Frontotemporal Dementia

A 63-year-old man was brought to the clinic by his family because of his memory difficulties, apathy, and inappropriate behavior. They reported that the problems began 3–4 years ago; at that time he did not wash, dress, eat, or take his medications without prompting. Although he used to be very kind and caring, he now appeared unconcerned with others, and did not show any emotion over his wife’s recent diagnosis of cancer and need for surgery. Overall, he seemed like a different person to them. Most recently they have had to put a lock on the refrigerator because he began eating continually. They now do not feel comfortable leaving him at home alone for fear he would “get into something” that could be dangerous or cause damage.

Quick Start

Definition	• Frontotemporal dementia is a progressive neurodegenerative disorder with three common clinical presentations and seven different patterns of pathology. The three common clinical presentations are: • Behavioral (or frontal) variant frontotemporal dementia • Semantic variant primary progressive aphasia (also called semantic dementia or temporal variant frontotemporal dementia) • Non-fluent/agrammatic variant primary progressive aphasia (also called progressive non-fluent aphasia). • Clinical and imaging aspects of the primary progressive aphasias can be found in Chapter 7 .
Prevalence	• Frontotemporal dementia is found in 5–10% of cases of dementia. • Frontotemporal dementia is as common as Alzheimer’s disease in those with dementia younger than age 65, with approximately three-quarters of frontotemporal dementia cases presenting from ages 45 to 65. • Up to 10–15% of patients with frontotemporal dementia also show signs and symptoms of motor neuron disease (amyotrophic lateral sclerosis or ALS).
Genetic risk	• Up to 40% of cases of frontotemporal dementia are familial with an autosomal dominant pattern.
Cognitive and behavioral symptoms	• In behavioral variant frontotemporal dementia there are changes in personality and social conduct, including apathy, loss of insight, disinhibition, lack of empathy, inappropriate social remarks, abnormal eating behaviors, and neglect of self-care. • Neuropsychological testing will often show dysfunction of tests of attention, response inhibition, frontal/executive function, and language.
Diagnostic criteria	1. Required criterion—progressive deterioration of behavior and/or cognition by observation or history. 2. Possible behavioral variant frontotemporal dementia—3 of 6 required: a. Early behavioral disinhibition b. Early apathy or inertia c. Early loss of sympathy or empathy d. Early perseverative, stereotyped, or compulsive/ritualistic behavior e. Hyperorality and dietary changes f. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions. 3. Probable behavioral variant frontotemporal dementia (all required): a. Meets criteria for possible behavioral variant frontotemporal dementia b. Significant functional decline c. Imaging results consistent with behavioral variant frontotemporal dementia (frontal and/or anterior temporal atrophy on CT or MRI or hypoperfusion or hypometabolism on SPECT or PET). 4. Behavioral variant frontotemporal dementia with definite frontotemporal lobar degeneration pathology (a and either b or c required): a. Meets criteria for possible or probable behavioral variant frontotemporal dementia b. Histopathological evidence of frontotemporal lobar degeneration on biopsy or at postmortem c. Presence of a known pathogenic mutation. 5. Exclusion criteria for behavioral variant frontotemporal dementia—Criteria a and b must both be answered negatively; criterion c can be positive for possible but must be negative for probable: a. Pattern of deficits is better accounted for by other nervous system or medical disorders b. Behavioral disturbance is better accounted for by a psychiatric diagnosis. c. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process.
Treatment	• There are no FDA approved medications to treat frontotemporal dementia. • The treatment of frontotemporal dementia consists of supportive management. • Many medications, including SSRIs and atypical antipsychotics, can be used to treat the symptoms.
Top differential diagnoses	• Alzheimer’s disease, vascular dementia, corticobasal degeneration, progressive supranuclear palsy, normal-pressure hydrocephalus, Huntington’s disease, as well as other causes of frontal lobe dysfunction (such as a frontal tumor).

Prevalence, Prognosis, and Definition

Frontotemporal dementia is a progressive neurodegenerative disorder with three common clinical presentations and at least seven different patterns of pathology. The three common clinical presentations are:

•

Behavioral (or frontal) variant frontotemporal dementia (often abbreviated to bvFTD or fvFTD)
•

Semantic variant primary progressive aphasia (also called semantic dementia or temporal variant frontotemporal dementia; often abbreviated svPPA, SD, or tvFTD)
•

Non-fluent/agrammatic variant primary progressive aphasia (also called progressive non-fluent aphasia; often abbreviated to naPPA, agPPA, nfvPPA, or PNFA).

Clinical and imaging aspects of the primary progressive aphasias can be found in Chapter 7 . Note that after a few years many patients with frontotemporal dementia with one initial presentation show signs and symptoms of the other types of frontotemporal dementias as well.

Frontotemporal dementia is equally as common as Alzheimer’s disease in those with dementia aged younger than 65. In studies of memory clinics, frontotemporal dementia has been found in 5–10% of cases, with our experience closer to 5%. Frontotemporal dementia tends to affect younger individuals, with approximately three-quarters of the cases presenting from ages 45 to 65, the remaining one-quarter presenting after age 65. Although there is considerable variability, the average time from symptom onset to death in behavioral variant frontotemporal dementia is 8.7 years.

Criteria

The International Behavioral Variant Frontotemporal Dementia Criteria were published in 2011 ( ) ( Box 8-1 ) and are now the gold standard; we use this version with the specificity added for several items by LaMarre and colleagues ( ). DSM-5 also has criteria for Major or Mild Frontotemporal Neurocognitive disorder ( Box 8-2 ; see Chapter 3 for the general criteria for major and mild neurocognitive disorder).

Box 8-1

International Behavioral Variant Frontotemporal Dementia Criteria

1.

Shows progressive deterioration of behavior and/or cognition by observation or history (as provided by knowledgeable informant)
2.

Possible behavioral variant frontotemporal dementia : Three of the following behavioral/cognitive symptoms [a-f] must be present as persistent or recurrent events:
- a.
  
  * Early behavioral disinhibition (one of the following must be present)
  
  * Early refers to symptoms within the first three years.
  :
  - 1)
    
    Socially inappropriate behavior
  - 2)
    
    Loss of manners or decorum
  - 3)
    
    Impulsive, rash, or careless actions
- b.
  
  Early apathy or inertia (one of the following must be present):
  - 1)
    
    Apathy: loss of interest, drive or motivation
  - 2)
    
    Inertia: decreased initiation of behavior
- c.
  
  Early loss of sympathy or empathy (one of the following must be present):
  - 1)
    
    Diminished response to other people’s needs or feelings: positive rating should be based on specific examples that reflect a lack of understanding or indifference to other people’s feelings
  - 2)
    
    Diminished social interest, interrelatedness or personal warmth: general decrease in social engagement
- d.
  
  Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following must be present):
  - 1)
    
    Simple repetitive movements
  - 2)
    
    Complex, compulsive, or ritualistic behaviors
  - 3)
    
    Stereotypy of speech
- e.
  
  Hyperorality and dietary changes (one of the following must be present):
  - 1)
    
    Altered food preferences
  - 2)
    
    Binge eating, increased consumption of alcohol or cigarettes
  - 3)
    
    Oral exploration or consumption of inedible objects
- f.
  
  Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (all of the following must be present):
  - 1)
    
    Deficits in executive tasks
  - 2)
    
    Relative sparing of episodic memory (compared to degree of executive dysfunction)
  - 3)
    
    Relative sparing of visuospatial skills (compared to degree of executive dysfunction)
3.

Probable behavioral variant frontotemporal dementia : All criteria must be met
- a.
  
  Meets criteria for possible behavioral variant frontotemporal dementia
- b.
  
  Exhibits significant functional decline (by caregiver report, clinician rating, or functional questionnaire)
- c.
  
  Imaging results consistent with behavioral variant frontotemporal dementia
  - 1)
    
    Frontal and/or anterior temporal atrophy on CT or MRI, and/or
  - 2)
    
    Frontal and/or anterior temporal hypoperfusion or hypometabolism on SPECT or PET
4.

Behavioral variant frontotemporal dementia with definite frontotemporal lobar degeneration pathology. Criterion a and either b or c must be present:
- a.
  
  Meets criteria for possible or probable behavioral variant frontotemporal dementia
- b.
  
  Histopathological evidence of frontotemporal lobar degeneration on biopsy or at postmortem
- c.
  
  Presence of a known pathogenic mutation
5.

Exclusionary criteria for behavioral variant frontotemporal dementia. Criteria a and b must be answered negatively. Criteria c can be positive for possible (but not probable) behavioral variant frontotemporal dementia.
- a.
  
  Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders
- b.
  
  Behavioral disturbance is better accounted for by a psychiatric diagnosis
- c.
  
  Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process