases. It is caused by the accumulation of glucosylceramide (glucocerebroside) due to deficient activity of the enzyme glucosylceramide-beta-glucosidase (glucocerebrosidase). As with other glycosphingolipidoses, severe neurodegeneration is present in types 2 and 3 Gaucher disease. We have used Serial Analysis of Gene Expression (SAGE) to characterize the gene expression profiles in brain of patients with glycosphingolipid storage diseases to understand the molecular details of neurodegeneration. In the current study we have determined the gene expression profile from the brain of a patient with type 2 Gaucher disease, the acute neuronopathic form of the disorder. We found that the expression profile of the type 2 Gaucher brain is significantly altered relative to the normal control brain profile. There were also differences when compared with profiles from Tay-Sachs and Sandhoff patients, in particular in levels of genes related to macrophage activation. Intriguingly we found that gamma-synuclein, a family member of proteins involved the pathogenesis of other neurodegenerative disorders, was elevated in the one Gaucher type 2 patient brain we examined.
Cerebral Cortex↗
Evidence for a membrane defect in Alzheimer disease brain.
To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.
Aged↗
Computed tomography in the diagnosis of degenerative brain disease.
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Atrophy↗
The microglial phagocytic role with specific plaque types in the Alzheimer disease brain.
Alzheimer disease (AD) involves glial inflammation associated with amyloid plaques. The role of the microglial cells in the AD brain is controversial, as it remains unclear if the microglia form the amyloid fibrils of plaques or react to them in a macrophage-phagocytic role. Also, it is not known why microglia are preferentially associated with some amyloid plaque types. This review will provide substantial evidence to support the phagocytic role of microglia in the brain as well as explain why microglia are generally associated with specific plaque types that may be explained through their unique mechanisms of formation. In summary, the data presented suggests that plaque associated microglial activation is typically subsequent to specific amyloid plaque formations in the AD brain.
Alzheimer Disease↗
Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases.
The blood-brain barrier (BBB) serves as a protective mechanism for the brain by preventing entry of potentially harmful substances from free access to the central nervous system (CNS). Tight junctions present between the brain microvessel endothelial cells form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the barrier properties of the brain capillary endothelial cells. Because of these properties, the BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrates for drug efflux transporters such as P-glycoprotein (Pgp), multidrug resistance proteins (MRPs) or organic anion transporting polypeptides (OATPs) that are expressed at brain capillary endothelial cells and/or astrocytic end-feet and are key elements of the molecular machinery that confers the special permeability properties to the BBB. The combined action of these carrier systems results in rapid efflux of xenobiotics from the CNS. The objective of this review is to summarize transporter characteristics (cellular localization, specificity, regulation, and potential inhibition) for drug efflux transport systems identified in the BBB and blood-cerebrospinal fluid (CSF) barrier. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on brain access of therapeutic drugs also are described and critically discussed. The potential impact of efflux transport on the pharmacodynamics of agents acting in the CNS is illustrated. Furthermore, the current knowledge about drug efflux transporters as a major determinant of multidrug resistance of brain diseases such as epilepsy is reviewed. Finally, we summarize strategies for modulating or by-passing drug efflux transporters at the BBB as novel therapeutic approaches to drug-resistant brain diseases.
Animals↗
The significance of determination of the fraction of creatinine-phosphokinase in patients with acute ischemic brain disease.
Heart and brain vascular diseases are the leading causes of mortality in the world. Cardiac complications can frequently occur during the development of cerebral ischemia. The aim of this study was to establish the possible changes in fractions of creatinine-phosphokinase as the sensitive laboratory index of parenchymal lesion of brain parenchyma and the presence/absence of risk factors for ischemic brain and heart disease. The study comprised 80 patients with acute ischemic brain disease (AIBD), without the history of previous coronary disease. Blood samples were taken in all patients within the first 48 hours from AIBD onset aiming to determine a total (muscular MM) and heart fraction of creatinine-phosphokinase (MB), and brain parenchyma ischemia was confirmed by CT or MR scan of the head. A detailed history of the risk factors for ischemic brain disease (IBD) and ischemic heart disease was taken from all patients with AIBD, and the profile of glycemia and lipid status were determined, and blood pressure was measured 6 times a day. Independent variables in statistical analysis were: age, degree of severity and the side of neurologic event, size of ischemic lesion and maximal values of systolic and dyastolic pressure. Dependent variables were the values of fractions of creatinine-phosphokinase (CPK). Control group (n = 40) comprised patients with neurologic diseases of non-vascular origin. All parameters as well as their interrelations were statistically analyzed. The results revealed significant correlation of the increased levels of CPK of MM and MB fraction with the size and place of ischemic lesion in the right cerebral hemisphere, which was highly significant for MB fraction in the total group of patients with AIBD, and for MM fraction, only for cases of more severe IBD. Highly significant increased values of those fractions were also observed compared to the control group of patients.
Acute Disease↗
Coping with illness after brain diseases--a comparison between patients with malignant brain tumors, stroke, Parkinson's disease and traumatic brain injury.
PURPOSE: This study investigates coping styles in patients suffering from different brain disorders (malignant brain tumors, stroke, Parkinson's disease and traumatic brain injury). METHOD: In a combined analysis of four prospective studies we investigated 21 patients with malignant glioma at the end radiochemotherapy, 30 patients one year after ischemic stroke, 54 patients suffering from various stages of Parkinson's disease, and 58 patients 6 to 8.5 months after traumatic brain injury. The assessment of coping with illness was based on the Freiburg Questionnaire on Coping with illness. RESULTS: With few exceptions, coping styles did not differ across the various brain pathologies. Differences occurred with respect to 'active, problem-oriented coping' (decreased in stroke patients), and coping by search for religious relief or quest for sense (increased in patients with Parkinson's disease). CONCLUSION: Differences in coping styles could be mainly related to age and social factors. Individual coping strategies seem only to be little related to the type of brain pathology.
Acute Disease↗
The influence of the degree of cerebral atherosclerosis on the changes in hemostatic system in patients with ischemic brain disease and atherosclerotic encephalopathy.
Vascular brain diseases are ranked the third as the cause of morbidity and mortality, in spite of the progress in diagnostic, therapeutic and preventive procedures. In the majority of cases of vascular brain diseases, it is ischemic brain disease, which is the final and the most severe stage of cerebral arteries atherosclerosis. Etiopathogenesis of atherosclerosis is not closer defined yet, but oxidative hypothesis is distinguished among the numerous theories. Within this theory, main place is attached to oxidative modification of LDL and Lp(a), together with numerous physiopathologic facts with the central role of reactive oxidative matters, where endothelial dysfunction is the main disorder responsible for the onset of numerous impairments, such as changes in coagulation-anticoagulation system. Considering these facts, it was established the hypothesis that in patients with IBD existed changes in hemostatic system, which were in positive correlation with the degree of cerebral atherosclerosis. The study comprised 36 patients with acute IBD and 28 patients with atherosclerotic encephalopathy. Control group was comprised of 30 patients with non-vascular diseases of similar characteristics. We investigated the correlation of the changes in hemostatic system (platelet aggregation, anti-thrombin III, D-dimer, protein C, factor VII, factor VIII, PAI-1) compared to the degree of cerebral atherosclerosis (ultrasonographically) and compared to the observed groups of patients. On the basis of all, the results of this study revealed significant increase of procoagulant factors concentration in patients with IBD, and similar changes were observed in patients with atherosclerotic encephalopathy, but less pronounced. All these changes in the total sample of patients, and particularly in patients with the pronounced cerebral atherosclerosis, are of primary and chronic character.
Acute Disease↗
GASTRODUODENAL ULCERS IN CHILDREN WITH BRAIN DISEASE.
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Autonomic Nervous System Diseases↗
Alzheimer's disease is a laminar, regional, and neural system specific disease, not a global brain disease.
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Aged↗
[Brain diseases, with special reference to brain neoplasms].
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Brain Diseases↗
Clinical predictors of cardiac complications in patients with acute ischemic brain disease.
Heart and brain vascular diseases present leading causes of death in civilized world. During development of brain ischemia cardiac complications are possible. The aim of this study was to determine the existence of cardiac complications' clinical predictors by assessing certain electrocardiographic changes in patients with acute ischemic brain disease (AIBD). Forty patients with AIBD, without previous coronary disease history were included in the study. All patients underwent 24 hour Holter monitoring during first 48 hours after the onset of AIBD which was diagnosed by computerized brain tomography. ECG-s were analyzed by computer and interpreted by the same cardiologist. Independent variables in statistical analyses were: age, AIBD, cardiological therapy atherosclerosis risk factors, heart disease history, degree of severity and lateralization of neurological incident and maximal arterial blood pressure values. Dependent variables were: presence/absence of ST depression and presence/absence of ventricular arrhythmias (VA). All parameters as well as their interreaction, were statistically analyzed. Results point that age and side of neurological incident present independent important predictive factors for appearance of ST depression, as well as simultaneous heart ischemia, while the same parameters have border value as predictive factors for VA.
Acute Disease↗
Muscle-eye-brain disease: clinical features, visual evoked potentials and brain imaging in 20 patients.
Clinical features, magnetic resonance imaging and visual evoked potentials were analysed and correlated in 20 Finnish patients with muscle-eye-brain disease. Significantly enhanced visual evoked potentials were found in 15 patients (giant in 14 of them). Magnetic resonance images were available in 17 cases. The images of 12 patients with giant visual evoked potentials showed typical brain malformation pachygyria with a nodular cortical surface i.e. cobblestone cortex, midline defect and hypoplastic pons but no significant abnormalities in the grey-white matter. One male had typical structural changes but flat visual evoked potentials. His extreme hydrocephalus with optic nerve compression may explain the findings. No structural changes on magnetic resonance images were found in the remaining four patients; however, in two of them marked alterations in the white matter were found. Three of these patients showed normal and one flat visual evoked potentials. Only one patient with giant visual evoked potentials and typical structural findings on magnetic resonance imaging had changes in a large area in the white matter (several attacks of status epilepticus might have caused the alterations in the white matter). Thus, the combination of giant visual evoked potentials and typical structural changes on magnetic resonance imaging with normal intensities of white matter and deep grey matter seems to be a good marker for patients with muscle-eye-brain disease.
Abnormalities, Multiple↗
A pool of beta-tubulin is hyperphosphorylated at serine residues in Alzheimer disease brain.
In Alzheimer disease (AD) brain, activities of protein phosphatase (PP)-2A/PP-1 which are known to be associated with microtubules are compromised and are probably a cause of neurofibrillary degeneration through hyperphosphorylation of microtubule proteins. In the present study, an increase of approximately 11 pmol phosphate/microg protein in 100,000 x g pellet from AD compared with age-matched control brains was found. Tau protein, which is hyperphosphorylated in AD can only account for approximately 4 pmol phosphate/microg protein, suggesting the presence of non-tau hyperphosphorylated proteins in the diseased brain. Western blot analysis with phosphoserine antibodies revealed a approximately 54 kDa non-tau protein to be significantly hyperphosphorylated in AD compared with age-matched control cases in the particulate fraction. The approximately 54 kDa protein was purified by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified as beta-tubulin by immunolabeling with specific antibodies, mass spectrometry analysis and by N-terminal amino acid sequencing. The purified protein was hyperphosphorylated at serine residues in AD.
Aged↗
Downregulation of myelination, energy, and translational genes in Menkes disease brain.
Menkes disease (MD) is an X-linked recessive neurodegenerative disorder caused by mutations in a copper-transporting p-type ATPase (ATP7A) that normally delivers copper to the central nervous system. The precise reasons for neurodegeneration in MD are poorly understood. We hypothesized that gene expression changes in a MD patient with a lethal ATP7A mutation would indicate pathophysiological cascades relevant to the effects of copper deficiency in the developing brain. To test this hypothesis, oligonucleotide probes for 12,000 genes arrayed on Affymetrix Human Genome U95 GeneChips were used for expression profiling of fluorescently labeled primary cRNAs from post-mortem cerebral cortex and cerebellum of a MD patient who died at 6 months of age and a normal control brain matched for age, gender, and race. Histopathologic analysis of the proband's brain showed preservation of neuronal integrity and no hypoxic effects. However, cerebrospinal fluid and brain copper levels were subnormal, and expression profiling identified over 350 known dysregulated genes. For a subset of genes (approximately 12%) analyzed by quantitative RT-PCR, the correct cross-validation rate was 88%. Thirty known genes were altered in both cortex and cerebellum. Downregulation of genes involved in myelination, energy metabolism, and translation was the major finding. The cerebellum was more sensitive to copper deficiency.
Brain↗
Caspase Activation in the Alzheimer's Disease Brain: Tortuous and Torturous.
Alzheimer's disease is characterized by the presence of neurofibrillary tangles and senile plaques. Although much is known about the molecular events leading to the formation of plaques and tangles as well as their relevance in neuronal cell loss associated with Alzheimer's disease, the link between these two pathologies is presently unknown. The exact mechanism of neuronal cell death in the Alzheimer's disease brain has been a debated issue with both the necrosis and apoptosis pathways having been implicated. The activation of apoptosis in the Alzheimer's disease brain has recently gained momentum, namely because of the development of specific markers for caspase activation. These markers consist of antibodies, termed caspase-cleavage site-directed antibodies that are designed to detect either the active enzymatic fragments of caspases following their activation or protein products targeted for caspase cleavage. The use of these markers has demonstrated the widespread activation of caspases in the Alzheimer's disease brain. In addition, many of these markers have been co-localized with markers for neurofibrillary tangles, suggesting that caspases may play a role in the formation of neurofibrillary tangles and, thus, do not simply represent end-stage events associated with Alzheimer's disease. In this review, recent studies documenting the role of caspases in the Alzheimer's disease brain will be discussed, along with the methodology behind the synthesis of site-directed caspase-cleavage antibodies. A model will be presented whereby caspases serve not simply as end-game players, but may actually serve as a link between senile plaques and neurofibrillary tangles. In this context, a discussion of the therapeutic value of targeting caspase inhibition in the treatment of Alzheimer's disease will be evaluated. (c) 2002 Prous Science. All rights reserved.
Journal Article↗