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In the present immunohistochemical study, we investigated the characteristics of altered neurites in the frontal cortex of 10 Alzheimer's disease (AD) brains and 15 age-matched non-demented control brains. In both AD and control cases, the altered neurites in coronas of the classical plaques (CP) were frequently immunostained by antibodies to growth-promoting factors, N and C termini of amyloid precursor protein (APP), GAP43, collagen IV, laminin and the integrin receptor VLA6. The altered neurites in CP coronas in AD but not in controls were also immunostained by antibodies against normally and abnormally phosphorylated tau. Immunolabeling for microtubule-associated protein 2 was not found in CP from either group. Extensive neuropil threads (NT) and many neurofibrillary tangles (NFT), immunostained with tau and Alz50 antibodies, were present in AD neocortex but not seen in control cases. NT and NFT could not be stained by antibodies to the N termini of APP, GAP43, collagen IV, laminin and VLA6. Our findings indicate that in AD cases altered neurites in CP are undergoing both an aberrant sprouting process and a degenerating process. These altered neurites are probably of axon origin. NT and NFT may represent destructive changes. The presence of amyloid plaques, but absence of tau-related cytoskeletal pathology, in non-demented cases suggests that beta/A4 peptide is necessary but not sufficient to induce neurofibrillary pathology.

In the intracerebral 9L rat gliosarcoma, the spatial distribution of the photosensitizer haematoporphyrin derivative (HpD) was studied after intratumoral injection. The fluorescence volume was measured in histological sections from 10 min up to 5 days after injection. Complete sensitization of the tumours could not be achieved by slow stereotactical injection of 4 mm3 HpD (mean HpD fluorescence volume, 13 +/- 11 mm3). Larger parts of the tumour could be loaded with HpD (39 +/- 23 mm3, p = 0.0001) by increasing the injection velocity and the volume to 50 mm3. Again, complete sensitization of the tumours was not achieved during a time scale of 5 days after intratumoral injection. Although the fluorescence volume did not change significantly with time, it was influenced by the injection site within the tumour. Injection of HpD within 1 mm from the tumour border resulted in significantly smaller fluorescence volumes in the tumour than injection into the tumour centre. Large injection volumes caused an increased leakage of HpD to normal brain, leading to the loss of selectivity of photosensitizer content and the occurrence of dark toxicity of normal brain while the tumours still appeared vital.

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)

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.

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.

Integrins belonging to different subfamilies can be identified immunohistochemically in cerebral amyloid plaques. Monoclonal antibodies against the VLA family beta 1-integrins show staining of the corona of classical amyloid plaques for beta 1, alpha 3 and alpha 6. Immunostaining reveal also the presence of collagen and laminin in the corona. Activated microglial cells in classical plaques strongly express receptors belonging to the LeuCAM family (beta 2 integrins). The ligands ICAM and activated complement C3 are found in both amorphous and classical plaques. Vitronectin receptor (alpha v) is found in glial cells in classical plaques but its ligand vitronectin is seen in both amorphous and classical plaques. The data presented here demonstrate the presence of different cellular and substrate adhesive molecules (integrins) and their ligands in classical plaques. The findings suggest that amyloid plaques show signs of regeneration and tissue remodelling.

A patient with the clinical diagnosis of Alzheimer's disease is presented in whom pre-mortem T2-weighted MRI revealed a periventricular white matter lesion. Postmortem T2 weighted MRIs of the formalin fixed brain revealed the same white matter lesion. Microscopically, classical Alzheimer changes were found and, unsuspectedly, the histopathological correlate of the white matter lesion proved to be an old, inactive, MS plaque. A similar lesion was discovered in the cervical myelum. These findings illustrate that T2-weighted post-mortem MRIs are highly comparable to pre-mortem images and that MRI is sensitive in detecting clinically silent white matter lesions. The histopathology of such lesions may also include MS plaques.

Brain amyloidosis with abundant beta/A4 protein deposition in plaques and cortical and meningeal vessels is found in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). In contrast to AD, no neuritic pathology or classical congophilic plaques are found in HCHWA-D. Unlike most AD cases, the congophilic angiopathy in HCHWA-D is very severe. It is still unknown whether beta/A4 deposits in plaques and vessels have the same origin. In this study, we have used frozen cortical tissue of HCHWA-D and AD patients to investigate the beta/A4 amyloid protein and the amyloid precursor protein (APP) in different types of plaques and congophilic angiopathy. Immunohistochemical staining was conducted using antibodies against synthetic beta/A4 proteins and antibodies against APP including MAbP2-1, a monoclonal antibody against purified protease nexin-2, which is the secreted form of APP. In contrast to immunohistochemical studies on formalin-fixed, paraffin-embedded tissue, frozen tissue of HCHWA-D patients revealed a very high number of beta/A4 plaques resembling AD. All plaques were of the diffuse type. Double-staining with MabP2-1 and beta/A4 antisera revealed: 1) the presence of APP immunoreactivity in classical plaques and transitional forms; 2) the absence of APP immunoreactivity in diffuse plaques in HCHWA-D and AD; and 3) pronounced APP immunoreactivity in congophilic vessels in HCHWA-D in contrast to weak APP staining in congophilic vessels in AD. Together these findings suggest that: a) the presence of APP in plaques is related to neuritic changes; b) different processes occur in amyloid formation in plaques and vessels; and c) differences exist between the process of amyloid formation in HCHWA-D and AD.

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.

We present a case of spinal subarachnoid hemorrhage due to an ependymoma of the filum terminale in a 23-year-old male. Clinical signs indicating a spinal origin of the subarachnoid hemorrhage are discussed. Subarachnoid hemorrhages are only rarely caused by an intraspinal tumor, most of which are located in the cauda equina. Our findings in this case proved the value of MRI examination in tumors of the cauda equina.

A literature review of pregnancy-related vertebral haemangiomas, pregnancy-related haemangiomas outside the nervous system and its coverings, and pregnancy-related meningiomas was performed. All three conditions tended to occur during the first pregnancy, the second or third trimester, to ameliorate postpartum, and to recur during a subsequent pregnancy. These results suggested a hormonal influence on the clinical expression of haemangiomas and meningiomas. To test whether a hormonal factor is also operative in the (not pregnancy related) symptomatic and asymptomatic counterparts of these conditions we also reviewed the literature concerning the symptomatic and asymptomatic haemangiomas and meningiomas for the following: frequency, sex and age distribution. No arguments were found to suggest that steroid hormones are strong factors in the development of asymptomatic and symptomatic lesions. The pregnancy-related counterparts have to be considered as subsets with their own behaviour.

In this study we applied the technique described in the previous paper (see pp. 103-106 of previous issue (1991); 13(2)) to rats with experimental saccular aneurysms. We found that the mean sizes and some growth ratios of experimental aneurysms were significantly larger in the intermittent blood pressure elevation groups than in the control groups. The increase of growth ratios was proportional to the number of transient blood pressure elevations. The morphological structure of these saccular aneurysms showed that the regenerative processes in the aneurysm wall had obviously been interfered with in animals with intermittent blood pressure elevation. The effective mechanism of this influential factor is discussed.

The case of a 7-year-old boy with a spinal epidural extraosseous Ewing's sarcoma (EES) is presented. He is in complete remission without neurologic deficit 40 months after diagnosis. Another 15 cases were found in the literature and are discussed together with this patient. Twelve of them were male patients. The mean age of the patients was 17.5 years (range, 4 to 47). Symptoms included back pain and/or radicular pain (100%), paresis of one or both legs (83%), sensory disturbances, and bladder and bowel dysfunction. The mean diagnostic delay was 5.8 months. Each patient underwent laminectomy; complete resection of the tumor was impossible in more than 50% of the cases. Most patients received radiation therapy and/or chemotherapy. Four patients suffered from local recurrence, eight from metastases. Ten (63%) patients died, 1 to 48 months (mean, 16) after diagnosis. The differential diagnosis is discussed, including disk herniation and several benign and malignant tumors.

Haemodynamic factors in the formation and development of saccular aneurysms have been widely studied. Saccular aneurysms could appear and grow at the side of the increased blood flow. The effects of contralateral carotid ligation on the formation and growth of our experimental saccular aneurysms were studied. Measurement and pathological examination showed that the haemodynamic changes could facilitate the development of saccular aneurysms, but by itself could not bring about their formation.

Although the reason for development of saccular aneurysms in humans has still not been elucidated, the process might be observed and explained using a reproducible aneurysm model in vivo. In this paper, a sequential pathological study of the experimental saccular aneurysms was made. No additional influential factors were applied. At all stages of the development between the induction and 6 months, the histology of the aneurysm wall was similar to that of human aneurysms. The imbalance of the degeneration and regeneration processes during the development of these experimental aneurysms is discussed according to the pathological findings in different periods. Haemodynamic stress and different regenerative speeds in different arterial tissues must be responsible for the saccular aneurysm formation and growth.

After 2 and 3 months we re-exposed 20 experimental saccular aneurysms. Under the operating microscope, we measured their sizes and compared them with the sizes immediately after induction. All aneurysms had grown significantly and none was thrombosed. Pathological examinations showed that the sac of the aneurysm was similar to that of the human saccular aneurysms. Based on the operating microscopy and pathological findings we postulate that abnormal histological structure and haemodynamic stress are the major causes of aneurysm enlargement. We also noted that there were some regenerative processes in these experimental aneurysm walls. The results prove that this model is reliable, because these aneurysms have the main characteristics of human saccular aneurysms, not only grossly but also microscopically.

A new and reproducible saccular aneurysm model has been developed at the bifurcation of the common carotid artery in rats. The details of the experimental methods and results are described. It is strongly suggested that the internal elastic lamina is a critical layer in saccular aneurysm formation, because an experimental saccular aneurysm can be produced immediately by transluminally damaging the inside of the arterial wall at the bifurcation of the common carotid artery. This saccular aneurysm model has several advantages: (i) it can be induced quickly and the success rate approaches 100% in rats; (ii) this technique can produce satisfactory experimental saccular aneurysms for other aneurysm studies, and in the future it will also be possible to use this technique to produce experimental saccular aneurysms in cerebral arteries of large animals.

The clinical data and computed tomographic findings of 64 patients with solitary supratentorial brain lesions were presented to two panels of six experienced clinicians. The diagnoses predicted by these clinicians were compared with each other (interobserver variation) and with the definite diagnosis, which in almost all cases was based on histologic examination of the involved tissue (validity of predicted diagnosis). The interobserver agreement was only moderate. The predicted diagnoses agreed with the definite diagnoses in only 57% of cases. A high number of errors were made in distinguishing between high-grade and low-grade glioma and between high-grade glioma and cerebral metastasis, and in the detection of primary cerebral lymphoma. Possible implications of these findings for clinical practice are discussed.

We reviewed the literature concerning primary brain and spinal tumors with first manifestation or acceleration of symptoms during pregnancy or within the first postpartum week and encountered four new cases in our center. The incidence of brain tumors that become symptomatic during pregnancy appears to be decreased compared with that in age-matched women. The relative frequency of the different primary brain tumor types is not changed by pregnancy. The number of meningiomas gradually tends to increase during pregnancy, with gliomas and spinal vascular tumors accumulating in the first and third trimesters, respectively. Postpartum amelioration of symptoms has especially been described for meningiomas and spinal vascular tumors. We conclude that different types of tumors are influenced at different stages of pregnancy. Although progesterone receptors predominate compared with estrogen receptors, no definite causal relationship with progesterone has been established.

With immunohistoperoxidase techniques the presence of plasma (serum) proteins was investigated in senile plaques, congophilic angiopathy, neurons and glial cells in brains of patients with Alzheimer's dementia. Other investigators have found plasma proteins in brain parenchyma and suggested that blood-brain barrier dysfunction might be a primary factor in the pathogenesis of Alzheimer's dementia. These studies were performed on formol-fixed brains of patients with Alzheimer's dementia. In the present study we investigated both frozen and formol-fixed brain tissues. The influence of post-mortem delay, prolonged formol fixation and differences in clinical course on detection of plasma proteins by immunocytochemical techniques was also studied. Findings in cases with Alzheimer's dementia were compared with findings in nondemented controls with or without neurological disorders. Plasma proteins could not be demonstrated in the neuropil of a number of patients with Alzheimer's dementia. Moreover, plasma proteins were also found in neuronal cells and astrocytes in brains of nondemented controls. We discussed whether or not cytochemical detection of plasma proteins in the neuropil of post-mortem obtained brains is a reliable technique to investigate blood-brain barrier dysfunction. In our opinion there are, at the moment, no convincing arguments for blood-brain barrier dysfunction in Alzheimer's dementia.

A very rare hemangioblastoma of the filum terminale with sciatic pain and partial cauda syndrome in a 36-year-old man is presented. The difference between solitary hemangioblastoma, hemangioblastomatosis and von Hippel-Lindau disease is stressed. The literature is reviewed and the diagnosis of cauda equina neoplasms is discussed. Even nowadays often the final diagnosis is made late and only after operation and microscopical tissue examination.

Cytogenetic studies on neuroblastomas arising in children have revealed consistent abnormalities of the short arm of chromosome number 1. Partly because of the rare occurrence of neuroblastomas in adults, extensive cytogenetic studies in this group of patients have not been performed. We report a case of a neuroepithelioma (neuroblastoma) arising in a 50-year-old male patient. On chromosome analysis of a metastasis, a stemline with karyotype 47,XY, +der1 (1 qter---1 cen::1q21---1 qter) was identified. The possible consequences of this result and those of results previously reported in the literature are discussed.