Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica
Published in: Acta Neuropathologica 2/2011

01-02-2011 | Original Paper

The spectrum and severity of FUS-immunoreactive inclusions in the frontal and temporal lobes of ten cases of neuronal intermediate filament inclusion disease

Authors: Richard A. Armstrong, Marla Gearing, Eileen H. Bigio, Felix F. Cruz-Sanchez, Charles Duyckaerts, Ian R. A. Mackenzie, Robert H. Perry, Kari Skullerud, Hedeaki Yokoo, Nigel J. Cairns

Published in: Acta Neuropathologica | Issue 2/2011

Login to get access

Abstract

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament proteins. Recently, the ‘fused in sarcoma’ (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of familial amyotrophic lateral sclerosis with FUS mutation, NIFID, basophilic inclusion body disease, and atypical FTLD with ubiquitin-immunoreactive inclusions (aFTLD-U). To further characterize FUS proteinopathy in NIFID, and to determine whether the pathology revealed by FUS immunohistochemistry (IHC) is more extensive than α-internexin, we have undertaken a quantitative assessment of ten clinically and neuropathologically well-characterized cases using FUS IHC. The densities of NCI were greatest in the dentate gyrus (DG) and in sectors CA1/2 of the hippocampus. Anti-FUS antibodies also labeled glial inclusions (GI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN). Vacuolation was extensive across upper and lower cortical layers. Significantly greater densities of abnormally enlarged neurons and glial cell nuclei were present in the lower compared with the upper cortical laminae. FUS IHC revealed significantly greater numbers of NCI in all brain regions especially the DG. Our data suggest: (1) significant densities of FUS-immunoreactive NCI in NIFID especially in the DG and CA1/2; (2) infrequent FUS-immunoreactive GI, NII, and DN; (3) widely distributed vacuolation across the cortex, and (4) significantly more NCI revealed by FUS than α-internexin IHC.
Literature
1.
Armstrong RA (1996) Correlations between the morphology of diffuse and primitive β-amyloid (Aβ) deposits and the frequency of associated cells in Down’s syndrome. Neuropathol Appl Neurobiol 22:527–530CrossRefPubMed
2.
Armstrong RA, Cairns NJ (2006) Topography of α-internexin-positive neuronal aggregates in 10 patients with neuronal intermediate filament inclusion disease. Eur J Neurol 13:528–532CrossRefPubMed
3.
Armstrong RA, Cairns NJ (2006) Laminar degeneration of the frontal and temporal cortex in neuronal intermediate filament inclusion disease (NIFID). A study using α-internexin immunohistochenistry. Clin Neuropathol 25:209–215PubMed
4.
Armstrong RA, Cairns NJ (2007) Spatial patterns of the pathological changes in neuronal intermediate filament inclusion disease (NIFID), an α-internexin immunohistochemical study. J Neural Transm 114:451–456CrossRefPubMed
5.
Armstrong RA, Cairns NJ, Lantos PL (1999) Quantification of pathological lesions in the frontal and temporal lobe of ten patients diagnosed with Pick’s disease. Acta Neuropathol 97:456–462CrossRefPubMed
6.
Armstrong RA, Cairns NJ, Lantos PL (2000) A quantitative study of the pathological lesions in the neocortex and hippocampus of 12 patients with corticobasal degeneration. Exp Neurol 163:348–356CrossRefPubMed
7.
Armstrong RA, Lantos PL, Cairns NJ (2000) Laminar distribution of ballooned neurons and tau positive neurons with inclusions in patients with corticobasal degeneration. Neurosci Res Commun 27:85–93CrossRef
8.
Armstrong RA, Lantos PL, Cairns NJ (2001) Spatial correlations between the vacuolation, prion protein deposits, and surviving neurons in the cerebral cortex in sporadic Creutzfeldt–Jakob disease. Neuropathology 21:266–271CrossRefPubMed
9.
Armstrong RA, Kerty E, Skullerud K, Cairns NJ (2006) Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID): a study using α-internexin immunohistochemistry and principal components analysis (PCA). J Neural Transm 113:1207–1215CrossRefPubMed
10.
Armstrong RA, Ironside J, Lantos PL, Cairns NJ (2009) A quantitative study of the pathological changes in the cerebellum of 15 cases of variant Creutzfeldt–Jakob disease. Neuropathol Appl Neurobiol 35:36–45CrossRefPubMed
11.
Armstrong RA, Ellis W, Hamilton RL et al (2010) Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis. J Neural Transm 117:227–239CrossRefPubMed
12.
Belly A, Moreau-Gachelin F, Sadoue R, Goldberg Y (2005) Delocalization of the multifunctional RNA splicing factor TLS/FUS in hippocampal neurons: exclusion from the nucleus and accumulation in dendritic granules and spine heads. Neurosci Lett 379:152–157CrossRefPubMed
13.
Bigio EH, Lipton AM, White CL, Dickson DW, Hirano A (2003) Frontotemporal dementia and motor neurone degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS. Neuropathol Appl Neurobiol 29:239–253CrossRefPubMed
14.
Broe M, Hodges JR, Schofield E, Shepherd CE, Kril JJ, Halliday GM (2003) Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology 60:1005–1011PubMed
15.
Cairns NJ, Armstrong RA (2003) Clustering of neuronal inclusions in “dementia with neurofilament inclusions”. Acta Neuropathol 106:125–128CrossRefPubMed
16.
Cairns NJ, Perry RH, Jaros E et al (2003) Patients with a novel neurofilamentopathy: dementia with neurofilament inclusions. Neurosci Lett 341:177–180CrossRefPubMed
17.
Cairns NJ, Zhukareva V, Uryu K et al (2004) α-Internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease. Am J Pathol 164:2153–2161PubMed
18.
Cairns NJ, Jaros E, Perry RH, Armstrong RA (2004) Temporal lobe pathology of human patients with neurofilament inclusion disease. Neurosci Lett 354:245–247CrossRefPubMed
19.
Cairns NJ, Grossman M, Arnold SE et al (2004) Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease (NIFID). Neurology 63:1376–1384PubMed
20.
Ching GY, Liein RKH (1998) Roles of head and tail domains in alpha-internexin’s self-assembly and coassembly with the neurofilament triplet proteins. J Cell Sci 111:321–333PubMed
21.
Ching GY, Chien CL, Flores R, Liein RKH (1999) Overexpression of alpha-internexin causes abnormal neurofilamentous accumulations and motor coordination deficits in transgenic mice. J Neurosci 19:2974–2986PubMed
22.
Chio A, Restagno G, Brunetti M et al (2009) Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation. Neurobiol Aging 30:1272–1275CrossRefPubMed
23.
Ikeda K, Akiyama H, Kondo H et al (1995) Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles. Acta Neuropathol 90:620–625CrossRefPubMed
24.
Josephs KA, Holton JL, Rossor MN et al (2003) Neurofilament inclusion body disease: a new proteinopathy? Brain 126:2291–2303CrossRefPubMed
25.
Komori T (1999) Tau positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol 9:663–679CrossRefPubMed
26.
Kwiatkowski TJ, Bosco DA, LeClerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208CrossRefPubMed
27.
Mackenzie IR, Neumann M, Bigio EH et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4CrossRefPubMed
28.
Matsumoto S, Udaka F, Kameyama M, Kusaka H, Itoh H, Imai T (1996) Subcortical neurofibrillary tangles, neuropil threads and argentophilic glial inclusions in corticobasal degeneration. Clin Neuropath 15:209–214
29.
Munoz DG, Neumann M, Kusaka H, Yokata O, Ishihara K, Terada S, Kuroda S, Mackenzie IR (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627CrossRefPubMed
30.
Neumann M, Roeher S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IRA (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease (NIFID). Acta Neuropathol 118:605–616CrossRefPubMed
31.
Neumann M, Eademakers R, Roeher S, Baker M, Kretzschmar HA, Mackenzie IRA (2009) A new type of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931CrossRefPubMed
32.
Pirici D, Vandenberghe R, Rademakers R et al (2006) Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family. J Neuropathol Exp Neurol 65:289–301PubMed
33.
Probst A, Tolnay M (2002) Argyrophilic grain disease, a frequent and largely underestimated cause of dementia in old patients. Rev Neurol 158:155–165PubMed
34.
Valdmanis PN, Daoud H, Dion PA, Rouleau GA (2009) Recent advances in the genetics of amyotrophic lateral sclerosis. Curr Neurol Neurosci Rep 9:198–205CrossRefPubMed
35.
Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS an RNA processing protein cause familial amyotrophic lateral sclerosis Type 6. Science 323:1208–1211CrossRefPubMed
36.
Yamada T, McGeer PL, McGeer EG (1992) Appearance of paired nucleated tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neurosci Lett 135:99–102CrossRefPubMed
37.
Yokota O, Tsuchiya K, Terada S et al (2008) Basophilic inclusion body disease and neuronal intermediate filament inclusion disease: a comparative clinicopathological study. Acta Neuropathol 115:561–575CrossRefPubMed
Metadata
Title
The spectrum and severity of FUS-immunoreactive inclusions in the frontal and temporal lobes of ten cases of neuronal intermediate filament inclusion disease
Authors
Richard A. Armstrong
Marla Gearing
Eileen H. Bigio
Felix F. Cruz-Sanchez
Charles Duyckaerts
Ian R. A. Mackenzie
Robert H. Perry
Kari Skullerud
Hedeaki Yokoo
Nigel J. Cairns
Publication date
01-02-2011
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 2/2011
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-010-0753-3

Other articles of this Issue 2/2011

Acta Neuropathologica 2/2011 Go to the issue

Original Paper

Distinct pathological subtypes of FTLD-FUS

Original Paper

Brain aging and Aβ1–42 neurotoxicity converge via deterioration in autophagy–lysosomal system: a conditional Drosophila model linking Alzheimer’s neurodegeneration with aging

Case Report

Four-repeat tauopathy clinically presenting as posterior cortical atrophy: atypical corticobasal degeneration?

Correspondence

Absence of chromosome 19q13.41 amplification in a case of atypical teratoid/rhabdoid tumor with ependymoblastic differentiation

Original Paper

Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma

Review

Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly