Frontotemporal dementia (FTD), also known as frontotemporal degeneration, and historically as Pick's disease, is a family of neurodegenerative disorders, caused by frontotemporal lobar degeneration that affects the frontal and temporal lobes. The FTD family includes behavioral variant FTD, primary progressive aphasia (PPA) and its semantic and nonfluent/agrammatic variants, primary progressive apraxia of speech (PPAOS), progressive supranuclear palsy, and corticobasal syndrome.
Through a mutual risk gene, FTD and amyotrophic lateral sclerosis (ALS) share a clinical spectrum, where symptoms of both disorders can co-occur. Symptoms of FTD will typically match a specific disorder at first, though symptoms of other disorders will begin to show as the disease progresses to different areas of the brain. FTD disorders are a common young-onset dementia occurring under the age of 60.
Approximately 60% of people diagnosed with FTD have no known cause and no family history of FTD or related conditions; this is known as sporadic FTD. While environmental causes and unidentified gene variants are suspected causes of sporadic FTD, research in this area is still ongoing. When people have a family history of FTD, other dementias, or conditions like depression or anxiety, it is referred to as familial FTD, and roughly 20% have an underlying genetic basis. Variants in three genes are responsible for most genetic FTD. Notably, in about 10% of people with seemingly sporadic FTD, a genetic variant is identified.
FTD diagnosis currently relies on clinical examination based on the signs and symptoms experienced and imaging of the brain through magnetic resonance imaging or positron emission tomography. FTD disorders have heterogeneous symptoms and pathological features, which contribute to a lengthy differential diagnostic process and high rates of misdiagnosis. A neuropathological examination after death usually provides a definitive diagnosis by identifying the specific features of FTD subtypes.
There is no cure for FTD, nor are any disease-modifying treatments approved that could slow disease progression. The aim of treatment is to manage symptoms, which is primarily accomplished through non-pharmacological interventions such as person-centric care strategies or physical and occupational therapy. Medication can be used to address symptoms like depression or anxiety, but some drugs, like sleep or antipsychotic medicines, carry a considerable risk of side effects for people with FTD. Death is usually the result of complications of FTD, such as pneumonia or fall-related injuries. The average life expectancy after symptoms start is 7 to 13 years, but varies significantly by individual and FTD subtype.
The clinical features of FTD were first described by Czech-German psychiatrist Arnold Pick between 1892 and 1906. Pick's observations were followed by Alois Alzheimer's first description of tau aggregations in neurons (called "Pick bodies") in 1911. The disorder described by Pick was named "Pick's disease" in 1922. The first research criteria were created in 1994, and the publication was the first to use the term "frontotemporal dementia".
Classification FTD refers to a diverse group of neurodegenerative diseases whose pathology initially affects neurons in the brain's frontal and temporal lobes. These brain regions control functions such as goal-directed behavior, communication, movement, and muscle control.
FTD subtypes are classified based on the signs and symptoms experienced by the person diagnosed, but the classification criteria do not entirely reflect the deeply heterogeneous pathological underpinnings and clinical phenotypes of FTD. Even among people with the same subtype of FTD, symptoms and pathology are diverse, contributing significantly to an already challenging diagnostic process.
Behavioral Variant FTD (bvFTD) The most common type of FTD, bvFTD, is characterized by personality changes, apathy, hyperorality, and a progressive decline in self-control, empathy, and recognition of social norms. Cognition is also commonly affected in bvFTD, with diagnosed people experiencing difficulties with planning and problem-solving. Over time, behavioral and cognitive impairments will affect a person's ability to perform basic activities such as eating and bathing.
Symptoms of bvFTD can overlap with motor-dominant FTD disorders such as PSP, CBS, and ALS-FTD. BvFTD can at first be misdiagnosed as a psychiatric disorder due to overlapping symptoms.
Primary Progressive Aphasia (PPA) PPA refers to a family of disorders characterized by language impairment, with a person's diagnosis reflecting the specific language skills affected at symptom onset. Two variants of PPA are more commonly associated with brain pathology seen in FTD: semantic (svPPA) and nonfluent/agrammatic (nfvPPA). In svPPA, people are progressively diagnosed with a loss of word meaning and difficulty recalling object names, making it increasingly difficult to communicate fluently. In nfvPPA, the apraxia of speech makes an affected person's speech gradually slower and more effortful, with aphasia leading to word omission in sentences and a reduced ability to comprehend long sentences.
The logopenic variant (lvPPA), which is associated with difficulty finding words while speaking, is more commonly associated with brain pathology seen in Alzheimer's disease.
Primary Progressive Apraxia of Speech (PPAOS) PPAOS is a disorder associated with the progressive loss of the brain's ability to control muscle movements that allow for speech, without loss of the meanings of words or object names. People diagnosed with PPAOS experience features such as slowed speech, increased speech distortions, and longer pauses between words.
As the pathology progresses, people with PPAOS may begin to experience additional motor/movement symptoms and may later receive an additional diagnosis of PSP or CBS.
Progressive Supranuclear Palsy (PSP) PSP is a disorder considered by some to be under the FTD umbrella. The disorder is traditionally associated with motor-based symptoms that are commonly referred to as "atypical Parkinsonism." However, emerging research has found that cognitive, behavioral, and communication symptoms are more common in PSP than previously established, heightening the chance for misdiagnosis. PSP with "classic" movement symptoms is classified as PSP Richardson Syndrome or Richardson-Steele variant (PSP-RS) and makes up between 24-46% of cases. PSP-RS symptoms include gaze palsies, postural instability, and akinesia.
The PSP Speech and Language variant (PSP-SL) features language-based symptoms like non-fluent/agrammatic aphasia and primary progressive apraxia of speech, demonstrating the variable presentation of the disorder.
Corticobasal Syndrome (CBS) CBS, like PSP, is a traditionally movement-associated disorder considered by some to be under the FTD umbrella, though, like PSP, research is increasingly finding evidence of behavioral, cognitive, and communication symptoms. Typical symptoms of CBS include limb rigidity, bradykinesia, and tremors. A hallmark symptom of CBS is alien limb syndrome, which results in people diagnosed with the disorder experiencing involuntary limb movements and a sense of a limb not belonging to them or feeling "foreign". CBS is the most common cause of alien limb syndrome, comprising at least two-thirds of documented cases.
While accurate estimates for the occurrence of neuropsychiatric symptoms in CBS are lacking, depression, apathy, anxiety, and agitation are commonly documented symptoms experienced by people diagnosed.
FTD-ALS Spectrum Disorders FTD and ALS caused by pathogenic variants in specific genes share a clinical spectrum, with it possible for symptoms of either or both disorders to develop in carriers of the gene. In addition to the hallmark motor symptoms of ALS, spectrum disorders can cause behavioral changes like apathy or disinhibition. Language difficulties may also develop, including difficulty recalling correct words in a sentence or omitting words. Not all manifestations of behavioral or language in ALS qualify as FTD-ALS according to diagnostic criteria, nor do all incidents of muscle weakness symptoms in FTD.
Due to the overlap of two challenging symptomologies, FTD-ALS can be an exceptionally difficult disease for people diagnosed and their families. Life expectancy after symptoms start for people diagnosed with FTD-ALS is also shorter than that of other FTD disorders, averaging between 2.7-4.4 years.
Signs and symptoms Because of the diverse functions of the frontal and temporal lobes, the symptoms of FTD disorders are similarly varied. Even within a specific FTD subtype, the presentation of symptoms and difficulties encountered is typically unique to each person. It is not uncommon for a person experiencing predominant symptoms of one FTD disorder to also have some symptoms of another disorder. The presentation of FTD also varies based on the race of the person diagnosed, with the underlying mechanisms being similarly poorly understood.
While research is ongoing to determine the mechanisms for these varied presentations, it is generally understood that overlap between underlying proteins, genetics, and affected brain regions contribute significantly to the heterogeneity of FTD symptoms.
Behavioral, personality, and cognitive When such symptoms occur, uncharacteristic changes in personality are one of the most noticeable signs of FTD for families and friends of people diagnosed. Changes in overall personality, apathy, disinhibition, loss of empathy, and compulsive behaviors are among the more common behavioral symptoms associated with FTD disorders. Often, symptoms such as apathy or loss of empathy are misdiagnosed as being related to depression, work stress, or a recent adverse life event.
Changes in diet, such as compulsive ingestion of sweets or carbohydrates, are also common in people experiencing behavioral symptoms. In addition to changes in diet, hyperoral symptoms like a compulsive need to place inedible and edible objects in one's mouth or grinding of teeth can occur.
Resistant and aggressive behaviors are also possible as behavioral symptoms. Aggression in FTD frequently results from frustration, though aggressive behaviors can arise seemingly at random. Determining triggers for aggression or resistance can be difficult for caregivers and family members of people with such symptoms due to possible communication-based symptoms or anosognosia. Still, research has found that anticipating and working to negate triggers can help prevent them, while maintaining calm and finding ways to redirect frustration can help safely negate aggression or resistance when it occurs.
Especially in bvFTD, behavioral symptoms can come with cognitive impairments, such as difficulties with executive functioning. People with cognitive symptoms of FTD may experience trouble planning the day, making questionable financial choices, or making uncharacteristic mistakes at work.
Speech and language Speech and language symptoms in FTD typically revolve around the progressive loss of the ability to speak, read, write, and understand spoken language. Apraxia of speech, anomia, and impaired word comprehension are common symptoms. These symptoms are typically associated with PPA or PPAOS. When a non-PPA or PPAOS FTD disorder develops speech and language symptoms, the diagnostic process is further complicated by the overlap of behavioral and movement-based symptoms with other dementias and neuropsychiatric disorders.
Apraxia of speech is a motor speech symptom that affects a person's ability to coordinate the movements of the muscles involved in speaking. People with AOS describe knowing what they want to say but having difficulty coordinating the precise movements of the mouth, tongue, and lips required to produce speech sounds, words, and sentences, and to do so quickly.