[Show abstract][Hide abstract] ABSTRACT: Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often 'Pick body-like' in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.
[Show abstract][Hide abstract] ABSTRACT: Two hereditary forms of cerebrovascular amyloidosis, familial British and Danish dementias (FBD and FDD), share striking similarities with Alzheimer's disease (AD) despite structural differences among their amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD). Neuropathological lesions in these disorders include neurofibrillary tangles, parenchymal amyloid and pre-amyloid deposits and overwhelming cerebral amyloid angiopathy co-localizing with reactive microglia and multiple amyloid associated proteins including activation products of the complement cascade. Immunohistochemical analysis of FBD and FDD brain lesions unveiled the presence of serum amyloid P-component (SAP) primarily associated with thioflavin positive amyloid deposits in spite of the significant pre-amyloid burden existing in both disorders. Using affinity chromatography and ELISA binding assays we demonstrated specific, calcium-dependent, saturable, high affinity binding interactions between SAP and ABri/ADan peptides, with dissociation constant values in the sub-nanomolar range and within the same order of magnitude as those resulting from the interaction of SAP with Alzheimer's Abeta1-40 and Abeta1-42. The preferential association of SAP with fibrillar amyloid lesions and not with non-fibrillar pre-amyloid deposits is puzzling, suggesting that SAP modulates the assembly and stability of the final fibril rather than participating in the early steps of protein misfolding and oligomerization.
No preview · Article · Jul 2007 · Journal of the Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Nov 2006 · Neuropathology and Applied Neurobiology
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and beta-amyloid (Abeta)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with Abeta-(1-42) and Abeta-(4-42) in approximately 1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas Abeta was mainly Abeta-(4-42). In all cases, the presence of Abeta-(X-40) was negligible, a surprising finding in view of the prevalence of Abeta40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and Abeta molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.
Full-text · Article · Dec 2005 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the
BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules
(Danish amyloid (ADan) and β-amyloid (Aβ)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable
from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis
of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity
and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34)
and its N-terminally modified (pyroglutamate) counterpart together with Aβ-(1-42) and Aβ-(4-42) in ∼1:1 mixture. The post-translational
modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was
heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally
modified (pyroglutamate), whereas Aβ was mainly Aβ-(4-42). In all cases, the presence of Aβ-(X-40) was negligible, a surprising
finding in view of the prevalence of Aβ40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal
aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational
mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and Aβ molecules was demonstrated
in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar
degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the
mechanism of dementia.
No preview · Article · Nov 2005 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Clinical usefulness and safety of percutaneous conchotome biopsy of the deltoid muscle and of the quadriceps muscle was compared in patients suspected to have a neuromuscular disorder. In 121 samples from the quadriceps muscle and in 39 samples from the deltoid muscle, the quantity of muscle fibers was equal and the fraction of biopsies resulting in a specific diagnosis was similar (50% and 56%, respectively). Also, biopsy from the 2 locations resulted in the same distribution of neurogenic, inflammatory, and myopathic disorders. After quadriceps muscle biopsy, 2 patients developed vasovagal syncopes and one patient a local hematoma, whereas no complications occurred in the patients subjected to deltoid muscle biopsy. We conclude that biopsy from the deltoid muscle is clinically as useful and safe as biopsy from the quadriceps muscle.
No preview · Article · Oct 2005 · Journal of clinical neuromuscular disease
[Show abstract][Hide abstract] ABSTRACT: The objectives were to identify prognostic factors for the survival of children with cerebellar astrocytoma, and to evaluate the reproducibility and prognostic value of histological sub-classification and grading.
Children aged 0-14 years treated in Denmark for a cerebellar astrocytoma in the period 1960-1984 were included and followed until January 2001 or until their death. The histological specimens from each patient were reviewed for revised grading and classification according to three different classification schemes: the WHO, the Kernohan and the Daumas-Duport grading systems.
The overall survival rate was 81% after a follow-up time of 15-40 years. The significant positive prognostic factors for survival were "surgically gross-total removal" of the tumour at surgery and location of the tumour in the cerebellum proper as opposed to location in the fourth ventricle. No difference in survival time was demonstrated when we compared pilocytic astrocytoma and fibrillary astrocytoma. Moreover, we found that the Kernohan and the WHO classification systems had no predictive value and that the Daumas-Duport system is unsuitable as a prognostic tool for low-grade posterior fossa astrocytomas.
Discordant observations due to interobserver variability make histological sub-classification of low-grade cerebellar astrocytomas in children insufficient for predicting prognosis and biological behaviour. Similar survival rates in a population of paediatric low-grade cerebellar astrocytomas of grades I and II indicate that tumour grade has no prognostic significance within this group of patients. "Surgically gross-total removal", especially if the tumour is located in the fourth ventricle is of the highest importance for long-term survival. Histological sub-classification of the tumours has no predictive value.
No preview · Article · Dec 2003 · Child s Nervous System
[Show abstract][Hide abstract] ABSTRACT: Chromosome 13 dementias, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with neurodegeneration and cerebrovascular amyloidosis, with striking neuropathological similarities to Alzheimer's disease (AD). Despite the structural differences among the amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD), these disorders are all characterized by the presence of neurofibrillary tangles and parenchymal and vascular amyloid deposits co-localizing with markers of glial activation, suggestive of local inflammation. Proteins of the complement system and their pro-inflammatory activation products are among the inflammation markers associated with AD lesions. Immunohistochemistry of FBD and FDD brain sections demonstrated the presence of complement activation components of the classical and alternative pathways as well as the neo-epitope of the membrane attack complex. Hemolytic experiments and enzyme-linked immunosorbent assays specific for the activation products iC3b, C4d, Bb, and C5b-9 indicated that ABri and ADan are able to fully activate the complement cascade at levels comparable to those generated by Abeta1-42. ABri and ADan specifically bound C1q with high affinity and formed stable complexes in physiological conditions. Activation proceeds approximately 70-75% through the classical pathway while only approximately 25-30% seems to occur through the alternative pathway. The data suggest that the chronic inflammatory response generated by the amyloid peptides in vivo might be a contributing factor for the pathogenesis of FBD and FDD and, in more general terms, to other neurodegenerative conditions.
No preview · Article · Jan 2003 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Familial Danish dementia (FDD) is pathologically characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal protein deposits, and neurofibrillary degeneration. FDD is associated with a mutation of the BRI2 gene located on chromosome 13. In FDD there is a decamer duplication, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan. The aim of this study was to describe the major neuropathological changes in FDD and to assess the distribution of ADan lesions, neurofibrillary pathology, glial, and microglial response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non-fibrillary) lesions was found. Abeta was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive neurofibrillary degeneration occurring with parenchymal, predominantly pre-amyloid rather than amyloid, deposition. These findings support the notion that parenchymal amyloid fibril formation is not a prerequisite for the development of neurofibrillary tangles. The significance of concurrent ADan and Abeta deposition in FDD is under further investigation.
Preview · Article · Apr 2002 · Journal of Neuropathology and Experimental Neurology
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jul 2001 · Journal of endocrinological investigation
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: To discuss the possible relationship between stereotactic radiation therapy and the development of a meningosarcoma.
Retrospective case review.
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.
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.
On the basis of statistical considerations, the development of the reported mesenchymal sarcoma was most likely caused by the stereotactic radiation therapy.
No preview · Article · Jun 2000 · The American journal of otology
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · May 2000 · Proceedings of the National Academy of Sciences