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At least 235 records · Page 13Linked to original sources
PubMed1997

Muscle-eye-brain disease: a neuropathological study.

A combination of congenital central nervous, ocular and muscular abnormalities is characteristic of muscle-eye-brain disease (MEB), of Fukuyama congenital muscular dystrophy (FCMD), and of Walker-Warburg syndrome (WWS). The nosological relationship of these inherited malformative disorders is still unestablished, although the genetic locus for FCMD has been excluded in MEB. We present the first postmortem neuropathological study of MEB based on 2 male patients. Apart from sharply limited occipital agyric areas, their brains showed coarse gyri with an abnormally nodular surface ("cobblestone cortex"). Both the cerebral and cerebellar cortices showed a total disorganization without horizontal lamination. The haphazardly oriented cortical neurons formed irregular clusters or islands, separated by gliovascular strands extending from the pia. The ocular abnormalities included a pronounced glial preretinal membrane. Although MEB shares the cobblestone cortex-type malformation with FCMD and WWS, the cerebral and ocular manifestations are less severe than in WWS. Furthermore, a consistently weak staining for laminin alpha2 chain (merosin) was found in muscle biopsy specimens from 4 MEB patients, while normal immunoreactivity was observed for the laminin beta2 chain, reported to be severely deficient in WWS. These findings support nosological independence of MEB.

Adult↗
PubMed1991

Studies on the proteolytic degradation of the beta-protein precursor by proteases purified from Alzheimer's disease brain.

In Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of Dutch origin, and normal aging, amyloid accumulates in the brain parenchyma and blood vessels. The major protein in the deposits is the beta-protein, a 4-kD peptide possibly generated by an abnormal degradation of its precursor, the beta-protein precursor (beta PP). We found, as a second component of the brain amyloid, the serine protease inhibitor alpha 1-antichymotrypsin (ACT). Inasmuch as ACT is tightly associated with the beta-protein and is never found in other amyloidoses, we hypothesized a role for ACT in the degradation of the beta PP. We used synthetic peptides made according to the sequence flanking the N-terminus of the beta-protein to screen brain fractions for protease activity. After several purification steps, two protease fractions were found that can cleave the peptide between methionine and aspartic acid, aspartic acid being the N-terminus of the beta-protein. One protease is activated by calcium and inhibited by ACT, beta PP containing the Kunitz-type inhibitory domain, diisofluorophosphate, and 1,10-phenanthroline. This protease fraction is also able to degrade the beta PP in vitro. The second protease is a metal-dependent cysteine protease.

Alzheimer Disease↗
PubMed2005

Focally elevated creatine detected in amyloid precursor protein (APP) transgenic mice and Alzheimer disease brain tissue.

The creatine/phosphocreatine system, regulated by creatine kinase, plays an important role in maintaining energy balance in the brain. Energy metabolism and the function of creatine kinase are known to be affected in Alzheimer diseased brain and in cells exposed to the beta-amyloid peptide. We used infrared microspectroscopy to examine hippocampal, cortical, and caudal tissue from 21-89-week-old transgenic mice expressing doubly mutant (K670N/M671L and V717F) amyloid precursor protein and displaying robust pathology from an early age. Microcrystalline deposits of creatine, suggestive of perturbed energetic status, were detected by infrared microspectroscopy in all animals with advanced plaque pathology. Relatively large creatine deposits were also found in hippocampal sections from post-mortem Alzheimer diseased human brain, compared with hippocampus from non-demented brain. We therefore speculate that this molecule is a marker of the disease process.

Alzheimer Disease↗
PubMedDate not supplied

Longitudinal progression of subclinical structural brain disease in normal aging.

OBJECTIVE: The authors describe four types of brain structural change in "normal aging:" cortical atrophy, central atrophy, deep white-matter hyperintensities (DWMH), and periventricular hyperintensities (PVH). Cross-sectional investigations have reported that greater volumes of these forms of "subclinical structural brain disease" (SSBD) were found with increasing age. Greater volumes were also associated with poorer cognition, even though subjects performed within the normal range. The natural history of these forms of SSBD and their functional impact are not well established. METHODS: Twenty-nine normal subjects, ages 60-89, were examined longitudinally by volumetric magnetic resonance imagery, with two assessments performed at least 2 years apart; 26 also completed neuropsychological testing to evaluate processing speed, executive functions, language, and other cognitive functions. Associations between structure and function were evaluated with regression models. RESULTS: For most subjects, the volumes for signs of all types of SSBD were found to have increased; for many subjects, increases were small, and a few showed no change or small decreases. PVH and DWMH increases were predicted by baseline cerebrovascular risk factors. Cognitive test performance changed little over time for these normal subjects. CONCLUSIONS: SSBD volumes increased for most subjects over time, with small average increases for most types. Pretreatment cerebrovascular risk factors were associated with greater increases of PVH and DWMH, suggesting that progression of these types of SSBD may be amenable to intervention.

Aged↗
PubMed2006

Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics.

Alzheimer's disease, an age-related neurodegenerative disorder, is characterized clinically by a progressive loss of memory and cognitive functions. Neuropathologically, Alzheimer's disease is defined by the accumulation of extracellular amyloid protein deposited senile plaques and intracellular neurofibrillary tangles made of abnormal and hyperphosphorylated tau protein, regionalized neuronal death, and loss of synaptic connections within selective brain regions. Evidence has suggested a critical role for amyloid-beta peptide metabolism and oxidative stress in Alzheimer's disease pathogenesis and progression. Among the other indices of oxidative stress in Alzheimer's disease brain are protein carbonyls and 3-nitrotyrosine, which are the markers of protein oxidation. Thus, in this review, we discuss the application of redox proteomics for the identification of oxidatively modified proteins in Alzheimer's disease brain and also discuss the functions associated with the identified oxidized proteins in relation to Alzheimer's disease pathology. The information obtained from proteomics may be helpful in understanding the molecular mechanisms involved in the development and progression of Alzheimer's disease as well as of other neurodegenerative disorders. Further, redox proteomics may provide potential targets for drug therapy in Alzheimer's disease.

Actins↗
PubMedDate not supplied

Principles of contrast enhancement in the evaluation of brain diseases: an overview.

Intravenous contrast media are widely used in MR imaging of the brain. Clinical utility is high in both neoplastic and non-neoplastic disease. The agents approved to date are all gadolinium chelates, with extracellular distribution and renal excretion. The agents differ in regard to the maximum dose that can be administered and the theoretical safety margin. When administered at the same dose, the efficacy of the different available agents is comparable. Described in the following review article are the diagnostic use of contrast media and the patterns of enhancement encountered in neoplastic disease, infection, vascular disorders, and diseases of white matter. Only in congenital brain disease, when acute abnormalities are not suspected clinically and neoplastic disease is not a question, is contrast enhancement not indicated. The gadolinium chelates play a major role in the evaluation of patients by MR with known or suspected brain disease. These agents improve both the sensitivity and specificity of the examination. In many cases, lesions cannot be identified before contrast administration. Lesion delineation, assessment of lesion activity, and differential diagnosis are all improved, in general, with the addition of postcontrast scans. The scope of applications continues to expand as the modality and clinical experience matures.

Brain Diseases↗
PubMed1976

Piperacetazine versus thioridazine in the treatment of organic brain disease: a controlled double-blind study.

In a double-blind cross-over study, 50 geriatric patients with organic brain disease were divided into two groups. One group first received piperacetazine for 15 days and then thioridazine for 15 days. For the other group the sequence was reversed. Piperacetazine proved to be at least as effective as thioridazine and seemed to be more effective against certain target symptoms; side effects were less common and less severe.

Aged↗
PubMed1978

[Autoimmune processes in the pathogenesis of traumatic brain disease].

The authors give immunological characteristics of the brain traumatical disease on the basis of a dynamic study of autoimmune reactions in direct and retarded type with brain tissue antigenes in 156 patients. The conclusion is made of an interconnection of these indices and the dependence of the clinical syndrome and the type of development of the pathological process to these data.

Autoantibodies↗
PubMed1992

Differential inhibition of acetylcholinesterase molecular forms in normal and Alzheimer disease brain.

Molecular forms of acetylcholinesterase were studied in three brain regions from Alzheimer disease patients and non-demented, age-matched controls. In Alzheimer disease patients, the membrane-bound G4 form was decreased in frontal (-71%) and parietal cortex (-45%) and in the caudate-putamen (-47%) from control levels. We also found a decrease of aqueous-soluble acetylcholinesterase molecular forms in the aqueous-soluble acetylcholinesterase molecular forms in the caudate-putamen region. The effect of three clinically significant acetylcholinesterase inhibitors, heptyl-physostigmine, physostigmine and edrophonium, on aqueous-soluble acetylcholinesterase molecular forms of the caudate-putamen was investigated. Heptyl-physostigmine, a physostigmine analogue, showed preferential inhibition for the G1 form. On the contrary, edrophonium inhibited the G4 form more potently than the G1 form. Physostigmine inhibited both forms with similar potency. The clinical implications of selective acetylcholinesterase inhibitors are discussed.

Acetylcholinesterase↗
PubMed2002

Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer's disease brain.

The amyloid beta (A beta) peptide that accumulates in Alzheimer's disease brain is derived from the proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase activities. The beta-secretase enzyme beta-site amyloid precursor protein-cleaving enzyme (BACE) generates the N terminus of A beta by cleavage at either Asp(1) (beta-site) or Glu(11) (beta'-site), ultimately leading to the production of full-length A beta 1-40/42 or truncated A beta 11-40/42. The functional significance of this variable cleavage site specificity as well as the relative pathological impact of full-length versus N-terminally truncated A beta remains largely unknown. In our analysis of BACE reactivity in cell culture, we found that the preference of the protease for either beta- or beta'-cleavage was strongly dependent on intracellular localization. Within the endoplasmic reticulum, beta-site proteolysis predominated, whereas in the trans-Golgi network, beta'-cleavage was favored. Furthermore, the contrasting cleavage site specificities of BACE were not simply due to differences in organelle pH or the oligosaccharide composition of the glycoproteins involved. Examination of post-mortem brain specimens revealed significant levels of A beta 11-40/42 within insoluble amyloid pools. Taken together, these data support an important role for beta'-cleavage in the process of cerebral amyloid deposition and localize the processing event to the trans-Golgi network.

Alzheimer Disease↗
PubMed2000

Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains.

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is one of the dominantly inherited cerebellar ataxias. The gene responsible for the disease, a novel gene of unknown function, encodes ataxin-3 containing a polyglutamine stretch. Although it has been known that ataxin-3 is incorporated into neuronal intranuclear inclusions (NIIs) in neurons of affected regions, the relationship between NII formation and neuronal degeneration still remains uncertain. In the present study we show two different conditions in which ataxin-3 is recruited into the nucleus and suggest a process to form nuclear inclusions. In normal brains, wild-type ataxin-3 localizes within the ubiquitin-positive nuclear inclusion, the Marinesco body, indicating that ataxin-3 is recruited into the nuclear inclusion even in the absence of pathologically expanded polyglutamine. In MJD/SCA3 brains, immunohistochemical analyses with anti-ataxin-3 antibody, anti-ubiquitin antibody, and monoclonal antibody 1C2 known to recognize expanded polyglutamine revealed differences in frequency and in diameter among NIIs recognized by each antibody. These results were confirmed in the same inclusions by double immunofluorescent staining, suggesting that expanded ataxin-3 forms a core, thereby recruiting wild-type ataxin-3 into the nucleus around the core portion, and then followed by activation of the ubiquitin/ATP-dependent pathway. Recruitment of ataxin-3 into the nucleus and formation of nuclear inclusion under two different conditions suggest that ataxin-3 may be translocated into the nucleus under certain conditions stressful on neuronal cells such as aging and polyglutamine neurotoxicity.

Ataxin-3↗
PubMed2005

Neuroimaging of metastatic brain disease.

This review discusses imaging techniques for the diagnosis, treatment, and monitoring of brain metastases. It assesses the various modalities on the basis of their respective advantages and limitations. Recent advances in imaging technologies provide evaluation that is more accurate for tumor localization, morphology, physiology, and biology. When used in combination, these technologies provide clinicians with a powerful diagnostic and prognostic tool for managing metastatic brain disease.

Brain Neoplasms↗
PubMedDate not supplied

Clinical, genetic and histopathologic findings in two siblings with muscle-eye-brain disease.

PURPOSE: We present the clinical, genetic and histopathologic findings in two siblings with Muscle-Eye-Brain Disease (MEB-D), an autosomal recessive disease characterized by mental retardation, muscular dystrophy, retinal hypoplasia and brain abnormalities. METHODS: Clinical, histopathologic and gene mapping studies of a family with two normal and two children with MEB-D. RESULTS: Two siblings presented in the first few months of life with developmental delay, hypotonia, and strabismus. MRI of the brain showed colpocephaly, pontine and cerebellar atrophy, and diffuse white matter disease. Both patients were blind and had high myopia, strabismus, and retinal and optic nerve abnormalities. The older boy had glaucoma. Both children died from uncontrolled seizures. There was retinal, choroidal and RPE atrophy and optic nerve hypoplasia on ocular histopathology. Both patients shared the same parental haplotypes at the MEB locus on chromosome 1p, while an unaffected sibling did not, indicating possible linkage to the MEB locus. CONCLUSIONS: Patients with MEB-D have severe visual impairment from retinal and optic nerve hypoplasia. High myopia appears to be a consistent finding. The ocular manifestations of MEB-D appear to be distinct from those of patients with Walker-Warburg syndrome.

Abnormalities, Multiple↗
PubMed2007

Prenatal diagnosis of muscle-eye-brain disease.

OBJECTIVES: To present a family in which it was possible to perform prenatal diagnosis for the recessively inherited muscle-eye-brain disease (MEB) using linkage analysis. METHODS: Linkage analysis and direct sequencing of the POMGNT1 gene were carried out in a Turkish MEB family with one affected individual. Fetal DNA was obtained from an ongoing pregnancy by chorionic villus sampling (CVS). RESULTS: Both linkage analysis of the POMGNT1/1p32-p34 region and direct sequencing for the novel familial mutation (R605H) demonstrated that the fetus did not have MEB. CONCLUSION: We report the first case of prenatal diagnosis in MEB by molecular genetic analysis.

Adolescent↗
PubMed2002

Regional quantitative study of formation process of neurofibrillary tangles in the hippocampus of non-demented elderly brains: comparison with late-onset Alzheimer's disease brains.

We quantitatively investigated the formation process of neurofibrillary tangles (NFT) in the hippocampus of 32 brains from non-demented elderly persons using tau-immunohistochemistry, compared with 13 brains from patients with late-onset Alzheimer's disease (AD). The 32 non-demented elderly brains were classified into 16 brains in group I and 16 brains in group II mainly based on the distribution of tau-positive neurons in the hippocampus. Tau-positive neurons were found predominantly in the CA2 in group I, while they were found predominantly in the subiculum-pre-CA1 in group II. Most late-onset AD brains showed a distribution of tau-positive neurons similar to that in group II. In addition, the distribution pattern of tau-positive neurons in the hippocampus was closely related to degeneration of the perforant pathway with the accumulation of tau. These findings suggest that NFT occur first in the CA2 and extend to the subiculum-pre-CA1 in group I, while they occur first in the subiculum-pre-CA1 and extend to the CA2 later in group II, and that the NFT occurring in the subiculum-pre-CA1 are mainly related to degeneration of the perforating route and in the CA2 are related to the degeneration of the non-perforating route.

Aged↗
PubMed2004

Clinical spectrum of muscle-eye-brain disease: from the typical presentation to severe autistic features.

Muscle-eye-brain disease (MEB) is an autosomal recessive congenital muscular dystrophy with ocular abnormalities and type II lissencephaly. MEB is caused by mutations in the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) gene on chromosome 1q33. POMGnT1 is a glycosylation enzyme that participates in the synthesis of O-mannosyl glycan. The disease is characterized by altered glycosylation of alpha-dystroglycan. The clinical spectrum of MEB phenotype and POMGnT1 mutations are significantly expanded. We would like to present two cases with MEB disease with POMGnT1 mutations, whose clinical picture shows heterogeneity. The patient with R442H mutation had the classical form of the disease although the one with IVS17-2A-->G homozygous mutation had severe autistic features as the dominating presenting sign. These two cases represent different spectrums of one disorder. To the best of our knowledge, autistic features and stereotypical movements have not been included thus far as a part of broad and heterogeneous MEB spectrum.

Adolescent↗