bluuebunny/crossref_metadata_2025 huggingface dataset:
ALZHEIMER'S DISEASE: PAIRED HELICAL FILAMENTS AND CYTOMEMBRANES
Authors: GRAY E. G. , PAULA‐BARBOSA M. , ROHER A.
Published: May 2008

Observations were made with the electron microscope on biopsies from the frontal cerebral cortex of four patients showing the clinical symptoms of advanced Alzheimer's disease (AD). Sections from all four biopsies showed neuronal dendrites, and to a lesser extent, perikarya, packed with paired helical filaments (PHFs) and a correlated complete loss of the normal content of microtubules. It was usually impossible to visualize the beginning and end of the PHF since it passed out of the plane of section. However, not infrequently, PHFs could be seen apparently arising at or from the surfaces of eytomembranes. Such membranes (in perikarya or dendrite) often formed irregular stacks or lamellated bodies. These membranes were invariably agranular (i.e. not studded with ribosomes) and so might be considered as pathological forms of smooth endoplasmic reticulum (SER). A correlation is established between the known biochemical nature of PHFs and their postulated membrane origin.
A UNIFYING CONCEPT ON THE PATHOGENESIS OF BRAIN OEDEMAS
Authors: JOÓ F.
Published: May 2008

The molecular mechanisms operating within the cerebral endothelium have been analysed in relation to the formation of brain oedema states. With respect to their pathogenesis, the activation of a cyclic nucleotide‐generating system and lipolysis seems in particular to be of neuropathological importance. As these molecular mechanisms were seen to be activated in oedemas with primary vascular reactions and in those following ischaemic brain injury, it is proposed that, from a pathogenetic point of view, brain oedemas have a common vascular origin.
NEUROTOXICITY IN PRIMARY SENSORY NEURONS OF ADRIAMYCIN ADMINISTERED THROUGH RETROGRADE AXOPLASMIC TRANSPORT IN RATS
Authors: KONDO A. , OHNISHI A. , NAGARA H. , TATEISHI J.
Published: May 2008

Neurotoxic effects of adriamycin (ADM) were examined in rats. The drug was administered through retrograde axoplasmic transport from the transected sciatic nerve in very small amounts (0.05 mg of adriamycin). Using the autofluorescence specific to adriamycin as a histological tracer, alterations in primary sensory neurons in dorsal root ganglia (DRG) and in motor neurons in the spinal cord were observed chronologically by light and electron microscopy. In the DRG at the fifth and sixth lumbar levels, small neurons initially showed alterations in mitochondria, wavy nuclear membranes and enlarged cisternae of rough endoplasmic reticulum, and disappeared early in the experiments. Large neurons, which showed accumulation of neurofilaments, dense bodies and vacuoles in the perikarya in addition to nucleolar and nuclear chromatin alterations, degenerated slowly. In contrast, motor neurons in the anterior horn at the sixth lumbar level survived throughout the administration of adriamycin despite the presence of transient weak adriamycin autofluorescence and vacuoles in the cytoplasm. Thus, the susceptibility and vulnerability of motor neurons in spinal cord to adriamycin differed from that of primary sensory neurons; small neurons in the DRG were more susceptible than large sensory neurons. Administration through retrograde axoplasmic transport proved to be a useful technique for the evaluation of the neurotoxicity of adriamycin without the complications of systemic effects.
TRIPHENYL PHOSPHITE NEUROPATHY DIFFERS FROM ORGANOPHOSPHORUS‐INDUCED DELAYED NEUROPATHY IN RATS
Authors: VERONESI B. , DVERGSTEN C.
Published: May 2008

The topographies of neuropathic damage produced by triphenyl phosphite (TPP) and tri‐ortho‐cresyl phosphate (TOCP) are contrasted in the present study. Long‐Evans, male rats were exposed (sc) to single (0.1ml kg‐1; 1.0 ml kg‐1) or multiple (2×1.0 ml kg‐1; 3×1.0 ml kg‐1) doses of TPP, and sampled 1–3 weeks after exposure. Additional animals were dosed acutely with TOCP (1160 mg kg‐1, p.o.) alone or in combination with multiple doses of TPP (2×1 ml kg‐1). Functional changes, seen in multiple‐dosed TPP‐rats included tail‐kinking, circling, and ataxia. Neuropathological damage seen in all but the 0.1 ml kg‐1 treated animals consisted of degeneration of the ventrolateral and ventral columns of the spinal cord at all levels, and moderate peripheral nerve fibre damage. Medullary brainstem involvement consisted of axonal swellings and fragmented axons in the medial longitudinal fasciculus, the reticular formation, and the inferior cerebellar peduncles. Tissues examined from TOCP‐treated rats displayed severe degeneration of the fasciculus gracilis at the cervical level, mild involvement of the dorsolateral columns at the lumbar levels and a sparing of all other cord and brainstem regions. Rats treated with neuropathic doses of both TPP and TOCP showed a composite pattern of degeneration that included damaged sites characteristic of the individual neurotoxicants. These data indicate that the neuropathic profile of TPP differs markedly from the delayed neuropathy (OPIDN) associated with exposure to model organophosphorus compounds such as TOCP.
BRAIN DAMAGE IN NON‐MISSILE HEAD INJURY SECONDARY TO HIGH INTRACRANIAL PRESSURE*
Authors: GRAHAM D. I. , LAWRENCE A. E. , ADAMS J. H. , DOYLE D. , McLELLAN D. R.
Published: May 2008

A comprehensive neuropathological analysis was undertaken on 434 patients who died as a result of a non‐missile head injury in order to determine the frequency and extent of brain damage secondary to high intracranial pressure (ICP) in head injury. Using the criterion of pressure necrosis in the parahippocampal gyrus as evidence of high ICP due to a supratentorial expanding lesion, it was established that the ICP had been high in 324 cases. In 42 of these there was no other brain damage attributable to a high ICP. There was evidence of secondary brain stem damage in 221 cases and in 44 of these the damage could be seen only microscopically. In 54 cases there was a contralateral peduncular lesion. Other abnormalities were infarction in the territories of various arteries and in the anterior lobe of the pituitary. There was a supracallosal hernia in 80 cases and haemorrhage in the oculomotor nerves in 48 cases. These results further emphasise the frequency and range of brain damage due to secondary vascular factors brought about by high ICP in a patient who has sustained a head injury.
ANTIGENIC EXPRESSION BY CELLS DERIVED FROM HUMAN GLIOMAS DOES NOT CORRELATE WITH MORPHOLOGICAL CLASSIFICATION
Authors: KENNEDY P. G. E. , WATKINS B. A. , THOMAS D. G. T. , NOBLE M. D.
Published: May 2008

Antigenic expression by cells derived from human gliomas does not correlate with morphological classification

We have found that cell populations derived from human gliomas can be divided into antigenic classes which are not predictable on the basis of standard morphological analysis and which, most frequently, do not support the lineage assignations of various tumours as determined by traditional neuropathological methods. For example, only 6/60 cultures derived from astrocytomas expressed glial fibrillary acidic protein (GFAP), an astrocyte specific marker, and all six of these cultures were derived from morphological categories which more frequently gave rise to populations which did not express GFAP. None of the seven oligodendrogliomas or four oligo‐astrocytomas examined expressed antigens specifically expressed by oligodendrocytes. Most tumour‐derived populations, from all classes of tumour and all grades of malignancy, expressed cell‐surface fibronectin, an extracellular matrix protein only rarely found on the surfaces of CNS macroglia; such cells did not express glial‐specific antigens (e.g., GFAP) in vitro. Investigation of antigen expression in tumour biopsies indicated that some tumours also consisted largely or wholly of cells which expressed fibronectin in situ. Fibronectin‐expressing cells were aneuploid and were not contact inhibited in their growth, indicating that they were transformed cells. We have also identified two previously unknown antigenic phenotypes among the gliomas.
1,3‐DINITROBENZENE‐INDUCED ENCEPHALOPATHY IN RATS
Authors: PHILBERT M. A. , NOLAN C. C. , CREMER J. E. , TUCKER D. , BROWN A. W.
Published: May 2008

1,3‐Dinitrobenzene‐induced encephalopathy in rats

Exposure to 1,3‐dinitrobenzene (1,3‐DNB) in humans induces methaemoglobinaemia, nausea and nervous symptoms. When given to conventional rats, twice‐daily oral doses of 10mgkg‐1 1,3‐DNB produce methaemoglobinaemia and frequently ataxia after four or five doses. In germ free rats given only a single oral dose of 20mgkg‐1, similar symptoms occur but are of more rapid onset. Light and electron microscope examinations reveal an acute thiamine deficiency‐like lesion in the brain stems of both ataxic and apparently normal rats. Bilaterally symmetrical vacuolated lesions involve cerebellar roof, vestibular and superior olivary nuclei and the inferior colliculi. Frequent petechial haemorrhages are associated with these lesions, the erythrocytes usually being limited to enlarged Virchow‐Robin spaces but sometimes spreading more widely. The primary cellular targets appear to be astrocytes, oligodendrocytes and vascular elements with secondary neuronal involvement. It is suggested that 1,3‐DNB interferes with intracellular redox mechanisms resulting in impaired glucose oxidation.
EPITHELIAL MEMBRANE ANTIGEN EXPRESSION IN EPENDYMOMAS
Authors: CRUZ–SANCHEZ F. F. , ROSSI M. L. , ESIRI M. M. , READING M.
Published: May 2008

Epithelial membrane antigen expression in ependymomas

Twenty–seven ependymomas were studied (18 ‘benign’ or low grade and nine ‘malignant’ or high grade) by means of a monoclonal antibody to epithelial membrane antigen (E29) and an antiserum to glial fibrillary acidic protein (GFAP). The E29 antibody reacted with ‘benign’ ependymomas but not with ‘malignant’ ones. Staining was located on the cell surface and especially that facing rosette lumina. Cells forming papillary structures and ependymal epithelium showed a similar distribution of staining. Glial fibrillary acidic protein (GFAP) reactivity was seen in all tumours, with a perivascular accentuation in ‘malignant’ ones. Staining occurred in the cytoplasm of scattered cells and in those forming papillary structures, ependymal epithelium and rosettes. Our results may have implications in relation to the cytogenesis of these tumours and may also be useful in the histological assessment of ‘benign’versus‘malignant’ ependymomas.
CORRELATION OF TRIPHENYLTETRAZOLIUM CHLORIDE PERFUSION STAINING WITH CONVENTIONAL NEUROHISTOLOGY IN THE DETECTION OF EARLY BRAIN ISCHAEMIA
Authors: PARK C. K. , MENDELOW A. D. , GRAHAM D. I. , McCULLOCH J. , TEASDALE G. M.
Published: May 2008

Correlation of triphenyltetrazolium chloride perfusion staining with conventional neurohistology in the detection of early brain ischaemia

Triphenyltetrazolium chloride (TTC) has been used to detect experimental brain ischaemia but its accuracy has not been established fully, especially in models of early brain ischaemia. We have developed a technique that combines TTC–staining and perfusion–fixation with formalin in the same specimen.

The left middle cerebral artery of 12 rats, anaesthetized with halothane were exposed via a subtemporal approach and occluded for 4 h. The animals were perfused transcardially with TTC (2%) and formalin (10%). The forebrain was sliced and the size of the ischaemic area, delineated by TTC, was measured. The brain slices were then processed for light microscopy, and the amount of ischaemic damage determined. The ischaemic volumes of the hemisphere and cortex assessed by TTC (127–4 ± 21–7 mm3 and 18–4 ± 30 mm3) were larger than the volumes measured by microscopy (104–3 ± 16–6 mm3 and 15–2 ± 3–6 mm3) but there was no statistical difference between them. Correlation of the ischaemic volumes in hemisphere and cortex between the two methods was good (r2= 0–9221, P < 001 and r2= 0–9243, P < 0001), but the correlation of the ischaemic areas at specific coronal planes was poor. The ischaemic volume of caudate nucleus measured by TTC (15–2 ± 3–6 mm3) was smaller than the volume assessed by microscopy (18–4 ± 3–0 mm3) and the correlation was poor (r2= 0–6650)

It is concluded that TTC–staining provides only an approximation of the amount of early ischaemic brain damage subsequently identified by conventional light microscopy.
THE mdx MOUSE SKELETAL MUSCLE MYOPATHY: II. CONTRACTILE PROPERTIES
Authors: COULTON G. R. , CURTIN N. A. , MORGAN J. E. , PARTRIDGE T. A.
Published: May 2008

The mdx mouse skeletal muscle myopathy: II. Contractile properties

The contractile properties of soleus muscles from mdx and control mice aged between 26 and 350 days were compared with those of muscles from similarly aged control mice. Mdx mice were in general heavier (their individual soleus muscles were also heavier), of greater cross–sectional area and greater standard length than age–matched controls. Isometric forces produced by soleus muscles from young mdx mice (≤ 100 days) were similar to controls, but were weaker when force was normalized for crosssectional area. Conversely, although the absolute isometric forces produced by older (>100 days) mdx muscles were greater than age–matched controls, when normalized for cross–sectional area they were similar. No differences were found between mdx and control muscles in terms of length–force or force–velocity relationships.

Thus, young mdx control muscles produce similar absolute isometric force but mdx mouse muscles are larger. When muscle size is accounted for, in terms of cross–sectional area, younger mdx muscles are, therefore, weaker than controls. Inefficient contraction of young mdx muscles may result from lack of contractile fibres, physiological inefficiency of contractile fibres, or loss of tendon–fibre continuity during muscle fibre necrosis and regeneration. The striking supernormal size and strength of older mdx muscles reflects their considerable regenerative capacity; whether this is due to an increase in muscle fibre number rather than fibre hypertrophy remains unclear.
FOCAL DENDRITIC SWELLINGS IN PURKINJE CELLS IN MUCOPOLYSACCHARIDOSES TYPES I, II AND III. A GOLGI AND ULTRASTRUCTURAL STUDY
Authors: FERRER I. , CUSÍ V. , PINEDA M. , GALOFRÉ E. , VILA J.
Published: May 2008

Focal dendritic swellings in Purkinje cells in mucopolysaccharidoses types I, II and III

Focal dendritic swellings in secondary dendrites of Purkinje cells were observed in post–mortem samples of the cerebellum processed by the Golgi method from three patients affected by mucopolysaccharidoses (MPS) types I–H, II and III. These focal dendritic swellings exhibited smooth surfaces but secondary formation of spine–like appendages was absent; in contrast, terminal, spiny branchlets were preserved. Complementary electron–microscopical examination of these samples revealed that membranous cytoplasmic bodies and zebra–like inclusions accounted for the material stored in these focal swellings in MPS I–H and MPS II; in addition, granulomembranous cytosomes with fine, densely–packed membranous profiles were encountered in MPS III.

Focal dendritic swellings in Purkinje cells may result in abnormal electrical activity, thus producing informational imbalance on the Purkinje cell dendritic arborization in human mucopolysaccharidoses.
IMMUNOSTAINING OF SCRAPIE CEREBRAL AMYLOID PLAQUES WITH ANTISERA RAISED TO SCRAPIE–ASSOCIATED FIBRILS (SAF)
Authors: McBRIDE P. A. , BRUCE M. E. , FRASER H.
Published: May 2008

Immunostaining of scrapie cerebral amyloid plaques with antisera raised to scrapie–associated fibrils (SAF)

Brain sections from 16 different mouse scrapie models were immunostained with antisera to scrapie–associated fibrils (SAF) from three experimental scrapie sources (hamster 263K, mouse ME7 and mouse 22L). These models involved seven strains of scrapie injected intracerebrally or intraperitoneally into a range of inbred mouse strains, producing a wide variety of neuropathological changes. The only brain structures which were positively immunostained were amyloid plaque cores in those models in which plaques could be readily identified using traditional amyloid stains. The intensity of immunostaining correlated with the density of amyloid in the cores, as detected by Congo red and thiofiavine S staining. No differences in immunostaining specificity were found between antisera or between plaques in different combinations of scrapie strain and mouse genotype. There were also no differences in immunoreactivity between plaques in different parts of the brain. These results strongly suggest that SAF and histologically detectable amyloid in scrapie mice are derived from the same precursor protein. Scrapie–associated cerebrovascular amyloid and plaques in sheep and goats also gave positive immunostaining with SAF antisera, although the lesions in the natural disease could only be stained after formic acid pretreatment. Senile plaques in Alzheimer's disease and Down's syndrome, although structurally similar to scrapie amyloid plaques, were found to be completely negative for SAF, in agreement with previous biochemical and immunocytochemical findings.
NECROTIZING VASCULITIS OF THE NERVOUS SYSTEM IN A PATIENT WITH AIDS–RELATED COMPLEX
Authors: VINTERS H. V. , GUERRA W. F. , EPPOLITO L. , III P. E. KEITH
Published: May 2008

Necrotizing vasculitis of the nervous system in a patient with AIDS‐related complex

A patient with AIDS‐related complex (ARC) presented with a fulminant neurologic syndrome suggestive of ascending myelopathy, and died approximately 48 h after admission to hospital. At necropsy, there was evidence of a severe necrotizing vasculitis affecting the nervous system most severely, with multifocal haemorrhagic necroses of the spinal cord and cauda equina. Although a rare intranuclear inclusion suggestive of herpesvirus infection was seen in the predominantly lympho‐histiocytic infiltrate in and around blood vessel walls, the precise aetiology of the angiitis was not apparent. It may represent a response to AIDS virus infection of one or more components of the blood vessel wall.
STRUCTURAL CHANGES IN THE RAT BRAIN AFTER CAROTID INFUSIONS OF HYPEROSMOLAR SOLUTIONS: A LIGHT MICROSCOPIC AND IMMUNOHISTOCHEMICAL STUDY
Authors: SALAHUDDIN T. S. , JOHANSSON B. B. , KALIMO H. , OLSSON Y.
Published: May 2008

Salahuddin T. S., Johansson B. B., Kalimo H. & Olsson Y. (1988)Neuropathology and Applied Neurobiology14, 467–482

Structural changes in the rat brain after carotid infusions of hyperosmolar solutions: a light microscopic immunohistochemical study

A solution of mannitol or urea was infused into the carotid artery of rats to open the blood–brain barrier (BBB) and to find out if such a procedure results in brain injury. Paraformaldehyde–fixed, paraffin–embedded material was available to determine the localization and extent of albumin extravasation by immunochemistry. Other light microscopic and immunocytochemical techniques were applied on consecutive sections to find out if structural damage had occurred.

The cerebral cortex, the hippocampus and the basal ganglia of the infused brain hemisphere contained within regions of albumin extravasation scattered, collapsed, acidophilic neurons. In addition, there were multifocal lesions with marked sponginess of the neuropil which contained numerous shrunken, acidophilic neurons and a perifocal astrocytic gliosis. A moderate macrophage infiltration was present in rats with 72 h survival.

In conclusion, infusion of hypertonic mannitol or urea into the carotid artery of the rat may result in structural brain damage within regions showing BBB injury. The presence of acidophilic neurons and the macrophage response indicate that some of the brain changes are irreversible.
THE SIGNIFICANCE OF THE LEWY BODY IN THE DIAGNOSIS OF IDIOPATHIC PARKINSON'S DISEASE
Authors: GIBB W. R. G. , LEES A. J.
Published: May 2008

The significance of the Lewy body in the diagnosis of idiopathic Parkinson's disease

A retrospective study of 269 patients with a clinical diagnosis of Parkinson's syndrome was carried out. Seventy‐eight were selected as cases of Parkinson's disease on the basis of generally accepted criteria. Of these, 73 were found to have Lewy bodies and cell loss in the substantia nigra, two had the pathological changes of striatonigral degeneration, two had extensive neurofibrillary tangles and nigral cell loss compatible with post‐encephalitic parkinsonian syndrome, and one had Lewy bodies and striatonigral degeneration. Pathological examination of the remaining brains revealed Lewy bodies with cell loss in the nigra, a different pathological diagnosis, or normal basal ganglia. No unclassifiable ‘senile’ patients, or cases with neurofibrillary tangle degeneration or extranigral pathology of unknown cause were found. As a result of these findings clinico‐pathological diagnostic criteria for Parkinson's disease are proposed. All patients with this diagnosis had Lewy bodies in surviving neurons of two unilateral 7 m̈mi sections of the mid‐part of the substantia nigra. The frequency of Lewy bodies in multiple system atrophy, Steele‐Richardson‐Olszewski syndrome and Alzheimer's disease was low and similar to that in age‐matched ‘normal’ controls. Pathological findings were compatible with the notion that these individuals have preclinical or coincidental Parkinson's disease.
THE IMMUNOHISTOCHEMICAL DEMONSTRATION OF SUBSEQUENCES OF THE PRECURSOR OF THE AMYLOID A4 PROTEIN IN SENILE PLAQUES IN ALZHEIMER'S DISEASE
Authors: ISHII T. , KAMETANI F. , HAGA S. , SATO M.
Published: May 2008

The actual presence of the predicted precursor of Alzheimer's disease amyloid A4 protein, reported by Kang et al. (1987) in the Alzheimer brain, has yet to be verified. To identify the various regions of this precursor, antibodies were raised against three synthetic polypeptides, R35 (residues 274–286), R36 (residues 527–540), and R37 (residues 681–695), subsequences of the precursor protein; the specificity of these antibodies was ascertained by ELISA. Upon immunohistochemical examination, the antibody to R35 failed to react, but the antibody to R36 (the extracellular part) stained the amyloid of senile plaques and the staining pattern was identical to that of anti–A4 antibody. The antibody to R37 (the C–terminal intracellular part) stained what may be degenerating neurites in senile plaques whereas the amyloid remained unstained. An anti–neurofilament (NF) antibody reacted with some of the R37–positive grains, but R37–negative grains also were seen. Further, some R37–positive grains were not stained by the anti–NF antibody. The anti–GFAP antibody and the anti–macrophage antibody did not stain the R37–positive grains. These findings indicate that the amyloid protein in senile plaques actually contains a larger polypeptide than the A4 protein, and suggest that the intracellular C–terminal part of the precursor may exist in the degenerated neurites seen in senile plaques.
IMMUNOELECTRON MICROSCOPY OF ALZHEIMER AND PICK BRAIN TISSUE LABELLED WITH THE MONOCLONAL ANTIBODY ALZ–50
Authors: LOVE S. , BURROLA P. , TERRY R. D. , WILEY C. A.
Published: May 2008

Previous studies have shown that Alzheimer and Pick brains contain abnormally elevated amounts of a 68Kd protein detected by the monoclonal antibody Alz–50. We have used immunoperoxidase and immunological techniques to localize Alz–50–reactive epitopes in sections from Alzheimer and Pick brains at the ultrastructural level. Detectable immunoreactivity was restricted to the paired helical filaments of Alzheimer neurofibrillary tangles and to the paired helical and straight filaments of Pick bodies. In Alzheimer tissue, the antibody also labelled scattered neuronal paired helical filaments that were not aggregated into neurofibrillary tangles. Amorphous components of Pick bodies and other constituents in the Alzheimer and Pick brain tissue were not immunostained.
PROGNOSIS IN MALIGNANT GLIOMA: A RETROSPECTIVE STUDY OF BIOPSY SPECIMENS BY FLOW CYTOMETRY
Authors: JIMENEZ O. , TIMMS A. , QUIRKE P. , McLAUGHLIN J. E.
Published: May 2008

The DNA ploidy of a series of 78 gliomas has been estimated by flow cytometry using cell suspensions prepared from paraffin embedded material. Apart from two oligodendrogliomas the tumours were all astrocytomas. Forty–nine (63%) tumours were found to have a diploid DNA distribution and 29 (37%) an aneuploid DNA distribution. The two oligodendrogliomas were both DNA aneuploid. No correlation was found between DNA ploidy and histological grade or DNA ploidy and survival. Both ploidy groups appear to have responded equally to therapy. In this study the factors associated with a short survival were advancing age and the presence of vascular endothelial proliferation, while the DNA ploidy and the cytological features do not appear as useful in predicting survival when examining biopsy material.
EARLY SENILE PLAQUES IN DOWN'S SYNDROME BRAINS SHOW A CLOSE RELATIONSHIP WITH CELL BODIES OF NEURONS
Authors: ALLSOP D. , HAGA S. I. , HAGA C. , IKEDA S. I. , MANN D. M. A. , ISHII T.
Published: May 2008

A sensitive methenamine silver/Nissl stain was used to study the morphology and relationship of pre–plaques (presumed early senile plaques) in Down's syndrome brains to glial nuclei, capillaries and neuronal perikarya. The larger pre–plaques (> 50 μm) usually encompassed all of these tissue elements. However, the smaller pre–plaques (< 50 μm) were almost always found immediately adjacent to, or around the cell bodies of neurons (often with associated satellite cells), and they failed to show any consistent, close spatial relationship to the other tissue components. Thus we consider an early stage of pre–plaque formation to be the deposition of amyloid adjacent to the cell body of a morphologically normal neuron. Based on the study of transitional forms, we suggest that the amyloid progressively accumulates around the cell body until the enclosed neuron degenerates. How these pre–plaque lesions might eventually develop into the typical plaque structure is uncertain. Our observations support the theory of a neuronal origin for plaque amyloid.
COMPARISON OF SEVEN STAINING METHODS FOR SENILE PLAQUES AND NEUROFIBRILLARY TANGLES IN A PROSPECTIVE SERIES OF 15 ELDERLY PATIENTS
Authors: LAMY C. , DUYCKAERTS C. , DELAERE P. , PAYAN CH. , FERMANIAN J. , POULAIN V. , HAUW J. J.
Published: May 2008

Samples of brain from 15 prospectively tested women over 75 years of age, living in the same institution and with a Blessed test score between 0 and 28 were studied to evaluate seven different staining techniques for counting senile plaques and neurofibrillary tangles. The methods included Bielschowsky (modified by Yamamoto & Hirano, 1986), Cross, Gallyas, Naoumenko–Feigin, silver methenamine, Bodian coupled with luxol fast blue, and thioflavine S; these techniques were performed on contiguous slides of the first temporal gyrus (Brodmann's area 22). The cost, difficulty and variability of the methods were evaluated. Modified Bielschowsky method revealed both amyloid and neurites. Cross, Bodian and Gallyas stained neurites preferentially and were more sensitive for neurofibrillary tangles than for senile plaques. Silver methenamine revealed amyloid in much the same way as thioflavine S. The highest count of senile plaques and neurofibrillary tangles was obtained with the modified Bielschowsky method. Best correlations between density of senile plaques and Blessed test score were obtained with modified Bielschowsky impregnation, silver methenamine, and Bodian and those for neurofibrillary tangles, with modified Bielschowsky, Naoumenko–Feigin, and Gallyas methods. Naoumenko–Feigin impregnation, even if fitted to the linear model, revealed very few changes (four times less than modified Bielschowsky) and appeared to be insensitive. All the techniques except Naoumenko–Feigin, were equally able to distinguish two groups of cases, i.e. those affected by Alzheimer's disease and those not affected. A multiple regression analysis indicated that the statistical relationship between the density of changes, evaluated after the modified Bielschowsky method, and the Blessed test score could not be improved by the additional use of other staining techniques.

These data have direct implications for the evaluation of diagnostic criteria in Alzheimer's dementia. In this study, modified Bielschowsky impregnation was found to give the most complete picture of the lesions and, as such, could be considered a reference method. This technique is, however, expensive and difficult to perform. It stains a large number of normal structures and the recognition of the lesions is more subjective than with other selective stains. It is therefore difficult to recommend this technique for routine use. Other techniques alone, or in combination, can be recommended but the diagnostic criteria should be adapted for each of them.
Notes from the graveyard: neuropathology and schizophrenia*
Authors: ROBERTS G. W. , BRUTON C. J.
Published: May 2008

Schizophrenia is commonly regarded as a ‘functional’ psychosis, the implication being that the delusions, hallucinations and cognitive impairment characteristic of the disease have no organic basis. This view is due in no small way to the failure of pathologists to find convincing pathological changes associated with the disease in the first seven decades of the century. Over the last 10 years things have changed considerably. Recent CT and MRI scan studies have provided convincing evidence of significant ventricular enlargement in the brains of schizophrenics and post‐mortem studies have shown that schizophrenic brains are about 6% lighter than controls and have a reduced volume and reduced antero‐posterior length.

Planimetric studies on post‐mortem material and a recent MRI study show that medial temporal lobe structures (parahippocampal gyrus, hippocampus and amygdala) are preferentially affected. Although other brain regions (e.g. cingulate gyrus, frontal cortex) also show alterations they appear to be ‘downstream’ from the regions primarily affected. Morphological studies show that there is a loss of neurons from medial temporal lobe structures and indicate irregularities in their cytoarchitectonic arrangement. The alterations in structure are not associated with degenerative, inflammatory, or abnormal vascular processes. There has been much debate as to the possible causes of the structural changes and whether they are limited to particular ‘types’ or sub‐groups of schizophrenics. At present it seems simpler to suppose that all schizophrenics have a degree of structural abnormality which may differ in degree but not in kind.

It has been proposed that the changes in brain structure in schizophrenia are the result of an anomaly of brain development. In the last year CT and MRI studies have shown that ventricular enlargement precedes clinical symptoms and is not progressive. These studies support the developmental interpretation. Future studies will need to focus on (a) the mechanisms (Probably genetic) which can cause such developmental anomalies, (b) the neurochemical perturbations occurring as a result of such anomalies and (c) how both relate to clinical symptoms.
A morphological analysis of senile plaques in the brains of nondemented persons of different ages using silver, immunocytochemical and lectin histochemical staining techniques
Authors: MANN D. M. A. , BROWN A. M. T. , PRINJA D. , JONES D. , DAVIES C. A.
Published: May 2008

The prevalence and severity of senile plaque (SP) formation was investigated in the cerebral cortex, hippocampus and amygdala of 60 non‐demented individuals of age range 6–84 years, using immunocytochemical (anti‐A4 amyloid, anti‐PHF protein), lectin histochemical (Con A binding) and silver (Methenamine (MS) and Palmgren), staining methods. By at least one of these methods, 18 patients showed the presence of SP within one or more of these brain regions; 15 of these patients were over 60 years of age. Comparisons between each staining method showed that, in the hippocampus and amygdala all five methods detected the presence and number of SP equally well, whereas, in the cerebral cortex, MS and anti‐A4 staining demonstrated more SP in a greater number of patients than did either Con A or Palmgren silver and anti‐PHF staining. The additional SP detected by these former two staining methods contained diffuse deposits of amyloid (A4) protein, and sometimes also large clumps of Con A positive material, but no neurites as detected by Palmgren or anti‐PHF staining. Such SP closely resemble those seen in the cerebral cortex of young patients with Down's syndrome, and which are thought to be an early form of SP. The relationship between the pathological changes in these non‐demented patients and a possible diagnosis of early Alzheimer's disease is discussed.
Repair of the ependyma in hydrocephalic brains
Authors: COLLINS P. , FAIRMAN S.
Published: May 2008

Hydrocephalus was induced in 12‐day‐old rats by the cisternal infusion of concentrated kaolin suspension. At 19 days of age, a lesion, 100 or 150 μm in diameter, was made in the ependymal lining of the lateral ventricles. Animals were killed at intervals from 1 h to 20 days after the lesion was made. The damaged area was examined by scanning electron microscopy, light and transmission electron microscopy. Between 1 h and 48 h the hole was still open. Small round cells, identified as free subependymal cells, were associated with the edges of the hole from 1 h after the lesion was made. From 48 h, the lesion was completely covered with cell bodies and their processes and no hole was present. Signs of differentiation were seen in the free subependymal cells from 4 days, the cells becoming more electron lucent. By 15 days, three types of cell arrangement were seen within the damaged area: 1 clusters of small cells, with few processes, resembling subependymal cells; 2 small numbers of cells with flat cytoplasmic processes which formed the lining of the ventricular wall; 3 clusters of cells with long thin processes attached to the surface of the ventricular wall but not forming the ependymal lining. The results of this study suggest that, in the hydrocephalic brain, ependymal damage and the repair of a defect within the ventricular wall is initiated by subependymal cells.
Pathogenicity of Semliki Forest virus for the rat central nervous system and primary rat neural cell cultures: possible implications for the pathogenesis of multiple sclerosis
Authors: ATKINS G. J. , SHEAHAN B. J. , MOONEY D. A.
Published: May 2008

The neurovirulent L10 strain of Semliki Forest virus (SFV) causes extensive neuronal damage in the central nervous system (CNS) of infected rats, and is probably the cause of death. The avirulent A7 and M9 strains do not cause extensive neuronal damage, but do induce immune‐mediated CNS demyelination. In primary CNS cell cultures derived from rats, L10 multiplies more rapidly in neurons than avirulent strains, but infection with both virulent and avirulent strains causes depletion of oligodendrocytes from mixed glial cell cultures. It is proposed that the immune‐mediated demyelination, which follows infection with avirulent strains, is induced by phagocytosis of myelin debris from infected oligodendrocytes, and the presentation of antigens derived from such debris to T‐helper lymphocytes. Based on these and previous results, a scheme for the pathogenicity of defined strains of SFV is proposed. The applicability of this scheme to the understanding of human demyelinating disease such as multiple sclerosis is discussed.
New insights in motor neuron disease
Authors: MARTIN J. E. , SWASH M. , SCHWARTZ M. S.
Published: May 2008

In motor neuron disease there is a characteristic pattern of nerve cell loss and degeneration of related pathways. In surviving anterior horn cells several morphologically distinct, but generally non‐specific, intracytoplasmic inclusion bodies have been recognized. Recently accumulations of previously unrecognized ubiquitinated material have been described in surviving neurons, which cannot be demonstrated with routine histological methods. These changes appear unique to this disease, and provide a new insight into the underlying pathology that may help understand the pathogenesis of this intriguing disorder. In this article we review the new information on the clinical, toxicological and pathological features of the disease.
A study of glutamine synthetase in normal human brain and intracranial tumours
Authors: McCORMICK D. , McQUAID S. , McCUSKER C. , ALLEN I. V.
Published: May 2008

A study of glutamine synthetase in normal human brain and intracranial tumours. Glutamine synthetase (GS) activity was measured in selected areas of three normal brains and in 262 biopsies from patients with suspected intracranial tumours. In general, levels were higher in grey matter than in white matter and the highest activities of all were found in the hypothalamus which is consistent with its high glutamatergic activity. In the biopsy material, GS activity was greatest in gliotic brain, in keeping with the predominantly astrocytic localization of the enzyme. High levels were also found in astrocytomas and oligodendrogliomas but there was considerable variation between tumours, suggesting a random loss of GS expression during neoplastic transformation or heterogeneity in their cellular origin. The immunocytochemical demonstration of GS in neoplastic oligodendrocytes and in meningioma cells argues against absolute cell‐type specificity for this enzyme.
Ubiquitin, cell stress and diseases of the nervous system
Authors: LOWE J. , MAYER R. J.
Published: May 2008

Cells, including those of the nervous system, respond to damage by an increase in the synthesis of a family of proteins called ‘stress proteins’ which are amongst the most conserved gene products in evolution suggesting fundamental roles in cell metabolism. Stress‐induced proteins have functions in normal cells, particularly for the importation of protein into membrane‐limited organelles, and their up‐regulation following stress is thought to be cytoprotective, by protecting proteins and organelles from damage. Ubiquitin is an important protein induced by cell stress. It is only found in nucleated cells and has several known functions; the most investigated being as a co‐factor for the non‐lysosomal intracellular degradation of abnormal or short lived proteins.

Morphological studies using immunohistochemistry to localize ubiquitin protein conjugates have revealed that ubiquitin is a component of many of the filamentous inclusion bodies characteristic of neurodegenerative diseases, suggesting activation of a common neuronal response in this type of disease process. Immunohistochemical localization of ubiquitin conjugates has provided a new tool for the sensitive detection of such inclusions and has resulted in the identification of novel inclusion bodies in all cases of motor neuron disease.

Preliminary work on enzymes involved in ubiquitin metabolism suggest that there are several possible mechanisms for the formation of inclusion bodies and may provide indirect evidence for the dynamics of inclusion body formation.

Work in other areas of pathology indicate important roles for the stress proteins in immune surveillance and autoimmunity and it is likely that the general principles which are currently evolving will also have an impact in neuropathology
Glutathione S‐transferase in human brain
Authors: CARDER P. J. , HUME R. , FRYER A. A. , STRANGE R. C. , LAUDER J. , BELL J. E.
Published: May 2008

The glutathione S‐transferases are a complex group of multifunctional enzymes which may detoxify a wide range of toxic substances including drugs and carcinogens. Different isoenzymes vary in substrate specificity, tissue distribution and level of expression during development. Following reports of cell‐specific and age‐dependent expression in rat brain we have studied, immunohistochemically, expression of the Pi and Alpha class isoenzymes in 10 adult and 21 human fetal brains. Whilst Alpha isoenzyme is expressed only in adult brain, and then only focally, Pi isoenzyme is strongly expressed from as early as 12 weeks gestation. In the adult, expression is localized to choroid plexus, vascular endothelium, ventricular lining cells, pia‐arachnoid and astrocytes. In fetal brain, expression is also strong in cells with the morphology of tanycytes and in the cell bodies of radial glia. Neurons are consistently negative. Pi isoenzyme thus localizes to the sites of the blood‐CSF barrier, blood‐brain barrier, CSF‐brain barrier and pia‐arachnoid‐brain barrier. It is ideally placed to regulate neuronal exposure to potentially toxic substances derived from blood or cerebrospinal fluid. Expression so early in gestation is of significance and may imply a role in protection of the developing human brain.
Spinal cord disease in children with HIV‐1 infection: a combined molecular biological and neuropathological study*
Authors: SHARER L. R. , DOWLING P. C. , MICHAELS J. , COOK S. D. , MENONNA J. , BLUMBERGH B. M. , EPSTEIN L. G.
Published: May 2008

An autopsy study was performed on spinal cords from 18 children who died with HIV‐1 infection, using standard histopathologic techniques as well as in situ hybridization and immunocytochemistry for HIV‐1. Of 16 spinal cords examined by histology, nine had inflammatory cell infiltrates and six had multinucleated cells; both types of lesion are associated with the presence of HIV‐1 in central nervous system tissue. HIV‐1 type lesions were often present in the spinal cord and brain from the same patient. Pallor of myelin in corticospinal tracts in the cord was present in half of the cases; this change correlated with diffuse myelin pallor in the corresponding brains, but not with the HIV‐1 associated changes in the cords. In situ hybridization for HIV‐1 nucleic acid sequences gave positive results in seven of 18 spinal cords, with hybridizing signal usually localized to inflammatory cell infiltrates and multinucleated cells. Positive in situ hybridization, on frozen sections, correlated with the presence of HIV‐1 associated changes on paraffin sections from the same cases. Immunocytochemistry for p25 core protein of HIV‐1, using a monoclonal antibody on frozen sections, was positive in multinucleated cells, macrophages, and microglia. In this series there were two cases of vacuolar myelopathy, one a 30–month‐old boy who had concomitant measles virus in the spinal cord grey matter, and the other nine‐year‐old girl who had severe HIV‐1 infection of the cord. Other than the single case of measles virus, there were no opportunistic infections in the cords in this series. HIV‐1 frequently involves the spinal cord in children with AIDS, while opportunistic infections are rare. Vacuolar myelopathy occurs in children with HIV‐1 infection, although its occurrence is much less frequent than in adults with AIDS.
What have we learnt from Graham Frederick Young? Reflections on the mechanism of thallium neurotoxicity
Authors: CAVANAGH J. B.
Published: May 2008

The recent death of the psychopathic poisoner, Graham Frederick Young, prompts the question: has our knowledge of the toxic effects of thallium been increased as a result of his activities? The answer is ‘yes’ but very little. However, the poisonings led to a re–examination of the topography and pathogenesis of thallium intoxication and the suggestion that there are close similarities with chronic thiamine deficiency neuropathy and arsenical neuropathy. They might be termed chronic energy deprivation neuropathies and are associated with damage to other organs with high energy requirements, namely skin and its appendages, testis and heart. While the exact metabolic ‘lesion’ in thallium intoxication is not yet known, circumstantial evidence continues to suggest that it may be related to the known interaction of this ion with riboflavin, with consequent effects upon energy generation mechanisms associated with tissue flavoproteins.
The incidence of prenatal brain injury
Authors: SQUIER M. , KEELING J. W.
Published: May 2008

Recent epidemiological studies have shown that cerebral palsy is only rarely associated with birth asphyxia and that there may be more important causative factors in the prenatal period. For this reason a series of 165 brains of infants who were stillborn or died in the early neonatal period was examined in order to identify the incidence and nature of prenatal brain damage.

Seventeen (44%) of the stillborn infants showed evidence of brain damage thought to be related to circulatory disorders. The most frequent abnormality, widespread ischaemic damage to the white matter of the cerebral hemispheres, occurred in 10 (26%). Criteria for white matter ischaemia were reactive astrocytosis, macrophage infiltration, karyorrhexis and endothelial swelling or reduplication. This abnormality was only seen after 27 weeks gestation. In five (13%) of the stillborn infants, haemorrhage was seen in association with ischaemic damage and in only two (5%) did brain haemorrhage occur in utero without evidence of co–existing ischaemic damage.

Of the 90 live–born infants, 12 (16%) of those surviving less than 3 days and three (20%) of 15 infants who lived between 3 and 7 days after birth showed ischaemic damage which was of prenatal origin.

The most frequent pathological change in the infants studied was white matter gliosis occurring in infants who survived into or beyond the last trimester. This may interfere with normal myelination by diverting glial stem cells into reactive astrocytes and thus reduce the population of oligodendrocytes available to synthesize myelin and so cause permanent neurological damage.
Triphenyltetrazolium chloride (TTC) as a marker for ischaemic changes in rat brain following permanent middle cerebral artery occlusion
Authors: HATFIELD R. H. , MENDELOW A. D. , PERRY R. H. , ALVAREZS L. M. , MODHA P.
Published: May 2008

Triphenyltetrazolium chloride (TTC) was used to delineate ischaemic lesions in the rat brain at various times following middle cerebral artery occlusion. A comparison was made of TTC staining by immersion and perfusion techniques and conventional light microscopy. The lesions were quantified by measuring the ischaemic area at the sections corresponding to 7 mm in front of the AO line (atlas of Konig and Klippel). In animals examined 24 h after middle cerebral artery occlusion (MCAO), the area of infarction was 17.4 ± 1.3 mm2 on the TTC perfused slices and 17.6 ± 1.6 mm2 on the TTC immersed slices (mean ± SEM). By contrast, there was a marked difference between the two TTC methods when tissues were examined at shorter intervals after artery occlusion. In the TTC–perfused animals, there was no significant difference between the mean areas of infarction measured at 5–20 min, 3–4 h, or 24 h post occlusion. Immersion in TTC, however, failed to reveal any consistent ischaemic damage when applied at the earlier post–occlusion times. Conventional histopathology demonstrated minimal lesions at 5–20 min but at 4 h or more the lesions were not significantly different from those demonstrated by TTC perfusion. TTC immersion staining can, thus, only be used as a reliable marker of cerebral ischaemia damage with post–occlusion survival periods of 24 h. TTC perfusion staining gives results not significantly different from histopathology at 4 h or more post–occlusion but at earlier intervals than 24 h it differs significantly from TTC immersion staining. Thus at times of less than 24 h it may reflect mainly changes in stain perfusion, rather than ischaemic damage.