Laboratory Diagnosis in Neurology, 1 Ed.

Frontotemporal Lobar Degeneration

M. Otto

Definition and Classification of Frontotemporal Lobar Degeneration

The term frontotemporal lobar degeneration (FTLD) covers three clinical syndromes (Benke and Donnemiller, 2002; Snowden et al., 2002):

• Frontotemporal dementia (FTD)

• Primary progressive aphasia

• Semantic dementia

“Pick's disease” was the name first given to FTLD. However, the term was poorly defined and covered a heterogeneous group of diseases that differed both histopathologically and etiologically. The group of diseases then became known as the “Pick complex.” Finally, following a consensus report, it was agreed to use the term “frontotemporal lobar degeneration.” FTD is the most common variant in this group; semantic dementia accounts for about 15% and primary progressive aphasia for about 10%.

Epidemiology

The incidence of FTLD is the same in men and women, and the average duration is about 8 years. The family history frequently reveals dementia syndromes.

Clinical Features

The onset of the disease is usually between the age of 45 and 65, although younger patients have also been described.

Table 11.5 Lund-Manchester criteria for the clinical diagnosis of frontotemporal dementia (FTD) (Snowden et al., 2002)

Core features

• Insidious onset and gradual progression

• Early decline in social interpersonal conduct (breaches of interpersonal etiquette, tactlessness)

• Early impairment in regulation of personal conduct (sexual disinhibition, restless wandering, aggressiveness, inappropriate jocularity)

• Early emotional blunting (emotional lethargy, loss of interest, loss of empathy)

• Early loss of insight and judgment

Supportive features

A Behavioral disorder

• Decline in personal hygiene and grooming

• Mental rigidity and inflexibility

• Distractibility and impersistence

• Hyperorality and dietary changes (overeating, preference for sweet foods, alcoholism)

• Perseverative and stereotyped behavior

• Utilization behavior

B Speech and language

• Altered speech output (aspontaneity and economy of speech, press of speech)

• Stereotypy of speech, echolalia, perseveration, and later mutism

C Physical signs

• Primitive reflexes at an early stage

• Incontinence

• Akinesia, rigidity, and tremor at an advanced stage

• Low and labile blood pressure

D Examination findings

• Neuropsychology: significant impairment on frontal lobe tests in the absence of severe amnesia, aphasia, or visuospatial deficits

• Electroencephalography: normal on conventional EEG despite clinically evident dementia

• Brain imaging (functional and/or structural): predominant frontal and/or temporal abnormalities

E Supporting findings

• Onset before age 65

• Positive family history, with a similar disease in a first-degree relative; bulbar paralysis, muscle weakness, fasciculation (in concomitant motor neuron disease)

F Exclusion criteria

• Sudden onset with epileptic seizures, or early stage of pronounced amnesia after craniocerebral injury; disturbed spatial orientation, logoclonia, myoclonia; paresis with pyramidal signs; bulbar, spinal, cerebellar, or athetotic symptoms

• Predominant postcentral structural or functional changes in CT or MRI

• Multifocal lesions in CT or MRI; postcentral structural or functional lesions

• Laboratory evidence of CNS involvement in metabolic or inflammatory diseases

G Relative exclusion criteria

• Chronic alcoholism in the patient's history

• History of vascular disease and hypertension

Changes in social behavior. The core criteria of FTD include radical changes in social behavior (Table 11.5).

Speech. Insidious changes may also appear in speech and language behavior. They include speech aspontaneity, press of speech, speech stereotypy, and perseveration.

Other symptoms. Primitive reflexes, like the snout reflex, may appear in the later stage. Incontinence, parkinsonian symptoms, pyramidal tract signs, and motor neuron involvement are much less frequent.

Diagnosis

EEG and neuroimaging. EEG is normal. Brain CT and MRI show mainly frontal and temporal atrophy. SPECT is considered the most sensitive imaging procedure for this disease, since frontal and/or temporal hypoperfusion may manifest at an early stage.

CSF analysis. The CSF shows slightly elevated levels of tau protein, while Aβ peptide1–42 levels are mostly normal. Unlike in Alzheimer's disease, CSF levels of S 100B protein are increased, although reliable threshold values for diagnosis are not yet available.

Histology. Macroscopically, atrophy of varying severity of the frontal and/or temporal regions is prominent. Histological changes also vary. The round cellular inclusions (Pick bodies) initially considered pathognomonic of Pick's disease are not found in all FTLD patients. In particular, the clinical syndrome does not seem to predict the histological type.

Genetics. Recent genetic studies have shown that some patients initially assigned to the frontotemporal dementia group carry a mutation on chromosome 17. Several mutations have been identified in the gene coding for tau protein (both exon and intron mutations). This group is now described as a separate entity, namely, familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). It is expected that more entities will be discovered within the next few years based on other mutations and histopathological findings, thus necessitating yet another refinement in the clinical diagnosis of FTLD.

References

Benke T, Donnemiller E. The diagnosis of frontotemporal dementia. Fortschr Neurol Psychiatr 2002;70:243–251

Snowden JS, Neary D, Mann, DMA. Frontotemporal dementia. Br J Psychiatry 2002;180:140–143

Further Reading

Hüll H, Bauer J. Demenzen. In: Berlit P, ed. Klinische Neurologie. Heidelberg: Springer; 1999:829–856

Kretzschmar HA, Neumann M. Neuropathological diagnosis of neurodegenerative and dementia diseases. Pathologe 2000;21:364–374

Neary D, Snowden JS, Gustafson I, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554