TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death.

Self-aggregation of transforming growth factor ß (TGF-ß)1-induced antiapoptotic factor (TIAF1) is known in the nondemented human hippocampus, and the aggregating process may lead to generation of amyloid ß (Aß) for causing neurodegeneration. Here, we determined that overexpressed TIAF1 exhibits as aggregates together with Smad4 and Aß in the cancer stroma and peritumor capsules of solid tumors. Also, TIAF1/Aß aggregates are shown on the interface between brain neural cells and the metastatic cancer cell mass. TIAF1 is upregulated in developing tumors, but may disappear in established metastatic cancer cells. Growing neuroblastoma cells on the extracellular matrices from other cancer cell types induced production of aggregated TIAF1 and Aß. In vitro induction of TIAF1 self-association upregulated the expression of tumor suppressors Smad4 and WW domain-containing oxidoreductase (WOX1 or WWOX), and WOX1 in turn increased the TIAF1 expression. TIAF1/Smad4 interaction further enhanced Aß formation. TIAF1 is known to suppress SMAD-regulated promoter activation. Intriguingly, without p53, self-aggregating TIAF1 spontaneously activated the SMAD-regulated promoter. TIAF1 was essential for p53-, WOX1- and dominant-negative JNK1-induced cell death. TIAF1, p53 and WOX1 acted synergistically in suppressing anchorage-independent growth, blocking cell migration and causing apoptosis. Together, TIAF1 shows an aggregation-dependent control of tumor progression and metastasis, and regulation of cell death.

TGF-ß induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid ß plaques in Alzheimer's disease.

The role of a small transforming growth factor beta (TGF-ß)-induced TIAF1 (TGF-ß1-induced antiapoptotic factor) in the pathogenesis of Alzheimer's disease (AD) was investigated. TIAF1 physically interacts with mothers against DPP homolog 4 (Smad4), and blocks SMAD-dependent promoter activation when overexpressed. Accordingly, knockdown of TIAF1 by small interfering RNA resulted in spontaneous accumulation of Smad proteins in the nucleus and activation of the promoter governed by the SMAD complex. TGF-ß1 and environmental stress (e.g., alterations in pericellular environment) may induce TIAF1 self-aggregation in a type II TGF-ß receptor-independent manner in cells, and Smad4 interrupts the aggregation. Aggregated TIAF1 induces apoptosis in a caspase-dependent manner. By filter retardation assay, TIAF1 aggregates were found in the hippocampi of nondemented humans and AD patients. Total TIAF1-positive samples containing amyloid ß (Aß) aggregates are 17 and 48%, respectively, in the nondemented and AD groups, suggesting that TIAF1 aggregation occurs preceding formation of Aß. To test this hypothesis, in vitro analysis showed that TGF-ß-regulated TIAF1 aggregation leads to dephosphorylation of amyloid precursor protein (APP) at Thr668, followed by degradation and generation of APP intracellular domain (AICD), Aß and amyloid fibrils. Polymerized TIAF1 physically interacts with amyloid fibrils, which would favorably support plaque formation in vivo.

X-ray microbeams: Tumor therapy and central nervous system research.

Irradiation with parallel arrays of thin, planar slices of X-ray beams (microplanar beams, or microbeams) spares normal tissue, including the central nervous system (CNS), and preferentially damages tumors. The effects are mediated, at least in part, by the tissue's microvasculature that seems to effectively repair itself in normal tissue but fails to do so in tumors. Consequently, the therapeutic index of single-fraction unidirectional microbeam irradiations has been shown to be larger than that of single-fraction unidirectional unsegmented beams in treating the intracranial rat 9L gliosarcoma tumor model (9LGS) and the subcutaneous murine mammary carcinoma EMT-6. This paper presents results demonstrating that individual microbeams, or arrays of parallel ones, can also be used for targeted, selective cell ablation in the CNS, and also to induce demyelination. The results highlight the value of the method as a powerful tool for studying the CNS through selective cell ablation, besides its potential as a treatment modality in clinical oncology.

Synovial excrescences and cysts of the spine: clinicopathological features and contributions to spinal stenosis.

Synovial cysts occur throughout the body and are generally benign lesions with limited clinical consequences. Juxtafacet cysts of the spine, in contrast, often press on a nerve root as it exits in the foramen, causing radiculopathy. Synovial tissue that emanates from the facet joint but extends medially, is an additional important cause of spinal stenosis. Over the past 5 years, neurosurgeons at our institution have operated on a large number of patients with back pain, with removal of abnormal synovial tissues. Histological examination of these tissues distinguishes the different types of pathologic processes responsible for producing symptoms. Juxtafacet cysts may be either mucin-filled ganglion cysts devoid of cyst lining or true synovial cysts with watery content and lined by synovial cells. Ganglion cysts arise in degenerated ligament at the facet joint, and occasionally within synovial stroma. Synovial cysts arise within synovium and, unlike synovial cysts in the extremities, have a thick wall containing granulation tissue, numerous histiocytes and giant cells. This hyperplastic, irritated synovium of the spine, which we term "synovial excrescences", is voluminous and this reactive part overshadows the cystic portion of the lesion in most instances. Iron pigment deposition and inflammation are mild to absent, making synovial excrescences different from pigmented villonodular synovitis. Synovial excrescences of the spine are an important cause of spinal stenosis, predominantly in elderly patients. Surgical removal of excrescences protruding into the spinal canal provides prompt and durable relief of symptoms, usually without the need for extensive bony laminectomy or spinal fusion. Several patients in our study had both spinal ganglion cysts and synovial excrescences, suggesting common risk factors for both lesions.

Intracalvarial cholesterol granulomas--clinicopathologic correlates of three cases.

Cholesterol granulomas (CGs) are tumor-like lesions seldom encountered by neuropathologists. CGs develop in reaction to localized hemorrhage, often occurring in bony sites with possible impaired drainage of blood and blood products. The most common bony location is the petrous apex, although orbital, frontal sinus, and maxillary sinus sites have been reported. We compare and contrast three recent cases seen at our institution that illustrate the spectrum of clinical, radiographic, and pathologic features that can be seen with these mass lesions. One case demonstrated the unique pathological features of Gamma-Gandy body formation, epithelioid histiocytes heavily encrusted with iron pigments, and extensive tophi. The latter most likely represented aggregates of calcium pyrophosphate crystals associated with extensive iron deposition.

Suprasellar cavernous malformation presenting with extensive subarachnoid hemorrhage.

Cavernous malformations are usually intraparenchymal, extra-axial lesions being uncommon. They have very rarely been reported as the cause of subarachnoid hemorrhage. We present a case of hemorrhage related to a cavernous malformation, unusual in two ways. First, it is rare for an intracranial cavernous malformation to present with massive subarachnoid hemorrhage. Secondly, this cavernous malformation lay in the chiasmatic cistern.

Histologic inflammation in the maternal and fetal compartments in a rabbit model of acute intra-amniotic infection.

OBJECTIVE: This study was undertaken to determine the course of acute inflammation in the maternal and fetal compartments during experimentally induced ascending intra-amniotic infection. STUDY DESIGN: Forty pregnant rabbits at 70% gestation were inoculated endocervically with 10(5) colony-forming units of Escherichia coli. Does were killed at 0, 4, 8, 16, 24, and 30 hours after inoculation. At necropsy, blood, peritoneal fluid, amniotic fluid, and uterine tissue were cultured. Fetal brain, lung, heart, gut, and kidney were collected for histologic examination. Necrosis, infiltrates, congestion, and edema were each assessed semiquantitatively, and mean composite histologic-inflammation scores were compared with analysis of variance. Inflammation, mitotic activity, and apoptosis were evaluated in the fetal brain, and groups were compared with analysis of variance. RESULTS: Twenty-six animals were evaluated after 14 were excluded (lack of fever or positive culture results). A significant increase in histologic inflammation score was seen in the uterus (P<.001), placenta(P = .011), and fetal lung (P = .001) but not in other fetal tissues. These changes were seen earlier in the uterus and placenta and later in the fetal lung. Mitotic activity in the fetal brain decreased significantly by 8 hours after cervical inoculation. There was no inflammation in the fetal brain, and apoptosis in the fetal brain did not increase with time. CONCLUSIONS: Histologic inflammation occurs early in both the uterus and the placenta and later in the fetal lung in the rabbit model of acute intra-amniotic infection. This contrasts with the previously reported chronic model of intra-amniotic infection in the rabbit.

Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains.

We tested whether regional or selective alterations in presynaptic proteins occur in Alzheimer's disease (AD) and correlate with tests of cognitive function. We measured the levels of seven presynaptic proteins (synaptobrevin, synaptotagmin, SNAP-25, syntaxin, SV2, Rab3a, and synapsin I) by immunoblotting in postmortem tissue from four brain regions (hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex). Three subject groups were studied: AD, possible/early AD (p-AD), and age-matched controls. Synaptobrevin and synaptotagmin were significantly reduced (29%, P<0.08; 38%, P<0. 07) in hippocampus in p-AD compared to controls. In definite AD compared to controls, selective regional reductions in vesicle proteins were found: synaptobrevin (46%, P<0.05), synaptotagmin (52%, P<0.01), and Rab3a (30%, P<0.05) in hippocampus; synaptobrevin (31%, P<0.01), synaptotagmin (15%, P<0.05), and Rab3a (44%, P<0.05) in entorhinal cortex. In contrast, the levels of two vesicle proteins (synapsin I and SV2) and two presynaptic membrane proteins (syntaxin and SNAP-25) were similar to controls. Synaptobrevin was the only vesicle protein reduced in AD in all four brain regions (occipital cortex 37%, P<0.05; caudate nucleus 31%, P<0.05). By univariate analysis of all cases, Mini-Mental State Examination, Blessed (BIMC) and Free Recall scores were strongly correlated with reduced levels of synaptic vesicle proteins synaptobrevin, synaptotagmin, and Rab3a in hippocampus and entorhinal cortex. These results suggest that there are selective and early defects in presynaptic vesicle proteins, but not synaptic plasma membrane proteins in AD and that defects correlate with cognitive dysfunction in this disease.

Cervical spine abnormalities in Down Syndrome.

Down Syndrome (DS) is the most common of the chromosomal disorders and manifests abnormalities in several organ systems. While mental retardation, skull and brain anomalies, and the development of Alzheimer-type neuropathological changes in patients greater than age 40 years are well recognized by neurologists and neuropathologists, less appreciated are the various cervical spine abnormalities that can occur. Widening of the anterior atlanto-odontoid distance (AAOD) and atlantooccipital instability occur in up to 21% and 63% of DS patients, respectively, but neurologic complaints are uncommon and rarely are severe enough to contribute to the patient's demise. We present a case of 49-year-old DS patient whose triplegia, subacute progressive respiratory failure, and death could be attributed to severe degenerative joint disease of the cervical spine with osteophyte formation and severe spinal canal stenosis. We provide the first detailed correlation study between pre-mortem magnetic resonance imaging (MRI) and extensive autoptic dissection in an adult DS patient with cervical spine abnormalities, as well as a review of the literature.

White matter dementia in CADASIL.

Cerebral white matter disorders may be associated with profound neurobehavioral dysfunction. We report a 62-year-old man who had a slowly progressive 25-year history of personality change, psychosis, mood disorder, and dementia. Neurologic examination disclosed abulia, impaired memory retrieval, and preserved language, with only minimal motor impairment. Neuropsychological testing found a sustained attention deficit, cognitive slowing, impaired learning with intact recognition, and perseveration. Magnetic resonance imaging of the brain revealed extensive leukoencephalopathy. Right frontal brain biopsy showed ill-defined white matter pallor with hyaline narrowing of white matter arterioles. Granular osmiophilic material adjacent to vascular smooth muscle cells on electron microscopy of a skin biopsy, and an arginine for cysteine replacement at position 169 in the 4 EGF motif of the notch 3 region on chromosome 19q12 established the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This case illustrates that CADASIL can manifest as an isolated neurobehavioral disorder over an extended time period. The dementia associated with CADASIL closely resembles that which may occur with other white matter disorders, and represents an example of white matter dementia.

Attempts to identify herpes simplex virus DNA in normal and diseased human peripheral nerve.

PCR analysis of DNA extracted from 31 sections of formalin-fixed sural nerve biopsies did not reveal herpes simplex virus (HSV) DNA. Unlike the presence of HSV DNA sequences in normal human brain, spinal cord, and ganglia, HSV DNA is not present in normal or diseased human distal peripheral nerve.

Telomerase expression shows differences across multiple regions of oligodendroglioma versus high grade astrocytomas but shows correlation with Mib-1 labelling.

AIMS/BACKGROUND: Telomerase is an enzyme that is expressed in most human neoplasms and is associated with tumour immortality. Determination of the point in neoplastic transformation at which telomerase is expressed may aid the understanding of tumour pathogenesis and progression. Despite numerous reports on telomerase, few studies have investigated its expression in high grade glial tumours. These studies, performed on archival banked, single brain tumour specimens, have shown conflicting results for oligodendrogliomas and unexpectedly negative results for telomerase expression in high grade astrocytomas, with one third to one half of glioblastoma multiformes being negative. METHODS: 34 rapidly banked glioma specimens taken from patients undergoing gross total surgical resection of their tumours were studied. Telomerase expression was assessed across 3-8 sampled regions from each tumour by the telomeric repeat amplification protocol (TRAP) assay. Matched mirror image tissue samples were taken for histological analysis of tissue adequacy, statistical correlation of telomerase with tumour histological features, Mib-1 (a marker for cell cycling) labelling, and p53 immunohistochemistry. RESULTS: All five well differentiated oligodendrogliomas were homogeneously telomerase negative and two of three untreated anaplastic oligodendrogliomas were homogeneously positive. In contrast, 10 of 14 high grade astrocytomas showed heterogeneity for telomerase expression across the multiple regions sampled. All glioblastoma multiformes and two of three anaplastic astrocytomas showed at least one region positive for telomerase. When test samples were individually assessed in both oligodendrogliomas and high grade astrocytomas, telomerase expression was associated with Mib-1 labelling (p < 0.001). For the entire group, telomerase expression was associated with grade of tumour, age of patient, and vascular endothelial proliferation (all p < 0.001). CONCLUSIONS: This regional study clarifies that all glioblastoma multiformes are at least focally positive and that telomerase expression correlates with tumour grade in oligodendrogliomas. Homogeneity versus heterogeneity for telomerase expression across multiple regions of oligodendrogliomas versus high grade astrocytomas may provide important preclinical data on the use of antitelomerase agents in these adult glial tumours.

Unusual dural and skull-based mesenchymal neoplasms: a report of four cases.

Dural and skull-base mesenchymal neoplasms other than meningiomas are rare. We report four such tumors, some of which are uncommon even in nonintracranial sites, in three adults and one child. The adult tumors consisted of a synovial sarcoma of the third ventricle region in a 19-year-old woman, a leiomyoma of the suprasellar region in a 57-year-old woman, and an Epstein-Barr virus (EBV)-associated smooth muscle tumor of the cavernous sinus in a 35-year-old woman with acquired immunodeficiency syndrome (AIDS). The pediatric tumor was an EBV-associated leiomyosarcoma of the left dural transverse sinus in a 14-year-old girl with common variable immunodeficiency syndrome. All tumors were thought to be primary in their dural or skull-base locations. The two EBV-associated smooth muscle tumors in immunocompromised patients expand the locations for EBV-associated smooth muscle tumors to dural and skull-base sites, the synovial sarcoma is unique to the intracranial space, and the sellar leiomyoma represents the third reported sellar smooth muscle tumor.

Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease.

We tested the hypothesis that synaptic defects in the hippocampus of individuals with Alzheimer disease (AD) correlate with the severity of cognitive impairment. Three postmortem groups were studied: controls with normal and stable cognition; cognitively intact subjects with senile plaque densities diagnostic for possible AD (p-AD) and neurofibrillary changes characteristic of early AD (Braak stage III); and individuals with definite AD and neurofibrillary changes typical of incipient to severe AD (Braak stage III, V, or VI). Synaptophysin (a presynaptic vesicle protein) levels were quantified by immunoblotting of synaptic membrane fractions isolated from hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex. Average synaptophysin levels were reduced in hippocampus when comparing definite AD to controls (55%, p < 0.0001), p-AD to control (25%, p < 0.005), and definite AD to p-AD (30%, p < 0.05), but levels in entorhinal cortex, occipital cortex, and caudate nucleus were either unchanged or less significantly altered than in hippocampus. By univariate analysis, hippocampal synaptophysin levels correlated with neuropsychological measurements, including Mini-mental state examination scores (r = 0.83, p < 0.0001) and Blessed scores (r = 0.74, P < 0.001), and with senile plaque densities (r = 0.89, p < 0.0001). We conclude that synaptic abnormalities in the hippocampus correlate with the severity of neuropathology and memory deficit in individuals with AD, and that this defect may predate neuropsychological evidence for cognitive impairment early in AD.

Expression and distribution of amyloid precursor protein-like protein-2 in Alzheimer's disease and in normal brain.

Amyloid precursor-like protein-2 (APLP-2) belongs to a family of homologous amyloid precursor-like proteins. In the present study we report on the expression and distribution of APLP-2 in fetal and adult human brain and in brains of patients with Alzheimer's disease. We demonstrate that APLP-2 mRNAs encoding isoforms predicted to undergo post-translational modification by chondroitin sulfate glycosaminoglycans are elevated in fetal and aging brains relative to the brains of young adults. Immunocytochemical labeling with APLP-2-specific antibodies demonstrates APLP-2 immunoreactivity in cytoplasmic compartments in neurons and astrocytes, in large part overlapping the distribution of the amyloid precursor protein. In Alzheimer's disease brain, APLP-2 antibodies also label a subset of neuritic plaques. APLP-2 immunoreactivity is particularly conspicuous in large dystrophic neurites that also label with antibodies specific for APP and chromogranin A. In view of the age-dependent increase in levels of chondroitin sulfate glycosaminoglycan-modified forms of APLP-2 in aging brain and the accumulation of APLP-2 in dystrophic presynaptic elements, we suggest that APLP-2 may play roles in neuronal sprouting or in the aggregation, deposition, and/or persistence of beta-amyloid deposits.