Frontotemporal Dementia was first described over 100 years ago by Arnold Pick and is often referred to as Pick’s disease. It is a cause of dementia which is in some ways similar to Alzheimer’s disease involving a progressive decline in a person’s mental powers over a number of years. Both are what we call neurodegenerative disorders but because different regions of the brain are affected the symptom profile in FTD and Alzheimer’s disease are distinct, at least in the early stages.
General information on FTD
Frontotemporal dementia, sometimes called frontotemporal lobar degeneration, was first described 100 years ago by Arnold Pick and was previously referred to as Pick’s disease. It is the second most common degenerative disease causing dementia in younger adults. The age of onset is typically in the 50s or 60s but can be as young as 30.
Damage to brain cells is more localised than in Alzheimer’s disease, and begins in the frontal and/or temporal lobe. In FTD the clinical presentation varies, depending on whether the frontal or temporal lobe is affected first. When the initial pathology affects the frontal lobes, the main changes are in personality and behaviour (Behavioural-variant FTD). Individuals with predominant temporal lobe involvement present with loss of language skills (Progressive Non-fluent Aphasia, Semantic Dementia) known as progressive aphasia (aphasia is the loss of the ability to produce or understand language).
The pathology of FTD is much more complex and variable than the pathology of Alzheimer’s disease. Instead of the ‘plaques and tangles’ which characterise Alzheimer’s disease, the brains of people with FTD brains show a severe loss of brain cells (neurons). In some individuals, the tau protein, which is also involved in Alzheimer’s disease, collects in neurons known as ‘Pick bodies’. Asmall proportion of people with tau accumulations have a mutation of the tau gene on chromosome 17. More commonly, the brains of people with FTD shows an accumulation of another cell protein – ubiquitin. Ubiquitin is involved in clearing waste products from brain cells but for reasons that are currently unknown, this protein builds up in some people with FTD. Very recent research has suggested that the accumulation of ubiquitin is attached to another protein (called TDP-43) which has a fundamental role in cell nuclei. Again, a small proportion of people with ubiquitin accumulation have a genetic mutation, this time of the progranulin gene which is also located on chromosome 17.
Overview of brain structure and function in FTD
Topography of the brain
The brain is made of two halves, the “hemispheres”, which are connected by a thick bundle of nerve fibres. The hemispheres can be divided into four main regions or lobes. The diagram below (Click picture to enlarge) shows the left hemisphere with the lobes highlighted in different colours: frontal (blue), temporal (green), parietal (yellow) and occipital (pink). Another important brain structure, the hippocampus, is buried within the temporal lobe and is not visible in this diagram. The hippocampus plays a central role in the formation of new memories.
Organisation of the brain
Each lobe is composed of an outer layer (“the grey matter”) and an inner layer (“the white matter”). The grey matter is where the nerve cells, or neurons, reside. The neurons are the source of information within the brain. The neurons are what allows us to think, reason, learn and feel. In contrast, the white matter consists of connecting fibres. These fibres transmit information among neurons within or across different brain regions.
Functions of the brain
Each lobe of the brain supports one or several thinking abilities, such as memory, language or emotion processing. The function(s) of each lobe are summarised in the diagram. In recent years, functional neuroimaging (e.g., PET or fMRI) has revealed that a particular function commonly involves multiple brain regions. In other words, similar to the close structural connections that exist across different brain regions and between the hemispheres, close functional relations across regions are also present within the brain.
Brain changes with dementia
In the event of dementia, diseases affecting the brain such as frontotemporal dementia and Alzheimer’s disease, various pathological processes take place as the disease unfolds. These changes, which can only be seen under the microscope, include loss of nerve cells and abnormal accumulation of protein in and around the cells. The kind(s) and severity of changes in the brain, as well as the location in which they occur, is specific for each dementia type.
In frontotemporal dementia, as the name suggests, pathology may be present in the frontal lobes, the temporal lobes or both. The regions that are most vulnerable to the disease are shown in dark in the diagram above. As the disease progresses, these brain regions show shrinkage, which is noticeable on brain imaging.
Deficits in frontotemporal dementia
Deficits associated with frontotemporal dementia are varied and depend on the location and severity of pathology in the brain. Most common deficits are changes in behaviour and personality, difficulty relating to other people and difficulty organising day‐to‐day activities. In these patients, the underlying brain changes affect predominantly the frontal lobes (Behavioural- variant FTD). In contrast, other patients show change in language proficiency, either in the form of a difficulty understanding the meaning of words (Semantic Dementia), or a difficulty using the correct words (Progressive Non-fluent Aphasia) . This may be accompanied by a difficulty judging emotional state in self and others accurately. In these patients, the pathology is more pronounced in the anterior portion of the temporal lobe, or in the region where the frontal lobe meets the parietal and temporal lobes. Over time, and as the disease progresses, pathology tends to become more diffuse. As a consequence, clinical presentations tend to merge and deficits become more pronounced.
Managing frontotemporal dementia
Not uncommonly, individuals with frontotemporal dementia show a limited awareness of their deficits in thinking and changes in behaviour and a reduced understanding of the impact of their condition on friends and families. This limited insight may create significant challenges for carers. Although each situation is unique, a number of simple guidelines may be helpful. First, carers need to recognise that behavioural changes are the result of changes in the brain. In most instances, the person is not being difficult intentionally. As such, direct confrontation to change a difficult or inappropriate behaviour is unlikely to be successful. You are more likely to succeed by changing the environment, for example by redirecting attention or removing what triggered the behaviour, than by trying to change the person.
In individuals where language deficits are the most prominent symptoms, difficulty understanding others or being understood by others may result in frustration. Simple, rather than complex, commands or instructions and the use of simple words are likely to improve comprehension. Use of visual supports, such as drawings or photos, may also be helpful in situations where verbal expression is disrupted.
In the frontal or behavioural variant of frontotemporal dementia, the person’s mood and behaviour may become fixed and difficult to change, making individuals appear selfish and unfeeling. A loss of empathy and emotional warmth is very common. In contrast to Alzheimer’s disease, recent memory is typically preserved.
Apathy or lack of motivation is very common, leading people with FTD to abandon hobbies and avoid social contact. Others lose normal inhibitions and start talking to strangers or exhibiting embarrassing behaviour in public.
Difficulty in reasoning, judgement, organisation and planning is frequent, along with a reduction in spontaneous conversation. Changes in eating patterns are very common often with a craving for sweet food, a tendency to overeat and a restriction in food preferences.
A decline in self-care and a reduction in the ability to perform activities of daily living is another early feature. As the disease progresses, the person may become ‘obsessional’, repeating patterns of movement and behaviours like handwringing or echoing back whatever is said.
In patients with the temporal lobe form of Frontotemporal Dementia, the initial symptom is usually a decline in language abilities. The left temporal lobe is critical for the fluent production of words and especially for assigning meaning to words. Because the language disorder associated with temporal lobe pathology reflects a breakdown in the meaning (or semantic) system underlying language, we prefer the term semantic dementia which conveys the core deficit and progressive nature of the disorder.
Patients typically complain of a “loss of memory for words” involving, at first, less common words and particularly the names of peoples’. As the disease progresses impairment of word comprehension is noticeable which again affects less common words. Reading and spelling are also typically affected, although numerical abilities can be remarkably well spared.
If the right temporal lobe is involved then patients (or carers) often notice problems recognising previously familiar people. It is not uncommon for patients to talk to people as if they were strangers only to discover later that were old friends.
Day-to-day memory is relatively spared but may appear poor due to difficulty with expression. In later stages, the disease spreads to the frontal lobes so that many of the features listed above, especially the changes in emotional responses, empathy and food preference. We have noticed that many patients with semantic dementia are extremely good at puzzles, bingo and jigsaws, and retain sporting abilities such as bowls or golf until very late in their illness.
Skills associated with posterior brain regions such as navigation, route finding and eye-hand coordination are spared at least until very late in the disease.
Progressive Non-fluent Aphasia
Progressive non-fluent aphasia (PNFA) is the least common form of Frontotemporal Dementia and affects the ability to speak fluently. Patients present with difficulty communicating due to slow and laboured production of words often with distortion of speech and a tendency to produce the wrong word.
Some patients have slurring of speech whereas others are able to articulate words but produce frequent near misses (e.g. they say “silter” for “sister”). Understanding of word meaning is preserved, but patients with PNFA have problems comprehending sentences and following conversations, especially if there are a number of speakers. Using the telephone and communicating with groups of people is particularly difficult.
Spelling is frequently impaired from an early stage and some patients develop difficulties reading (so called dyslexia). Subtle deficits in problem solving, mental flexibility and decision making are often present from an early stage. Changes in behaviour are uncommon in the early stages but do occur later.
Some people develop clumsiness of handuse, known as apraxia. In later stages, the disease spreads to the frontal lobes, so that many of the features described above, especially the changes in emotional responses and empathy occur. There is considerable overlap between progressive nonfluent aphasia and corticobasal degeneration (see section on Overlap with Corticobasal Degeneration).
How is the diagnosis established?
Consulting a doctor to obtain a diagnosis at an early stage is critical. A complete medical and psychological assessment may identify a treatable condition. A number of conditions exist that produce symptoms similar to dementia. These include vitamin and hormone deficiencies, depression, overmedication, infections and brain tumours. If the symptoms are caused by dementia, an early diagnosis will mean early access to support, information, and medication.
It is important that anyone with suspected dementia has a thorough assessment by a neurologist, geriatrician or psychiatrist with a special interest in dementia to establish the diagnosis. Another option is to attend a memory clinic. A referral can be obtained from a general practitioner. A typical work-up is likely to include the following:
Unlike other neurodegenerative conditions, people with FTD may have one of a number different underlying cellular brain changes. These various cellular changes currently can not be distinguished during life, and instead, a definitive pathological diagnosis is achieved by close examination of cells after brain autopsy.
Both neurons and their supporting cells (glia) are affected in FTD. Along with neuron degeneration, various proteins have been found to accumulate within these cells that can be identified under the microscope (see pictures). Cellular studies of the brain have shown that there are two types of protein which accumulate in neurons in FTD; “tau” and “Tar DNA binding protein 43” (TDP-43). The latter was only recently discovered in 2006, as is present in the majority of cases.
Future treatments will be targeted at halting, or altering the course of these kinds of pathological cellular changes occurring in FTD. We are using the precious resources of the brain donor programme, to work on a better understanding how different cellular changes relate to measurable clinical factors such as symptoms, brain imaging and progression of FTD over time.
The Genetics of Frontotemporal Dementia
Genes are the building blocks of cells, which provides information to enable our bodies to function properly. When one or a number of these genes are abnormal it can lead to the development of diseases such as frontotemporal dementia (FTD). These abnormal genes can be passed down through generations and can affect both males and females.
Genetics is a term that relates to the study of genes and their role in inheritance. When 1 or more close family members have a history of young onset dementia or a related disease (such as Motor neuron Disease), this is known as familial disease and indicates that the disease was passed down through the family line. In FTD, a familial pattern of inheritance has been determined in approximately 15% to 20% of patients. Where there is only a weak indication of family history (such as an elderly relative with dementia), or no other known relatives affected, the presentation of illness is classed as sporadic.
Motor Neurone Disease (MND) is closely related to FTD, and family members of patients with FTD can develop features of MND, FTD or a combination of FTD and MND. This association has been recognised for a number of years but only recently has the genetic evidence for the overlap come to light. In 2011 a gene abnormality on chromosome 9, known as the C9ORF72 genetic mutation, was described. This mutation explains at least one-third of cases of familial FTD as well as a small proportion of sporadic FTD. The presence of this mutation in a small proportion of apparently sporadic cases has important implications for genetic testing, as we can no longer rely totally on family history to determine which patients are at risk of this mutation. Inheritance of this mutation remains to be fully elucidated so although a patient may not have a known family history, we may still consider testing for this mutation.
Two other genetic causes of familial FTD are the Progranulin and Tau mutations (both on chromosome 17) and together with C9ORF72 account for the majority of familial FTD. By performing tests on a person’s DNA (commonly through a blood or saliva sample), it is now possible to identify a mutation in most instances of familial FTD. Both the Progranulin and Tau mutations are Autosomal Dominant with a 50% risk of passing on the mutation to offspring. Major technological advances have been made in genetic screening processes and it seems likely that further genes will be discovered over the coming years as more of the human genome is mapped.
The study of genetics in FTD is valuable for both patients and researchers. Most of the FTD genes are Autosomal Dominant which means that the risk to offspring is 50%. Knowing the mutation status of each patient allows for better management of the illness and identifies potential health implications to both siblings and offspring of the affected person.
When we have a research finding of a genetic change or mutation, the centre has arrangements in place to ensure appropriate referral to a clinical genetics team to confirm the gene mutation and to allow patients and their families to access genetic counselling and predictive testing for those at risk. Genetic counselling is essential to ensure patients and their family members are fully informed regarding risk and implications of finding a mutation, particularly in those who do not express any symptoms of FTD illness.From a research perspective the study of genetics is vital to help us understand the factors involved in disease development, expression and progression. By further understanding these disease mechanisms it allows accurate information to be made available to mutation carriers and their relatives, and ultimately aids the advancement towards effective drug development.
Is treatment possible?
The risk factors for Frontotemporal Dementia are less well understood than for Alzheimer’s disease.
Some people with Frontotemporal Dementia can live for a very long period of time, while others have a more rapid progression.
Motor problems are common with increasing immobility and swallowing problems in the late stages.
A small proportion of patients develop full blown features of motor neurone disease or MND (see section on Overlap with Motor Neurone Disease).
The average survival from diagnosis is in the order of 5-10 years, but depends upon a number of clinical variables. Some patients live for another 20 years, but this is exceptional.
Overlap with Motor Neurone Disease (MND)
Motor Neurone Disease (MND) and Frontotemporal Dementia (FTD) can overlap in their presenting symptoms, which makes it difficult to distinguish the two diseases from each other in the early stages. The exact degree of overlap is, however, not yet known.
Below we outline in more detail the cognitive and behavioural deficits in Motor Neurone Disease and the overlap with FTD.
Cognition and Behaviour in Motor Neurone Disease
What are the features of Motor Neurone Disease?
Motor neurone disease (MND) includes a group of neurological conditions characterised by progressive loss of motor neurones, which have an essential role in voluntary movement. There are 2 types of motor neurones present in the brain and spinal cord:
– Upper motor neurones: in the motor cortex (brain)
– Lower motor neurones: in the brainstem and anterior horn of spinal cord.
The most frequent form of presentation of MND is Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. This disease affects the upper and lower motor neurone. It is more frequent in males than females (2:1) and the mean age of onset is the sixth decade. MND may also present with isolated speech or swallowing difficulty known as bulbar palsy. Clinically, MND has a wide range of presentation, including:
What causes Motor Neurone Disease?
Advances in genetic and pathological studies have increased our understanding of MND, although the exact cause of this disease remains unknown yet, except in a minority of familial cases.
In around 10% of the cases MND is a familial disease and a number of genes have been identified, the commonest is mutation of the gene for Cu/Zn superoxide dismutase (SOD1). People with this mutation appear not to have cognitive impairment. Another recently identified mutation involves the gene coding for the TAR-DNA binding protein (TDP-43). This protein has an essential role in brain cells and accumulates to an abnormal extent in the motor neurones and other regions of the nervous system in both sporadic and familial cases with MND.
What are the Cognition and behavioural changes in MND?
The patterns of cognitive and behavioural changes in MND are variable across cases, and include:
Do the behavioural or motor features come first?
Either can occur first. Some patients with Frontotemporal Dementia, around 10-20%, develop frank Motor Neurone Disease. Such patients typically have rapidly evolving dementia and then develop bulbar (speech slurring or swallowing problems) or limb symptoms usually within 2 years of onset. This combination of features makes management very difficult.
The proportion of patients with classic MND who develop Frontotemporal Dementia is less clear but might be around 15%. A higher proportion has more subtle changes in behaviour or cognition.
The importance of recognising cognition and behaviour impairment is their potential impact on daily life and carer burden. Further work in this area could, we hope, identify strategies to improve the quality of life of people with MND and their carers.
What is the prognosis?
The survival in MND is extremely variable, depending of age, form of presentation and medical complications such as respiratory problems. Different studies have reported a survival of approximately 3-5 years in the 50% of the cases, but in some cases is more than 10 years. The most serious and potentially life threatening complications of MND are problems swallowing and respiratory difficulties. Survival in uncomplicated Frontotemporal Dementia is similar but when MND and FTD co-occur is generally poorer than when they occur separately.
Overlap with Corticobasal Degeneration (CBD)
Corticobasal degeneration (CBD) is a progressive neurodegenerative disease closely related to frontotemporal dementia (FTD). CBD is associated with atrophy (shrinkage) of various regions of the brain, particularly the frontal lobes as well as more posterior regions. CBD was first recognised some 40 years ago as a cause of motor problems but has since been shown to produce symptoms identical to those seen in FTD.
This disease usually begins between the age of 50 and 70 with some of the following symptoms:
As the disease progresses, many patients with CBD develop prominent apathy, loss of empathy towards others, and poor decision making. Other patients develop features of Progressive Non-Fluent Aphasia (PNFA), characterised by difficulty speaking (due to poor articulation), slurring of words and grammatical errors. Comprehension is typically normal. Problems with writing and spelling are often a pronounced early feature. (See other fact sheets)
The majority of patients with CBD present with motor problems. In some patients, however, cognitive, emotional and/or language problems may be the first signs. It can sometimes be very difficult to separate CBD from Alzheimer’s disease and from Parkinson’s disease which can also present with coordination and speech problems.
No single test exists for CBD. It is diagnosed on the basis of clinical assessment, neuropsychological testing and brain imaging to detect the telltale pattern of brain atrophy. CBD has a slow progression over a number of years. No cure or treatment currently exists for this disease and its management requires the expertise of health practitioners, neuropsychologists, and speech and occupational therapists. It is, in general, not an inherited disorder.
In the brain, CBD causes a loss of brain cells (neurons) in the frontal and parietal lobes. When sections of the brain stained with special dyes, are looked under the microscope, CBD patients show an increase of a protein called ‘tau’. Tau is also one of the proteins implicated in the causation of FTD. The pathology of CBD is extremely similar to classic Pick’s disease with accumulations of ‘tau’ protein within neurons which look very similar to Picks bodies.
Overlap with progressive supranuclear palsy (PSP)
Progressive supranuclear palsy (PSP) is a progressive brain disorder closely related to frontotemporal dementia (FTD). PSP primarily causes changes in the brain similar to Parkinson’s disease, but also causes shrinkage (atrophy) of the frontal lobes similar to FTD. For this reason, patients with PSP show features similar to Parkinson’s disease and, in addition, have features in common with FTD.
PSP affects approximately 6 in 100,000 people, most commonly between the ages of 60 and 70 years and lasts 6 to 7 years on average.
The common signs in PSP are usually changes in mobility and posture, with slowness of movements. Falls (most often backwards) are also common and may be the first sign. On examination, a reduction of vertical eye movements, or “vertical gaze palsy” is observed—and is the sign which gives this disorder its name. Stiffness (rigidity) of the muscles, particularly in the neck and spine, is also commonly present.
Later, behavioural and cognitive symptoms such as apathy, problems with reasoning, problem solving and motivation commonly appear and can be very disabling. A reduction in conversation and huskiness or slurring of speech can also occur.
In the brain, PSP causes a loss of nerve cells (neurons) predominantly in the brain stem and the frontal lobes. When examined under the microscope, neurons show an increase in the protein “tau”. Tau is also one of the proteins implicated in the causation of FTD. In other words, tau represents a strong common link between PSP and FTD although the distribution differs between the two diseases.
No simple diagnostic test is currently available for PSP. PSP diagnosis is based on clinical assessment, neuropsychological testing, brain imaging and the exclusion of other neurological or neurodegenerative disorders.
No cure or treatment is currently available for PSP. Unfortunately, the response to drugs used to treat Parkinson’s disease is rather poor. The management of PSP requires the expertise of health practitioners, neuropsychologists, speech and occupational therapists. Unlike some forms of dementia, PSP is very rarely inherited.
Several PSP support groups exist. These groups improve awareness about PSP and to raise funding for new research. Their websites also provide information about PSP and forums for discussion. Links to these sites are listed below:
Dennis Frost was diagnosed with frontotemporal dementia at age 59. In honour of Frontotemporal Awareness Week, he has shared with us some of the impacts the diagnosis has had on his life. Here, he shares how the music of his youth holds even greater relevance to him now and offers him a pathway to the past once again. It is well […]