| Frontotemporal dementia | |
|---|---|
| Specialty | Psychiatry, neurology |
| Causes | frontotemporal lobar degeneration |
The frontotemporal dementias (FTD) encompass six types of dementia involving the frontal or temporal lobes. They are: behavioral variant of FTD, semantic variant primary progressive aphasia, nonfluent agrammatic variant primary progressive aphasia, corticobasal syndrome, progressive supranuclear palsy, and FTD associated with motor neuron disease.
One variant is the clinical presentation of frontotemporal lobar degeneration, which is characterized by progressive neuronal loss predominantly involving the frontal or temporal lobes, and typical loss of over 70% of spindle neurons, while other neuron types remain intact.
It was first described by Arnold Pick in 1892 and was originally called "Pick's disease", a term now reserved for Pick disease, one specific type of frontotemporal dementia. Second only to Alzheimer's disease (AD) in prevalence, FTD accounts for 20% of young-onset dementia cases. Signs and symptoms typically manifest in late adulthood, more commonly between the ages of 45 and 65, approximately equally affecting men and women.
Common signs and symptoms include significant changes in social and personal behavior, apathy, blunting of emotions, and deficits in both expressive and receptive language. Currently, there is no cure for FTD, but there are treatments that help alleviate symptoms.
Signs and symptoms
Frontotemporal
dementia (FTD) classically affects adults in their fifth to sixth
decade of life.These patients usually describe a gradual onset and
progression of changes in behavior or language deficits for several
years prior to presentation to a neurologist.
FTD is traditionally difficult to diagnose due to the
heterogeneity of the associated symptoms. Signs and symptoms are
classified into three groups based on the functions of the frontal and
temporal lobes:
- Behavioural variant frontotemporal dementia (BvFTD) is characterized by changes in social behavior and conduct, with loss of social awareness and poor impulse control.
- Semantic dementia (SD) is characterized by the loss of semantic understanding, resulting in impaired word comprehension, although speech remains fluent and grammatically faultless.
- Progressive nonfluent aphasia (PNFA) is characterized by progressive difficulties in speech production.
However, the following abilities in the person with FTD are preserved:
- Perception
- Spatial skills
- Memory
- Praxis (motor planning to perform tasks or movements)
In later stages of FTD, the clinical phenotypes may overlap. FTD patients tend to struggle with binge eating and compulsive behaviors.
These binge eating habits are often associated with abnormal eating
behavior including overeating, stuffing oneself with food, changes in
food preferences (cravings for more sweets, carbohydrates), eating
inedible objects and snatching food from others. Recent findings from
structural MRI research have indicated that eating changes in FTD are
associated with atrophy (wasting) in the right ventral insula, striatum, and orbitofrontal cortex.
Patients with FTD show marked deficiencies in executive functioning and working memory. Most FTD patients become unable to perform skills that require complex planning or sequencing. In addition to the characteristic cognitive dysfunction, a number of primitive reflexes known as frontal release signs are often able to be elicited. Usually the first of these frontal release signs to appear is the palmomental reflex which appears relatively early in the disease course whereas the palmar grasp reflex and rooting reflex appear late in the disease course.
In rare cases, FTD can occur in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis). The prognosis for people with MND is worse when combined with FTD, shortening survival by about a year.
Genetics
A higher proportion of FTD cases seem to have a familial component than more common neurodegenerative diseases like Alzheimer's disease.
More and more mutations and genetic variants are being identified all
the time, so the lists of genetic influences require consistent
updating.
- Tau-positive frontotemporal dementia with parkinsonism (FTDP-17) is caused by mutations in the MAPT gene on chromosome 17 that encodes the Tau protein It has been determined that there is a direct relationship between the type of tau mutation and the neuropathology of gene mutations. The mutations at the splice junction of exon 10 of tau lead to the selective deposition of the repetitive tau in neurons and glia. The pathological phenotype associated with mutations elsewhere in tau is less predictable with both typical neurofibrillary tangles (consisting of both 3 repeat and 4 repeat tau) and Pick bodies (consisting of 3 repeat tau) having been described. The presence of tau deposits within glia is also variable in families with mutations outside of exon 10. This disease is now informally designated FTDP-17T. FTD shows a linkage to the region of the tau locus on chromosome 17, but it is believed that there are two loci leading to FTD within megabases of each other on chromosome 17.
- FTD caused by FTLD-TDP43 has numerous genetic causes. Some cases are due to mutations in the GRN gene, also located on chromosome 17. Others are caused by VCP mutations, although these patients present with a complex picture of multisystem proteinopathy that can include amyotrophic lateral sclerosis, inclusion body myopathy, Paget's disease of bone, and FTD. The most recent addition to the list is a hexanucleotide repeat expansion in intron 1 of C9ORF72. Only one or two cases have been reported describing TARDBP (the TDP-43 gene) mutations in a clinically pure FTD (FTD without MND).
- No genetic causes of FUS pathology in FTD have yet been reported.
Pathology
There
are three main histological subtypes found at post-mortem: FTLD-tau,
FTLD-TDP, and FTLD-FUS. Dementia lacking distinctive histology (DLDH) is
a rare and controversial entity. New analyses has allowed many cases
previously described as DLDH to be reclassified into one of the
positively defined subgroups. In rare cases, patients with clinical FTD
were found to have changes consistent with Alzheimer's disease on autopsy.[13] The most severe brain atrophy appears to be associated with Pick's disease, corticobasal degeneration, and TDP pathology associated with behavioral-variant FTD.
With regard to the genetic defects that have been found, repeat expansion in the C9orf72 gene is considered a major contribution to frontotemporal lobar degeneration, although defects in the GRN and MAPT genes are also associated with it.
Diagnosis
Structural
MRI scans often reveal frontal lobe and/or anterior temporal lobe
atrophy but in early cases the scan may seem normal. Atrophy can be
either bilateral or asymmetric.
Registration of images at different points of time (e.g., one year
apart) can show evidence of atrophy that otherwise (at individual time
points) may be reported as normal. Many research groups have begun using
techniques such as magnetic resonance spectroscopy, functional imaging
and cortical thickness measurements in an attempt to offer an earlier
diagnosis to the FTD patient. Fluorine-18-fluorodeoxyglucose positron
emission tomography (FDG-PET) scans classically show frontal and/or
anterior temporal hypometabolism, which helps differentiate the disease
from Alzheimer's disease. The PET
scan in Alzheimer's disease classically shows biparietal
hypometabolism. Meta-analyses based on imaging methods have shown that
frontotemporal dementia mainly affects a frontomedial network discussed
in the context of social cognition or 'theory of mind'.
This is entirely in keeping with the notion that on the basis of
cognitive neuropsychological evidence, the ventromedial prefrontal
cortex is a major locus of dysfunction early on in the course of the
behavioural variant of frontotemporal degeneration.
The language subtypes of frontotemporal lobar degeneration (semantic
dementia and progressive nonfluent aphasia) can be regionally
dissociated by imaging approaches in vivo.
The confusion between Alzheimer's and FTD is justifiable due to
the similarities between their initial symptoms. Patients do not have
difficulty with movement and other motor tasks.
As FTD symptoms appear, it is difficult to differentiate between a
diagnosis of Alzheimer's disease and FTD. There are distinct
differences in the behavioral and emotional symptoms of the two
dementias, notably, the blunting of emotions seen in FTD patients.
In the early stages of FTD, anxiety and depression are common, which
may result in an ambiguous diagnosis. However, over time, these
ambiguities fade away as this dementia progresses and defining symptoms
of apathy, unique to FTD, start to appear.
Recent studies over several years have developed new criteria for
the diagnosis of behavioral variant frontotemporal dementia (bvFTD).
Six distinct clinical features have been identified as symptoms of
bvFTD.
- Disinhibition
- Apathy/Inertia
- Loss of Sympathy/Empathy
- Perseverative/compulsive behaviors
- Hyperorality
- Dysexecutive neuropsychological profile
Of the six features, three must be present in a patient to diagnose
one with possible bvFTD. Similar to standard FTD, the primary diagnosis
stems from clinical trials that identify the associated symptoms,
instead of imaging studies.
The above criteria are used to distinguish bvFTD from disorders such as
Alzheimer's and other causes of dementia. In addition, the new
criteria allow for a diagnostic hierarchy distinguished possible,
probable, and definite bvFTD based on the number of symptoms present.
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 cortex. In later stages, it
gradually expands its area to the dorsolateral cortex and the temporal
lobe.
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 behavioural 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.
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. Both the Iowa gambling task and the Faux Pas test are known to be sensitive to dysfunction of the orbitofrontal cortex.
Faux Pas Recognition test is intended to measure one’s ability to
detect faux pas types of social blunders (accidentally make 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.
Self-monitoring is the ability of individuals to evaluate their
behaviour to make sure that their behaviour 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 signal the individual to adapt social
behaviour 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 behaviour because they
fail to generate social emotions that promote adaptive social behaviour.
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 marker)
are associated with their outcomes and it 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 behaviours while avoiding others. It is thought that somatic marker is processed in orbitofrontal cortex.
The symptoms observed in bvFTD are caused by dysfunction of the
orbitofrontal cortex, thus these two neuropsychological tests might be
useful in detecting the 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 not specific to it. The
weakness of these tests is that they do not necessarily show dysfunction
of the orbitofrontal cortex.
In order to solve this problem, some researchers combined
neuropsychological tests which detect the dysfunction of orbitofrontal
cortex into one so that it increases its specificity to the degeneration
of the frontal lobe in order to detect the early-stage bvFTD. They
invented the Executive and Social Cognition Battery which comprises five neuropsychological tests.
- Iowa gambling task
- Faux Pas test
- Hotel 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.
Management
Currently,
there is no cure for FTD. Treatments are available to manage the
behavioral symptoms. Disinhibition and compulsive behaviors can be
controlled by selective serotonin reuptake inhibitors (SSRIs). Although Alzheimer's and FTD share certain symptoms, they cannot be treated with the same pharmacological agents because the cholinergic systems are not affected in FTD.
Because FTD often occurs in younger people (i.e. in their 40s or
50s), it can severely affect families. Patients often still have
children living in the home. Financially, it can be devastating as the
disease strikes at the time of life that often includes the top
wage-earning years.
Prognosis
Symptoms
of frontotemporal dementia progress at a rapid, steady rate. Patients
suffering from the disease can survive between 2–20 years. Eventually
patients will need 24-hour care for daily function.
CSF leaks are a known cause of reversible frontotemporal dementia.
History
Frontotemporal dementia was first described by Pick in 1892.
In 1989, Snowden suggested the term “semantic dementia” to describe
the patient with predominant left temporal atrophy and aphasia that Pick
described. The first research criteria for FTD “Clinical and
neuropathological criteria for frontotemporal dementia. The Lund and
Manchester Groups,” was developed in 1994.The clinical diagnostic
criteria were revised in the late 1990s, when the FTD spectrum was
divided into a behavioral variant, a nonfluent aphasia variant and a
semantic dementia variant.
The most recent revision of the clinical research criteria was by
International Behavioural Variant FTD Criteria Consortium (FTDC) in
2011.
