Introduction

Definition and overview of frontotemporal dementia (FTD)

FTD is a neurodegenerative disease defined by the lobes of the brain it affects - the frontal and temporal lobes.¹ It differs from other types of dementia in several ways, including the age of diagnosis, symptoms, and its impacts on the brain. It is also one of the rarer forms of dementia, affecting 15-22 persons per 100,000 people.²

Despite its low prevalence, understanding the causes and genetic factors contributing to FTD is important in order to grasp its impact on individuals and their families. This article explores the subtypes, causes, risk factors, diagnosis, and treatment of FTD, aiming to provide a clearer understanding of the disease and its aetiology.

Importance of understanding aetiology

Before discussing the causes, it is important to consider why understanding the aetiology of FTD matters. By identifying the factors contributing to FTD, scientists can improve diagnosis and treatment. Additionally, there is a proven connection between aetiology and therapeutic strategies, as better identification of the causes allows the exploration of more effective treatment options.³

Overview of frontotemporal dementia

FTD is an umbrella term encompassing three main subtypes: behavioural variant FTD, primary nonfluent aphasia, and semantic dementia.⁴ Subtypes are categorised based on various anatomic, genetic, and neuropathologic factors.⁵ Neuropathologic factors refer to the effect on nervous system tissue which includes the brain, spinal cord, and the body’s nerve network.⁶

Clinical subtypes of FTD

Behavioural variant FTD (bvFTD)

This is the most common subtype of FTD and it is defined by a change in social, interpersonal, and emotional behaviour. These include symptoms such as apathy, loss of empathy, emotional bluntness, change in patterns, a loss of attention span, and more. 

bvFTDI initially affects areas at the front of the brain, which are involved in decision-making, behavioural control, and personality. As bvFTD progresses, regions responsible for planning, problem-solving, and organising are also affected.⁴

Primary progressive aphasia (PPA) 

PPA is an overarching term which describes a group of neurodegenerative diseases marked by gradual speech and language impairment being the primary symptoms. The 2 main types of PPA associated with FTD are progressive nonfluent aphasia (PNFA) and semantic dementia (SEMD), otherwise known as semantic PPA variant.

PNFA 

Accounting for approximately 25% of FTD cases,⁴ PNFA is a condition which affects a person’s ability to use language. It can lead to symptoms such as slow or hesitant speech, difficulty understanding complex sentences, and an increase in grammatical mistakes in speech.⁷ This is because PNFA affects the brain regions responsible for language, speech, and voluntary motor movements.^8,9

SEMD

The frequency of SEMD in patients is similar to PNFA, with SEMD accounting for approximately 20-25% of cases in people with FTD.⁴ SEMD and PNFA are both similar in that they cause language problems and anomia (difficulty recalling names of common objects). However, SEMD differs from PNFA in that it primarily affects a person’s comprehension abilities whilst PNFA causes a deficit in speech production, with particular effects on a person’s ability to temporarily store and manipulate verbal information.¹⁰

Causes of frontotemporal dementia

In most cases, FTD is not hereditary - this means people with FTD tend to not have any family history of the disease. However, a family history of FTD can increase the likelihood of a person developing FTD. In fact, approximately 10-30% of behavioural FTD is linked to genetic causes.¹¹ As such, FTD can be categorised as familial FTD or sporadic FTD, with the latter referring to when there is no family history of FTD or related conditions.¹²

Sporadic FTD

The cause of sporadic FTD is often unknown; with a lack of genetic basis, it’s difficult to track what can cause FTD by chance in most people. However, a study comparing the risk profile of sporadic and familial FTD revealed that impaired cardiovascular health could be associated with sporadic FTD, especially of the behavioural subtype. Having said that, this study did have several limitations given it only tested a small sample size - Finnish and Italian people - on a very limited number of variables, where they only looked at the presence of a few cardiovascular and other lifestyle-related diseases.¹³ Hence, it remains that the exact environmental and lifestyle factors affecting the development of sporadic FTD remain unknown, with further tests on the matter needed. 

Genetic factors

Although the causes of most cases of FTD are unknown, the primary genetic factors which contribute to familial FTD have been tracked. These are mutations in the microtubule-associated protein tau (MAPT) gene, progranulin (GRN) gene, and chromosome 9 open reading frame 72 (C9orf72) gene. It has been found that each genetic group causes approximately 5-10% of all FTD.¹⁴

MAPT (Microtubule-associated protein tau) gene

MAPT was the first gene linked to familial FTD. It is responsible for coding for the protein tau and so, people with MAPT mutations have abnormal accumulations of the tau protein in affected regions of the brain.¹⁵ It has been found that families with MAPT mutations usually have a strong family history of bvFTD, with generations affected back-to-back.¹² Aside from bvFTD, MAPT mutations have also been associated with other clinical subtypes including semantic variant PPA. FTD symptoms associated with mutations in the MAPT gene can be wide-ranging, with varying symptoms of disease progression and ages of onset within the same family.¹⁵

GRN (progranulin) gene 

The GRN gene codes for the protein progranulin, which has a key role in the development and survival of neurons and brain cells.¹⁶ GRN mutations lead to insufficient production of progranulin,¹⁷ which can cause abnormal accumulation of the TDP-43 protein in affected neurons.¹⁵ It’s estimated that GRN mutations account for 5-10% of FTD cases. Similar to the MAPT mutation, GRN mutations have been linked to a wide range of FTD subtypes including bvFTD and PNFA. However, the range of ages affected by GRN mutations causing FTD is greater (35-87 years) compared to those linked to MAPT mutations (40-60 years).¹⁵

C9orf72 (Chromosome 9 open reading frame 72) gene 

Another primary genetic factor of FTD is the chromosome 9 mutation. The gene C9orf72 codes for a protein which is abundant in the nerve cells in the outer layers of the brain and in motor neurons.¹⁸ C9orf72 mutations manifest in the form of abnormal expansion of a specific DNA sequence in the gene - as a result, this can lead to FTD via 3 main processes:¹⁹

• Loss of function of C9orf72 gene 
• Toxic effects via the production of abnormal RNA which disrupts the normal functioning of cells 
• Toxic effects via the production of abnormal proteins which are toxic to nerve cells 

There are also other genetic factors which can contribute to FTD, however these only account for 5% of FTD cases.¹¹

Diagnosis and genetic testing

FTD’s symptoms make it hard to diagnose early due to their overlap with other disorders. Diagnosis becomes even more difficult if the person happens to be much younger than the average age of onset, as dementia is less likely to be considered by doctors in younger people. Additionally, given that bvFTD is most common, these behavioural symptoms can often be mistaken for depression, anxiety, schizophrenia, and other similar conditions.²⁰

Typically, diagnosis involves obtaining the patient’s medical history (including their family history), conducting blood tests, full physical examinations, and relevant brain scans (e.g. MRI, PET, etc.)²¹ Furthermore, to investigate possible causes of FTD, genetic tests may also be conducted. This can help doctors make a more precise diagnosis which can help them better understand the changes in the person’s brain as well as ensure that FTD is accurately diagnosed by investigating whether variants of genes increasing the risk of FTD are present.²² 

Therapeutic implications

There is currently no cure for FTD and no way to slow down its progression, however, there are treatments to help manage the symptoms of FTD such as managing behavioural changes and treating language problems.¹¹

Current treatment approaches

FTD can be particularly challenging for a person’s family, as the behavioural changes associated with the condition can lead to confusion, frustration, and emotional strain among loved ones. Some recommendations for managing these symptoms are listed below.¹¹

• Remember that the person with FTD can not control their behaviours; focus on accepting rather than challenging their behavioural symptoms Maintain a regular schedule to reduce confusion 
• If you are feeling frustrated, consider giving yourself space, e.g. by temporarily leaving the room

Treatment of PNFA and SEMD involves using new tools to communicate, whilst also trying to maintain language skills where possible.  Working with a speech-language expert can help in choosing the correct tools and strategies as these can differ from person to person. Family members of people with PPA can also do the following to help them.¹¹

• Speak slowly and clearly 
• Use simple sentences
• Be patient - wait for responses and ask for clarification if needed

Future directions

There is ongoing research in the FTD field, especially concerning the development of disease-modifying treatments.²⁴ Disease-modifying treatments refer to treatments which aim to slow down, or stop, the progression of a condition.²⁵ There is also potential for further development of precision medicine to treat FTD. This involves using a person’s genetic profile to develop highly personalised, and thus more effective, treatments with few side effects.²⁶

Summary 

Understanding the aetiology of FTD is crucial for the development of effective treatment and enables better support for individuals with the condition. Additionally, a thorough understanding of the causes and symptoms can assist loved ones in managing the challenges associated with FTD. Although there is currently no cure or treatment to slow the progression of the disease, it is hoped that future advancements will lead to the development of disease-modifying therapies for FTD.