Frontotemporal dementia

Frontotemporal dementia is a neurodegenerative disorder characterised by focal degeneration of the frontal & temporal lobes.

Frontotemporal dementia (FTD) is a type of dementia that is characterised by predominant disturbances in social behaviour, personality and language (e.g. aphasia). This is accompanied by preferential degeneration of frontal and temporal lobes.

FTD is a heterogeneous condition with various subtypes. It is an uncommon cause of dementia, but typically affects patients at a younger age (< 65 years).

Dementia

Dementia describes a clinical syndrome that is characterised by a significant deterioration in mental function that leads impairment of normal function.

In healthcare, we measure ‘normal function’ by activities of daily living (ADLs). These are a series of routine activities that people should be able to do without assistance. They can be broadly divided into personal tasks and domestic tasks.

• Personal: washing, dressing, toileting, continence, transferring (e.g. bed to chair)
• Domestic: cooking, cleaning, shopping, managing finances, taking medication

Types of dementia

Dementia can be caused by several conditions, which all manifest with poor mental performance and impaired normal functioning. The clinical manifestations of dementia can reflect the underlying aetiology.

• Alzheimer’s disease (AD): 50-75%
• Vascular dementia (VD): 20%
• Dementia with Lewy-body (DLB): 15-20%
• Frontotemporal dementia (FTD): 2%
• Rare causes: Parkinson’s disease dementia (PDD), Huntington’s disease (HD), Prion disease, others.

FTD is a common cause of early onset dementia (< 65 years old).

FTD is overall uncommon compared to other forms of dementia. It is more commonly seen in patients with early onset dementia with a similar frequency to AD. The mean age of onset is 58 years old. The onset before 40 years old and after 75 years old is uncommon.

The sex prevalence is generally equal with some reporting a slight male predominance.

FTD was first described in 1892 by Arnold Pick leading to the term ‘Pick disease’.

Pick disease is an old clinical term that now refers to a pathological finding of Pick bodies, which contain tau protein inclusions. These may be seen in certain subtypes of FTD.

Clinical subtypes

FTD is an umbrella term that refers to three clinical disease subtypes:

• Behavioural variant (bvFTD): most common. Occurs in 50%. Characterised by progressive personality and behaviour change.
• Primary progressive aphasia (PPA): characterised by insidious onset of progressive language defects (e.g. word finding, aphasia). There are two different types of PPA.
  • Non-fluent PPA: characterised by articulatory difficulty
  • Semantic PPA: characterised by impaired single-word comprehension

FTD shows a strong genetic predisposition.

The exact cause of FTD is unknown, but is characterised by tissue deposition of aggregated proteins including phosphorylated tau or transactive response DNA-binding protein 43 (TDP-43). Tau is the major protein of ‘Pick bodies’ that may be seen in certain pathological subtypes. Tau is seen in other neurodegenerative diseases including motor neuron disease (MND) and corticobasal syndrome (CBS).

FTD shows a strong genetic predisposition. In 10-25% of cases, there is an autosomal dominant pattern of inheritance. In up to 40% of cases there is a family history of dementia or neuropsychiatric conditions without a clear inheritance pattern.

Commonly implicated genes include:

• Microtubule associated protein tau (MAPT): found on chromosome 17. Multiple identified mutations. Leads to a propensity of tau to form neurotoxic aggregates.
• Granulin precursor (GRN): found on chromosome 17. Multiple identified mutations. Role in FTD is unclear.
• C9ORF72 gene: found on chromosome 9. Most common genetic cause of inherited FTD. Also implicated in hereditary motor neuron disease. Usually results in bvFTD with or without MND.

These three genes explain approximately 15% of familial cases.

FTD is characterised by degeneration of frontal and/or temporal lobes.

On gross pathological assessment, FTD is characterised by atrophy of the frontal and/or temporal lobes. Under the microscopic there is neuronal loss among several other findings.

Like many neurodegenerative conditions, abnormal proteins inclusions may be seen in the cytoplasm and/or nuclei of both neuronal cells and glial cells (i.e. connective tissue cells of the central nervous system). It is the constitutes of these abnormal protein inclusions that define the pathological subtypes seen in FTD. The correct term for these pathological subtypes is ‘frontotemporal lobar degeneration’ (FTLD).

The pathological subtypes of FTLD include:

• FTLD-Tau: characterised by hyperphosphorylated tau protein inclusions
• FTLD-TDP: characterised by inclusions of abnormal phosphorylated and ubiquitinated TDP-43 proteins. Differentiated into subtypes A-D.
• FTLD-ALS/DPR
• FTLD-FUS

These pathological subtypes are associated with particular clinical features and subtypes of FTD. For example, FTLD-Tau is most commonly associated with the bvFTD. However, the location and composition of inclusions correlate poorly with clinical features.

The clinical presentation of FTD depends of the underlying subtype.

Behavioural variant

The behavioural variant of FTD is most commonly seen (~ 50%). It is characterised by progressive change to personality and behaviour.

Typical features:

• Disinhibition (e.g. socially inappropriate behaviour)
• Loss of empathy
• Apathy (losing interest and/or motivation)
• Hyperorality (e.g. dietary changes, attempt to consume non-edible products, eat beyond satiety)
• Compulsive behaviour (e.g. cleaning, checking, hoarding)

Primary progressive aphasia

PPA subtypes are less common and characterised by insidious changes to language. In the early stages of the disease, defects in language are typically isolated. The presentation varies depending on the subtype.

Typical language features:

• Effortful speech
• Halting speech
• Speech-sound errors
• Speech apraxia (i.e. difficulty in articulation)
• Word-finding difficulty
• Surface dyslexia or dysgraphia: mispronouncing difficult words (e.g. yacht)

As the conditions progresses, patients develop more behavioural symptoms and overtime memory impairment. However, language dysfunction remains a dominant feature.

Motor syndromes

FTD may be present with motor symptoms, which is due to three clinical syndromes that occur as a result of FTLD (the pathological term for certain abnormal protein inclusions such as tau).

These syndromes include MND, CBS and progressive supranuclear palsy (PSP). FTD with MND is a particular subtype, while CBS and PSP represent an alternative diagnosis with similar clinical features to FTD.

Clinical syndromes:

• FTD with motor neuron disease: diagnosis of MND may precede or follow diagnosis of FTD. Behavioural and cognitive features consistent with bvFTD seen in 15-20% of the amyotrophic lateral sclerosis subtype. Causes upper and lower motor neuron symptoms (e.g. spasticity, weakness, atrophy, fasciculations).
• Corticobasal syndrome: a rare neurodegenerative disorder with significant overlap with FTD. Characterised by abnormal tau deposition (i.e. taupathy). Usually begins with cognitive or behavioural disturbance with development of characteristic motor features. Classical motor features include asymmetrical akinesia, dystonia, ideomotor apraxia or alien-limb phenomenon.
• Progressive supranuclear palsy: a rare neurogenerative disorder characterised by supranuclear gaze palsy (i.e. difficulty looking up). Clinical features cross over with FTD (cognitive and behavioural) and parkinson’s (bradykinesia, rigidity).

Patients may perform well on cognitive assessment during the early disease course.

A formal mental status examination should be completed using a recognised cognitive assessment tool. Patients may perform well on cognitive assessments during the early course of the disease or show patterns distinct from classical amnestic dementias (e.g. AD).

There are multiple cognitive assessment tools, which are designed to test different areas of high cortical functioning. It is the pattern of cognitive dysfunction that helps determine the diagnosis (i.e. predominantly behaviour, language or memory?). As the disease progresses, it starts to affect more cognitive domains and to a greater extent.

Cognitive domains:

• Attention and concentration
• Recent and remote memory
• Language
• Praxis: planned motor movement (e.g. perform a task)
• Executive function
• Visuospatial function

There are a variety of different cognitive assessment tools that range from basic screening tools, to in-depth assessments of each cognitive domain. They are important to assess the severity of suspected dementia and determine the subtype.

A comprehensive summary of cognitive assessment tools can be found in our Dementia note.

Diagnosis of FTD is based on diagnostic criteria, which is supported with imaging.

Baseline investigations including blood tests and neuroimaging are important to exclude other causes of dementia (e.g. AD, vascular dementia) or altered mental status (e.g. psychiatric presentations, drug abuse, delirium, cerebrovascular disease, space-occupying lesion).

In patients with symptoms at a young age, it is not uncommon to be misdiagnosed with Alzheimer’s disease and vice versa.

Clinical assessment

Essential to determine characteristic clinical features. Patients may have poor insight so interviewing family members is important, especially for altered behaviour and personality. Cognitive tests are completed as part of the assessment.

The presence of typical features (e.g. abnormal social behaviour, eating disorder, stereotyped behaviour, apathy) in the absence of significant memory impairment is very specific to bvFTD. In the PPA subtype, it is characterised by progressive language defects with relative sparing of other cognitive domains during the early disease course.

Neuroimaging

Imaging of the brain with MRI is useful to exclude an alternative diagnosis and to look at the pattern of involvement (e.g. frontal and/or temporal atrophy). Whilst imaging is supportive, it cannot be used solely to determine the diagnosis.

Typical features on neuroimaging:

• bvFTD: frontal and temporal atrophy in up to 65%. Particularly anterior insula, anterior cingulate cortex, and amygdala. May be asymmetrical.
• Nonfluent PPA: early atrophy and hypoperfusion in the left posterior fronto-insular cortex.
• Semantic PPA: significant anterior temporal atrophy. Often asymmetric.

Diagnostic criteria

There are different diagnostic criteria for each clinical subtype of FTD.

Diagnosis of bvFTD is based on the International Behavioral Variant FTD Criteria Consortium (FTDC) that uses clinical features, neuroimaging, neuropathology and genetic testing. Diagnosis of PPA is based on clinical criteria developed in 2011. These include clinical, neuroimaging and biomarker data to help diagnosis PPA and then determine the subtype.

There are no specific treatments for FTD and management is aimed at improving activities of daily living.

Unfortunately, there are no disease modifying treatments that can be used in FTD. Management focuses on treatment of behaviour and cognitive decline. This may require pharmacological intervention, but it does not alter the disease progression.

Non-pharmacological interventions

Simple interventions are important to give patients as much independence as possible, while maintaining their safety.

• Financial advice: particularly important due to behaviour and personality changes leading to impaired judgement. May need simple financial supervision initially but often a lasting power of attorney for finances once they lose capacity.
• Physical supervision: particularly if behaviour is problematic
• Exercise: regular exercise and cardiovascular fitness encouraged
• Mobility: assessment by a physiotherapy and providing aids (e.g. walking stick, frame) as needed. May require occupational therapy assessment with adaptation of home environment
• Speech and language: assessment by a speech and language therapist is important with communication aids and swallow assessment in later stages of disease
• Behavioural modification: variety of methods effective, keeping a behaviour chart can be useful and ensuring carers get respite.

Medical therapy

Pharmacological treatments may be needed to help with behaviour and cognitive dysfunction. It is important to recognise these help control symptoms and are not disease modifying.

Usually need a specialist in old age psychiatry or neurology to initiate because medications can also exaggerate symptoms, cause motor symptoms and lead to deterioration in cognition.

Example options:

• Serotonin reuptake inhibitors (SSRI): used for difficult behavioural symptoms. Have been shown to decrease disinhibition, anxiety, impulsivity and repetitive behaviours.
• Atypical anti-psychotics: can help with agitation and behavioural symptoms. Due to side-effect profile, should be trialled after SSRIs.

Overall survival is 8-10 years from symptoms onset.

Survival is often shorter in patents with bvFTD compared to PPA. Patients usually have increasing dependancy for activities of daily living requiring carers and eventually permanent nursing home residence if care needs cannot be met in their own home.

It is critical that family and close friends are involved in the patients care to help with care needs, treatment decisions and appropriate advanced care planning.

Last updated: May 2022