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8 - Molecular neuropathology in familial and sporadic frontotemporal dementia
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- By Laura Gasparini, University of Cambridge, Maria Grazia Spillantini, University of Cambridge
- Edited by John R. Hodges, University of Cambridge
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- Book:
- Frontotemporal Dementia Syndromes
- Published online:
- 05 August 2016
- Print publication:
- 08 November 2007, pp 208-256
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Summary
Introduction
Frontotemporal dementia (FTD) is heterogeneous in terms of clinical presentation and pathological features. From the pathological point of view, subtypes of FTD are defined on the pattern of protein accumulation in the brain and they are collectively referred to as frontotemporal lobar degeneration (FTLD; Table 8.1). In general, FTLD is classified as tau–positive and tau-negative. The tau-positive cases show inclusions made of insoluble aggregates of the microtubule–associated protein tau. The tau-negative cases represent about 50–66% of all FTLD cases (Table 8.1) and could be divided in three groups: (1) those characterised by the presence of ubiquitin-positive, tau-negative intraneuronal inclusions; (2) FTLD cases with intraneuronal cytoplasmic inclusions made of neurofilament and internexin protein (i.e. neuronal intermediate filament inclusion disease, NIFID); (3) FTLD cases in which none of these kinds of inclusions are present (i.e. dementia lacking distinctive histology, DLDH).
The majority of FTD cases are sporadic, but about 40%of patients have a positive family history of dementia (Rosso et al. 2003). Numerous mutations in the tau gene on chromosome 17 have been identified and account for 10–40% of familial FTD. These cases are defined as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP–17; Foster et al., 1997) and are invariably characterised by tau-positive pathology. Recently, mutations in the progranulin (PRGN) gene on chromosome 17 have been reported in several FTD kindreds (Baker et al., 2006; Cruts et al., 2006). Progranulin mutations account for about 26% of familial FTD in the Belgian population (Cruts et al., 2006) and are associated with ubiquitinpositive tau-negative pathology (Baker et al., 2006; Cruts et al., 2006). Genetic analyses of other cases of hereditary FTD uncovered significant linkage to loci on different chromosomes, but the causative genes have not yet been identified.
While a vast literature is available on the pathology and primary pathogenic mechanisms of FTDP-17, little is known about other hereditary and sporadic FTLD cases. Therefore, the main part of this chapter will cover FTDP-17 molecular pathology and mechanisms. After a brief overview on the biology of tau protein, we will present the different types of mutations reported in the tau gene and their primary molecular mechanisms in relation to the type of fibrillar deposits they are associated with. We will discuss how knowledge gained on genetic cases of FTDP-17 highlights basic neurodegenerative mechanisms that could also apply to sporadic FTLD.
12 - The neurobiology of the tauopathies
- from Part IV - Recent advances in dementia
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- By Maria Grazia Spillantini, Department of Neurology, University of Cambridge, Cambridge, UK, Michel Goedert, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
- Edited by Maria A. Ron, Institute of Neurology, London, Trevor W. Robbins, University of Cambridge
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- Book:
- Disorders of Brain and Mind
- Published online:
- 19 January 2010
- Print publication:
- 27 March 2003, pp 245-261
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Summary
Introduction
Current concepts of neurodegenerative diseases began to develop over a century ago, when the German school of neuropathologists described the salient histological features of what we now know to be the most common of these diseases. In 1907, Alois Alzheimer described the neuritic plaques and neurofibrillary lesions in the disease that was subsequently named after him (Alzheimer 1907). In 1911, Alzheimer also described the presence of Pick bodies as the characteristic neuropathological lesion of Pick's disease, a form of frontotemporal dementia (Alzheimer 1911). In 1912, Friederich Lewy described the inclusions characteristic of Parkinson's disease, the so-called ‘Lewy bodies’ (Lewy 1912). In the 1960s, electron microscopy was used to show that the above inclusions are made of abnormal filaments (Kidd 1963; Duffy and Tennyson 1965; Rewcastle and Ball 1968). At the time, the identification of these lesions was instrumental in establishing the various diseases as discrete entities. However, this work did not indicate a role for the lesions in the aetiology and pathogenesis of neurodegeneration. Over the past 20 years, a direct correspondence between the formation of the neuropathological lesions and the degenerative process has emerged. Besides the above diseases, this is also true of the prion diseases, of Huntington's disease and the other glutamine repeat diseases, as well as of several other, rarer conditions.
Progress was made possible by the merging of two independent lines of research. On the one hand, the biochemical study of the neuropathological lesions led to the identification of their main molecular components.