Introduction

Dementia is an umbrella term for a collection of syndromes/diseases which result in a significant decline in cognitive function unrelated to natural decline due to age. The dementia syndrome can be acquired by neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease, or through non-degenerative conditions like cerebrovascular disease. Commonly, dementia patients may have a mix of degenerative and non-degenerative conditions/diseases that result in dementia diagnosis.¹

Frontotemporal dementia (FTD) is another umbrella term for neurodegenerative diseases that involve the degeneration of areas of the brain associated with executive function, language, and behaviour, which are found within the frontal and temporal lobes. The FTD encompasses types of dementias such as the various types of frontotemporal lobar degeneration; Tau, TDP, and FUS.²

Symptoms

Symptoms are usually separated into 3 different variants:^2,3

Behavioural

Early behavioural and executive dysfunctions.

• Changes in behaviour:
  • Repetitive movements
  • Compulsive ritualistic behaviours
  • Repetitive use of verbal phrases
  • Binge eating - increased consumption of sweets or alcohol, and weight gain
• Behavioural disinhibition (lack of stopping certain behaviours):
  • Inappropriate and tactless actions
  • New criminal actions/behaviours
  • Impulsive and careless/dangerous actions
  • Embarrassing remarks
  • Apathy: reduced interest in anything from work and hobbies to basic hygiene. Decreased response to others also occurs, which is observed as decreased empathy and sympathy

12.5% of patients develop motor neuron disease, resulting in major issues with movement. It can occur in other variants but is much less common. However, around 40% of patients suffer from more minor symptoms of motor neuron disease.

The other two variants have primary progressive aphasia, a progressive decline in speech ability, both in producing and understanding speech.

Non-fluent

Progressive decline in speech, grammar and word output.

• Issues with speech production
  • Slow/laboured or halted
  • Misuse or omission of grammar
• Inconsistent speech (insertion, removal, and change of sounds)
• Difficulty understanding complex sentences
• Word comprehension and object recognition remain intact with some anomia for verbs.

Semantic

Progressive decline in naming and semantic knowledge. Asymmetrical degeneration of the amygdala and anterior temporal lobes.

• Anomia (primarily nouns – people, places objects)
• Word-finding difficulties
• Impaired word comprehension
• Grammar and speech are initially spared

Due to the asymmetrical degeneration, there are right and left-side variants:

• Right – Behavioural changes
  • May develop verbal compulsions
• Left (3x as common) – Linguistic semantic loss
  • May develop visual compulsions

Spread of disease can cause behaviour changes such as insomnia, selective eating, irritability, and more.

Similar conditions

FTDs can also share similar symptoms with Alzheimer's disease, another neurodegenerative disease involving tau protein. Alzheimer’s disease can affect speech and spread towards the frontal lobe in the late stages of the disease, causing dysfunction later on.²

Some similar symptoms such as executive dysfunction, hallucinations, and issues with movement are seen in both parkinsonism and Lewy-body dementia, but to different effects.

Cognitive decline

Cognitive decline occurs due to the degenerative aspect of the disease. This is due to the degeneration of neurons, gliosis, and microvascular changes in the areas of the frontal and temporal lobes, and the anterior cingulate and insular cortices. They degenerate primarily due to the toxic effects of different kinds of abnormal protein deposition.^1,2,3

As neurons die and become non-functional, the function of the brain which contains those neurons fails and causes particular symptoms. As the disease progresses, and more neurons die, the symptoms get worse and become more abundant and prevalent.

The initial symptoms are extremely different to the late-stage symptoms. Brain imaging shows that there is a physical difference as time progresses, showing the degeneration of neurons over time, and the disease spreading as it propagates from one area to the next.^1,3,4

Early stages

• The symptoms described above reference the early-mid stages of FTDs, where the variants tend to be segregated
• As the symptoms manifest, there is a slow worsening of symptoms as the degeneration spreads

Middle stages

• Symptoms from different variants start to converge, and degeneration of neurons spreads throughout different areas now²
• The symptoms have and will continue to worsen not only from the original variant but others too. Changes in behaviour and language are more common as are motor issues

Late stages

• Severe cognitive impairment, as major areas of the brain become completely depleted of neurons
• Lack of memory and learning
• Development of movement disorders
• Loss of independence, as there is a severe lack of functionality and ability to look after themselves

Areas of decline

There are three different types of produced proteins that cause toxicity, with many different genes in each to cause them to malfunction.^2,3

Depending on the origin of the degeneration and the type of degenerative protein mutation, different areas of the brain can be affected.

Tau

This represents 36-50% of FTD cases. Tau is a protein within the brain that helps maintain the structure and growth of neuronal axons and stabilises the microtubule network. Hyperphosphorylation of tau can cause it to fold and aggregate into tubules and plaques, leading to toxic events and the breakdown of neuronal structure. 

Subtypes include:

• Pick’s disease: 30% FTD-tau, knife-edge atrophy along frontal, temporal, and cingulate gyri
• Corticobasal degeneration: 35% FTD-tau, focused degeneration in the dorsal prefrontal cortex, supplemental motor area, subcortical nuclei, and peri-Rolandic cortex
• Progressive supranuclear palsy: 31% FTD-tau, degeneration of the frontal convexity to a milder degree than above. Severe atrophy in globus pallidus, subthalamic nuclei, and brainstem nuclei

TPD

This represents 50% of FTD cases. TDP is involved in the regulation of RNA processing which leads to gene expression. TDP involved in dementias migrate to the cytoplasmic surfaces forming inclusions instead of the ribosome.

There are three types of FTD-TDPs ( A, B, and C) depending on the pattern of the pathology of the disease and cortical association.

Type A 

 This accounts for 50% of non-fluent primary aphasia cases, 25% of corticobasal degeneration cases, and a small number of behavioural cases. Asymmetrical dorsal pattern of atrophy in frontal and temporal lobes, as well as the striatum, thalamus, orbitofrontal cortex, and more.

Type B 

This accounts for 2/3 of FTD dementia motor neuron disease and 25% of behavioural cases. Medial pattern of atrophy involving medial and polar temporal lobe, anterior insula, cingulate, and medial prefrontal cortices, and orbitofrontal cortex. The frontal cortex is only affected posteriorly.

Type C 

This accounts for 90% of semantic FTD. Either right or left anterior temporal atrophy, involving the amygdala, hippocampus, orbitofrontal cortex, and insular cortex.

FUS

FUS protein is primarily involved in the behavioural variant of FTD, accounting for 10% of FTD cases. FUS regulates the transcription of DNA. Mutations cause migration and inclusion of the protein out of the nucleus and halt the transcription process much like TDP.

FUS cases showcase an early onset that can cause severe personality and behavioural disinhibition and possibly psychosis, while not having motor or linguistic deficits. Atrophy is severe in the striatum and dentate gyrus.

As we can see, the pattern of decline in FTD  varies depending on which protein is at fault, what the specific mutation is, and the location of the degeneration origin. Degeneration will continue along these areas in early-mid stage FTD, and propagate to new areas as the mid-late stage sets in.⁴

Summary

Frontotemporal dementia is a degenerative neurological disease which causes neurons in the frontal and temporal lobes to become dysfunctional and die. This degeneration of neurons can cause symptoms such as behavioural changes, changes in speech, neurological disorders, and more.

Symptoms are categorised into three different types, behavioural, non-fluent, and semantic. They all are affected by the degeneration of certain areas of function. As degeneration continues, the symptoms worsen especially as degeneration propagates throughout the brain.

The symptoms gained are dependent on the pattern of degeneration, which is dependent on the protein, the protein mutation, and the originating site of the degeneration which dictates where the disease spreads.

In FTD, there are three proteins that cause degeneration:

• Tau
• TDP- the most abundant protein in FTD, which primarily causes both kinds of primary aphasia
• FUS- the primary cause of the behavioural variant of FTD

As the disease progresses, the atrophy pattern observed causes certain areas of the brain to degenerate, leaving the function of those areas to fail, which leads to the symptoms. This atrophy leads to the cognitive decline of the individual and the disease spreading (following the pattern dictated by the mutated gene).