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Basic Information ⬇

AUTHOR: Joseph S. Kass, MD, JD, FAAN

Definition

Frontotemporal dementia (FTD) is an umbrella term that encompasses three distinct syndromes: Behavioral variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). All three syndromes are marked by frontal and/or temporal lobe atrophy; however, they manifest with different clinical presentations. The most common subtype is bvFTD, which is marked by changes in behavior and personality with disinhibition, lack of empathy, and the breaking of social norms. SD is characterized by a loss of word comprehension and meaning, and PNFA presents with agrammatic, nonfluent speech.

Synonyms

FTD

FTLD

Frontotemporal lobar degeneration (FTLD) is the term used for the neuropathologic findings seen in the different FTD syndromes.

Pick disease: This term was historically used to refer to FTD. However, it is now strictly a neuropathologic diagnosis for patients found to have Pick bodies at autopsy, as very few diagnoses of FTD are associated with these neuropathologic findings.

ICD-10CM CODES
G31.0Frontotemporal dementia
G31.01Pick disease
G31.09Other frontotemporal dementia
Epidemiology & Demographics

The current data on epidemiology of FTD are variable due to misdiagnosis and underreporting. The following data are estimations obtained through systematic reviews.

Incidence

The estimated annual incidence is 2.7 to 4.1 per 100,000 persons.

Prevalence

The estimated point prevalence is 15 to 22 per 100,000 persons.

Predominant Sex & Age

There is a nearly equal distribution by sex, and the average age of presentation is 58 yr.

Genetics

Approximately 40% of FTD cases have a positive family history, and several genes (Table 1) have been associated with the development of familial FTD. The most common are mutations in C9ORF72, MAPT, and GRN (Table 2).

TABLE 2 Gene Mutations Associated With Frontotemporal Dementia

GeneChromosomeProteinProtein FunctionMode of InheritanceMutation Frequency in Familial FTDMutation Frequency in Sporadic FTDAge of Onset (Mean, Range)
C9ORF729p21.2UnknownUnknownAD21%6%50s (mid 20-80s)
MAPT17q21.31Microtubule-associated tau proteinMicrotubule stabilization and assemblyAD6.3%1.5%Mid-50s (20-80s)
GRN17q21.31ProgranulinActivates signaling cascades for development, inflammation, and wound repairAD5%-15%5%60s (mid 30-80s)

AD, Autosomal dominant; FTD, frontotemporal dementia.

From Deleon J, Miller BL: Frontotemporal dementia. In Daniel CK et al (eds): Handbook of clinical neurology, ed 148, Philadelphia, 2018, Elsevier, pp. 409-430.

TABLE 1 Clinical, Genetic, and Pathologic Correlations in Frontotemporal Lobar Degeneration

ComorbiditiesNeuropathologic Subtypes
Clinical Presentation% of FTLDAssociatedGenesParkinsonismMNDIBM PDBFTLD-tauFTLD-TDPFTLD-FUSFTLD-UPSFTLD-ni
bvFTD57%+++/–++++++/–+/–
C9orf72+++++Type B >A+/–
GRN++Type A
MAPT+++
VCP+/–+/–+Type D
CHMP2B+/–+/–+/–+
nfvPPA24%++/–+++
C9orf72+
GRN+++Type A
MAPT+++
svPPA19%+/–+/–+/–++ (Type C)
Rarely genetic

Number of plus signs (+) signifies relative frequency of the observation; +/– indicates rare observation. bv, Behavioral variant; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; FUS, fused in sarcoma; IBM, inclusion body myopathy; MND, motor neuron disease; nfv, agrammatic or nonfluent variant; ni, no inclusions; PDB, Paget disease of the bone; PPA, primary progressive aphasia; sv, semantic variant; TDP, TAR DNA-binding protein; UPS, ubiquitin-proteasome system.

From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

Physical Findings & Clinical Presentation

  • The early stage of bvFTD is characterized by changes in behavior and personality. Patients display a lack of insight into these changes, and family members may initially think they are suffering a midlife crisis or a new-onset psychiatric disorder. Therefore careful history-taking is required.
  • Behavioral changes include disinhibition, impulsivity, distractibility, violation of social norms (such as offensive, insensitive, or inappropriate sexual remarks; inappropriate behaviors; inappropriately explicit or personal conversations; or encroachment on the personal space of others), as well as increased irritability and impulsive criminal behavior (such as shoplifting or violating traffic laws).
  • Patients also display decreased ability to empathize with others, insensitivity to the needs and emotions of their loved ones, and detachment in their personal relationships.
  • Apathy and inertia are also common symptoms, with possible development of immobility as the disorder progresses.
  • Other associated symptoms that may develop are changes in language and speech (verbal aspontaneity, stereotyped phrases, mutism in late stages), repetitive motor movements, or hyperphagia, especially for sweet foods.
  • Physical exam findings for bv FTD can include abnormal cognition (e.g., clock drawing test [Fig. 1]), upper and/or lower motor neuron signs, dysarthria, dysphagia, and pseudobulbar affect. Some patients meet criteria for both FTD and amyotrophic lateral sclerosis. This overlap is typically related to a C9ORF72 mutation.
  • Although behavioral changes can also occur in the other FTD syndromes SD and PNFA, these two primarily have language deficits that precede the behavioral changes.
    1. SD is characterized by a gradual loss of the knowledge of words, objects, and concepts, with preservation of speech fluency and syntax.
    2. PNFA is characterized by effortful, nonfluent speech, word-finding difficulties, and agrammatism, with preservation of single-word comprehension.
Figure 1 The Clock Drawing Test

The Patient is Provided with a Circular Outline and Asked to Draw the Numbers as They Appear on the Face of a Clock. Once the Numbering is Complete, the Patient is Asked to Set the Hands to a Particular Time (Often “ten Past” the Hour to Test if the Patient Can Suppress the Impulse to Include the Number 10). (A) This Drawing Demonstrates Good Planning and Use of Space. (B) This Drawing Features Some Impulsiveness Because the Numbers are Drawn Out Without Regard for Actual Location, and the Time “ten Past Four” is Represented by Hands Pointing to the Digits 10 and 4. Note the Perseveration Indicated by the Extra Loops on the Digits 3 and 6. Impulsiveness and Perseveration Indicate Frontal Lobe Dysfunction. (C) This Drawing Demonstrates Gross Disorganization, Although the Patient Took Several Minutes to Draw the Clock and Believed It to Be a Good Representation.

From Stern TA: Massachusetts General Hospital handbook of general hospital psychiatry, ed 7, 2018, Philadelphia, Elsevier.

Diagnosis ⬆ ⬇

Diagnosis of bvFTD is primarily clinical, with neuroimaging, genetics, and pathology required for further confirmation. In 2011, the International Behavioral Variant FTD Consortium (FTDC) developed revised criteria for the diagnosis of bvFTD (Table 3).

TABLE 3 International Consensus Criteria for Behavioral Variant FTD

Must be present for any FTD clinical syndrome:
  • Shows progressive deterioration of behavior and/or cognition by observation or history

Possible bvFTD
  • Three of the features (A-F) must be present; symptoms should occur repeatedly, not just as a single instance:
    1. Early (3 yr) behavioral disinhibition
    2. Early (3 yr) apathy or inertia
    3. Early (3 yr) loss of sympathy or empathy
    4. Early (3 yr) perseverative, stereotyped, or compulsive/ritualistic behavior
    5. Hyperorality and dietary changes
    6. Neuropsychologic profile: Executive function deficits with relative sparing of memory and visuospatial functions

Probable bvFTD
  • All the following criteria must be present to meet diagnosis:
    1. Meets criteria for possible bvFTD
    2. Significant functional decline
    3. Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)

Definite bvFTD
  • Criteria A and either B or C must be present to meet diagnosis:
    1. Meets criteria for possible or probable bvFTD
    2. Histopathologic evidence of FTLD on biopsy at post mortem
    3. Presence of a known pathogenic mutation

Exclusion criteria for bvFTD
  • Criteria A and B must both be answered negatively; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD:
    1. Pattern of deficits is better accounted for by other nondegenerative nervous system or medical disorders
    2. Behavioral disturbance is better accounted for by a psychiatric diagnosis
    3. Biomarkers strongly indicative of Alzheimer disease or other neurodegenerative process

Additional features
  • Presence of motor neuron findings suggestive of motor neuron disease
  • Motor symptoms and signs similar to corticobasal degeneration and progressive supranuclear palsy
  • Impaired word and object knowledge
  • Motor speech deficits
  • Substantial grammatical deficits

bvFTD, Behavioral variant frontotemporal dementia; CT, computed tomography; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

From Rascovsky K et al: Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia TT, Brain 2011;134:1-22.

Differential Diagnosis

  • Other neurodegenerative disorders, including Alzheimer disease (AD), Parkinson disease, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, and chronic traumatic encephalopathy
  • Psychiatric disorders (bipolar disorder, schizophrenia, obsessive-compulsive disorder, depression, personality disorders)
  • Spontaneous low intracranial pressure with sagging of the front lobes
  • Chronic subdural hematomas, especially frontal
  • Central nervous system (CNS) tumors in the prefrontal cortex or compressing the prefrontal cortex
  • Metabolic disturbances or nutritional deficiencies (thyroid disease, B12 deficiency)
  • Substance abuse/toxicities (ethanol, drugs of abuse, heavy metal poisoning)
  • Infections (chronic meningitis, HIV-associated dementia, neurosyphilis)
  • Cerebrovascular disease (stroke, vascular dementia, lacunar infarctions)
  • Autoimmune encephalitis, sarcoidosis
Workup

  • Careful history-taking with specific attention paid to initial symptoms, time course, progression of symptoms, family history, psychiatric history, and other medical history
  • Comprehensive neurologic physical exam to help rule out other CNS etiologies
  • Use of the International Behavioral Variant FTD Criteria for diagnosis (Table 3)
  • Genetic testing for causal mutations of FTD (C9ORF72, MAPT, and GRN)
  • Medication review (especially drugs that may alter mental status, such as anticholinergics, opiates, benzodiazepines, barbiturates, and neuroleptics)
  • Neuropsychologic tests of executive function, memory, and social cognition to rule out other neurodegenerative disorders
  • Psychiatric evaluation to rule out psychiatric disorders
Laboratory Tests

  • CBC, serum electrolytes, glucose, blood urea nitrogen (BUN)/creatinine, liver function tests
  • Cerebrospinal fluid (CSF) analysis for infection and measurement of CSF tau and amyloid (which can help differentiate between FTD and AD-not typically measured in clinical practice)
  • Vitamin B12, thyroid function tests, HIV, and syphilis screening
  • Urine toxicity screen
  • In vivo histopathology:
    1. Almost all cases of FTLD have one of the following protein inclusions found on pathologic examination: TAR DNA-binding protein with molecular weight 43 kDa (TDP-43), microtubule-associated protein tau (MAPT), or fused-in-sarcoma protein (FUS).
Imaging Studies

  • In general, structural MRI and computed tomography (CT) will show gray matter atrophy in the frontal and/or temporal lobes, anterior cingulate cortex, and insula with variation in distribution between the different FTD subtypes.
    1. Patients with bvFTD specifically will usually show atrophy in the orbitofrontal, anterior cingulate, anterior insular, and anterior temporal cortices.
    2. SD is associated with atrophy in the temporal poles, and PNFA with atrophy in the left perisylvian region.
  • A normal MRI scan does not exclude FTD, however, because changes may not be seen in early stages of the disorder. In these cases, PET or SPECT can be used to visualize areas of hypoperfusion/hypometabolism.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

  • Due to the impulsivity and the risk for injury seen in bvFTD, discussions with family members about driving, the patient’s access to finances, and safety of the physical environment should be conducted early in management.
  • For patients with motor symptoms, regular exercise and physical therapy are helpful.
  • Speech therapy is helpful for patients with language deficits.
  • Diet counseling can aid in prevention of weight gain in patients with hyperphagia.
Acute General Rx

None

Chronic Rx

  • There are conflicting reports of the efficacy of several medications in the symptomatic treatment of FTD. These include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, and antipsychotics.
  • SSRIs have the most consensus for their benefit in the management of FTD. They have been shown to help decrease the severity of disinhibition, impulsivity, eating disorders, and repetitive behaviors.
  • The use of antipsychotics is controversial, but they are sometimes given to control symptoms of aggression, agitation, and psychosis. However, patients with FTD are also at an increased risk for extrapyramidal side effects due to poorly functioning dopaminergic pathways and thus are usually used only when SSRIs are not successful.
Disposition

  • Patients with FTD benefit from having the social support and specialized care offered in dementia-focused care homes and skilled nursing facilities.
  • The range and severity of behaviors seen in FTD can put a great burden on family and friends. Education, counseling, and connection with social support or referral to a dementia-focused care home can help reduce caregiver stress.
Referral

Patients who have severe or complex presentations should be referred to a neurologist with expertise in dementia or neurodegenerative disorders.

Pearls & Considerations ⬆ ⬇

FTD is a complex neurologic disorder with a wide variety of presenting symptoms. The most common syndrome seen is bvFTD; therefore patients with gradual-onset changes in personality, disinhibition, and increased impulsivity should be investigated for FTD. Therapy is aimed at management of the behavioral symptoms, most commonly through the use of SSRIs. Social support and dementia-specific care facilities are helpful for both patients and family members.

Patient & Family Education

The Association for Frontotemporal Degeneration (https://www.theaftd.org; 866-507-7222)

Related Content

Alzheimer Disease (Related Key Topic)

Parkinson Disease (Related Key Topic)

Dementia with Lewy Bodies (Related Key Topic)

Suggested Readings ⬆

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    2. Burrell J.R. : Motor neuron dysfunction in frontotemporal dementiaBrain. ;134(9):2582-2594, 2011.doi:10.1093/brain/awr195
    3. Deleon J., Miller B.L. : Frontotemporal dementiaHandb Clin Neurol. ;148:409-430, 2018.doi:10.1016/B978-0-444-64076-5.00027-2
    4. Hogan D.B. : The prevalence and incidence of frontotemporal dementia: a systematic reviewCan J Neurol Sci. ;43(S1):S96-S109, 2016.doi:10.1017/cjn.2016.25
    5. Knopman D.S., Roberts R.O. : Estimating the number of persons with frontotemporal lobar degeneration in the US populationJ Mol Neurosci. ;45(3):330-335, 2011.doi:10.1007/s12031-011-9538-y
    6. Laforce R. : Behavioral and language variants of frontotemporal dementia: a review of key symptomsClin Neurol Neurosurg. ;115:2405-2410, 2013.doi:10.1016/j.clineuro.2013.09.031
    7. Miller B., Llibre Guerra J.J. : Frontotemporal dementiaHandb Clin Neurol. ;165:33-45, 2019.doi:10.1016/B978-0-444-64012-3.00003-4
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    9. Pressman P.S., Miller B.L. : Diagnosis and management of behavioral variant frontotemporal dementiaBiol Psychiatry. ;75:574-581, 2014.doi:10.1016/j.biopsych.2013.11.006
    10. Riedl L. : Frontotemporal lobar degeneration: current perspectivesNeuropsychiatric Dis Treat. ;10:297-310, 2014.doi:10.2147/NDT.S38706
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