Understanding Frontotemporal Dementia: Symptoms, Genetics, and Prognosis

It is associated with atrophy of the frontal and temporal lobes.

There is a progressive change in personality and behavior with variable degrees of impairment in language and other cognitive domains.

History of Frontotemporal Dementia

It was described by Arnold Pick as the syndrome of dementia associated with atrophy of the frontal and temporal lobes.

Subsequently, Alzheimer's was also described as an important intra-neural inclusion and ballooned neural lobes.

Dementia with frontotemporal atrophy along with pick bodies is also called Pick Disease.

Mutations in Several Genes Identified

1. The most common gene that is mutated is C90RF72.
   • C90RF72 is a hexanucleotide repeat expansion.
   • It results not only in frontotemporal dementia but also in amyotrophic lateral sclerosis
   • These are observed in about 26% of familial cases and about 5% of sporadic cases.
   • The frontotemporal dementia due to C90RF72 mostly results as a behavioral variant. Around 30% may have concomitant motor neuron disease.

2. Mutation in GRN (Chromosome 17) results in loss of function and accounts for about 5-10% of the frontotemporal dementia cases.
3. Mutation can also be observed in the MAPT gene (chromosome 17). This is a relatively rare cause of frontotemporal dementia.

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Clinical Features

There are two variants of frontotemporal dementia: the behavioral variant-frontal lobe is affected (predominant symptoms are of behavior), and the language variant-temporal lobe is affected (predominant symptoms are of language). 

Diagnostic Criteria

According to the DSM-5, the criteria for the major and minor variants of the frontotemporal neurocognitive disorder are:

1. Criteria should meet for the major or mild frontotemporal neurocognitive disorder.
2. There should be an insidious onset and gradual progression.
3. Either (1) or (2) is present.
   • Behavioral variant criteria are:
     • Three or more behavioral symptoms can be observed among disinhibition, apathy, reduced sympathy or empathy, perseveration, stereotypies, hyperorality, and dietary changes.
     • Low social cognition or executive abilities.
   • Language variant criteria include:
     • Decreased language ability (word finding, naming, grammar, reduced speech production) 
4. These intraneural inclusions are also known as pick bodies, named after Arnold Pick.

Familial Dementia

The family history may be present in about 50% of the cases, and typically, the transfer is observed to be autosomal dominant in such cases.

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Sporadic Dementia

In most sporadic frontotemporal dementia cases, the etiology is unknown.

Laboratory Examination

• Structural imaging: atrophy may correlate to the prominent symptoms.
• In SPECT or PET, that is, in functional imaging, the blood flow or metabolism may be reduced.
• Frontal and/or anterior temporal areas of the brain may be affected, which may suggest frontotemporal dementia.

Pathology

• Macroscopic findings usually might show atrophy of the frontal/temporal/both lobes.
• Usually, these findings are symmetric, although asymmetric may also be observed.

Microscopic Findings

• Immunocytochemistry using antibodies against:
  • Tao (τ)
  • Ubiquitin
  • P62 (sequestrum-1)
  • α-synuclein

• It helps us identify the inclusion bodies. Even pick bodies can be identified. Neural loss and gliosis can also be observed.
• TDP-43 intracellular inclusions may also be seen in some cases.
• Genetic mutations in terms of TDP-43 and ubiquitin/P62, it is seen that:
  • With GRN and VCP mutations, TDP-43 is positive.
  • With CHMP2B mutations, ubiquitin/P62 is positive
  • C40RF72 is both TDP-43 and ubiquitin/P62 positive, and some inclusions may also be TDP-43 negative, mostly seen in the cerebellum.

We favor the diagnosis of FTD when

1. If the patient is younger
2. If there is relative preservation of memory, visuospatial functions.
3. There may be some additional symptoms in favor of FTD, like frontotemporal atrophy and a selective decrease in frontotemporal blood flow/metabolism.

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Course and Prognosis

• It usually has progressive deterioration.
• There may be changes in behavior, personality, and language.
• Motor symptoms may be present.
• There may be loss of the other cognitive symptoms.
• The average survival of frontotemporal dementia is around 8 years from the onset and around 4-5 years from diagnosis.
• FTD with motor neuron disease shows signs of a shorter survival rate.
• FTD, in comparison to Alzheimer's, is more rapid and has more rapid cognitive and functional decline.

Treatment

Non-pharmacological interventions: These are prioritized for behavioral symptoms like aggression, agitation, etc.

• Currently, we don't have any treatment for cognitive deficits or prevention of the progress of frontotemporal dementia.
• Data is insufficient to recommend cholinesterase inhibitors or memantine to treat cognitive symptoms.

Symptomatic treatment includes SSRI's treatment for frontotemporal dementia. Other drugs are tazodone, 2nd generation anti-psychotics, and anti-convulsants.

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FAQ’S

Q. How is FTD affected?

Ans. Usually FTD is not life-threatening, but in cases of serious illness, the patient may lead to pneumonia.

Q. Is FTD hereditary?

Ans. Yes, it is heridatary—40 percent cases with family history.

Hope you found this blog helpful for your Psychiatry residency Neurology and General Medicine preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.