Chronic subthalamic high-frequency deep brain stimulation in Parkinson's disease--a histopathological study.

This study describes the pathological findings in the brain of a patient with Parkinson's disease (PD) treated with bilateral subthalamic high-frequency deep brain stimulation (STN DBS) for 29 months prior to death. After routine neuropathological examination, tissue blocks containing the electrode tracts, the subthalamic nucleus (STN), the substantia nigra and the pre-frontal cortex were paraffin embedded and cut into 5-microm-thick serial sections and stained with several conventional staining methods and immunohistochemistry. Bilateral nigral depigmentation, cell loss and Lewy body formation confirmed the diagnosis of PD. Microscopic evaluation furthermore confirmed the location of the electrodes in the STN. The electrode tracts were surrounded by a 150-microm-wide glial fibrillary acidic protein (GFAP)-positive capsule consisting of a thin collagen layer lining the lumen of the tract, whilst an area with few cells and axons constituted the capsule wall towards the surrounding normal brain tissue. The brain tissue appeared normal outside the capsule boundaries with no difference in areas of stimulation compared with areas of no stimulation. Our results correspond with previous studies performed after fewer months of STN DBS and indicate mild histopathological changes in the vicinity of the electrode tract, appearing to result from the electrode placement and not from the electrical stimulation.

Molecular chaperons, amyloid and preamyloid lesions in the BRI2 gene-related dementias: a morphological study.

Molecular chaperons or amyloid-associated proteins (AAPs) are deposited in vascular and parenchymal amyloid lesions in Alzheimer's disease (AD) and other amyloidoses. AAPs, such as apolipoprotein E (ApoE) or apolipoprotein J (ApoJ) have been strongly implicated in the pathogenesis of AD in vitro and in vivo. Furthermore the possession of the ApoE in4 allele is a well-studied risk factor for AD. In view of the similarities between AD and both familial British dementia (FBD) and familial Danish dementia (FDD), we investigated the presence of AAPs in these two diseases to understand better their role in the general process of amyloidogenesis. Immunohistochemistry for ApoE, ApoJ, serum amyloid P (SAP), alpha-1-antichymotrypsin, cystatin C, heparan sulphate proteoglycans, such as agrin, perlecan, syndecans, glypican-1 and for heparan sulphate glycosaminoglycan (HS GAG) side chains was carried out together with immunohistochemical preparations specific to the amyloid subunits. Significant or extensive staining for ApoE, ApoJ, agrin, glypican-1 and HS GAG side chains was found in both amyloid (fibrillar) and preamyloid (nonfibrillar) deposits in FBD and FDD. The remaining AAPs, including SAP, were predominantly found in amyloid lesions. Only very weak staining was present in a small proportion of the amyloid lesions using perlecan immunohistochemistry. These findings suggest that the deposition patterns of AAPs in FBD and FDD are mostly similar to those in AD. The presence of AAPs in the preamyloid lesions supports the notion that chaperon molecules may play a role in the early steps of fibrillogenesis.

Genetic alterations of the BRI2 gene: familial British and Danish dementias.

Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid beta (Abeta) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre-amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early-onset conditions are linked to specific mutations in the BRI2 gene, causing the generation of longer-than-normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits and their relation to cognitive impairment remain to be clarified, new evidence indicates that, independent of the differences in their primary structures, Abeta, ABri, and ADan subunits are able to form morphologically compatible ion-channel-like structures and elicit single ion-channel currents in reconstituted lipid membranes. These findings reaffirm the notion that non-Abeta amyloidosis constitute suitable alternative models to study the role of amyloid deposition in the mechanism of neuronal cell death.

Expression of somatostatin receptors on human pituitary adenomas in vivo and ex vivo.

UNLABELLED: The distribution and biologic activity of somatostatin receptor subtypes (SSTR) in pituitary adenomas is not clarified, especially regarding clinically non-functioning adenomas (NFPA). We therefore characterized SSTR in human pituitary adenomas by combining molecular biology and in vivo scintigraphy. Co-expression of gonadotropin-releasing hormone receptor (GnRH-R) mRNA was also assessed to see whether this feature was associated with adenoma subtype and SSTR status. Pituitary tumor biopsies were obtained during transsphenoidal adenomectomy from 21 patients (11 NFPA, 7 acromegalics, 2 prolactinomas, 1 Cushing's disease). Expression of mRNA encoding the 5 known SSTR subtypes and the GnRH-R was determined by RT-PCR. Twelve patients also underwent a pre-operative somatostatin receptor scintigraphy. Most adenomas (no.=18) expressed mRNA for more than one SSTR. SSTR2 mRNA was expressed in 18 cases, whereas SSTR4 was absent in all but one. SSTR3 was frequently expressed in NFPAs. Somatostatin receptor scintigraphy was positive in most cases, and with a significantly higher uptake index in GH-producing adenomas all of which expressed SSTR2 mRNA. The uptake index appeared to be related to receptor density rather than tumor volume. Expression of GnRH-R mRNA was found in both NFPAs and GH-producing adenomas and was not significantly associated with a particular SSTR subtype population. IN CONCLUSION: 1) the distribution of SSTR is not significantly different between NFPA and GH-producing adenomas; and 2) somatostatin receptor scintigraphy reveals a higher uptake in GH-producing adenomas which is not significantly related to either SSTR distribution or tumor volume.

Creutzfeldt-Jakob disease segregating in a three generation Danish family.

A three generation family is presented in which rapidly progressive, early-onset Creutzfeldt-Jakob disease without typical EEG changes segregates as an autosomal dominant disease. An aspartic acid to asparagine mutation at codon 178 of the prion gene, PRNP, co-segregates with the disease. As expected, the disease allele also carries the valine codon of the polymorphic valine/methionine codon 129 of the gene. In family members homozygous for this valine codon the disease was more rapidly progressive than in a heterozygous family member, who had a variant clinical phenotype. Definite neuropathological diagnosis required prion staining with specific antibodies.

Chromosome 13 dementia syndromes as models of neurodegeneration.

Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.

Intracranial sarcoma in a patient with neurofibromatosis type 2 treated with gamma knife radiosurgery for vestibular schwannoma.

OBJECTIVE: To discuss the possible relationship between stereotactic radiation therapy and the development of a meningosarcoma. STUDY DESIGN: Retrospective case review. PATIENT: A 19-year-old woman with bilateral vestibular schwannomas (neurofibromatosis type 2). One large tumor was removed totally by the translabyrinthine approach; the other smaller tumor was treated with stereotactic radiation (SRT). Six years after SRT, a malignant tumor (meningosarcoma) developed at the exact site of radiation. The patient subsequently died of this tumor. OUTCOME MEASURE: On the basis of literature surveys, the possibility and risk of postirradiation neoplasia after SRT is discussed. Furthermore, the possible causal association between SRT and the development of the meningosarcoma in this case is evaluated. CONCLUSION: On the basis of statistical considerations, the development of the reported mesenchymal sarcoma was most likely caused by the stereotactic radiation therapy.

A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred.

Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.

October 1998--61 year old male with brain tumor and oral, lung, and palpebral masses.

In Jan. 97 a gliosarcoma was diagnosed in a 61-year- old man after a 6-month history with neurological deficits. A total physical examination, laboratory tests, chest x-ray and abdominal ultrasound scanning revealed no gross abnormalities. Surgery was followed by brain radiation therapy and 6 months later there were metastases to the oral cavity, right palpebra and both lungs. The histological findings of the oral and palpebral metastases revealed only the sarcomatous component. We are aware of 15 cases of gliosarcoma with extraneural metastases, and in 4 of these, the metastases contained only the sarcomatous component. We believe that our case represents the fifth case of pure sarcomatous metastases.

Immunoglobulins in granular corneal dystrophy Groenouw type I.

Three patients with granular corneal dystrophy Groenouw type I underwent corneal grafting, and cryostat sections of the corneal buttons were examined immunohistochemically for immunoglobulins. Positive results were obtained for IgG, Kappa-, and Lambda chains with immunofluorescence technique. The reactions were seen exclusively in the same localizations as the Masson trichrome positive deposits.

Differential diagnosis between granular corneal dystrophy Groenouw type I and paraproteinemic crystalline keratopathy.

A case of corneal opacities in a leukemic patient with an M-component in the serum proteins is presented, and a comparison is made to patients with granular corneal dystrophy Groenouw type I. The corneal deposits associated with the two conditions may appear identical with slit-lamp biomicroscopy. Granular dystrophy patients, however, show a normal serum immunoglobulin pattern in contrast to patients with paraproteinemic crystalline keratopathy. The two entities can therefore be distinguished from each other by a serum electrophoresis.

Stereological estimates of nuclear volume and other quantitative variables in supratentorial brain tumors. Practical technique and use in prognostic evaluation.

The use of morphometry and modern stereology in malignancy grading of brain tumors is only poorly investigated. The aim of this study was to present these quantitative methods. A retrospective feasibility study of 46 patients with supratentorial brain tumors was carried out to demonstrate the practical technique. The continuous variables were correlated with the subjective, qualitative WHO classification of brain tumors, and the prognostic value of the parameters was assessed. Well differentiated astrocytomas (n = 14) had smaller estimates of the volume-weighted mean nuclear volume and mean nuclear profile area, than those of anaplastic astrocytomas (n = 13) (2p = 3.1.10(-3) and 2p = 4.8.10(-3), respectively). No differences were seen between the latter type of tumor and glioblastomas (n = 19). The nuclear index was of the same magnitude in all three tumor types, whereas the mitotic index was significantly increased in glioblastomas (2p = 0.01). Three-dimensional, shape-independent estimates of macroscopical tumor volume were not different in anaplastic astrocytomas and glioblastomas (2p = 0.39). Histological type of tumor and mitotic index were of significant prognostic value (2p = 8.2.10(-6) and 2p approximately 0.05, respectively). Age above the median and short duration of symptoms were significantly associated with short survival (2p = 0.01). Further investigations of larger series of patients are needed to define the clinical usefulness of these objective, reproducible, and quantitative techniques in the prognostic evaluation of primary brain tumors.

Fibrous dysplasia of the skull with acromegaly and sarcomatous transformation. Two cases with a review of the literature.

Two cases of fibrous dysplasia of the skull are reported. Both patients were young women with acromegaly and were treated with radiotherapy. Progressive pareses of cranial nerves, pain, and a malignant course of the disease were characteristic in both patients, and the diagnosis of osteogenous sarcoma proved in one of them by histological examination. The clinical picture of fibrous dysplasia of the skull and the role of radiotherapy with the risk of development of malignancy is discussed.

Frequency of Alzheimer's disease in a postmortem study of psychiatric patients.

The brains from 100 consecutive patients dying in psychiatric departments were subjected to a neuropathological study with a quantitative evaluation of neurofibrillary tangles and senile plaques. Histologically, Alzheimer changes were found in 63.4% of the group with the clinical diagnosis of senile dementia and in 60% of the arteriosclerotic dementia group. In other clinical groups (schizophrenic, manic-depressive, and "other disorders") the percentage of Alzheimer changes was about 30. Thus, Alzheimer changes were not only present in the group of patients with the "correct" psychiatric diagnosis senile dementia, but were also frequent among patients with other psychiatric diseases where no clinical suspicion of Alzheimer's disease had been forecast. Alzheimer's disease may, thus, contribute to or be concealed by other psychiatric diseases and should be considered in all geronto-psychiatric cases.

Vowel perception: a neuroradiological localization of the perception of vowels in the human cortex.

Whether the perception of vowels takes place in the right or left cerebral hemisphere, or is dependent on bilateral cortical processes, is of importance in our treatment of patients with language deficiencies. To investigate this problem a phonetic test with a series of vowellike stimuli was administered to 68 right-handed adult patients with cerebral lesions, mainly of vascular origin. The results were compared to the results in a control group of 19 speech therapists. Second, a neuroradiologic method was developed in order to visualize the anatomic site of Wernicke's area in the left hemisphere on CT scans. This method formed the basis for an evaluation of the extent and localization of the patients' lesions in Wernicke's area. Of 46 patients with lesions in the left hemisphere, 19 had no perceptual disturbances and 27 had severe perceptual disturbances with lesions predominantly located in Wernicke's area. Twenty-two patients with lesions in the corresponding area in the right hemisphere showed no perceptual disturbances. The results of this investigation appear to indicate that the perception of vowels in right-handed persons is unilaterally located in Wernicke's area in the left hemisphere.

A consecutive series of 30 malignant schwannomas. Survival in relation to clinico-pathological parameters and treatment.

Thirty malignant schwannomas from an 18-year period were studied, and the patients were divided into 3 groups: one with Recklinghausen's disease, one with tumours related to nerves but without Recklinghausen's disease and finally one with a histopathology best compatible with malignant schwannoma. On all tumours a histopathological grading was performed, and all except two were found to be high-grade malignant. The follow-up is from 2 to 20 years, and only two of the living patients have not yet been followed for 5 years. One patient has been lost during the follow-up period. In the remaining 27 patients the 5-year survival is 48%. The factors essential to the prognosis are: the tumour localization, size, grade of malignancy and radical surgical treatment. The coexistence of Recklinghausen's disease and malignant schwannoma seems not in itself to give a worse prognosis; it is rather the large tumours and unfavourable localizations in this group of patients that shortens the survival, the 5-year survival being 37.5%.

CNS involvement in leukaemia. An autopsy study of 100 consecutive patients.

The central nervous system has been examined in a consecutive autopsy material of 100 adult patients with acute (N = 67) or chronic (N = 33) leukaemia. In all patients the disease was active at the time of death, infiltrating several organs, and in 45% of the cases CNS was involved. 81% of the patients with ALL had leukaemic infiltrates in CNS, and in the total AML group they were seen in 46% (P less than 0.05). A comparison between the subtypes of the AML group revealed CNS involvement in 39% of M1 + M2 and in 69% of M4 + M5 (P less than 0.05). Only in a single case of CML was the central nervous system affected, whereas 8 of 16 patients with CLL has CNS involvement. Furthermore, other pathological findings such as haemorrhages and infarcts were registered at the time of death in 33% of all patients. Terminal neurological symptoms could be ascribed either to leukaemia, other CNS pathology or a combination of both. The rate of CNS involvement is higher than reported in similar studies, and it is supposed that this may partly be ascribed to the inclusion of the spinal cord in this investigation.

Midline rupture of the mesencephalon.

A midline rupture of the mesencephalon was found in 3 young males surviving closed head injury for 3-5 days. Other brain damage was relatively mild, but there was brain oedema with signs of herniation. In only one case were there symptoms of a hypothalamic lesion. The author suggests that a rupture is initiated by the compression of the brain stem against the clivus, whereby the pedunculi are displaced away from each other, and that the rupture naturally continues along the midline vessels to end in the aqueduct.

Phosphate addition to glucose solutions- effect on hypophosphataemia and risk of infusionthrombophlebitis.

The object of this study was to show (A) whether the transient fall in plasma phosphate during carbohydrate infusions could be prevented by adding 10 mmol phosphorus to 1 litre of 10% glucose solution, (B) whether this unphysiologically high concentration would change the vein damaging properties of the acid sugar solution, when the phosphorus was added as a phosphate buffer. Study A comprised 16 patients undergoing colonic surgery. On the second postoperative day the patients received 1 litre 10% glucose, half of the solutions were added 10 mmol phosphate buffer. Plasma phosphate dropped during the infusion in all the patients in the unsubstituted group, whereas there was no fall in the phosphate substituted group. The difference between the two groups was significant. Study B comprised 23 rabbits. Sequential analysis demonstrated that the phosphate addition did not change the vein damaging properties of a 10% glucose solution.