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PubMed1994

A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis: implications for treatment of inflammatory brain disease.

Glucocorticoid (GCC) therapy usually inhibits inflammatory diseases, but certain regimens can trigger relapses. Clinical use of steroids is not uniform and in some instances may be dangerous. In the present study, GCCs modified the course of experimental allergic encephalomyelitis (EAE) in Lewis rats, a model of inflammatory CNS disease. Continuous treatment with dexamethasone (DEX) completely blocked EAE. RU 486, a GCC antagonist, counteracted the effects of endogenous GCCs and worsened EAE. Sudden withdrawal of DEX also caused severe clinical and histologic exacerbations at a time when paired saline-treated animals had completely recovered. In rats that had complete clinical recovery from EAE, and would not have relapsed without this acute steroid deficit, a short pulse of DEX was followed by severe exacerbations. In contrast, a slow steroid taper prevented exacerbations. Abrupt discontinuation of GCCs provokes inflammatory brain disease.

Animals↗
PubMed2006

Aneuploidy in the normal and diseased brain.

The brain is remarkable for its complex organization and functions, which have been historically assumed to arise from cells with identical genomes. However, recent studies have shown that the brain is in fact a complex genetic mosaic of aneuploid and euploid cells. The precise function of neural aneuploidy and mosaicism are currently being examined on multiple fronts that include contributions to cellular diversity, cellular signaling and diseases of the central nervous system (CNS). Constitutive aneuploidy in genetic diseases has proven roles in brain dysfunction, as observed in Down syndrome (trisomy 21) and mosaic variegated aneuploidy. The existence of aneuploid cells within normal individuals raises the possibility that these cells might have distinct functions in the normal and diseased brain, the latter contributing to sporadic CNS disorders including cancer. Here we review what is known about neural aneuploidy, and offer speculations on its role in diseases of the brain.

Alzheimer Disease↗
PubMed2006

Age- and stage-dependent glyoxalase I expression and its activity in normal and Alzheimer's disease brains.

The reaction of lysine and arginine residues of proteins with 1,2-dicarbonyl compounds result in the formation of advanced glycation end products (AGEs). Accumulation of AGEs is a characteristic feature of the aging brain and contributes to the development of neurodegenerative diseases such as Alzheimer's disease (AD). Therefore, it is of particular interest to study the cellular defense mechanisms against AGE formation and particularly the detoxification of their precursors. AGE precursor compounds such as methylglyoxal and glyoxal were cellulary detoxified by the glyoxalase system, consisting of glyoxalases I and II. Glyoxalase I levels are diminished in old aged brains but elevated in AD brains. However, it is still unknown how glyoxalase I level of AD brains changes in a disease and in an age-dependent manner. Therefore, we investigated the AD stage- and the age-dependent levels of glyoxalase I in the Brodmann area 22 of AD brains (n=25) and healthy controls (n=10). Our results obtained from RT-PCR reveal reducing glyoxalase I RNA levels with advancing stage of AD and with increasing age. Western Blot analysis indicates that in comparison to healthy controls, glyoxalase I protein amounts are 1.5-fold increased in early AD subjects and continuously decrease in middle and late stages of AD. The glyoxalase I protein amounts of AD patients also decrease with age. Results obtained from glyoxalase I activity measurement show 1.05-1.2-fold diminished levels in AD brains compared to healthy controls and no significant decrease neither with the stage of AD nor with age. The immunohistochemical investigations demonstrate an elevated number of glyoxalase I stained neurons in brains of early and middle but not in late AD subjects compared to age-matched healthy controls. In addition, the stage-dependent immunohistochemical investigation demonstrates that with reduced glyoxalase I staining AGE deposits prevail, specifically in late stage of AD. In conclusion, the decrease of glyoxalase I expression with increasing AD stage might be one reason for methylglyoxal-induced neuronal impairment, apoptosis, and AGE formation in plaques and tangles.

Aged↗
PubMed1991

The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein.

We have purified and characterized the growth inhibitory factor (GIF) that is abundant in the normal human brain, but greatly reduced in the Alzheimer's disease (AD) brain. GIF inhibited survival and neurite formation of cortical neurons in vitro. Purified GIF is a 68 amino acid small protein, and its amino acid sequence is 70% identical to that of human metallothionein II with a 1 amino acid insert and a unique 6 amino acid insert in the NH2-terminal and the COOH-terminal portions, respectively. The antibodies to the unique sequence of GIF revealed a distinct subset of astrocytes in the gray matter that appears to be closely associated with neuronal perikarya and dendrites. In the AD cortex, the number of GIF-positive astrocytes was drastically reduced, suggesting that GIF is down-regulated in the subset of astrocytes during AD.

Aged↗
PubMed2003

Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains.

The endocannabinoid system is still poorly understood. Recently, the basic elements that constitute it, i.e., membrane receptors, endogenous ligands, and mechanisms for termination of the signaling process, have been partially characterized. There is a considerable lack of information, however, concerning the distribution, concentration, and function of those components in the human body, particularly during pathological events. We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1 and CB2 receptors, in postmortem brains from patients with Alzheimer's disease. Using specific polyclonal antibodies, we have performed immunohistochemical analysis in hippocampus and entorhinal cortex sections from brains of Alzheimer's disease patients. Our results show that both fatty acid amide hydrolase and cannabinoid CB2 receptors are abundantly and selectively expressed in neuritic plaque-associated astrocytes and microglia, respectively, whereas the expression of CB1 receptors remains unchanged. In addition, the hydrolase activity seems to be elevated in the plaques and surrounding areas. Thus, some elements of the endocannabinoid system may be postulated as possible modulators of the inflammatory response associated with this neurodegenerative process and as possible targets for new therapeutic approaches.

Aged↗
PubMed1998

Levels of tau phosphorylation at different sites in Alzheimer disease brain.

The microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) brain. To date, 21 phosphorylated sites of tau have been identified. In the present study the levels of phosphorylation at Ser199/Ser202, Thr231/Ser235, Ser262/Ser356 and Ser396/Ser404 of tau in AD brain homogenate and its 100,000 x g supernatant were determined using radioimmuno-dot-blot assay. In homogenate, Ser199/Ser202 and Ser262/Ser356 were phosphorylated to similar level and were more phosphorylated than Thr231 or Ser396/Ser404. In supernatant, there was no significant difference in phosphorylated tau level among the investigated sites except for Thr231/Ser235 which was least phosphorylated. These results suggest that Ser199/Ser202 and Ser262/Ser356 are major sites of phosphorylation of tau in AD brain.

Aged↗
PubMed2001

Neuronal and glial advanced glycation end product [Nepsilon-(carboxymethyl)lysine]] in Alzheimer's disease brains.

The cellular distribution of an advanced glycation end product [Nepsilon-(carboxymethyl)lysine (CML)] in aged and Alzheimer's disease (AD) brains was assessed immunohistochemically. CML was localized in the cytoplasm of neurons, astrocytes, and microglia in both aged and AD brains. Glial deposition was far more marked in AD brains than in aged brains, and neuronal deposition was also increased. On electron microscopic immunohistochemistry, neuronal CML formed granular or linear deposits associated with lipofuscin, and glial deposits formed lines around the vacuoles. Neuronal and glial deposits were prominent throughout the cerebral cortex and hippocampus, but were sparse in the putamen, globus pallidus, substantia nigra, and cerebellum, with glial deposits being far more prominent in AD brains. The distribution of neuronal and glial deposits did not correspond with the distribution of AD pathology. The extent of CML deposits was inversely correlated with neurofibrillary tangle formation, particularly in the hippocampus. Most hippocampal pyramidal neurons with neurofibrillary tangles did not have CML, and most of the neurons with heavy CML deposits did not have neurofibrillary tangles. In the hippocampus, neuronal CML was prominent in the region where neuronal loss was mild. These observations suggest that CML deposition does not directly cause neurofibrillary tangle formation or neuronal loss in AD.

Aged↗
PubMed1994

Plaque-associated neuronal proteins: a recurrent motif in neuritic amyloid deposits throughout diverse cortical areas of the Alzheimer's disease brain.

Diffuse and neuritic plaques are sites of accumulation of beta-amyloid peptides (A beta) in the brains of Alzheimer's disease (AD) patients. Although amyloid fibrils are formed from A beta, the contribution of other plaque-associated proteins and peptides to the pathogenesis of AD amyloidosis is unknown. To pursue this issue, we sought to identify proteins and peptides that were consistently associated with neuritic plaques in six different cortical areas of AD and control brains. We accomplished this by using quantitative, single and double label immunohistochemistry and a panel of antibodies to proteins or peptides that are known to be associated with neuritic plaques in the AD hippocampus. Our data showed that the molecular composition of neuritic plaques in association, limbic, sensory, and motor cortex was similar regardless of the type of cortex in which they were found or the apolipoprotein E genotype of the patient. Further, proteins and peptides associated with neuritic plaques in the cortical areas of the AD brain studied here were similar to those found in neuritic plaques of the AD hippocampus. Specifically, in addition to A beta 1-40 and A beta 1-42, these plaques contained immunoreactivity for other domains in A beta precursor proteins, neurofilament and tau proteins, as well as phosphotyrosine residues. We conclude that the recurrent association of a distinct group of neuronal and other proteins and peptides with neuritic plaques suggests that these plaque-associated components play a mechanistic role in the pathogenesis of amyloidosis in AD.

Aged↗
PubMed1991

Na+/Ca2+ exchange activity is increased in Alzheimer's disease brain tissues.

These studies were performed to determine the changes that occur in Na+/Ca2+ exchange activity in Alzheimer's disease (AD) brain tissues. Cerebral plasma membrane vesicles were purified by sucrose density gradient centrifugation from frozen postmortem hippocampal/temporal cortex tissue slices derived from age matched brains of normal, AD and non-Alzheimer dementia (NAD) origin (autopsy confirmed). Membrane marker assays (Na/K ATPase, muscarinic receptor, cytochrome c oxidase) revealed no change in membrane purity across different preparations. Thin-section electron microscopy revealed predominantly intact unilamellar vesicles. Vesicles were preincubated for 15 min (37 degrees C) in buffer containing 132 mM NaCl, 5 mM KCl, 1.3 mM MgCl2, 10 mM glucose and 10 mM HEPES (pH 7.4). Ca2+ uptake was initiated by diluting vesicles 20-fold with buffer containing either 132 mM NaCl or 132 mM choline chloride and 45CaCl2 then terminated by addition of 200 microM LaCl3 and rapid filtration. Ca2+ content increased rapidly at first and then maintained a steady plateau for up to 5 min. When the Ca2+ ionophore A23187 (10 microM) with 100 microM EGTA was added after 4 min, Ca2+ content was reduced to 10% of its original value. Ruthenium red (10 microM) had no effect on Ca2+ content. Na(+)-dependent Ca2+ uptake (Ca2+ content measured in choline chloride minus that measured in NaCl) was increased in AD brains as evidenced by both an increase in the initial rise in Ca2+ content and in elevated values of peak plateau Ca2+ content.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Neurotransmitter receptor/G-protein mediated signal transduction in Alzheimer's disease brain.

Recent evidence suggests that the neurochemical pathology of Alzheimer's disease includes severe disruptions of the neurotransmitter receptor/G-protein mediated phosphatidylinositol hydrolysis and adenylyl cyclase signal transduction pathways. The present article briefly reviews evidence from postmortem studies describing disruptions to these systems and speculates as to the importance of these changes in terms of contributing to disease pathology and limiting the success of neurotransmitter replacement strategies.

Alzheimer Disease↗
PubMed1996

Assessment of protein kinase C mRNA levels in Alzheimer's disease brains.

We have previously demonstrated that the protein level of type beta protein kinase C (PKC) was significantly reduced in Alzheimer's disease (AD) brains compared to controls. To clarify whether this is due to decreased synthesis and/or increased degradation of PKC, the present study was performed to examine mRNA levels of PKC isozymes in control and AD brains. The present study indicated that mRNA levels of types alpha, beta and gamma PKC were not significantly changed in the control and AD brains. Thus, the reduction of type beta PKC protein content in AD brains might be caused by increased degradation.

Aged↗
PubMedDate not supplied

[Electrometric method of studying taste in brain diseases].

Disorders of the sense of taste were studied in 355 patients with craniocerebral pathology, among whom 70 had tumors of the acoustic nerve, 64 had a craniocerebral trauma, 60 had tumors of the cerebral hemispheres. The most coarse disorders with the loss of the sense of taste on the anterior 2/3 of the tongue were encountered in tumors of the acoustic nerve and in transverse infracture of the pyramid of the temporal bone. Longitudinal infractures of the pyramid usually cause a diminished sense of taste on the anterior 2/3 of the tongue in the acute period, with improvment of the taste in the late periods after the trauma. The test for the sense of taste on the anterior 2/3 of the tongue in tumors of the acoustic nerve, in infractures of the temporal bone pyramid, and in arachnoiditis of the cerebellopontine angle is one of the diagnostic methods. Electrogustometry makes it possible to detect the earliest disorders in the sense of taste and make a more precise diagnosis.

Arachnoiditis↗
PubMed1992

Imaging of pediatric and congenital brain disease.

The etiology of hemiplegic cerebral palsy has been elucidated by surveys of affected children using CT. MR imaging has contributed to the more exact diagnosis of the nature and extent of hypoxic ischemic damage and allows the accurate estimation of the time of the insult. Serial MR imaging and MR spectroscopy may be useful for predicting the prognosis for cerebral palsy and neurodevelopmental delay. The damage caused by intrauterine infection is best appreciated on MR imaging, though CT is important in showing calcification. Similar considerations apply to tuberous sclerosis, and new observations may facilitate MR imaging diagnosis. Gadolinium-enhanced MR imaging is the most accurate modality for detection of tumor recurrence and metastatic spread. Enhancement due to reactions to and complications of surgery can usually be distinguished. The reliability of MR imaging in showing many congenital anomalies provides evidence of the incidence of these lesions and contributes to understanding the disordered embryology. Most of the changes described in inherited metabolic disorders are nonspecific, but they may suggest a particular diagnosis, and MR imaging is the most sensitive modality for monitoring progress. Lifesaving intervention for arteriovenous malformations involving the vein of Galen requires detailed noninvasive imaging for selecting the most effective approach. Technical developments in diffusion and in flow imaging promise to further increase our diagnostic capabilities and to limit the application of invasive techniques.

Brain↗
PubMedDate not supplied

The value of fast gradient-echo MR sequences in the evaluation of brain disease.

One-hundred-fifteen patients thought to have intracranial disease were studied with various two-dimensional short repetition time, partial-flip-angle gradient-echo techniques: at 1.0 T, fast low-angle short (FLASH) at 10 degrees and 30 degrees and fast imaging with steady-state precession (FISP) at 60 degrees; at 1.5 T, FLASH 10 degrees, 30 degrees, and 60 degrees, FISP 60 degrees, and contrast-enhanced fast steady state at 60 degrees. These sequences were compared with a T2-weighted spin-echo sequence to determine the relative sensitivities of these techniques in detecting parenchymal lesions. Except for hemorrhagic lesions a substantial number of abnormalities were either not visible or poorly seen on the partial-flip-angle gradient-echo sequences. Minimizing echo time (6-9 msec) to decrease magnetic susceptibility effects did not improve lesion detection. Current usage of two-dimensional gradient-echo techniques for lesion detection is limited, except when calcification or hemorrhage is involved. Their utility may be expanded via the incorporation of three-dimensional techniques and IV contrast agents.

Brain Diseases↗
PubMed1995

ApoE immunoreactivity and microglial cells in Alzheimer's disease brain.

The spatial relationship of apolipoprotein E (apoE)-like immunoreactivity (IR) to amyloid beta-peptide (A beta), astrocytes and microglial cells in the brain of Alzheimer's disease was studied by double immunolabelling. Diffuse apoE-like IR was seen in A beta diffuse deposits, and markedly increased in the core of classic senile plaques. Microglial cells, sometimes immunoreactive for apoE, were frequent in areas of apoE-like IR, where they often grouped into clusters in the core of apoE-labelled senile plaques. Although astrocytic processes were seen within these senile plaques, the cell bodies were always at a distance from the core. None of these astrocytes expressed apoE-like IR. Microglial cells, some of them immunoreactive for apoE, were seen in the center of apoE-labelled senile plaques. These data suggest that microglial cells play a more significant role than astrocytes in apoE deposition in senile plaques of Alzheimer disease.

Aged↗
PubMed2002

A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains.

P25, a calpain cleavage product of the cyclin-dependent kinase 5 (Cdk5) activator p35, causes prolonged activation of Cdk5. Although p25 has been shown to accumulate in brains of patients with Alzheimer's disease (AD), it is not known whether p25 accumulation in AD is brain region-specific. We analyzed the amounts of p25 and p35 in human autopsy samples from multiple brain regions including frontal cortex, inferior parietal cortex and hippocampus using immunoblotting assays. Our results show that the p25-p35 indices are higher in AD than in the control groups in all three brain regions. The most significant difference in p25-p35 indices between AD and control groups is in the frontal cortex. No significant difference in calpain activity between AD and control groups is observed, indicating that postmortem calpain activation cannot account for the elevation of p25/p35 ratios in AD brains. Our results support the notion that p25 accumulation deregulates Cdk5 activity in AD brains, and the deregulated Cdk5 activity may contribute to the pathogenesis of AD.

Alzheimer Disease↗
PubMed2002

Magnetic resonance spectroscopy in multiple sclerosis: window into the diseased brain.

Magnetic resonance spectroscopy provides noninvasive insight into the regional and global biochemical alterations that are concomitants of the dynamic processes that underlie the evolution of fundamental pathologic changes in multiple sclerosis. These include now well-recognized alterations of neuronal biochemical markers that accompany tissue destruction readily visualized by magnetic resonance imaging, but also dynamic changes in several metabolites that indicate pathological processes that precede the magnetic resonance imaging-defined lesion, or completely escape current high-resolution imaging.

Biomarkers↗