Introduction

Frontotemporal lobar degeneration (FTLD) is a primary neurodegenerative condition resulting in 2% of dementia cases. It is the second most common cause of dementia in patients under 65 and it is characterised by a progressive illness leading to behavioural changes and language problems. The aetiology is poorly understood however some genetic causes have been identified. There is currently no treatment and management follows a supportive approach.

Classification

Clinicians may use many different terms when referring to FTLD. This is due to FTLD being an umbrella term for many subtypes of the disease. Historically Pick's disease (specifically referring to cases that histologically had Pick inclusion bodies present) was a commonly used term however is rarely used in clinical practice.

FTLD can be classified into two main categories:
  • Behaviour variant frontotemporal dementia (bvFTD)
    • This is the most common subtype accounting for about 50% of cases
  • Primary progressive aphasia (PPA)
    • Nonfluent/agrammatic variant PPA
    • Semantic variant PPA
    • Logopenic variant PPA

Other variants that are also referenced are cases associated with Parkinsonism syndromes such as corticobasal degeneration (CBD) and supranuclear palsy (SNP) or those associated with amyotrophic lateral sclerosis (ALS).

The table below summarises some of the differences. In bold are the most common subtypes.

VariantDescription
bvFTDProgressive decline and deterioration with early behavioural changes such as coarsening personality and impulsiveness
PPALanguage difficulty is the most prominent feature
Nonfluent/agrammatic variant PPAApraxia and agrammatism.
Semantic variant PPADifficulty naming single items whilst other language domains are spared
Logopenic variant PPADifficulties with repetition and single word retrieval
Associated with parkinsonismParkinsonism such as bradykinesia, tremor, and rigidity
ALS associatedProgressive muscle weakness that may be asymmetric and involve bulbar muscles


Epidemiology

  • Incidence: 3.00 cases per 100,000 person-years
  • Peak incidence: 50-60 years
  • Sex ratio: 1:1
Condition Relative
incidence
Alzheimer's disease100.00
Vascular dementia23.33
Lewy body dementia6.67
Frontotemporal lobar degeneration1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

The aetiology of frontotemporal lobar degeneration is poorly characterised but is likely to be due to a combination of genetics and lifestyle factors.

Up to 50% of patients have a positive family history of dementia and 10% of cases show autosomal dominant inheritance.

Known genetic mutations have been identified in the following genes:
  • MAPT
    • Resulting in tau inclusion bodies
  • Progranulin gene (PGRN)
    • Resulting in TDP-43 inclusion bodies
  • C9orf72
    • Repeat expansions within this gene are commonly found in FTLD and amyotrophic lateral sclerosis.

Pathophysiology

The pathophysiology of FTLD includes degenerative change in the frontal and temporal lobes at both a macroscopic and microscopic level.

Macroscopic changes
The macroscopic changes differ between the different types as summarised below:
  • Behavioural variant FTD
    • MRI or CT shows symmetrical atrophy predominantly affecting the frontal lobes with some evidence of temporal lobes being affected.
  • Nonfluent/agrammatic variant PPA
    • MRI or CT shows variable atrophy most commonly in the posterior frontal lobe, insular cortex and temporal lobe, including the hippocampus. This is seen to affect the left side to a greater extent.
  • Semantic variant PPA
    • MRI or CT shows left sided temporal lobe and hippocampus atrophy. Frontal lobes are relatively spared early in disease.

Histological changes
Histopathology shows axonal injury and inclusion bodies concentrated in the frontal and temporal lobes. The two main variants are:
  • Tau inclusion bodies (also known as tauopathies, pick bodies or FTD-tau)
    • Tau is a microtubule-associated protein coded for by the microtubule-associated protein tau gene (MAPT)
  • Inclusions of immunoreactive ubiquitin (FTLD-U)
    • This subset is commonly associated with a mutation in the progranulin gene (PGRN) resulting in TAR-DNA binding protein (TDP)-43.

Clinical features

Patients with FTLD and their relatives may describe behaviours with an insidious onset showing progressive deterioration and associated with a function decline.

Symptoms described may include:
  • Behavioural changes - predominant feature in behavioral variant FTLD
    • Early apathy (85%)
    • Decline in social interpersonal conduct (80%)
    • Early disinhibition (75%)
    • Early loss of empathy (70%)
    • Early perseverative (65%)
    • Hyperorality (50%)
    • Decline in hygiene (50-60%)
    • Primitive reflexes (25%)
  • Difficulties with speech - predominant feature in PPA
    • Language difficulty as the predominant feature
    • Aphasia
    • Decrease in speed of speech
    • Difficulties with comprehension
    • Syntax
    • Object naming
  • Decline in executive functioning and cognition
    • Difficulty planning
    • Poor concentration
  • Memory problems
    • Short term memory problems
    • Difficulty with recall

An important aspect of the presentation is that behaviour or speech changes are noticed prior to memory problems and this can help distinguish it from other dementias. Up to 40% of patients have a positive family history with 10% showing an autosomal pattern of inheritance.

Examination
  • Patients may exhibit features of behavioural change and speech difficulties as above during the consultation.
  • Neurological exam is often grossly normal but they may present with:
    • Parkinsonism - tremor, rigidity and bradykinesia
    • Signs of ALS such as progressive muscle weakness including bulbar muscles (10-15%)
  • Cognitive testing may show impairment but may be normal.

Investigations

This condition is a clinical diagnosis. If FTLD is suspected based on history and examination it is important to perform the following investigations:

  • Dementia screening bloods to exclude organic causes:
    • FBC - to rule out anaemia
    • ESR & CRP - signs of infection or vasculitis
    • T4 and TSH - to rule out hypothyroidism
    • U&Es - evidence of renal failure or electrolyte disturbances (e.g. hypercalcaemia, hypocalcemia etc)
    • B12 and folate - vitamin deficiencies may cause dementia
    • Coagulation screen and albumin - assess liver function
    • Glucose
  • Midstream urine - if concerned about delirium
  • Syphilis serology and HIV testing if clinically indicated
  • Formal cognitive testing
    • Mini-mental state examination (MMSE)
    • Montreal clinical assessment (MoCA)

If FTLD is still suspected patients should be referred to specialist psychiatric or memory services.

Further investigations include:
  • Structural imaging such as MRI or CT scan
    • This may show atrophy in the frontal and temporal regions.
    • May also exclude other structural or reversible causes.
  • FDG-PET or SPECT scan
    • Only performed if the diagnosis is still unclear.
  • Genetic testing
    • Only performed if positive family history.

Differential diagnosis

FTLD may present similarly to other conditions that also affect behaviour, memory and cognitive functioning.

Possible differential diagnoses may include:

Alzheimer's disease (AD)
  • Similarities:
    • Loss of apathy
    • Subtle personality changes and loss of interest in daily activities
    • Grossly unremarkable physical exam
  • Differences:
    • Memory loss predominates in AD
    • CT brain shows global atrophy in AD
Vascular dementia
  • Similarities:
    • Loss of apathy
    • Loss of executive functions
    • Impulsivity and irritability
    • Relative preservation of memory
  • Differences:
    • Presence of cardiovascular risk factors
    • CT brain will show evidence of infarcts
Dementia with Lewy bodies (DLB)
  • Similarities:
    • Loss of apathy
    • Cognitive fluctuations
  • Differences:
    • Visual hallucinations and motor signs are key features in DLB
    • Personality is relatively preserved
Depression
  • Similarities:
    • Loss of apathy
    • Loss of empathy
    • Psychomotor retardation
    • Memory loss
  • Differences:
    • Anhedonia in depression
    • Patient reports feeling depressed

Less common differentials may also include:
  • Delirium
  • B12 deficiency
  • Hypothyroidism
  • Bipolar
  • OCD
  • Normal pressure hydrocephalus
  • Brain tumour
  • CJD
  • Syphilis
  • HIV

Management

There are no disease modifying treatments currently recommended for FTLD and therefore management is focused on supportive care and symptom management.

Management approach should include:

Supportive management
  • Referral to specialist psychiatry or neurology services
  • Patient and carer education
    • Explain the disease course and progression
    • Discuss driving - advise they are legally required to inform DVLA of diagnosis
  • Consider care needs and develop a care plan
    • Physiotherapy and occupational therapy assessment
    • Present day needs
    • Anticipated future needs
  • Follow up 6-12 monthly
  • Consider end of life care planning early on.

Symptomatic control
  • Non-drug therapy - this is recommended as first line therapy
    • Group therapy
    • Support groups
  • Pharmacological therapies - these should only be used if non-drug therapies have failed.
    • Benzodiazepines - for acute agitation and distress.
    • SSRIs - for associated depression, anxiety, irritability and disinhibition.
    • Antipsychotics - very low doses should be used and as a last resort.
    • Oxytocin - emerging evidence suggests this may help with improving empathy but is not yet approved.

Acetylcholinesterase inhibitors or memantine hydrochloride are not recommended in patients with FTLD.

Prognosis

FTLD is a progressive condition with no known cause. It is also an umbrella term for a group of heterogeneous conditions and therefore some variation between different subtypes may exist.

  • Clinical cohorts show survival of 7-13 years from diagnosis
  • Neuropathology series show survival from 6-8 years.
  • If associated with ALS survival is shorter at about 3-5 years.
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As the disease progresses patients may require increasing support and care and end of life planning short be carried out early to ensure the patient can participate in this.