Frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), a progressive dementia also known as Pick’s disease, is a neurodegenerative disease marked by deterioration of the physical structure of the frontal lobe of the brain. Pick's disease is relatively uncommon and accounts for less than 2% of all cases of adult-onset dementias. There are three clinical syndromes that result from this deterioration, frontotemporal dementia, progressive nonfluent aphasia and semantic dementia. These syndromes involve perception of self and others, social skills and language. Symptoms of this malady may include impaired social and personal conduct, blunted emotions and loss of insight, and language disorder that may include: nonfluent spontaneous speech; fluent, meaningless spontaneous speech; and impaired word meaning. Unlike Alzheimer's disease, FTLD patients’ memories remain intact and visuospatial skills are unimpaired. The causes are unknown although there are possible genetic precursors that indicate the disease is inherited. Genetic mutations of chromosome 17 have been identified in some cases but this is not consistent in all cases of the disorder.

History and initial descriptions

Czechoslovakian neurologist and psychiatrist Arnold Pick described Pick’s disease in 1892. His patients showed language impairment (he termed ‘amnestic aphasia’) and focal pattern brain atrophy in the temporal and frontal lobes. In 1911, the German physician Alois Alzheimer publicly noted that he had differentiated FTLD from Alzheimer's disease by showing there was a lack of senile plaques and tangles in the central nervous system which are typical of Alzheimer's disease. Alzheimer and E. Altman later provided histopathological description of agyrophilic inclusions (Pick bodies) and swollen achromatic cells (Pick cells).

Clinical criteria

Typically, there is a gradual onset before age of 65 without the presence of head trauma. Onset reaches a peak between the ages of 45 and 60 years and is rarely seen after the age of 75 or prior to middle age. Average duration of the disease is 5 to 10 years. There is a slightly higher rate of occurrence in women than in men. While there are clear family histories in some cases, more than 80% are sporadic in that they have no apparent familial history.

Core clinical features supporting diagnostic criteria of the subtypes:

Frontotemporal dementia

The most common clinical subtype of FTLD characterised by personality change and impaired social conduct in its initial stages:

• decline in social interpersonal conduct;
• impairment in regulation of personal conduct;
• emotional blunting;
• loss of insight.

Other common features:

• disinhibition;
• neglect of personal hygygiene, mental rigidity;
• perseverative behaviour;
• voracious appetite;
• hyperorality.

Progressive nonfluent aphasia

Nonfluent spontaneous speech with at least one of the following:

• agrammatism;
• phonemic paraphasias;
• anomia.

Semantic dementia

Language disorder characterized by fluent progressive aphasia:

• progressive, fluent, empty spontaneous speech;
• loss of word meaning, manifest by impaired naming and comprehension;
• semantic paraphasias;
• agnosia.

Perceptual disorder characterized by:

• prosopagnosia;
• associative agnosia.

Cognitive abilities that are preserved, i.e. not impaired:

• perceptual matching and drawing reproduction;
• single-word repetition;
• ability to read aloud and write to dictation orthographically regular words.

Clinical progression

Some typical symptom groups:

• Comprehension and ability to recall events intact, but at the same time there is a gradual increase in difficulty recalling names of objects or individuals;
• Anterograde memory intact-able to recall dates and current location (distinguishing this malady from Alzheimer's disease wherein the patient may not be able to recall where they are and what time it is);
• Orientation unimpaired and ability to move about without getting lost (e.g. driving or walking) is unimpaired but may act impulsively (e.g. running red lights);
• May persist in tasks and can only be distracted with difficulty;
• Talkative with fluent speech but difficult to interrupt;
• Divided attention and problem-solving skills impaired;
• Normal range on digit span forward and backward (tests of immediate attention), repetition, and judging line orientation and copying complex figures (tests of visuospatial skills);
• Impaired range on tests of verbal and visual memory, naming and verbal fluency (verbal fluency measuring the number of words in a certain category generated in one minute);
• Profound behavioural changes may be evident: lack of insight and impaired ability to plan ahead can cause difficulty in functioning at home and in social settings while at the same time neuropsychological tests that are not sensitive to frontal lobe impairment will show normal test scores.

Contraindications

Criteria that excludes a diagnosis of FTLD

• Onset after age of 65;
• Abrupt rather than gradual onset;
• Head trauma;
• Multifocal lesions as shown by neuroimaging.

Neuropathology

A common method of diagnosing FTLD patients is the use of scanning technology including MRI (magnetic resonance imaging), single photon emission computed tomography (SPECT) and PET (Positron Emission Tomography). These scans show that there is atrophy of certain areas of the brain, specifically a decrease in the size of the frontal and anterior temporal lobes.

Histopathology

Type 1

• prominent microvacuolar change in layer II and upper layer III of the cortical lamina
• no specific histologic features meaning the absence of staining with immunohistochemical markers
• in some cases neurons stain with an antibody to a B crystallin

Type 2

• severe astrocytic gliosis with or without ballooned neurons and inclusion bodies (Pick type or Pick's disease).
• when present, ballooned neurons and inclusion bodies of the Pick type stain with antibodies directed against tau protein.
• ballooned neurons also stain for neurofilament protein

Differential diagnosis

Alzheimer’s disease

• tau pathology in addition to amyloid pathology and generalised atrophy
• Onset of AD takes place over a older range of age and rarely before the age of 40. Pick's disease usually occurs between 45 and 60 and rarely presents after 65 years of age.

Corticalbasal ganglionic degeneration (CBD)

• tau pathology
• may start as clinical syndromes similar to FTLD

Progressive supranuclear palsy (PSP)

• tau pathology
• may start as clinical syndromes similar to FTLD

Motor neuron disease (MND)

• tau pathology

Differential diagnosis in young patients presenting with dementia includes degenerative diseases, metabolic imbalances, psychiatric illnesses, neoplasms, infections, posttraumatic sequelae, and vascular disease. Causes of dementia can be identified or eliminated by history and clinical methodologies.

Genetics

There have been familial studies that strongly indicate the disease may be inherited. Gene mutations of tau protein on chromosome 17 have been found in some cases. However, there are numerous cases which have no evidence of this mutation. Similarly, the apolipoprotein E4 allele which is a risk factor in Alzheimer’s shows no association with FTLD.

Prognosis

FTLD progresses steadily and often rapidly with a full course of degeneration lasting from less than two to more than ten years. Some individuals eventually need round-the-clock care and may even have to be institutionalised.

Treatment

At the present time there is no known treatment that has effectively retarded the progression of FTLD. Inappropriate and aggressive behaviour may be ameliorated with behavior modification but extreme behaviours may require medication. Antidepressants have been shown to improve some symptoms.