Geriatric MedicineTier 1Disease (DEADMAN)

Dementia syndromes - frontotemporal dementia

Description

Commonest dementia under 65 (equal with Alzheimer disease in that age group)
Focal degeneration of frontal and anterior temporal lobes -> behaviour or language fails first; memory and visuospatial function are relatively preserved

Three clinical syndromes

	Syndrome	Core deficit	Atrophy
bvFTD (~60%)	Behavioural variant	Personality and conduct	Frontal + anterior temporal, often right
svPPA	Semantic variant PPA	Loss of word meaning - "what is a fork?"; fluent, empty speech; surface dyslexia	Left anterior temporal
nfvPPA	Non-fluent/agrammatic PPA	Effortful, halting, agrammatic speech, apraxia of speech	Left posterior frontoinsular

bvFTD - the six core features

1. Early disinhibition - socially inappropriate remarks, impulsivity, shoplifting, loss of manners

2. Early apathy or inertia (commonly misdiagnosed as depression)

3. Early loss of sympathy or empathy - "he doesn't care any more"

4. Perseverative, stereotyped, compulsive or ritualistic behaviour - hoarding, clock-watching, fixed routes

5. Hyperorality and dietary change - carbohydrate/sweet craving, binge eating, oral exploration of objects, smoking or alcohol excess

6. Dysexecutive profile with relative sparing of memory and visuospatial skills

*Early hyperorality and early disinhibition are the discriminators from Alzheimer disease*, where such features are late or absent
Anosognosia is profound - the patient is unconcerned; the family is in crisis

Epidemiology

Prevalence ~15-22 per 100,000; peak onset 45-65 yr
~10-20% of all dementia; the commonest cause of dementia before 60
M=F overall (bvFTD slightly M>F)
~30-40% have a family history; ~10-20% autosomal dominant - far more heritable than Alzheimer disease
Mean delay to diagnosis 3-4 years, commonly after a psychiatric misdiagnosis

Aetiopathogenesis

Pathology - "FTLD" with three main protein subtypes

Inclusion	~%	Clinical association
FTLD-tau (Pick bodies, MAPT)	~40%	bvFTD, nfvPPA, PSP, CBD
FTLD-TDP-43	~50%	svPPA, bvFTD, FTD-MND
FTLD-FUS	~5-10%	Young-onset bvFTD

Genetics - AD, high penetrance

C9orf72 hexanucleotide (GGGGCC) repeat expansion - commonest genetic cause; the FTD-MND/ALS overlap gene; psychosis is common
GRN (progranulin) - haploinsufficiency; TDP-43 pathology; asymmetrical atrophy
MAPT (tau) - pure tauopathy, often early parkinsonism
Offer genetic counselling and testing where there is a family history of dementia, ALS or an early-onset psychiatric presentation

Mechanism

Selective vulnerability of von Economo neurons in the anterior cingulate and frontoinsular cortex -> loss of social cognition
Serotonergic and dopaminergic deficits predominate; the cholinergic system is relatively intact
- *This is why cholinesterase inhibitors do not work and may worsen behaviour*

Diagnosis

A. History - from an informant; the patient will deny everything

Change in personality, conduct, empathy, eating, routines - ask for specific examples
Financial mismanagement, legal trouble, workplace breakdown, marital crisis are frequent first presentations
Family history of dementia, motor neurone disease, or psychiatric illness

B. Cognitive testing

*MMSE is frequently normal - it does not test the frontal lobe* and falsely reassures
Test executive and social cognition: verbal fluency, Trails B, Frontal Assessment Battery, go/no-go, proverb interpretation, faux pas/emotion recognition
ACE-III (fluency and language subscores), Cambridge Behavioural Inventory from the carer
svPPA: naming and single-word comprehension fail; nfvPPA: agrammatism and speech apraxia

C. Imaging

MRI: focal frontal and/or anterior temporal atrophy, often strikingly asymmetrical ("knife-edge" gyri)
FDG-PET: frontal and anterior temporal hypometabolism - more sensitive than MRI early, and the key test when MRI looks normal
Amyloid PET/CSF is used to exclude Alzheimer pathology in an atypical young-onset case

D. Exclude - the young-onset differential is wide

Primary psychiatric illness - late-onset bipolar disorder, depression, schizophrenia (the commonest misdiagnosis; a C9orf72 expansion can present as psychosis)
Alzheimer disease (frontal variant), vascular dementia, autoimmune/limbic encephalitis, HIV, syphilis, Huntington disease, Wilson disease, alcohol-related brain injury, NPH, obstructive sleep apnoea, thyroid disease, B12 deficiency
Screen for motor neurone disease in every bvFTD patient - fasciculations, wasting, bulbar signs, brisk reflexes

Management

No disease-modifying therapy and no licensed symptomatic drug. Management is behavioural, environmental and protective - and the carer is the patient at risk.

A. Behaviour - non-pharmacological first

Identify triggers and antecedents; predictable routine; redirect rather than confront
Environmental modification - restrict access to food, money, car keys, internet and online shopping
Exercise and structured, engaging activity for apathy
Reasoning, correcting and arguing do not work and escalate distress

B. Pharmacological - limited evidence

SSRIs (sertraline, citalopram, fluvoxamine) or trazodone for disinhibition, compulsions, hyperorality and repetitive behaviours
Antipsychotics only if there is risk of harm - low-dose atypical, brief, reviewed
- FTD patients are at increased risk of extrapyramidal side effects; same mortality warning as in other dementias
*Cholinesterase inhibitors are NOT indicated - no benefit and may worsen behaviour*; memantine is ineffective
Treat comorbid sleep disorder and pain

C. Risk, capacity and law

Assess and document capacity early - financial, legal, driving, testamentary
Enduring power of attorney and guardianship early - capacity is often already lost at diagnosis despite a normal MMSE
Driving cessation is usually required early because of impulsivity and poor judgement, even with intact motor skills
Protect the estate; address firearms, alcohol and inappropriate sexual behaviour
Consider whether criminal behaviour is a disease manifestation - a medico-legal report may be needed

D. The family

Carer burden in FTD exceeds that of any other dementia - young patients, dependent children, lost income, socially embarrassing behaviour, no external sympathy
Carer counselling and respite, financial and Centrelink advice, young-onset dementia services, Dementia Australia
Genetic counselling and predictive testing for relatives where a mutation is identified

E. Anticipate

Screen for and manage motor neurone disease (dysphagia, aspiration, respiratory failure)
Advance care planning while capacity remains; speech pathology and dietitian for dysphagia and hyperorality

Associations

Motor neurone disease / ALS - in ~15% of bvFTD (FTD-MND), especially C9orf72; confers a much worse prognosis
Parkinsonism and atypical parkinsonian syndromes (PSP, corticobasal syndrome) - same tau spectrum
Psychiatric misdiagnosis - bipolar disorder, schizophrenia, depression, OCD
Alcohol and substance misuse arising de novo
Sleep disturbance; altered pain and temperature perception
Hoarding, obsessive-compulsive behaviour, altered musical or artistic interests

Natural history & complications

Median survival ~6-8 yr from onset in bvFTD; svPPA runs longer (~10-12 yr)
*FTD with motor neurone disease: ~2-3 yr* - the shortest survival of any dementia
Progression: focal behavioural or language syndrome -> global dementia with parkinsonism, mutism, dysphagia, incontinence and immobility
Death from aspiration pneumonia, respiratory failure (if MND) or complications of immobility
Institutionalisation occurs earlier than in Alzheimer disease despite preserved memory and physical ability - behaviour, not cognition, is the driver
A younger-onset, less impaired-looking, more disruptive patient is frequently refused by residential aged care - plan placement early

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