Frontotemporal dementia

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.^[17] Cognition is also commonly affected in bvFTD, with diagnosed people experiencing difficulties with planning and problem-solving.^[18] 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.^[19]

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.^[20]

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.^[21]

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.^[22] People diagnosed with PPAOS experience features such as slowed speech, increased speech distortions, and longer pauses between words.^[23]

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.^[24]

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.^[25] 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.^[26] PSP-RS symptoms include gaze palsies, postural instability, and akinesia.^[27]

The PSP Speech and Language variant (PSP-SL) features language-based symptoms like non-fluent/agrammatic aphasia and primary progressive apraxia of speech,^[28] 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.^[29] 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".^[30] CBS is the most common cause of alien limb syndrome, comprising at least two-thirds of documented cases.^[31]

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.^[32]

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.^[33] Language difficulties may also develop, including difficulty recalling correct words in a sentence or omitting words.^[34] 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.^[33]

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.^[35]

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.^[39]

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.^[39]

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.^[40]

Especially in bvFTD, behavioral symptoms can come with cognitive impairments, such as difficulties with executive functioning.^[40] People with cognitive symptoms of FTD may experience trouble planning the day, making questionable financial choices, or making uncharacteristic mistakes at work.^[41]

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.^[42] Apraxia of speech, anomia, and impaired word comprehension are common symptoms.^[43] 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.^[44]

Apraxia of speech is a motor speech symptom that affects a person's ability to coordinate the movements of the muscles involved in speaking.^[44] 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.^[45]

Nonfluent/agrammatic symptoms affect a person's speaking ability, making it progressively difficult while leaving single-word comprehension intact. Agrammatic symptoms typically result in speech becoming restricted to shorter sentences, with the ability to comprehend longer sentences usually becoming impaired over time. Mutism is possible due to a pathology that produces nonfluent/agrammatic symptoms.^[45]

Semantic symptoms of FTD impair a person's ability to comprehend what is being said to them, with the meanings of words progressively being lost. When speaking, it can be difficult for someone with such symptoms to find the right word (anomia) or recognize what objects are called and their purpose. Surface dyslexia and dysgraphia are also potential impairments that can develop, making reading and writing words difficult for people diagnosed.^[46]

While more common with Alzheimer's pathology, logopenic symptoms can still develop in FTD. Logopenic symptoms impact single-word retrieval, which can lead to people diagnosed pausing more or frequently engaging in circumlocution during conversation. Errors in phonological speech are also common with logopenic symptoms, with affected people substituting sounds made with one area of the mouth for another.^[47]

Motor functions

Motor symptoms of FTD can alternatively be categorized as atypical Parkinsonism or ALS-like, though in some people, both symptom types can co-occur. Common motor symptoms of FTD can include impairments to fine motor skills, postural instability, and dystonia. In FTD-ALS Spectrum Disorders, behavioral and cognitive symptoms typically develop first,^[48] which raises the risk for misdiagnosis as a neuropsychiatric disorder or a related form of dementia. Research has found that ALS-like motor symptoms are the most common in FTD, followed by Parkinsonian symptoms.^[49]

In people with FTD-ALS, common symptoms of ALS, such as gait disturbances, dysphagia, and falls, typically develop as the underlying disease spreads to the upper or lower motor neurons.^[50] There is evidence that some symptoms and anatomical features of FTD-ALS are specific to a gene; for example, bulbar symptoms are typically associated with a pathogenic expansion in C9orf72.^[51] Owing to their pathological overlap, some drugs for ALS and Parkinson's disease may provide relief for symptoms of FTD-ALS.^[52]

The symptom overlap of ALS and Parkinson's disease already creates an opportunity for misdiagnosis for either disorder, with the possibility of misdiagnosis raised for people experiencing Parkinsonian symptoms of FTD, due in part to unfamiliarity with the disorder.^[53] In addition to classic Parkinson's symptoms like postural instability and rigidity, people with FTD (in particular, PSP) can develop supranuclear gaze palsies.^[54] Because of the pathological and anatomical nature of PSP and CBS, visuospatial defects can manifest alongside Parkinsonian-like movement symptoms (though they are more common with CBS).^[55]

Progression

FTD disorders are some of the most common young-onset dementias affecting people younger than 60, though the mechanisms that cause them to develop earlier in life are not known. It is important to note, that the majority of people diagnosed with FTD are older than 60, but when a person has young onset dementia, FTD is a likely cause.^[56]

Due to the highly heterogeneous nature of FTD, even people with the same disorder may experience different symptoms at the initial onset. This heterogeneous presentation increases over time as the underlying disease spreads to other brain regions; while symptoms will initially resemble a specific FTD disorder, symptoms from different forms of FTD are likely to develop.^[57] In a person with FTD-ALS, for example, behavioral symptoms resembling bvFTD are likely to present before classic ALS motor symptoms,^[58] with language symptoms akin to svPPA developing after motor signs. Regardless of which category of FTD symptoms develops first, the progression of the disease will inevitably lead to impairment across multiple functional domains and require increasing levels of care.^[59][60]

The heterogeneity of FTD and the current lack of biomarkers specific to any FTD disorder make it difficult to track the progression of the disorder. Monitoring its progression is currently accomplished through clinical observation, with symptoms such as incontinence, loss of communication, loss of interest in eating, or increasing difficulty with walking or fine motor tasks typically signaling a shift into advanced disease stages.^[61] Impairments to speech and language and the presence of anosognosia can make late-stage FTD care difficult, especially for informal caregivers like family and friends.^[42]

The heightened risk of complications and the debilitating nature of advanced FTD typically require a shift to around-the-clock care. Additionally, advanced FTD will often leave people diagnosed unable to advocate for themselves, requiring family members to make complicated care decisions for their loved one if advance care directives are not in place.^[62] Even in situations where a person with advanced FTD is placed in a care facility or hospice setting, unfamiliarity with the heterogeneous nature of FTD and its effects on behavior can create challenges for healthcare providers and ultimately families.^[63]

Genetics

The majority of genetic FTD is caused by pathogenic variants in one of three genes: C9orf72, GRN, and MAPT. Additionally, pathogenic variants in the genes TARDBP, TBK1, SQSTM1, and VCP, and other genes are less common but documented causes of FTD.^[68] There are several other genes that are believed to cause FTD, but additional evidence for some of these genes is needed.^[69] It is also believed there are additional genes that have yet to be linked to FTD.

The wide variety of genes associated with FTD contributes to the heterogeneous presentation of symptoms across disorders. A significant factor in this heterogeneity is the association of variants of certain genes with specific FTD disorders; C9orf72, for example, is most associated with FTD-ALS spectrum disorders. However, the presence of a gene variant is not enough to predict the course of FTD due to the underlying heterogeneity of pathological mechanisms in each subtype.^[70] For instance, while it is uncommon, a person with a C9orf72 expansion can develop symptoms of PPA.^[71]

Despite shared pathological and genetic factors and a more frequent family history among people with FTD compared to those with ALS, genetic testing and counseling recommendations only exist for ALS.^[72] Genetic testing and counseling services are underutilized by people with FTD, only being offered or completed by 2-23%% of people diagnosed compared to approximately 73% in ALS.^[73][74] Experts are increasingly calling for genetic testing to become part of routine clinical practice for people affected by FTD, with an emphasis on providing genetic counseling to educate families on the various aspects of testing and the implications of test results.^[75]

Neuropsychological tests

The progression of the degeneration caused by bvFTD may follow a predictable course. The degeneration begins in the orbitofrontal cortex and medial aspects such as ventromedial prefrontal cortex. In later stages, it gradually expands its area to the dorsolateral prefrontal cortex and the temporal lobe.^[92] Thus, the detection of dysfunction of the orbitofrontal cortex and ventromedial cortex is important in the detection of early stage bvFTD. As stated above, a behavioral change may occur before the appearance of any atrophy in the brain in the course of the disease. Because of that, image scanning such as MRI can be insensitive to the early degeneration and it is difficult to detect early-stage bvFTD.^{[citation needed]}

In neuropsychology, there is an increasing interest in using neuropsychological tests such as the Iowa gambling task or Faux Pas Recognition test as an alternative to imaging for the diagnosis of bvFTD.^[93] Both the Iowa gambling task and the Faux Pas test are known to be sensitive to dysfunction of the orbitofrontal cortex.^{[citation needed]}

The Faux Pas Recognition test is intended to measure one's ability to detect faux pas types of social blunders (accidentally making a statement or an action that offends others). It is suggested that people with orbitofrontal cortex dysfunction show a tendency to make social blunders due to a deficit in self-monitoring.^[94] Self-monitoring is the ability of individuals to evaluate their own behavior to make sure that their behavior is appropriate in particular situations. The impairment in self-monitoring leads to a lack of social emotion signals. The social emotions such as embarrassment are important in the way that they alert the individual to adapt social behavior in an appropriate manner to maintain relationships with others. Though patients with damage to the OFC retain intact knowledge of social norms, they fail to apply it to actual behavior, because they fail to generate social emotions that promote adaptive social behavior.^[94]

The other test, the Iowa gambling task, is a psychological test intended to simulate real-life decision making. The underlying concept of this test is the somatic marker hypothesis. This hypothesis argues that when people have to make complex uncertain decisions, they employ both cognitive and emotional processes to assess the values of the choices available to them. Each time a person makes a decision, both physiological signals and evoked emotion (somatic markers) are associated with their outcomes, and this accumulates as experience. People tend to choose the choice which might produce the outcome reinforced with positive stimuli; thus it biases decision-making towards certain behaviors while avoiding others.^[95] It is thought that somatic markers are processed in the orbitofrontal cortex.^{[citation needed]}

The symptoms observed in bvFTD are caused by dysfunction of the orbitofrontal cortex; thus these two neuropsychological tests might be useful in detecting early-stage bvFTD. However, as self-monitoring and somatic marker processes are so complex, it likely involves other brain regions. Therefore, neuropsychological tests are sensitive to the dysfunction of orbitofrontal cortex, yet are not specific to it. The weakness of these tests is that they do not necessarily show dysfunction of the orbitofrontal cortex.^{[citation needed]}

In order to solve this problem, some researchers have combined neuropsychological tests which detect the dysfunction of orbitofrontal cortex into one grouping, so that it increases its specificity to the degeneration of the frontal lobe, in order to detect early-stage bvFTD. They invented the Executive and Social Cognition Battery which comprises five neuropsychological tests:^[93]

• Faux Pas test
• Hotel task
• Iowa gambling task
• Mind in the Eyes
• Multiple Errands task

The result has shown that this combined test is more sensitive in detecting the deficits in early bvFTD.^[93]