Neuropathologic Heterogeneity in HDDD1: A Familial Frontotemporal Lobar Degeneration With Ubiquitin-positive Inclusions and Progranulin Mutation

Alzheimer's Disease Research Center, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
Alzheimer Disease and Associated Disorders (Impact Factor: 2.44). 01/2007; 21(1):1-7. DOI: 10.1097/WAD.0b013e31803083f2
Source: PubMed


Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Abeta plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.

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    • "There are several sources of pathological heterogeneity within FTLD-TDP. First, a number of genetic defects have been identified in these cases; many being caused by mutations of the progranulin (GRN) gene (Baker et al. 2006; Cruts et al. 2006; Mukherjee et al. 2006; Mackenzie et al. 2006a; Behrens et al. 2007; Rademakers and Hutton 2007). A less prevalent disorder, FTLD with valosin-containing protein (VCP) gene mutation (Forman et al. 2006), also has TDP-43 immunoreactive inclusions and recently, variants in the ubiquitin associated binding protein 1 (UBAP1) gene (Luty et al. 2008; Rollinson et al. 2009) were shown to have TDP-43 inclusions. "
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    ABSTRACT: Aims: Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. Methods: Changes in density of histological features across cortical gyri were studied in 10 sporadic cases of FTLD-TDP using quantitative methods and polynomial curve fitting. Results: Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases; their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated. Conclusions: Laminar distribution of pathological features in 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP.
    Neuropathology and Applied Neurobiology 07/2012; 39(4). DOI:10.1111/j.1365-2990.2012.01291.x · 3.93 Impact Factor
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    • "Patients from different families with the same mutation do not necessarily show the same clinical phenotype or age at onset (Huey, Grafman et al. 2006). On microscopic examination, all cases with PGRN mutations share a common subtype, characterized by NCIs and irregular dystrophic neurites in the neocortex and subcortical nuclei (Josephs, Ahmed et al. 2007; Gass, Cannon et al. 2006; Behrens, Mukherjee et al. 2007; Lopez de Munain, Alzualde et al. 2008; Mackenzie, Baker et al. 2006; Snowden, Pickering- Brown et al. 2006; Spina, Murrell et al. 2007). This subtype is referred to as type A (Mackenzie, Neumann et al.). "
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    ABSTRACT: Frontotemporal lobar degeneration is the second most common form of cortical dementia in the presenium after Alzheimer’s disease. Clinically, based on consensus guidelines, three distinct disease entities can be distinguished: frontotemporal dementia, semantic dementia and progressive nonfluent aphasia. Dementia of frontal type and motor neuron disease inclusion dementia are the most frequent neuropathological subtypes of frontotemporal lobar degeneration. By using immunohistochemistry, the latter is characterized by the presence of filamentous ubiquitin-reactive but tau-negative inclusions in nerve cell bodies and neurites. In contrast, Pick‘s disease and familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) are both characterized by abundant filamentous nerve cell inclusions made up of the microtubule-associated protein tau. The recent discovery of more than 15 different mutations in the tau gene in FTDP-17 brought the tau protein to the centre stage. These findings had a major impact on our understanding of neurodegenerative disorders characterized by tau filamentous inclusions in neurones and/or glial cells which are grouped under the generic term of tauopathies. However, as exciting these new molecular insights are, it would be inappropriate to lump frontotemporal lobar degeneration as tauopathies. Recent neuropathological and genetic data strongly suggest that there is more than one genetic background for frontotemporal lobar degeneration.
    Advanced Understanding of Neurodegenerative Diseases, 12/2011; , ISBN: 978-953-307-529-7
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    • "A proportion of cases of FTLD-TDP cases are familial (Cairns et al., 2007a); the majority of cases being caused by mutations of the progranulin (GRN) gene (Baker et al., 2006; Cruts et al., 2006; Mukherjee et al., 2006; Behrens et al., 2007; Rademakers and Hutton, 2007). A less prevalent disorder, FTLD with valosin-containing protein (VCP) gene mutation (Forman et al., 2006), also has TDP-43 immunoreactive inclusions and recently, variants in the ubiquitin associated binding protein 1 (UBAP1) gene (Rollinson et al., 2009) were shown to have TDP-43 inclusions. "
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    ABSTRACT: Mutations of the progranulin (GRN) gene are a major cause of familial frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). We studied the spatial patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and neuronal intranuclear inclusions (NII) in histological sections of the frontal and temporal lobe in eight cases of FTLD-TDP with GRN mutation using morphometric methods and spatial pattern analysis. In neocortical regions, the NCI were clustered and the clusters were regularly distributed parallel to the pia mater; 58% of regions analysed exhibiting this pattern. The NII were present in regularly distributed clusters in 35% of regions but also randomly distributed in many areas. In neocortical regions, the sizes of the regular clusters of NCI and NII were 400-800 μm, approximating to the size of the modular columns of the cortico-cortical projections, in 31% and 36% of regions respectively. The NCI and NII also exhibited regularly spaced clustering in sectors CA1/2 of the hippocampus and in the dentate gyrus. The clusters of NCI and NII were not spatially correlated. The data suggest degeneration of the cortico-cortical and cortico-hippocampal pathways in FTLD-TDP with GRN mutation, the NCI and NII affecting different clusters of neurons.
    Histology and histopathology 02/2011; 26(2):185-90. · 2.10 Impact Factor
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