Introduction

Frontotemporal lobar degeneration, formerly called Pick's disease, is a progressive dementia that is associated with focal atrophy of the frontal and/or temporal lobes. For over 100 years, the key clinical and pathological feature of this disease has been recognized to be focal, often asymmetric cortical involvement. Histopathologically, frontotemporal lobar degeneration (FTLD) is distinct from Alzheimer's disease but heterogeneous, even among similar clinical syndromes. Recently, with the advent of specialized immunohistochemical stains and insights gained from molecular genetics, it has been recognized that FTLD is closely related to, and sometimes overlaps with three other neurodegenerative diseases: corticobasal ganglionic degeneration (CBD), progressive supranuclear palsy (PSP), and motor neuron disease (MND). The central role of the microtubule-associated protein, tau, in the pathogenesis of FTLD, has led to classification as a “tauopathy.”

First description and history of FTLD

The first case of what is now called frontotemporal lobar degeneration (FTLD) was described by Arnold Pick in 1892 (Pick, 1892). His subsequent description of six similar patients emphasized a language impairment, which he termed “amnestic aphasia,” and a focal pattern of brain atrophy involving the temporal and/or frontal lobes. A lack of senile plaques and tangles in the brains of similar patients was noted by Alzheimer in 1911. He and Altman provided the first histopathological description of argyrophilic inclusions (later termed Pick bodies) and swollen achromatic cells (later termed Pick cells) (Altman, 1923).

Introduction

A variety of sporadic and familial neurodegenerative disorders, characterized clinically by dementia and/or motor dysfunction, demonstrate intracellular accumulations of filamentous material composed of the microtubule-associated protein (MAP) tau (See chapters 29, ‘Neuropathology of Alzheimer's disease’, 34, ‘Pick's and other frontotemporal dementias’, 44, ‘Progressive supranuclear palsy’, and 45, ‘Corticobasal degeneration’). The term ‘tauopathies’ was coined to refer to this seemingly heterogeneous group of neurodegenerative disorders with filamentous tau deposits as their predominant histopathological feature. The progressive accumulation of filamentous tau inclusions in the absence of other disease-specific neuropathological abnormalities provided circumstantial evidence implicating tau dysfunction in disease onset and/or progression. However, the discovery of pathogenic tau mutations in a heterogeneous group of disorders termed frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) provided unequivocal confirmation of the central role of tau abnormalities in the etiology of neurodegenerative disorders (Foster et al., 1997; Poorkaj et al., 1998; Hutton et al., 1998; Spillantini et al., 1998c). This seminal finding has opened novel areas of investigation into the pathophysiologic mechanisms of tau dysfunction and the relationship of tau abnormalities to brain degeneration.

Familial frontotemporal dementia

In 1892, Arnold Pick described a woman with lobar brain atrophy, who presented clinically with presenile dementia and aphasia (Pick, 1892). Thus, this was the first description of what is now classified clinically as frontotemporal dementia (FTD) (McKhann et al., 2001).

Introduction

Synucleinopathies are a group of neurodegenerative disorders sharing in common the presence of intracellular fibrillar inclusions composed of polymerized α-synuclein (α-syn). Although the biological function of this presynaptic protein remains largely unknown, overwhelming evidence indicates that its self-aggregation in neurons and/or oligodendrocytes is associated with the impairment of nervous system function and cellular demise leading to disease. Pathological inclusions composed of α-syn have been the focus of enumerable clinical and pathological studies with the earliest dating almost to the beginning of the twentieth century. However, the finding that these inclusions are comprised of α-syn only became apparent in the past 5 years following the identification of a mutation in the α-syn gene in families with Parkinson's disease. α-Syn inclusions are the defining characteristics of several disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, they are also found in a significant percentage of other neurodegenerative disorders including neurodegeneration with brain iron accumulation type-1 (NBIA-1), Down's syndrome, and familial and sporadic Alzheimer's disease (AD) (Table 15.1). The understanding of the role of α-syn in neurodegenerative disease requires the determination of the normal function and properties of this protein, the clinicopathological assessment of the relationship between α-syn inclusions and disease, and the elucidation of the mechanism of pathogenesis. In this chapter, we will focus on the most recent developments in these aspects of synucleinopathies, but the description of these diseases also requires an overview of the most significant features that have been documented for over almost 100 years.

List of abbreviations

Aβ, β-amyloid; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; CBD, corticobasal degeneration; CHO, Chinese hamster ovary; CNS, central nervous system; ESE, exon-splicing enhancer; ESS, exon-splicing silencer; FTD, frontotemporal dementia; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; FTLD, frontotemporal lobar degeneration; IHC, immunohistochemistry; MAP, microtubule-associated protein; MND, motor neuron disease; MT, microtubule; NFT, neurofibrillary tangle; PD, Parkinson's disease; PDC, parkinsonism-dementia complex; PHF, paired helical filament; PiD, Pick's disease; PSG, progressive subcortical gliosis; PSP, progressive supranuclear palsy; SF, straight filament; TG, transgenic; WT, wild-type.

Introduction

In 1892, Arnold Pick described a woman with lobar brain atrophy who presented clinically with presenile dementia and aphasia (Pick, 1892), and thus, the first description of what is now classified clinically as frontotemporal dementia (FTD) (Neary et al., 1998; McKhann et al., 2001). The clinical syndromes of FTD are associated with several neuropathological abnormalities (Lund and Manchester Groups, 1994; McKhann et al., 2001). A subset of these disorders is characterized by the intracellular accumulations of filamentous material composed of the microtubule-associated protein (MAP) tau. The term ‘tauopathies’ was coined to refer to this seemingly heterogeneous group of neurodegenerative disorders that includes Pick's disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), neurofibrillary tangle dementia, and argyrophilic grain disease (see ‘Sporadic tauopathies’, Chapter 11). In FTD patients, there is a family history of a similar dementing illness in approximately 38 to 50% of patients (Knopman et al., 1990b; Stevens et al., 1998; Chow et al., 1999).

The first edition of this book was conceived with the intention of providing a practical guide to the neuropathological diagnosis of dementia. It was intended particularly for those who did not regard themselves as experts in this increasingly complex field. The relatively small number of authors was encouraged to share their diagnostic experience with others. This second edition still aims to provide practical assistance in this way, but it now goes further than that. The pace of scientific research advances in this field of dementia is such that it has become a formidable enough task for an expert to remain fully conversant with his or her own subfield, let alone with the field as a whole. Therefore we have aimed to widen the authorship greatly so that many chapters could be written by those specialists with research interests in the topic that is covered by each. We are delighted that those approached have responded so generously and enthusiastically since the outstanding contributions from the authors have made the second edition the most up-to-date and comprehensive monograph on the neuropathology of dementia. Because of the wider international authorship it has also been possible to extend the scope of the coverage of each topic to include more about research findings and the background science so that the book can now claim to provide comprehensive coverage of current understanding of the dementias rather than a more restricted practical guide. We hope, therefore, that a wider readership of neurobiologists and clinicians as well as pathologists will find much of interest here. Those familiar with the first edition will find that there are many new chapters and even more new authors contributing to the second edition.