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R Ravid

Publications and source records attributed to R Ravid.

At least 73 records · Page 4Linked to original sources
PubMed1995

Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging.

We investigated the histopathologic correlates of white matter changes in Alzheimer's disease (AD) patients (n = 6) and controls (n = 9) using postmortem MRI. White matter changes were rated on a 0 to 3 scale in 51 regions. Histopathologically, we subjectively rated the loss of myelinated axons in the deep and periventricular white matter, denudation of the ventricular ependyma, gliosis, width of the perivascular spaces, and leptomeningeal congophilic angiopathy; we measured structural changes in the walls of the blood vessels in the white matter in micrometers. The AD brains displayed significantly more white matter hyperintensities on MRI than controls. Histopathologically, the denudation of the ventricular ependyma and the gliosis were significantly more severe in AD than in controls, and there was a trend toward more loss of myelinated axons in the deep white matter in the AD brains (p = 0.07). The MRI abnormalities correlated with the loss of myelinated axons in the deep white matter (r' = 0.37; p < 0.01) and with the denudation of the ventricular lining (r' = 0.54; p < 0.01). We could not find any evidence for arteriolosclerosis, but the mean thickness of the adventitia of the arteries of the deep white matter in AD almost doubled the value in control brains (p = 0.0009). We conclude that white matter abnormalities in AD patients and controls consist of loss of myelinated axons, probably caused by arterial changes and breakdown of the ventricular lining. Since imaging/histopathologic correlation was similar in AD patients and controls, these changes probably represent some form of accelerated aging.

Aged↗
PubMed1994

The monoclonal antibody Alz-50, used to reveal cytoskeletal changes in Alzheimer's disease, also reacts with a large subpopulation of somatostatin neurons in the normal human hypothalamus and adjoining areas.

The monoclonal antibody Alz-50 is directed against Alzheimer's disease-related modified tau proteins and reveals cytoskeletal changes, i.e. neurofibrillary tangles and dystrophic neurites. The present study shows that, in the hypothalamus of non-demented control subjects, this same antibody gives a distinctive staining pattern of a subpopulation of somatostatin neurons and beaded fibres. Furthermore, Alz-50 occasionally recognizes somatostatin-containing cell bodies and dystrophic neurite-like fibers in the (neuritic) senile plaques of AD patients. These observations have direct consequences for the interpretation of Alz-50 staining in diagnostic usage and for the assessment of Alzheimer's disease-like changes induced by beta-amyloid in experimental animal brains. On dot spotting, Alz-50 was found to bind to a number of fragments from the somatostatin precursor, of which somatostatin 15-28 stained best. Preadsorption of Alz-50 by somatostatin 15-28, as well as other specificity tests, failed, however, to provide any clue to the nature of the unknown compound(s) stained in the control hypothalamus.

Adult↗
PubMed1994

Ubiquitin in cerebrospinal fluid: a rapid competitive enzyme-linked immunoflow assay.

The aims of this study were to develop a rapid immunoassay to determine the levels of ubiquitin in cerebrospinal fluid and to establish the ubiquitin levels in the spinal fluid of normal aged individuals. A competitive enzyme-linked immunoflow assay was developed. In this assay, ubiquitin is bound to nitrocellulose membrane, after which the primary antibody-test sample mixture and the enzyme-labeled secondary antibody under vacuum are applied sequentially. The final reaction product is collected in a microtiter plate by suction. This competitive assay requires only approximately 4 h and is potentially useful for determining in biological fluids the levels of any antigen or its antibodies that might be present. Employing this immunoassay, cerebrospinal fluid ubiquitin levels were found to be 147.5 +/- 5.2 ng ml-1 in non-neurological aged cases.

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PubMed1994

Stable vasopressin innervation in the degenerating human locus coeruleus in Alzheimer's disease.

The vasopressin (VP) innervation of the human locus coeruleus (LC) was immunocytochemically investigated in Alzheimer's disease (AD) patients and non-demented controls. A dense innervation of VP fibers was present throughout the entire rostro-caudal length of the LC in both, controls and AD-patients. The VP immunoreactivity was confined to fibers; no signs of cell body staining could be found. Comparison of five non-demented control subjects and five AD patients on fifteen different levels throughout the LC revealed that the VP innervation of this nucleus remained intact in AD, even in the rostral part of the LC, which is the most affected region with respect to neuronal loss.

Aged↗
PubMed1994

Alzheimer disease: correlation of cerebro-spinal fluid and brain ubiquitin levels.

Neurofibrillary degeneration is one of the histopathological hallmarks of Alzheimer disease (AD). Previous studies have shown an association of ubiquitin with the cytoskeletal protein pathology in AD. In the present study, we report (i) the measurement of ubiquitin levels in cerebrospinal fluid (CSF) from histopathologically confirmed AD and control cases, using a new rapid immunoassay, the competitive enzyme-linked immunoflow assay (CELIFA), (ii) the determination of ubiquitin levels in brain tissue taken from the same cases, using a competitive enzyme-linked immunosorbent assay (ELISA), and (iii) an evaluation of the correlation between levels of ubiquitin in CSF and in brain tissue. Ubiquitin levels in CSF of AD and neurological control groups are significantly higher than those of non-neurological aged controls. Ubiquitin levels in brain homogenates of the AD group are significantly higher than those of both non-neurological aged and neurological control groups. The source of this increase in brain ubiquitin in AD is the particulate fraction, because ubiquitin levels in the brain cytosol fraction are the same among the three groups. In AD and non-neurological aged controls, there is a significant positive correlation between ubiquitin levels in CSF and in homogenate of cerebral white matter. In contrast, the correlation in the non-AD neurological control group has a negative tendency. These studies suggest that in AD, elevated levels of ubiquitin in the CSF reflect the increased amount of the protein in the brain and, therefore, can serve as a biomarker of the neuropathology in this disease.

Alzheimer Disease↗
PubMed1994

Regionally selective alterations in G protein subunit levels in the Alzheimer's disease brain.

In the present study the relative densities of a number of G protein subunits were quantified in membranes prepared from the hippocampus, temporal cortex and angular gyrus of Alzheimer's disease and control post-mortem brain by immunoblotting with specific polyclonal antisera against Gs alpha, Gi alpha, Gi alpha-1, G(o) alpha and G beta protein subunits. In addition, basal, Gs-stimulated and Gi-inhibited adenylyl cyclase activities were measured in the same hippocampal membrane samples. Densitometric analysis of the immunoblot data revealed a 58% reduction in the levels of Gi alpha, and a 75% reduction in the levels of Gi alpha-1, in the Alzheimer's disease temporal cortex. Gi alpha levels were reduced, by 37% in the angular gyrus of the Alzheimer's disease cases. The ratio of large to small molecular weight isoforms of the Gs alpha subunit was significantly increased in both the hippocampus and the angular gyrus of the Alzheimer's disease samples when compared to control values, although the difference in individual Gs alpha isoform levels did not attain statistical significance when comparing groups. No statistically significant differences were observed in G(o) alpha or G beta levels when comparing control and Alzheimer's disease cases. Gs-stimulated adenylyl cyclase activity was significantly reduced in the Alzheimer's disease samples compared to controls, whereas Gi-inhibited adenylyl cyclase activity was unchanged. No significant differences were observed between the control and Alzheimer's disease samples for either basal or forskolin stimulated adenylyl cyclase activity. The ratio of hippocampal Gs-stimulated to basal adenylyl cyclase activity correlated significantly with the large to small Gs alpha subunit ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1994

The involvement of specific anti myelin basic protein antibody-forming cells in multiple sclerosis immunopathology.

Irrespective of the large body of literature on the putative role of antibodies in the development of multiple sclerosis (MS), the detection of specific antibody-forming B cells (AFCs) in the central nervous system (CNS) tissues has not been described. In this study we show that autoantigen-specific AFCs can be found in CSN tissue sections of MS patients. Applying a newly developed myelin basic protein (MBP)-enzyme conjugate technique, we have detected MBP-specific AFCs in autopsy periventricular white matter and cerebellum tissue sections of MS patients. We demonstrated the presence of MBP-specific AFCs in CNS tissue sections in five out of 12 MS patients. No MBP-specific AFCs were detected in CNS tissue sections of 11 patients with other neurological diseases, such as Parkinson's and Alzheimer's disease, or in brain tissue sections of eight deceased persons without neurological diseases. In MS patients, anti-MBP AFCs were present in brain tissue sections both with and without plaques. The proportion of MBP-specific AFCs in some of the MS patient brain tissues reached over 50% of all AFCs. The high relative frequency of the anti-MBP AFCs and their localization in periventricular white matter and cerebellum of MS patients only, suggests that anti-MBP AFCs represent a cell population, which could play an important role in MS immunopathology.

Adult↗
PubMed1994

Decreased neuronal activity in the nucleus basalis of Meynert in Alzheimer's disease as suggested by the size of the Golgi apparatus.

In order to study changes in neuronal activity in the nucleus basalis of Meynert in aging and Alzheimer's disease, we applied a polyclonal antibody directed against the Golgi apparatus on formalin-fixed, paraffin-embedded material. Subsequently, an image analysis system was used to measure the size of the Golgi apparatus in (i) all nucleus basalis neurons and also separately in (ii) the remaining large cells (perikaryonal diameter > 30 microns). A significant reduction of 49% in the size of the Golgi apparatus was found in the entire population of nucleus basalis neurons in Alzheimer's disease. Furthermore, although there was no significant decrease in the size of the persisting large neurons in the nucleus basalis of Meynert, a significantly decreased size of the Golgi apparatus was found in these neurons in Alzheimer's disease. These results suggest that the overall activity of nucleus basalis neurons is severely decreased in Alzheimer's disease. Furthermore, these data support the idea that atrophy and decreased activity are the main phenomena in the nucleus basalis in Alzheimer's disease; they also indicate that the size of the Golgi apparatus is a sensitive parameter to follow this process.

Adult↗
PubMed1994

Increased cortisol levels in aging and Alzheimer's disease in postmortem cerebrospinal fluid.

The hypothalamo-pituitary-adrenal (HPA) axis is activated during aging and even more so in dementia. Increased levels of corticosteroids may be neurotoxic. Therefore we have investigated cortisol levels in cerebrospinal fluid (CSF) of Alzheimer patients and controls. Ventricular postmortem CSF was collected from clinically and neuropathologically well-defined Alzheimer patients (n = 26) and control subjects (n = 21). In the group of Alzheimer patients the mean CSF total cortisol level was 83% higher than that in the controls. In presenile Alzheimer patients (< 65 years of age; n = 13) the CSF-cortisol level was 5 times higher than that of presenile controls (n = 7). In contrast, senile Alzheimer patients (n = 13) and controls of over 65 years of age (n = 14) did not show a significant difference in CSF-cortisol levels. The presence or absence of a difference in the cortisol-CSF levels in, respectively, presenile or senile Alzheimer patients as compared to controls was due to the 3.5-fold rise of CSF-cortisol in control subjects over 65 years of age as compared with controls under 65 years of age. The CSF-cortisol levels in presenile and senile Alzheimer patients were similar. No significant correlation was observed in the Alzheimer patients between age of onset of the dementia and CSF cortisol levels or duration of Alzheimer's disease and CSF cortisol levels. The finding that in senile Alzheimer patients cortisol levels were similar to those of unaffected age-matched controls does not seem to support the cortisol neurotoxicity hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Pathologic findings in a case of primary progressive aphasia.

We report the histopathologic and immunohistochemical findings of a patient who suffered from primary progressive aphasia for 13 years. During the course of his illness, he was diagnosed as having Pick's disease, based on gradually progressive mild personality changes and MRI findings of severe bilateral temporal lobe atrophy. There was severe neuronal loss in the temporal gyri, intense gliosis throughout the cortex, and mild gliosis of the temporal white matter, without any changes typical for Alzheimer's disease or Pick's disease. Using the antibody Alz-50, we found many Alz-50-positive neurons that exhibited a granular or diffuse cytoplasmic stain without fibrous structures in the temporal and parietal cortex, but no ubiquitin or beta (A4) protein-reactive cells, nor spongiform changes. Staining for Alz-50 and ubiquitin did not reveal the presence of Pick bodies or Lewy bodies. We consider this case to be an example of nonspecific cortical degeneration. Our findings stress the need for histopathologic verification of the primary progressive aphasia syndrome.

Amyloid beta-Peptides↗
PubMed1993

Activation of the human supraoptic and paraventricular nucleus neurons with aging and in Alzheimer's disease as judged from increasing size of the Golgi apparatus.

The supraoptic (SON) and paraventricular nucleus (PVN) of the human hypothalamus produce vasopressin (AVP) and oxytocin (OXT). Since in these nuclei no cells are lost during aging or Alzheimer's Disease (AD), factors are searched for which may be responsible for this remarkable stability. Earlier work in both rat and human indicated that the peptide synthesis of these neurons was activated in the oldest age groups as judged from increased neuronal and nuclear size and AVP plasma levels. The size of the Golgi Apparatus (GA) has proved to be a very sensitive parameter for the synthetic activity of these neurosecretory cells in animal experiments. In order to determine changes in the GA during aging and in Alzheimer's Disease, we applied a polyclonal antiserum against immunoaffinity purified MG-160, a sialoglycoprotein of the medial cisternae of the GA, on formalin-fixed and paraffin-embedded sections of the SON and PVN of patients ranging in age from 29 to 97 years. However, our standard fixation procedure masked antigenic sites resulting in a minimal immunocytochemical staining in most of the tissues examined. It appeared to be possible, however, to retrieve the antigen and to obtain an excellent staining of the GA by heating sections in a microwave oven before immunostaining. Following this procedure, an increase in size and intensity of the GA became apparent in individuals from about 70 years and older. In AD patients a similar increase in size and intensity of the immunostained GA was observed. Taken together, these results indicate that SON and PVN neurons are activated during the course of aging and also in AD and that this activation takes place at an earlier age than observed previously by other cellular parameters.

Adult↗
PubMed1993

Localization of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the human hypothalamus; age-dependent colocalization with vasopressin.

Immunocytochemical staining, using a monoclonal antibody against corticotropin-releasing hormone, was performed on hypothalami of 13 human subjects between 23 and 91 years of age who had not suffered from a primary neurological or psychiatric disease. Corticotropin-releasing hormone (CRH) immunoreactivity was present in neurons of the paraventricular nucleus (PVN) and in their fibers running to the median eminence. The CRH-positive neurons were scattered throughout the PVN, but in the rostral part relatively few cells were present. There were large individual differences in the number and staining intensity of CRH neurons in the PVN and in the staining intensity of the median eminence. These differences seemed not to be attributed to age, sex, postmortem delay, fixation time or hour of death. In the rat, too, no relationship was found between a postmortem delay of up to 24 h and CRH staining intensity of the median eminence. Since the distribution of CRH-immunoreactive neurons in the human PVN strongly overlap with vasopressin, colocalization of these peptides was investigated in a double label study and indeed found in subjects ranging between 43 and 91 years of age. However, cells staining for only one of the peptides were also observed. The vasopressin cells had a mean cellular profile area which was 2.3 times as large as the CRH cells and 2.2 times as large as the CRH and vasopressin containing neurons. In younger subjects (23-37 years of age) no colocalization of the two peptides was seen. The age-dependent colocalization of CRH with vasopressin is interpreted as a sign of increased activation of the CRH neurons with age.

Adult↗
PubMed1993

Disrupted beta 1-adrenoceptor-G protein coupling in the temporal cortex of patients with Alzheimer's disease.

The efficacy of beta 1-adrenoceptor-G protein coupling was studied in postmortem temporal cortex synaptic membranes from a series of control and Alzheimer's disease subjects. For the control cases, the non-hydrolysable GTP analogue 5'-guanylylimidodiphosphate (Gpp[NH]p) gave a significant reduction in the affinity of the agonist isoprenaline to displace binding of the radiolabelled antagonist (+/)-4-(3-t-butylamino-2-hydroxypropoxy)[5,7-3H]benzimidazol-2-one ([3H]CGP-12177). This effect was attributed to the conversion of high agonist-affinity sites to a lower-affinity state and was not found for the Alzheimer's disease cases. These data indicate that a disruption of beta 1-adrenoceptor-G protein coupling occurs in the temporal cortex of Alzheimer's disease patients.

Aged↗
PubMed1993

The distribution of Alz-50 immunoreactivity in the hypothalamus and adjoining areas of Alzheimer's disease patients.

The monoclonal antibody Alz-50 is directed against modified forms of tau proteins. Various hypotheses have been put forward concerning the meaning of Alz-50 staining in Alzheimer's disease brains. Cytoskeletal alterations are reported to occur exclusively in the cortex and the subcortical nuclei directly connected with the cortex. In addition, Alz-50 staining is presumed to be indicative of impending neuronal death. In order to test these hypotheses Alz-50 was applied to the hypothalamus and adjoining areas of five Alzheimer's disease patients of 40-90 years of age and five sex- and age-matched, non-demented controls. The results showed the following: (i) Alz-50 immunoreactivity is not restricted to Alzheimer's disease patients. Alz-50 immunoreactive beaded nerve fibres and patchy, granular cell bodies were observed in some hypothalamic nuclei of all controls with the exception of the youngest one. Dystrophic neurites were not only observed in all Alzheimer's disease hypothalami but also in that of the oldest control. (ii) In the hypothalamic area various nuclei had different Alz-50 staining patterns. Alz-50 staining could not, however, be related to neuronal death in the different nuclei. (iii) Histopathological changes in Alzheimer's disease patients are not restricted to the cortex or subcortical areas connected directly with the cortex. The present report indicates that the hypothalamus is considerably more affected in Alzheimer's disease than has often been assumed. However, these changes can also be found in non-demented old people.

Adult↗
PubMed1993

The Netherlands brain bank--a clinico-pathological link in aging and dementia research.

The number of sophisticated neurobiological techniques which can be applied on human brain has rapidly increased and causes an increased demand for post-mortem human brain tissue for research purposes. Brain banks, which collect post-mortem tissue from patients who suffered from neurological and psychiatric disorders, have become an important link between clinicians, scientists and neuropathologists involved in aging and dementia research. Due to the large variability of the material, there are many drawbacks in the use of post-mortem brains. Therefore, collecting human brain tissue for research should include matching for several factors, both ante-mortem and post-mortem. Some of the most important ante-mortem factors include age, sex, agonal state, seasonal alterations, circadian variation and clock time of death. The post-mortem factors which should be matched for include the post-mortem delay, fixation and storage time and lateralization. The material and data on aging and dementia, collected by the Netherlands Brain Bank in the past six years will serve in the present paper to illustrate the wide variety of potentialities and pitfalls in the use of post-mortem human brain tissue. Brain Bank organizations for various neurological diseases form at present an important clinico-pathological link in aging and dementia research and the availability of post-mortem human brain tissue makes it possible to investigate those diseases for which no animal model is available. In order to provide research groups with post-mortem brain tissue from Alzheimer's disease (AD) patients and controls, a brain bank was established by the end of 1985 in The Netherlands Institute for Brain Research. This brain bank is based upon research projects submitted in advance, specifying a variety of requirements such as: total number of brains needed, kind of fixation, agonal state, post-mortem delay, exact anatomical boundaries of the brain region, kind of fixation and other treatment requirements of the tissue. This Brain Bank has got two unique features: 1. Human brain tissue is obtained by means of rapid autopsies with a very short post-mortem delay, ranging between 2-4 hour. 2. Fresh brain dissection procedure is used, which is a difficult regime to establish, requiring qualified staff at inconvenient times. This dissection procedure is necessary for the immediate use of fresh tissue and advantageous in increasing the range of morphological, neurochemical, immunocytochemical, metabolic and other procedures which can be applied to tissues fixed in a different way or rapidly frozen brain tissue free of freezing artifacts.

Aging↗
PubMed1992

Tau and ubiquitin in the human hypothalamus in aging and Alzheimer's disease.

Immunocytochemical staining of hypothalamic cell groups with four antibodies to Alzheimer paired helical filaments (PHF) (i.e., anti-PHF serum 60e and monoclonal antibody (mAb) Alz-50, both directed against normal and abnormally phosphorylated tau; mAb tau-1, which recognizes tau; and mAb 3-39 to PHF, which recognizes the carboxy terminal domain of ubiquitin) revealed a clear distinction between 12 Alzheimer's disease (AD) patients and seven controls in the hypothalamus. Dystrophic neurites, which appeared to be the most specific components in AD, were most conspicuous after Alz-50 staining. However, Alz-50 also stained neuronal cytoplasm and normal, thin, beaded neurites in the paraventricular nucleus (PVN) of controls, even of young cases. This staining was clearly distinct from the staining of cytoplasm and dystrophic neurites in the PVN of Alzheimer patients. The abundant staining of dystrophic neurites and cell bodies in the nucleus tuberalis lateralis (NTL) in AD, in which no neuronal loss is observed, suggests that alterations in cytoskeletal markers do not necessarily indicate impending cell death. Moreover, the cytoskeletal changes in the NTL, sexually dimorphic and suprachiasmatic nuclei in AD indicate that this condition is not restricted to cortical areas or nuclei projecting to the cortex. Consequently, the pathophysiological implications of cytoskeletal staining in AD are at present far from clear. The human hypothalamus may not only provide a better insight into the pathogenesis of Alzheimer's disease, but could also be of help in the neuropathological diagnosis of this condition.

Aged↗