Signs and Symptoms of Frontotemporal Dementia

A Patient with Frontotemporal Dementia
A day in the life of an individual suffering from FTD.
Video Source: Youtube, Mayo Clinic

Frontotemporal Dementia (FTD) is a neurodegenerative disorder defined by atrophies in the temporal and frontal cortices [1]. However, atrophies implicated in FTD are not restricted to the frontal and temporal cortices, in recent brain imaging studies it has also been revealed that subcortical and limbic regions as well as more large scale brain networks also degenerate [2][10]. Human functionality is based on networks in the brain that exist through the cooperation and communication of different brain region. The result of atrophies, present in FTD, will alter these essential brain networks resulting in impaired functionality and symptom manifestation [1]. Thus, an understanding of the brain regions involved can elicit greater understanding of the impairments or symptoms that can arise in patients suffering from this form of dementia. These impairments can influence a variety of facets in a patient’s life, such as the social and cognitive domains. Lastly, the knowledge about the symptoms that arise from the degeneration of neuroanatomical structure and networks can further the understanding of the causes for FTD as well as suggest probable treatment options.

Overview of Neuroanatomical changes in FTD

Atrophies in FTD

Subcortical Atrophies in FTD
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Atrophies in the frontal, temporal and subcortical regions in FTD patients (middle and right)
compared to controls (left) (Chow et al., 2008).

In FTD, as the name suggests, the maximum amount of atrophies are likely to occur in the frontal and temporal lobes of the brain [1]. Even though the frontal and temporal lobes witness overall shrinkage, there are atrophies in specific areas within these lobes that are more pronounced. Voxel-based morphometric techniques have been employed to identify that patients with FTD had excessive loss of cell bodies in the left anterior temporal lobe, right temporal pole and the subcallosal gyrus, compared to the other areas of the temporal lobe [3]. For the frontal lobe, voxel-based morphometric techniques identified that in patients with FTD there was extensive reduction in grey matter in the dorso-medial frontal lobe as well in Brodmann's Area 6, 8 and 9 [3]. In addition, volumetric MRI methods identified that compared to similar age controls; FTD patients had more atrophy in the orbitofrontal region [4].

In recent studies, with the progression of FTD, various other subcortical and limbic structures have also been implicated to have atrophied away [2] [5]. One of the main relay centers of the brain, the thalamus, has been identified to have decreased in size in FTD patients [2]. In addition, structures of the basal ganglia that are important for movement, the putamen and the caudate nucleus, shrink with the progression of FTD [2]. In the limbic region, the areas that are identified to have atrophies are the amygdala, the insular cortex, and the hippocampus [5-7]. The amygdala and insular cortex are important for fear condition, while the hippocampus is essential for memory consolidation [5-7]. The size of the amygdala decreases in patients with FTD, more specifically, in a magnetic resonance scans it was identified that compared to controls there was more amygdala atrophy in patients with FTD [5]. In contrast, when magnetic resonance scans of FTD patients were compared to patients with Alzheimer's Disease (AD), AD patients had greater amygdala atrophy [5]. In regards to the insular cortex, it is the anterior insula that extensively atrophies away with the progression of the disease [6]. Lastly, a distinct pattern of hippocampus degeneration is seen in patients with FTD compared to those with AD [7]. Using magnetic resonance imaging (MRI), it was seen that in patients with AD, the pattern of atrophies is more diffuse, while in FTD, atrophies are largely seen in the anterior hippocampus [7]. This difference between the atrophies in FTD and AD are not seen in the entorhinal cortex and the pattern of atrophies in both groups was highly correlated [7]. Compared to equal aged controls, both demented groups had much greater atrophy in the hippocampus and the entorhinal cortex [7].

Atrophies, identified with the use of brain imaging tools can only be used as greater support for the diagnosis of FTD and not as the sole diagnostic criteria. Studies demonstrate that atrophies in the frontal and temporal cortices are the defining features of FTD; however degradation of these regions happens in normal aging as well [8]. Therefore, researchers have suggested that volumetric MRI processing maybe a better technique to include in the diagnostic criteria of FTD as it provides the ability for physicians to differentiate between what potentially could be FTD and normal aging [8].

Altered Brain Networks

Default Mode Network
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Changes in the default mode network associated with
FTD (Zhou et al., 2010).

Brain regions do not function independently of each other; rather different regions connect to each other to form networks which produce behaviours, movements, and all other facets of human functioning. In FTD, as a result of the atrophies in the frontal cortex, an isolation phenomenon is experienced in which the connectivity between the frontal and limbic regions of the brain is disrupted [9]. Brains of FTD patients were scanned using functional magnetic resonance imaging (fMRI) to identify that, while there was disrupted connectivity between the frontolimbic circuit, connectivity within different regions of the frontal cortex was enhanced [9].

Another major network in the brain is the default mode network [10]. This network is active in the absence of goal directed activity allowing individuals to introspect, daydream, and reflect on one’s past or imaging their future [10]. The brain regions that primarily make up this network include regions in the lateral and medial prefrontal cortices; the posterior cingulate, hippocampal formation, temporal pole and the lateral temporal cortex [10]. In FTD, due to the atrophies in the frontal and temporal cortices this network is largely disrupted resulting in a number of symptoms that are associated with FTD, such as impairment in emotional processing [10].

Frontotemporal interactions are also the basis of another key pathway which is associated with the identification of unpredictable auditory events [11]. Magnetoencephalography (MEG) was be employed to identify that the underlying neural mechanisms of this network [11]. Compared to similar aged controls, patients with FTD exhibited incoherent network connectivity between the frontal, temporal, and parietal regions[11]. This abnormal network connectivity is a result of inefficient, extensive networks which are produced due to the degeneration of the associated regions [12].

The satiety network, which is involved the regulation of feeding is also disrupted in patients with FTD [1]. The key brain regions associated with this network are the orbitofrontal cortex, insular cortex and the striatum. These regions have been identified in prior research to waste away in patients with FTD. This degeneration results in abnormal connectivity between these structures resulting in symptoms manifestations associated with eating [1].

In general, all networks that are associated with the frontal, temporal, subcortical and limbic regions will experience a disruption in network connectivity which primarily gives rise to the symptoms experienced by FTD patients [1-7].

Cognitive Impairments

Compulsive Behaviours

Compulsive behaviours are common symptom in FTD patients. There are a range of compulsive behaviours that have been identified in patients with FTD [13]. These behaviours preliminary arise from an individual’s inability to inhibit the urge to perform a compulsive action [13]. For instance, studies have identified that compared to AD patients; patients with FTD are more likely to engage in compulsive behaviours, such as repetitive checking [13]. Another compulsive behaviour seen in patients with FTD, that is not seen in healthy individual or patients with other forms of dementia, is the compulsion to binge eat. As a result of this compulsion, an individual would consume large amount of food even after self-reporting to be satiated [1]. It has been suggested that this satiety dysfunction is a result of the orbitofrontal-insular-striatal circuit degeneration [1]. Brain atrophies directly result in this compulsive behaviour as the regions, the orbitofrontal cortex, the insular cortex, and the striatum, that make up the satiety circuit are atrophied away in patients with FTD [2][4][6].

Neural Correlates of Disinhibition
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Voxel-based morphometric techniques identifying reduction in grey matter in the
nucleus accumbuns, the amygdala, and the hippocampus (Zamboni et al, 2008).

Many case studies have been published which provide an insight into rare forms of compulsions that may exist in individuals with FTD. One such compulsive behaviour that was reported in a woman with FTD was gambling [14]. A study was conducted to access her performance on the Iowa Gambling Task, a task that is designed to detect compulsive behaviour, in which it was identified that that she engaged in significantly greater risk-taking behaviour than healthy controls [14]. When considering a larger group of FTD patients, similar risk-taking compulsive gambling behavioural patterns were recognized [14]. In another case study, two patients had compulsive urination symptoms, in which the patients would urinate every 5-10 minutes [15]. This compulsive behaviour was not a result of urinary tract infection or other urinary tract dysfunction symptoms. In addition, other compulsions were development with the progression of FTD [15].

The loss of grey matter in the frontal and temporal cortices is directly correlated to this symptom manifestation. Voxel-based morphometric techniques were employed to identify that this inability to inhibit compulsions is correlated with atrophies in the right nucleus accumbus, part of the basal ganglia structures, right superior temporal sulcus and the right medial temporal limbic regions, such as the hippocampus and amygdala[16].

Stereotypical Movement

Stereotypical movements, such as frequent rubbing behaviour or self-injuring actions, are commonly seen in individuals suffering from autism [17]. However, these characteristic movements are also present in individuals with FTD[17]. In comparison to other more common form of dementia such as AD, FTD patients are more likely to exhibit stereotypical behaviour [17]. Additionally, these movements are correlated with the presence of some form of compulsive behaviour, suggesting that the underlying neural cause may be similar [16][17].

Primary Progressive Aphasia

Atrophied Brain Regions That Result in PPA
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Voxel-based Morphometric techniques used to show the degeneration of brain structures
that result in the different PPA variants (Wilson et al., 2012).

Primary Progressive Aphasia (PPA) is commonly classified into two subgroups, the semantic variant and the nonfluent variant [18]. Patients with FTD may have either of these variant forms of PPA, or they may not present with this condition at all. Nonfluent PPA is characterized by the lack of use of grammatical words and morphemes in speech [19]. Nonfluent PPA is also associated with the production of fewer words per minute during speech tasks [18]. On the other hand semantic PPA is characterized by fluent speech with the inclusion of word finding pauses [19][20]. Patients with semantic PPA have none to mild impairments in proper syntax production and these impairments are greater with the progression of the FTD, however, these patients experience much lower difficulty than Nonfluent PPA patients with proper syntax production [19]. In addition, semantic PPA patients may also have impairments with comprehension of single words [19]. Patients with either form of PPA will experience greater difficulty with engaging in tasks that require verb acquisition [20]. The difference between semantic PPA and nonfluent PPA is that patients with the latter variant will have greater impairment in tasks that correct grammatical form, while patients with the former variant will have greater impairments in tasks which require association of new words with pictures [20].

The difference in the two forms of PPA can be visualized with brain imaging techniques, as both variants are a result of atrophies in different regions of the brain [21]. Left inferior frontal and insular atrophied regions are largely associated with nonfluent PPA, while semantic PPA is associated with anterior temporal lobe atrophies [21]. As previously mentioned, these regions waste away in patients with FTD and as a result, these patients are extremely likely to experience one of these forms of PPA.

Social Impairments

Theory of Mind

Theory of Mind Task
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A ToM task in which participants are evaluation on their
ability to judge preference by asking them question such as:
"which cartoon the central facelikes the most?" and
"which cartoon is the face looking at?" (Snowden et al., 2003).

Theory of mind (ToM) is a theory that attempts to explain how an individual understands their own mental states, as well as the mental states of others [22]. Neuroimaging studies suggest that anterior regions of the medial frontal cortex are primarily active when doing ToM tasks [22]. Patients with FTD are known to have atrophies in this region which suggests that their performance in ToM tasks would be severely impaired [22]. For instance, when FTD patients are given a task in which they have to interpret mental states of cartoons, they experience difficulty completing the task as they are unable to attribute the mental states of others [23].

Social dilemmas can be a useful tool when accessing social cognitive abilities in FTD patients [24]. Social dilemma, whether personal or impersonal, requires one to understand one’s own mental states or other’s mental states before arriving at a solution [24]. When the footbridge dilemma task is administered to patients with FTD, those would say “yes” to killing an innocent bystander to save the lives of 5 people who would be run over by a train, has impairments in affective ToM [24]. Thus, those individual who find it immoral to kill the innocent bystander will have a better concept of the ToM [24].

Antisocial Behaviour and Acquired Sociopathy

Antisocial behaviour violates social norms, creating an uncomfortable environment for other individuals in the group or society [25]. The classification of antisocial behaviours includes behaviours such as shoplifting, indecent exposure, assault, traffic violations, unsolicited sexual acts or hit and run driving [25]. Antisocial behaviour is the hallmark feature of sociopathy [25]. When studying patients with FTD it is commonly identified that they acquire sociopathic tendencies with the progression of the dementia [25]. In comparison to patients with AD, FTD patients are more likely to engage in sociopathic behaviour and research suggests that this is highly correlated with frontal and temporal lobe atrophies [25]. This is a not a typical case of sociopathy as FTD patients understand that they have committed a wrongful action and feel remorseful, however, they do not take active measures to rectify the mistake or show concern for the consequences [25]. In interviews with FTD patients, it is commonly seen that they will admit to having no or limited control in preventing those actions; they felt a compulsion to perform the antisocial behaviour [25]. As previously mentioned, these compulsive actions are in all probability due to the atrophies in the frontal and temporal regions that, in normal conditions, functions to inhibit such compulsive or involuntary actions[16].

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