Frontotemporal dementia 2018

Frontotemporal Dementia
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Student-Selected Components
Year 2 – 2017/2018
Neuroscience module
Moath Mohammed madlool
Year 2 Medical Student
College of Medicine
Baghdad University

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Table contents
Introduction …………………………………………………………...…..3
History……………………………………………………………………...4
Etiology. …………………………………………………………………....5
Signs and symptoms…………………………………………………….…7
Diagnosis.. …………………………………………………………………8
Treatment. ………………………………………………………………..14
Epidemiology……………………………………………………………..15
Summary. ……………………………………………….………………..16
References. ……………………………………………………………….17

3
Introduction
Frontotemporal dementia (FTD) is a term used to describe a group of
neurocognitive disorders that encompass progressive dysfunction in executive
functioning, behavior, and language. It is considered the third most common form
of dementia following Alzheimer’s disease (AD) and dementia with Lewy
bodies.(1)
As per its namesake, it is a cluster of syndromes that result from
degeneration of the frontal and temporal lobes, and is subdivided into two
categories that are unique in respect to their predominating presentations; namely,
the behavioral subtype that accounts for about half of FTD cases, and the language
subtype.(2)
The language subtype is further subdivided into nonfluent and semantic
variants of primary progressive aphasia (PPA), which are characterized by
diverging localizations and underlying cerebral dysfunction.(2,3)
The semantic and
nonfluent variants of PPA are both characterized by prominent language
impairment, but also differ in neurological localization, severity of specific
symptoms, and the overall course of their presentations. Illustrative of this, the
semantic variant exhibits bilateral anterior temporal lobe atrophy and is associated
with dysfunction of emotional processing, compulsions, and decline in language
skills. In contrast, the nonfluent variant commonly presents with greater left
hemisphere atrophy, and is associated with speech problems earlier while
behavioral disturbances develop later in the disease course.(3)
As the population of
geriatric patients grow and neurocognitive disorders become more prevalent, there
will be an increased need for physicians with an expert understanding of the
diverse clinical findings that define the heterogeneous FTD subtypes. This review
will focus on the most recent findings concerning FTD neurobiology, current
classification and assessment systems, and the most up-to-date expert consensus on
the treatment of this unique collection of syndromes .

4
History
FTD was first described by Arnold
Pick in 1892, and since then it was known as
Pick's Disease, which is now considered as a
subtype of one of the types of FTD diseases.
So the Pick's Disease -a type of
frontotemporal dementia- is a rare
neurodegenerative disease that causes
progressive destruction of nerve cells in the
brain. Common symptoms that are noticed
early on in the diagnosis are personality and
emotional changes, as well as, deterioration
of language. Many who are diagnosed with
Pick's disease can be impulsive, apathetic,
and euphoric. While some of the symptoms
can initially be alleviated, the disease
progresses and patients often die within two
to ten years. A defining characteristic of the
disease is build-up of tau.(4)
Figure 1. Arnold Pick
1851-1924 (5)

5
Etiology
Considerable progress has been made with regard to understanding the
genetics and molecular pathology of frontotemporal lobe dementia (FTD). Prior to
the late 1990s, the FTD syndromes were defined by clinical syndromes and by
light microscopic histopathology only. FTD cases included Pick disease and non-
Pick lobar atrophy cases lacking the silver staining Pick bodies in neurons. This
pathology was referred to as "dementia lacking specific histologic
features. [6]
Kirshner and colleagues also described 2 cases of primary progressive
aphasia (PPA) in which autopsy documented only focal neuronal loss, gliosis, and
microvacuolation of the cortex, changes resembling a nonspecific dementia or
FTD.[7]
Tau protein
In 1998, Hutton and colleagues [8]
and Poorkaj and colleagues [9]
described
mutations in the microtubule-associated protein tau (MAPT) gene, located on
chromosome 17, associated with FTD syndromes and insoluble tau deposits. FTD
consequently changed from a lobar atrophy of syndromic definition to a group of
molecular genetic disorders. Many MAPT mutations have subsequently been
described, including the 2 large families reported by Morris and colleagues, under
the term “hereditary dysphasic dementia.” [10]
Tau is the major protein component of Pick bodies and is seen in a number
of other neurodegenerative diseases, including progressive supranuclear palsy
(PSP), [11]
corticobasal degeneration, and the amyotrophic lateral sclerosis (ALS) ̶
Parkinson dementia disease complex of Guam. These other diseases can produce
syndromes of primary language degeneration resembling PPA and FTD.
Interestingly, no MAPTmutations have been found in Alzheimer disease
. FTLD-U, Progranulin mutations, TDP-43, and FUS accumulation
Until the past few years, more than 50% of cases of FTD, even the familial
ones, were not associated with tau pathology, although many of these cases were
also linked to chromosome 17. Most such cases have been noted to have ubiquitin
immunoreactive inclusions in the cytoplasm or nucleus or ubiquitin
immunoreactive neurites. This group has been designated frontotemporal lobar

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degeneration-ubiquitin (FTLD-U), [12]
though as we shall see, this term is being
replaced by reference to specific mutations.
In 2006, 2 teams of investigators reported mutations in the progranulin
gene on chromosome 17 as the cause of this syndrome. [13, 14]
Many such cases have
now been reported, with mutations resulting in a premature termination codon,
causing haploinsufficiency. The progranulin mutations result in a loss of protein,
whereas the tau mutations result in a toxic gain of function. The TAR ̶
deoxyribonucleic acid (DNA) binding protein (TDP-43) is a major component of
the ubiquitinated inclusions in most of these cases. Progranulin mutations and the
TDP-43 positive inclusions have been found in cases of FTD, PPA, and
corticobasal degeneration. [15, 16]
Other mutations
Tau and progranulin mutations appear to account for the most cases of
FTD, and at least in familial cases, true examples of dementia lacking distinctive
histologic features have become much less common. Moreover, other gene loci
have been implicated in this family of disorders. Cases of inclusion body myopathy
with Paget disease of the bone associated with FTD have been reported and have
been associated with mutations involving chromosome 9, the valosin-containing
protein (VCP) gene. [17, 18]
In some of these cases, TDP-43 protein accumulation has
been reported. Other mutations on chromosome 9 have been associated with FTD-
ALS. [19]
The most common of these is the C9ORF72 gene, in which
hexanucleotide repeat expansions have been reported. This mutation can be seen in
patients with FTD, usually the behavioral variant, or familial ALS, or
both. [20]
Finally, mutations of the chromatin-modifying protein 2B (CHMP2B)
gene on chromosome 3 have also been reported in a Danish family. These
mutations have generally not been associated with TDP-43 protein
accumulation. [21]
Finally, there are a few FTD cases with ubiquitin deposition, but no TDP-
43 accumulation, in whom both tau and progranulin mutations are absent. Rather,
an accumulation of “fused in sarcoma” (FUS) proteins have been found. Reported
cases have included both FTD and ALS. [22]

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Signs and symptoms
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:(23)
 Behavioural variant frontotemporal dementia (BvFTD) is characterized by
changes in social behavior and conduct, with loss of social awareness and
poor impulse control.(24)
 Semantic dementia (SD) is characterized by the loss
of semantic understanding, resulting in impaired word comprehension,
although speech remains fluent and grammatically faultless.(25)
 Progressive nonfluent aphasia (PNFA) is characterized by progressive
difficulties in speech production.(25)
However, the following abilities in the person with FTD are preserved:(24)
 Perception
 Spatial skills
 Memory
 Praxis
In later stages of FTD, the clinical phenotypes may overlap.[25]
FTD patients tend
to struggle with binge eating and compulsive behaviors.[26]
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.[26]
Patients with FTD show marked deficiencies in executive functioning and working
memory.[27]
Most FTD patients become unable to perform skills that require

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complex planning or sequencing.[28]
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.[29]
Diagnosis
Physical examination
Physical and neurologic examinations reflect mainly the mental status
abnormalities described under Behavioral Changes. Characteristics of
frontotemporal lobe dementia (FTD), as found on physical examination, can be
further described as follows:
 Speech - Many patients have a nonfluent speech pattern, and virtually all
have some degree of difficulty in naming or word finding
 Behavior - Behavioral alterations and frontal lobe symptoms have been
previously outlined
 Ideation - Ideation tends to be concrete, with poor abstraction and
organization of responses and delayed shifting of cognitive sets
 Visual and spatial functions and constructional tasks – These are much less
affected, except as influenced by behavioral and organizational difficulties;
motor skills usually are spared, except for perseverative or inattentive
responses and difficulty with temporal sequencing of tasks
 Specific ideomotor apraxia – Rare, except in patients with language
difficulty associated with corticobasal degeneration (see below).

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 Memory - Memory is usually preserved for orientation, although
information retrieval may be difficult. Short-term memory deficits may be
present in some patients but are less characteristic and early than those
associated with Alzheimer disease.
 Frontal release signs - Frontal release signs, such as a positive glabellar sign,
snout, grasp, and palmomental responses, may develop [30]
In a minority of patients, extrapyramidal signs, such as rigidity or even a
full-blown parkinsonian syndrome of rigidity, akinesia, and tremor, may
develop. These cases may overlap with Lewy body dementia, in which
fluctuating mental status, early visual hallucinations, and REM sleep
behavior disorder (acting out of dreams) are characteristic, along with mild
parkinsonian motor symptoms[31].
An overlap also exists with the syndrome of corticobasal degeneration, in
which rigidity and apraxia of the upper limbs, typically starting in one arm
and remaining asymmetric, may coexist with neurobehavioral symptoms
much like those associated with the syndrome of primary progressive
aphasia (PPA).[32]
Differential diagnosis
Lab and EEG Studies
Routine testing (eg, blood, cerebrospinal fluid) in frontotemporal lobe
dementia (FTD) is usually unrevealing.
The genetic test for APOE-4 is less useful in FTD than in Alzheimer disease.
A study by Mesulam et al found no association between FTD and the APOE-
4 genotype. [33]
Other studies have had somewhat different results, but, in
general, APOE-4correlates much better with Alzheimer disease than with
FTD. [34]
The findings in electroencephalography (EEG) are commonly abnormal in
FTD, often showing focal slowing of electrical activity over 1 or both frontal
or temporal lobes. These findings are not sufficiently specific to be clinically
useful, and, in general, EEG is less useful than functional brain imaging with
PET scanning or even lobar atrophy on MRI.

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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
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. [35]
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. [36]
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
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 signal the individual to adapt social behavior in an
appropriate manner to maintain relationships with others. Though patients
with damage to the orbitofrontal cortex 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. [37]

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On the other hand, 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 behaviors while avoiding
others. It is thought that somatic marker is processed in orbitofrontal cortex. [38]
A scale of Faux Pas Recognition Test for the feelings of a patient with
FTD. You can notice the changes in the feelings before (grey) and after
(black) management.[38]
. The process of Iowa Gambling Test. [39]

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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. [40]
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. [41]
They invented the Executive and Social Cognition Battery which comprises five
neuropsychological tests and as follows:
 Iowa gambling task
 Faux Pas test
 Hotel task
 Mind in the Eyes
 Multiple Errands Task
And this battery is more sensitive in detecting BvFTD. [42]
Imaging stadies
Routine brain imaging with computed tomography (CT) scanning or MRI is
usually remarkable only for cerebral atrophy. Some patients show impressive
localized atrophy in the frontal or temporal lobe on 1 or both sides.[43]

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On MRI, temporal lobe atrophy is especially easy to detect in the coronal
projections. Cases differ as to the relative degree of atrophy in the frontal or
temporal lobe and on the left versus right side. Research studies using voxel-based
morphometry have provided more precise maps of the areas of focal atrophy.
Patients with frontal lobe neurobehavioral disorders (behavioral variant
frontotemporal lobe dementia) often have bilateral frontal atrophy, especially
involving the medial frontal cortex, sometimes with anterior temporal lobe atrophy
as well. [44]
Hypometabolism
Functional imaging techniques, particularly single-photon emission computed
tomography (SPECT) and positron emission tomography (PET) scanning, detect
focal lobar hypometabolism or hypoperfusion with great sensitivity. (See the image
below.). [45]
Histologic findings
Various pathologic findings have been reported in patients with primary
progressive aphasia (PPA) and frontotemporal lobe dementia (FTD). The central
theme of these reports is that these syndromes have a non-Alzheimer pathology.
(See the image below.) [46]
Patient with progressive nonfluent aphasia.
MRI showing focal, left temporal atrophy.
Reprinted from Neurology in Clinical
Practice, 4th ed. Kirshner H. Language and
Speech Disorders. [43]

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Treatment
Medication:
Treatment of depression with a selective serotonin reuptake inhibitor (SSRI), such
as paroxetine, sertraline, or citalopram, is frequently helpful. Trazodone may be
helpful for sleep and for behavioral aberrations. These agents have been shown to
be effective in small clinical trials. [47]
Neurotransmitter-based treatments, analogous to the use of dopaminergic agents in
Parkinson disease or anticholinesterase agents in Alzheimer disease, have not
proven beneficial in frontotemporal lobe dementia (FTD). There is not clearly a
rationale for use of anticholinesterase drugs, such as donepezil (Aricept),
rivastigmine (Exelon), or galantamine (Razadyne), since there is no definite
cholinergic deficiency in FTD, [48]
but these drugs are widely used. Anecdotally,
they may improve memory but may worsen behavioral symptoms. The drug
memantine has been thought to be helpful, but 2 recent, small clinical trials have
not supported a benefit of this agent. [49]
Therapy
People experiencing language difficulties may benefit from speech therapy to learn
alternate strategies for communication.[50]
Hematoxylin and eosin stain of the left
frontal cortex from a patient with primary
progressive aphasia. This shows loss of
neurons, plump astrocytes (arrow), and
microvacuolation of the superficial cortical
layers. Reproduced with permission of
John Wiley & Sons, Inc. [46]

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Epidemiology
According to the World Health Organization (WHO), there are an estimated 47.5
million people who have dementia with another 7.7 million new cases every
year.[51]
Although AD is the most common form of dementia, contributing to 60–
70% of cases, mixed types exist, and the overlap between different forms of
dementia is sizeable. FTD is the second most common cause of dementia in
patients aged < 65 years,[52]
with a further 25% of dementia cases in patients older
than 65 years also attributed to FTD disorders.[53]
However, determining the total
population with underlying FTD pathology is difficult due to the low disease
frequency in a relatively large at-risk population. Additionally, studies estimating
incidence and prevalence rates of FTD are limited by the inherent difficulty
identifying FTD disorders.[54]
In the USA, Knopman and Roberts estimated that the
prevalence of FTD between the ages of 45–65 years ranged from 15 to 22 per
100,000 people, with incidence estimates ranging from 2.7 to 4.1 per 100,000
members in the same age range. Overall, they estimated approximately 20,000 to
30,000 cases of FTD in the USA alone. Yet, these numbers may actually be
underestimating the occurrence of FTD syndromes. This is especially evident, as
older cases of FTD begin to echo symptoms of AD further confounding the
delineation between the neurocognitive disorders.[53]
Further emphasizing the
limitations of FTD epidemiologic studies, Lambert and colleagues[55]
conducted a
systematic review with the goal of estimating prevalence rates of early-onset
dementia. They found a significant disparity between studies estimating the
prevalence of early-onset FTD with estimates ranging from 1.0 to 15.4 per 100,000
members of the population. Adding to this, it appears that the data presented was
principally collected from populations studied in the UK, mainland Europe, and
Japan, suggesting that the information gathered may not be generalizable to the
world-wide population as a whole. For this reason, standardization of study designs
will likely aid in more precisely defining FTD epidemiology globally, a focus that
future studies should pursue in the future.

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Summary
Frontotemporal dementia (FTD) 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. Diagnosis include physical examination and differential
diagnosis which include laboratory tests, EEG and imaging studies. Currently,
there is no cure for FTD, but there are treatments that help alleviate symptoms.

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