FRONTOTEMPORAL DEMENTIA

Frontotemporal dementia (FTD) is a recently used terminology for clinical Pick's disease (PiD). Arnold Pick (1892) described aphasia and personality changes with progressive frontal and temporal degeneration, but later it became a pathological entity defined histologically by the presence of argyrophilic globular inclusions (Pick bodies) and swollen achromatic neurons (Pick cells). It also became apparent that cases of clinical PiD with frontal and temporal lobe atrophy may not show the typical Pick bodies on autopsy. Constantinidis and colleagues classified PiD as: (1) with Pick bodies; (2) only with swollen neurons; and (3) only scarring, and neuronal loss. They felt "in spite of the dissimilarities between these forms, considering the absence of sufficient knowledge about pathogenesis, it seems prudent at present to maintain the uniqueness of Pick's entity."

With the development of neuroimaging, frontal and temporal atrophy was demonstrated with increasing frequency in vivo. However, instead of shifting the diagnosis of PiD back to the clinic, more recent studies applied new labels such as dementia of the frontal lobe type, or frontal lobe dementia (FLD) (Brun) as new entities, while reserving the diagnosis of PiD for the pathologist. The groups who described dementia of the frontal lobe type further changed the terminology to frontotemporal degeneration (FTD) (The Lund and Manchester Groups), and frontotemporal lobar degeneration (Snowden et al.). Nevertheless, they acknowledged the clinical syndrome was the same whether or not the histology showed Pick bodies. They estimated the incidence at 20 percent of degenerative dementias.

The clinical syndrome of FTD (FLD)

The predominantly behavioral changes of the frontal lobe syndrome often begin under sixty-five years of age with apathy and disinterest, which may be mistaken for depression. On the other hand, the symptoms of disinhibition may suggest a manic psychosis. They may occur paradoxically at the same time. The behavioral manifestations, therefore, are more likely to be presented to a psychiatrist than to a neurologist. Some of the more florid manifestations of disinhibition such as hyperorality (in which patients overeat, or put objects in their mouths) and hypersexuality are interpreted as being due to involvement of both temporal lobes, a phenomenon known as Kluver-Bucy syndrome. Progressive decrease of language output frequently appears later but can be seen at the same time as the behavioral problems. Neuroimaging studies such as CT, MRI, and SPECT scans are important for diagnostic confirmation. Behavioral quantitation may be more useful than cognitive testing. Kertesz and others (1997) constructed a twenty-four-item Frontal Behavioral Inventory (FBI), to ask the caregiver about the most specific behaviors. The FBI is used at the initial interview or for retrospective diagnosis.

At times FTD is associated with motor neuron diseases (MND) such as amyotrophic lateral sclerosis. Recently it was shown that some cases of FTD with or without MND have specific ubiquitin positive, tau negative cytoplasmic inclusions similar to that found in MND.

Primary Progressive Aphasia

Mesulam described a series of cases of slowly progressive language problems (aphasia) and subsequently named the syndrome primary progressive aphasia. The clinical and pathological overlap of PPA and FTD is considerable and we suggested the term Pick complex (Kertesz et al., 1994) to emphasize the relationship.

The initial presentation of PPA is often word-finding difficulty, or anomia. In this respect, PPA patients are not much different from Alzheimer's patients, except they have relatively preserved memory and nonverbal cognition. Mesulam suggested a two-year period of relatively pure aphasia as the operational definition of PPA, although this may be too restrictive and in many publications it is not adhered to. The more typical clinical picture progresses from anomia to a non-fluent type of aphasia, in which there is increasing word-finding difficulty.

Some patients present with stuttering, slow speech, and articulatory difficulty and errors in speech. These patients are less likely to be mistaken for AD, but unfortunately an unexplained isolated articulatory disturbance in a younger person is often considered to be hysterical. Loss of speech (mutism) used to be considered characteristic of PiD as well, and it tends to be the end-stage of all forms of frontotemporal dementia, even those that start with behavioral abnormalities rather than language disturbance. End-stage mutism also occurs in AD, but usually in a patient who already has a global dementia with loss of comprehension and basic functions of daily living.

Another form of PPA that is different from the more common nonfluent variety was described as semantic dementia by Snowden and others (1989). These patients progressively lost the meaning of words, but retained fluency and were able to carry out a conversation.

Corticobasal degeneration

There have been many case descriptions of PiD where the patients had prominent signs of Parkinson's such as slow movements and rigid muscles, known as extrapyramidal features. When Rebeiz and colleagues described selected degeneration of the brain structures they recognized the similarity of the pathology to PiD. This was subsequently confirmed by several investigators who contributed further clinical details and relabelled it corticobasal degeneration (CBD) or corticobasal ganglionic degeneration (CBGD). The asymmetrical extrapyramidal syndrome combined with an inability to perform complete movements (apraxia) and "alien hand," unresponsive to levodopa (the usual treatment for Parkinson's disease), was subsequently described mainly in movement disorder clinics. The interest focused on the extrapyramidal syndrome may have led to the belief that behavioral changes are rare and dementia occurs only in a minority of CBD cases. However, when well-documented case descriptions are specifically reviewed, behavioral, cognitive, and language disturbances suggestive of frontal and temporal lobe involvement seem to be frequent features during the course of the disease.

Pick complex

Pick complex (Kertesz et al., 1994; Kertesz and Munoz) is a unifying concept of the overlapping clinical syndromes of FLD, PPA, CBD, FTD, and associated MND and the underlying neuropathological findings, emphasizing commonalities rather than differences between them. It designates both the pathological and the clinical overlap, avoids the restriction of pathology and clinical symptomatology to the frontotemporal cortex and acknowledges the relationship to PiD. The term frontotemporal degeneration or frontotemporal dementia does not include the frequent subcortical involvement, parietal pathology, and extrapyramidal symptomatology, and is mostly used for the behavioral syndrome.

Neurogenetics

The discovery of genetic linkage to chromosome 17 q21-22 of several large families with significant resemblance to Pick complex, supports the concept of syndrome (Wilhelmsen). The chromosome region common to all these families, called FTDP-17, contains the gene for the microtubule associated protein tau. At this point, several mutations in the tau gene have been identified in FTDP-17 families (Hutton et al.). Not all families with FTD have tau mutations, but some have ubiquitin-positive, tau-negative inclusions (Kertesz et al., 2000). Genetic biochemical and histochemical distinctions provide further understanding of the syndrome but we must be careful not to lose sight of the clinical, pathological, and genetic cohesiveness, and exercise caution in interpreting the differences.

Treatment

Treatment of FTD is aimed at controlling symptoms pharmacologically. Most of the drugs used were already approved medications, usually used for Parkinson's disease, AD, or depression. Attempts to use levodopa, selegiline, fluoxetine, or similar drugs have not altered the course significantly but may help restless, compulsive, or apathetic behavior. Until proper randomized clinical trials are carried out, these drugs can not be considered efficacious, especially considering the variability and the relatively long clinical course of FTD.

Andrew Kertesz

See also Alzheimer's Disease; Dementia; Dementia with Lewy Bodies; Vascular Dementia.

BIBLIOGRAPHY

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Hutton, M.; Lendon, C. L.; Rizzu, P.; et al. "Association of Missense and 5'-plice-site Mutations in Tau with the Inherited Dementia FTDP-17." Nature 393 (1998): 702–705.

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