Frontotemporal degenerations

The frontotemporal degenerations are a group of disorders which are considered together as they all share the characteristic feature of a degenerative process affecting the frontal and/or temporal lobes (Snowden et al. 1996). The anatomical distribution determines the clinical features, which may often be asymmetric. These disorders are characterized by disturbances of language, speech production, frontal dysexecutive, and behavioural features. Clinical descriptions of the prototypic syndromes, frontotemporal dementia, progressive non-fluent aphasia, and semantic dementia, have been published (Neary et al. 1998), but other presentations, for example, primary progressive prosopagnosia (Tyrrell et al. 1990b) also occur.

The neuropathological processes underlying these diseases are variable and include Pick's disease, non-specific frontal-lobe degeneration, hereditary tauopathies, corticobasal degeneration, and ubiquitin-positive tau-negative motor neuron disease type inclusions. The difficulty in predicting the underlying neuropathology from the clinical features demands a clinical descriptive approach to the frontotemporal degenerations before considering the potential diseases defined neuropathologically. The nosology surrounding these disorders is confused further by the terminology relating to Pick's disease.

Originally, Pick described cases of focal atrophy with the clinical features of dysphasia and/or a frontal-lobe syndrome. This purely descriptive clinical terminology has been championed by some who suggest the term ‘Pick syndrome’ (Kertesz and Munoz 1998), but in parallel, the development started by Alzheimer, who observed the swollen Pick cells and argentophilic inclusions (Pick bodies), has defined a particular type of neuropathology. More recently, our understanding of the molecular pathology of Pick's disease has further defined its nosological status.

The term ‘asymmetrical cortical degeneration’ is another term that was introduced by Caselli and Jack (1992) to refer to the group of slowly progressive focal degenerations. In a sense, all degenerative dementias start as a focal syndrome, even including Alzheimer's disease, which initially is that of a memory impairment. Most of these focal cortical degenerations are subsumed within the frontotemporal degenerative group, but primary progressive apraxia, often associated with corticobasal degeneration and posterior cortical atrophy (Benson et al., 988), usually associated with Alzheimer's disease, fall outside the general rubric of the frontotemporal degenerations.

Typically, the frontotemporal degenerations show structural or functional imaging changes indicative of frontotemporal degeneration. The EEG is characteristically normal by contrast to Alzheimer's disease (Stigsby et al. 1981). Cerebrospinal fluid examination is usually unremarkable.

Frontotemporal dementia

Although the term ‘frontotemporal dementia’ has been retained as one of the prototypic clinical syndromes of frontotemporal degeneration (Neary et al. 1998), the clinical features are those of a frontal syndrome, although the disease process does extend into the temporal lobes with time. It is, however, the behavioural change, as opposed to language or speech impairment, which characterizes this group of patients. Social skills deteriorate early, with difficulties at work, and the change in personality can be particularly distressing for the spouse. Some patients become disinhibited and overactive, reflecting predominant involvement of the orbitomedial frontal cortex, whereas others become apathetic, reflecting dorsolateral involvement.

Patients who are at first overactive and at times aggressive, may become quieter as the disease progresses. Other behavioural features include changes in food preference, usually towards sweet foods, ritualistic behaviours, and daily routines. Preservation of other cognitive skills means that the patient can go off walking on a stereotyped route, without ever getting lost. Dramatic failures on tests sensitive to frontal lobe function are apparent, although some patients may do well even on these tests, but fail on those of social cognition (Blair and Cipolotti 2000). Utilization behaviour may be observed. In some, speech gradually reduces with the features of a dynamic aphasia.

Some patients can develop a frontotemporal degeneration in association with motor neuron disease. Characteristically, this involves the anterior horn cells as opposed to long tracts, and fasciculation is seen characteristically in the proximal upper limb (Kew and Leigh 1992).

Progressive non-fluent aphasia

A non-fluent aphasia with relative preservation of comprehension was originally referred to as primary progressive aphasia (Mesulam 1982). Speech is non-fluent and effortful, although writing may be preserved early on. Comprehension is relatively preserved even as the disease progresses to mutism. At this stage, patients may travel alone or even drive a car without difficulty. Social skills are preserved early, but with disease progression, behavioural changes do emerge. Structural imaging shows left perisylvian atrophy, which can also be seen on functional imaging.

Semantic dementia

The third commonly encountered syndrome is referred to as semantic dementia and describes patients whose presenting feature is that of a verbal semantic memory impairment (Snowden et al. 1989; Hodges et al. 1992). Speech is fluent, and on first encounter the disorder may be missed. However, more detailed examination soon reveals the naming and comprehension deficit. At no time is speech production impaired, but it does become progressively more empty and communication more difficult. Regularization errors occur on reading aloud, indicative of a surface dyslexia. As the disease progresses, the semantic memory deficit may extend into the visual domain (rarely this can be the presenting feature) with the appearance of a visual associative agnosia. Behavioural changes with altered eating and ritualistic stereotypes occur. The disease starts with language impairment, reflecting left temporal lobe involvement, but with involvement of the right temporal lobe, patients can develop a prosopagnosia and an inability to recognize emotional expressions, impairing further their ability to communicate. The MRI and functional imaging reveal asymmetric left anterior temporal lobe atrophy (Fig. 1). In some patients, right temporal lobe atrophy predominates, with more florid behavioural changes, and, in some, prosopagnosia is the presenting feature (Tyrrell et al. 1990b; Hodges et al. 1992).

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Fig. 1. Coronal T1-weighted MR image of a patient with semantic dementia, showing left temporal lobe atrophy.

Neuropathology of the frontotemporal degenerations

A variety of neuropathological changes are associated with the frontotemporal degenerations. Although particular syndromes tend to be associated with certain pathologies, there is considerable overlap, such that the underlying disease process cannot at present be predicted reliably from the clinical presentation. Moreover, it is not yet clear whether the apparent neuropathological entities do indeed represent distinct nosological entities or merely a spectrum of patterns of neuronal degeneration. Recent advances in molecular pathology are helping to clarify this complex group of disorders.

Pick's disease

At a macroscopic level, there is striking asymmetric focal atrophy, usually with a distinct border. Affected gyri may be very thin with a ‘knife-edged’ appearance. The anterior temporal and frontal lobes are predominantly involved, with the superior temporal gyrus characteristically spared, particularly posteriorly. Astrocytic gliosis is variable. The hallmark lesion is the presence of tau-positive, ubiquitin-positive argentophilic inclusions (Pick bodies), which are widespread and typically prominent in the dentate gyrus; there may in addition, be ballooned neurons (Pick cells) (reviewed by Binetti et al. 1998).

Recent studies have demonstrated that the tau inclusions consist only of tau isoforms which contain the three repeat microtubule binding domains (‘three-repeat tau’); this now distinguishes Pick's disease from the other tauopathies (Delacourte et al. 1996). A wider neuropathological substrate has been attributed to Pick's disease in the past. Constantinidis et al. (1974) considered three types of Pick's disease.

Type A included Pick bodies together with Pick cells, and this would now be considered as typical Pick's disease. Type B cases were associated only with Pick cells in the absence of Pick bodies, and such cases would now be diagnosed as corticobasal degeneration. The balloon cells are tau positive and Aβ crystallin positive, and can be identified in a number of cases of frontotemporal degeneration as well as in typical cases of corticobasal degeneration. Pick's disease type C had no specific inclusion bodies, although gliosis was often present, and this group includes a variety of disorders.

Pick's disease is now seen as a very rare sporadic disorder. Criteria have been developed but are yet to be validated (ECAPD Consortium et al. 1998). The cases considered as familial Pick's disease in the past usually have a different neuropathological phenotype and many are now known to have mutations in the tau gene.

Hereditary tauopathies

Families with apparent autosomal dominant inheritance of frontotemporal degeneration have long been recognized. Many, but by no means all, are now linked to mutations in the tau gene (Hutton et al. 1998; Poorkaj et al.1998). Neuropathologically these are associated with glial tau inclusions, tau-positive ballooned neurons (Pick cells), and atypical Pick bodies. The clinical phenotype is variable and often includes an extrapyramidal syndrome and amyotrophy. Before the discovery of tau mutations, these cases were referred to as ‘frontotemporal dementia with Parkinsonism linked to chromosome 17’ (Foster et al. 1997).

Frontal lobe degeneration

Frontal lobe degeneration of the non-Alzheimer type (Brun 1993) lacks inclusion bodies or other hallmark features, and has also been referred to as ‘dementia lacking distinctive histology’, (Knopman et al. 1990) and non-specific dementia (Kim et al. 1981). Atrophy tends to be symmetrical, in contrast to the asymmetry of Pick's disease, but can be severe, affecting the frontal lobes. There is microvacuolation or mild spongiosis and astrocytic gliosis, particularly in laminae 1–3. There is no abnormal tau immunoreactivity or inclusions. This type of histology underlies many of the cases of progressive non-fluent aphasia.

Frontotemporal degeneration with motor neuron disease

This shows similar changes in the frontal lobe to those described under frontal lobe degeneration but with additional loss of motor neurons in the spinal cord. In addition, ubiquitin-positive, tau-positive inclusion bodies are found, particularly in layer 2 of the frontal and temporal cortex. Moreover, ubiquitin-positive, tau-negative inclusions have been reported in prototypical cases of semantic dementia without anterior horn cell disease involvement of motor neurons (Rossor et al. 2000). Rarely, cases with a phenotype of frontal lobe degeneration are reported in whom the underlying histopathology is that of Alzheimer's disease or prion disease.