Introduction

Frontotemporal dementia (FTD) is a term used to describe conditions associated with the loss of brain cells, specifically in the frontal and temporal regions of the brain. It typically occurs earlier than other forms of dementia, between the ages of 40 and 65 and is considered rare. FTD is a progressive disorder, meaning symptoms will typically get worse over time as more changes occur in the brain. There are two forms of FTD: behavioural variant FTD (bvFTD), which causes changes in behaviour and primary progressive aphasia (PPA), relating to language.  Symptoms can vary depending on the regions affected, but typically are categorised into behavioural, language, executive function and physical, for example:

Behavioural:

• Inappropriate social behaviours (e.g., rudeness, impulsivity)
• Loss of inhibition
• Appearing subdued or depressed
• Loss of interest in people and activities
• Decreased motivation
• Difficulties with empathy
• Repetitive behaviours (e.g., foot tapping, hand-rubbing)
• Changes in food preferences
• Neglecting personal hygiene

Language:

• Misnaming objects and loss of vocabulary
• Repetition of phrases
• Slow, hesitant speech and pronunciation issues
• Forgetting the meaning of words and placing them in the wrong order
• Echolalia (repeating others' words)
• Gradual loss of speech, potentially leading to mutism

Executive Function:

• Poor planning, judgment, and organisation
• Easily distracted, rigid thinking
• Difficulty with abstract concepts
• Memory difficulties (less common early on)

Physical:

• Parkinson-like symptoms (e.g., slow, stiff movements)
• Difficulties with eating and swallowing
• Loss of bladder and bowel control

Understanding FTS is important for patients, carers and the general public. A clear understanding of what is causing FTD and its effects on the brain and body can help patients make informed decisions regarding their future care. For caregivers, family and friends, it’s important to understand the unique challenges this may present and the reasons the behaviour change is occurring. As FTD is less common, it is often misunderstood and less recognised than other forms of dementia, such as Alzheimer's. Raising awareness helps improve the quality of life for everyone affected.

The Brain Regions Affected by FTD

Our brains can be divided into four lobes: frontal, parietal, temporal and occipital. In the case of FTD specifically, the frontal and temporal lobes of the brain are affected.

The frontal lobe has a variety of functions. It has been associated with voluntary movements, higher-level executive functioning, self-control and language. Executive function refers to the ability to problem solve, make decisions and control responses. This region of the brain is considered to make up our personality and control how we behave and our emotional regulation. With such a complex range of functions modulated by the frontal lobes, damage or changes in this area can have a variety of symptoms.

The temporal lobe is the second largest of the four lobes and is located just behind our ears. It's responsible for auditory processing and is associated with learning and memory, as the hippocampus is in this region. The processing of emotions, language and certain aspects of visual processing also takes place in this region.

The accumulation of abnormal proteins in the brain can cause neurons to die; in FTD, this specifically occurs in the frontal and temporal regions of the brain. In brain imaging studies, the brain can appear to have ‘shrunk’ (atrophy) in these areas in those who have FTD, caused by the loss of neurons. The loss of neurons in these areas can result in loss of function.

For example, atrophy in the frontal regions of the brain associated with executive functioning, language and impulse control can manifest as FTD symptoms like apathy, disinhibition and lack of empathy. Loss of neurons in the temporal regions, especially the left side, which is crucial for language processing, can lead to different language impairments. For example, in PPA, patients can struggle with understanding oral and written language and forming coherent sentences.

Pathophysiology: Mechanisms Behind FTD

Protein Misfolding and Aggregation

Autopsies of individuals who had FTD show that there can be an abnormal accumulation of proteins in the brain. For example, tau protein and TDP-43 play a role in the pathology of the disease. In healthy brains, these proteins play a role in normal and healthy cellular function; however, in FTD, abnormal proteins start to form through misfolding.

Tau is important in the brain for binding structures in neurons; however, when they are misfolded, the tau proteins start to clump together and aggregate inside neurons to form tau tangles. The aggregation inside neurons leads to disruption of the normal processes and eventually cell death.¹ Similarly, TDP-43 is involved in the processing and transport of RNA. When TDP-43 is misfolded, it accumulates in the cytoplasm of neurons and becomes toxic to the cell. The exact reasons why these proteins misfold in FTD are not fully understood, but it is believed to involve a combination of genetic mutations, cellular stress, and other molecular mechanisms.²

Genetic Factors

It has been proven that FTD in some cases has a genetic basis; those who have a family history of FTD are more likely to develop the disorder. One of the associated genes with this disorder is the tau gene (MAPT gene). Mutations in this gene can cause abnormalities in the formation of the tau protein that can ultimately lead to the formation of tau tangles in neurons and eventually lead to cell death. In individuals who have a variant of the Tau gene, developing FTD is highly likely, but currently, the exact age of onset and symptoms cannot be predicted.³

The GRN gene provides instructions to produce the protein progranulin. Mutations in the GRN gene can result in behavioural FTD, including changes in personality and judgment. The resulting symptoms of a mutation in this gene also include progressive speech and language problems (aphasia), which can cause problems in speaking and remembering names, which can eventually result in mutism. Sometimes degeneration in brain areas caused by mutations in this gene can lead to Parkinsonism, a movement disorder characterised by tremors and slow and rigid movements.⁴

The most prevalent genetic cause of FTD is mutations in the C9ORF72 gene. Mutations in this gene appear as behavioural changes, including deficits in executive function, socially inappropriate behaviour, apathy, etc Scientists are currently working to understand how mutations in this gene can lead to FTD and possible treatments.⁵

Summary

Frontotemporal dementia is a neurodegenerative disease affecting the frontal lobes of the brain and the temporal lobes. This type of dementia is marked by distinct changes in behaviour, language, and motor skills. FTD is progressive, typically shows itself in midlife, and slowly gets worse. The disease can make daily life challenging for patients and their loved ones. Understanding what causes FTD, including gene mutations and faulty proteins, is key to helping people with the illness. Better comprehension of the symptoms of FTD and the degeneration of the brain can help improve patient and caregiver support.