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Last updated:
June 13, 2016
Years published: 2016
NORD gratefully acknowledges the Association for Frontotemporal Degeneration for assistance in the preparation of this report.
Summary
Frontotemporal degeneration is a group of varied disorders that are characterized by neurodegenerative changes that affect the brain. The clinical presentation of frontotemporal degeneration is diverse. Affected individuals can experience gradual changes in their behavior and personality, and may have difficulties in thinking and communicating effectively. The progression and the specific symptoms that develop can vary from one person to another. Generally, the clinical symptoms of these disorders can be broadly grouped into three categories which display changes in behavior, language and/or motor function. Frontotemporal degeneration is caused by progressive damage and loss of nerve cells in the frontal and temporal lobes of the brain. In most people, this is accompanied by a buildup of one or the other of two proteins, tau or TDP-43. In FTD these proteins are misfolded (misshapen) which leads to their inappropriate buildup within brain cells and so interfering with or disrupting the normal function of these cells. The FTD clinical subtypes can also be classified as ‘tauopathies’ or TDP43-opathies, depending on which misfolded protein accumulates in the brain. In about 10% of cases, a third protein, FUS, accumulates instead of tau or TDP43. The accumulation of tau protein or TDP-43 protein can also be observed in other neurological disorders.
Although once used more broadly, the term Pick’s disease (after Dr. Arnold Pick, who first described it in 1892) is now reserved for a specific subtype of frontotemporal degeneration associated with a kind of abnormal tau protein known as 3R tau. In Pick’s disease, the clumps of 3R tau are found in distinctive round, silver-staining inclusions known as Pick bodies.
Introduction
There are many different terms and names that have been used to describe frontotemporal degeneration (FTD), also referred to as frontotemporal dementia. These names can be very confusing. Frontotemporal lobar degeneration is a general term that describes a group of disorders based on their neuropathology that cause damage and dysfunction of the frontal and temporal lobes of the brain. This is reflected in the spectrum of clinical subtypes listed above, which encompass behavioral, language and/or motor predominant decline in the ability to function normally. A clinical subtype refers to the symptoms that occur earliest and most prominently in a person.
Frontotemporal degeneration clinical subtypes are organized according to:
1.progressive behavior/personality decline – behavioral variant FTD (bvFTD), Pick’s disease
2.progressive language decline – primary progressive aphasia (PPA), which comes in semantic, nonfluent-agrammatic, or logopenic variants (svPPA, naPPA, lvPPA)
3.progressive motor function decline – progressive supranuclear palsy (PSP), corticobasal syndrome, FTD with amyotrophic lateral sclerosis (FTD-ALS), FTD with motor neuron disease (FTD-MND)
A person is classified into one of these three categories based on the signs and symptoms that first appear and appear most prominently. As the disorder progresses, individuals may begin to show signs and symptoms of other classifications, and their classifications may change.
It is difficult to predict the course of frontotemporal degeneration and the rate of disease progression can vary from one person to another. Ultimately, people with frontotemporal degeneration require fulltime caregiving and supervision.
Behavioral variant frontotemporal degeneration (bvFTD)
The behavioral variant is the most common subtype and accounts for about 50% of people with frontotemporal degeneration. This subtype is characterized by changes in personality and behavior. Specific, early changes in behavior include disinhibition, loss of insight, apathy, loss of empathy, hyperorality, and dietary changes, and compulsive behaviors. Some individuals have a decreased sensitivity to pain. Memory is usually intact, but some individuals can display some memory loss. More commonly, people exhibit deficits in executive function such as decision making, good judgment, organizational skills, and attention.
Disinhibition is defined as a loss or lack of restraint toward socially accepted norms in behavior. For example, people displaying disinhibition may engage in inappropriate or impulsive behaviors like ignoring peoples’ personal space, touching or kissing strangers, making derogatory or offensive comments to people, reckless spending of money, theft, or public urination.
Apathy is defined as a general indifference or lack of interest in life, including to things or activities that were once considered exciting or emotionally moving. Apathy may lead people to show no concern for personal relationships or social interaction, work, hobbies, or personal hygiene. They may stare out a window for hours. Apathy is often mistaken for depression. Affected individuals also show little concern or sympathy for family members or friends and little responsiveness toward the social needs of family or friends as well.
Affected individuals may show dramatic changes in their diet and eating habits including binge eating, eating or drinking more sweets and alcohol than normal, and putting excessive amounts of food into their mouths. Some individuals crave and eat lots of carbohydrates. Sometimes, they may attempt to eat spoiled foods or inedible objects. The term hyperorality may be used to describe placing inappropriate objects into the mouth. Some people may increase tobacco use or begin to use tobacco for the first time in their lives.
Compulsive behaviors are best described as actions that a person consistently performs and repeats for no obvious reason (there is no reward and the person gets no pleasure from the act). Simple repetitive movements, continually repeating certain phrases or words, and complex ritualistic behaviors such as hoarding are examples of compulsive behaviors that can occur in individuals with behavioral variant frontotemporal degeneration.
Primary progressive aphasia (PPA)
Primary progressive aphasia is characterized by changes in the ability to speak, write, read and understand language. Primary progressive aphasia is broken down into two main forms – the semantic variant and the nonfluent agrammatic variant. There is also a third form called the logopenic variant. Affected individuals have a slow, progressive loss of language skills. Aphasia, which is described as difficulties in understanding or expressing language, is the most common initial language deficit. Problems with language and loss of the ability to communicate impact a person’s day-to-day activities and living.
Semantic Variant
The semantic variant of PPA is characterized by problems remembering the correct word or failing to understand individual words, this is particularly true for words that are not used often by the person. Affected individuals may be unable to remember the names of familiar people, places or everyday objects (anomia).
Some individuals experience surface dyslexia or dysgraphia. Individuals with surface dyslexia have difficulty understanding written words. Individuals with dysgraphia may have difficulty writing words as well as problems with handwriting. They may have difficulty with words with irregular spellings such as yacht or colonel. These words may be mispronounced or misspelled.
Non-fluent Agrammatic Variant
People with the non-fluent variant will have problems speaking with proper grammar (agrammatism). They may misuse words or leave out words such as words that connect nouns and words (e.g. to, from, the). They have difficulty finding the right word when speaking. Their speech may be stilted, which is described as slow, labored and hesitating. They often speak less than they used to. Affected individuals also have difficulty understanding complex sentences. Sometimes individuals with this variant can have difficulty writing certain words.
Logopenic Variant
People with the logopenic variant have difficulties finding the right words when speaking. They will pause or hesitate frequently during speech because they must think to come up with the right word. Consequently, they have a slow rate of speech. They may have difficulties repeating short phrases or short sequences of numbers. They can understand words and sentences, even complex ones, early on but as the disease progresses may struggle to understand such information. Eventually, short term memory is affected and individuals may repeat themselves in conversation. Reading and writing ability is spared initially, but eventually problems develop with these forms of communication as well. Difficulty swallowing develops late in the course of the disease.
Frontotemporal degeneration and amyotrophic lateral sclerosis (ALS)
Frontotemporal degeneration and the motor neuron disease ALS can occur in the same individual. ALS also known as Lou Gehrig’s disease in the US, is sometimes used interchangeably with the term motor neuron disease. Motor neuron disease is also used as a general term for a group of progressive neurological disorders in which there is a loss of nerve cells called motor neurons. These cells control voluntary muscle activity such as speaking, walking, and talking. Individuals may exhibit weakness, muscle loss (atrophy), tiny involuntary muscle twitches (fasciculation), difficulty speaking (dysarthria) and difficult swallowing (dysphagia). Involuntary control of muscle activity such as breathing and increased tightness and stiffness of muscles (spasticity) is also affected. When people have symptoms of frontotemporal degeneration and motor neuron disease, they may be described as having FTD associated with motor neuron disease (FTD-MND), or FTD associated with amyotrophic lateral sclerosis (FTD-ALS).
Progressive supranuclear palsy, corticobasal syndrome
Corticobasal syndrome and progressive supranuclear palsy are rare movement disorders that are associated with the broad group of FTLD disorders. While a decline in motor function may be the earliest and most prominent clinical feature, these disorders can also demonstrate loss of language and behavioral or cognitive skills. Progressive supranuclear palsy causes difficulties with balance and walking resulting in frequent falls. Problems with eye movements are also seen particularly an inability to look down. Changes in behavior can also occur with time. Persons with corticobasal syndrome may have an inability to control movement, particularly with their hands and arms. Movement deficits may often appear only on one side, but eventually both sides are affected and difficulties with language can also occur. NORD has individual reports on progressive supranuclear palsy and corticobasal degeneration. For more information, choose the specific disorder name as your search term in the Rare Disease Database.
Some affected individuals exhibit early-onset parkinsonism, which is the development of symptoms associated with Parkinson disease including abnormal slowness of movement (bradykinesia), resting tremor, and an inability to remain in a stable or balanced position (postural instability). Parkinsonism most often occurs in behavioral variant frontotemporal degeneration.
Frontotemporal degeneration is caused by damage to the frontal and temporal lobes of the brain. The frontal lobe is the largest lobe in the brain and is located right behind the forehead. The frontal lobe is critical for thinking, planning, decision making and other higher mental processes. The frontal lobe helps people to manage and control emotional responses. The temporal lobes are located below and to both sides of the frontal lobe. The temporal lobes are believed to be involved in semantic memory, or our knowledge of objects, people, words and faces. They also play a role in language and emotion.
In individuals with frontotemporal degeneration there is an abnormal buildup of altered brain proteins in the frontal and temporal lobes of the brain. The two most common proteins involved are the tau protein and the transactive response DNA binding protein-43 (TDP-43). These proteins are normally found in the brain. Their specific functions are complex and not fully understood. However, these proteins are critical to the proper health and function of nerve cells (neurons). In individuals with frontotemporal degeneration these proteins are misfolded (misshapen); as a result, they clump together. As these protein clumps, or aggregates, build up in the brain, they interfere with or disrupt the normal functioning of nerve cells, which ultimately die. Nerve cell death within the frontal and temporal lobes causes these areas of the brain shrink (atrophy).
These clumps of misfolded proteins may be referred to as “bodies” or “inclusions”. So the terms, tau bodies or tau inclusions, refer to nerve cells that contain these clumps of misfolded proteins. These inclusions may have distinctive features even when the same protein is involved. For examples, Pick’s disease refers to distinctive, round, silver-staining inclusions called Pick’s bodies. Most inclusions associated with frontotemporal degeneration contain either variations of tau protein or TDP-43.
In about 60% of people, they are often the first person is their family to be affected by frontotemporal degeneration. These people are classified as having a sporadic or nonfamilial form of the disorder. Researchers do not know why these people have developed frontotemporal degeneration. Their family members do not appear to be at an increased risk of developing the disorder.
However, there is a strong genetic component to frontotemporal degeneration. In about 40% percent of people there is a history of neurodegeneration or psychiatric illness in the family. In some of these people, the cause of the disorder is unknown. Researchers do not know whether there is an altered gene in these families, but the disorder occurs with more frequency than it otherwise would by chance. One theory is that, in these families, frontotemporal degeneration occurs because of the interaction of multiple factors (multifactorial cause). This might mean that there is a gene or genes that cause people to be more likely (predisposed) to develop a disorder, but the disorder will not develop unless these gene(s) are triggered or “activated” under certain circumstances such as particular environmental factors. However, despite research, no evidence has been found linking any potential environmental factor to the development of frontotemporal degeneration. There is no known risk factor for the disorder other than a family history of frontotemporal degeneration or a similar disorder.
In about 10-25% of people diagnosed with FTD, an altered gene has been identified. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When an alteration of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The major genes that have been linked to frontotemporal degeneration include the MAPT, GRN, and C9ORF72 genes. The MAPT gene produces the brain protein known as tau. The GRN gene produces the brain protein known as progranulin, which is important for optimal functioning of the protein TDP-43. The C9ORF72 gene also produces a protein that is found in nerve cells although its role in not well understood. These three genes account for the majority of people with inherited frontotemporal degeneration. In rare instances, additional genes have been identified as causing frontotemporal degeneration including the VCP, TARDBP, FUS, CHMP2B and TBK1 genes.
The altered genes that cause frontotemporal degeneration are usually inherited in an autosomal dominant manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The altered gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Frontotemporal degeneration is the second most common form of dementia in people under the age of 65 after Alzheimer’s disease. The mean age of onset is usually given as the late 50s, with an age range of 20-80. However, onset before 40 or after 75 is less common. Frontotemporal degeneration is estimated to affect about 50,000-60,000 people in the United States. Researchers believe that many people go undiagnosed or misdiagnosed with another condition. This makes it difficult to determine the true frequency of frontotemporal degeneration in the general population.
A diagnosis of frontotemporal degeneration is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A neuropsychological evaluation involves an interview and certain tests, often pencil and paper type tests. This evaluation will allow a physician to assess behavior, language, memory, visual-spatial and other cognitive functions. Early in the course of the disorder, people with the behavioral variant of frontotemporal degeneration tend to score very well on neuropsychological testing.
Clinical Testing and Workup
Specialized imaging techniques may include magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. In SPECT, physicians use a radioactive substance and a special camera to create 3-D images of internal areas of the body, including the brain. SPECT can reveal characteristic changes such as reduced blood flow in certain areas of the brain. In PET scans of the brain, a radioactive atom is attached to glucose (blood sugar). This allows physicians to see the chemical activity (metabolism) in the brain. Individuals with frontotemporal degeneration exhibit reduced chemical activity (hypometabolism) in the frontal and temporal areas of the brain, a finding that can distinguish the disorder from Alzheimer disease. More recently, an amyloid PET tracer has been developed that can bind to misfolded amyloid proteins accumulated in the brain. This can support or rule out a diagnosis of Alzheimer’s disease which can then be ruled out during the diagnostic process for FTD. A spinal tap (lumbar puncture) can be performed to measure amyloid and tau proteins. This test can also support or decrease the likelihood of an Alzheimer’s diagnosis
Molecular genetic testing can confirm a diagnosis of frontotemporal degeneration in certain people. Molecular genetic testing can detect mutations in the MAPT, GRN or C9ORF72 genes known to cause FTD, but testing is currently available only as a diagnostic service at specialized laboratories or as part of a clinical research study. Genetic testing should only be performed after genetic counseling.
Treatment
There are no approved treatments for frontotemporal degeneration. Treatment is directed toward the specific clinical symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychologists, psychiatrists, neuropsychologists, speech pathologists, occupational and physical therapists, and other healthcare professionals may need to systematically and comprehensively plan an affected person’s treatment as the disease progresses. Genetic counseling is of benefit when frontotemporal degeneration is believed to run in families or an underlying genetic cause is known. Psychosocial support for the entire family is essential as well.
Frontotemporal degeneration slowly worsens over time. However, the rate of this decline and the specific symptoms that develop vary among affected individuals. Treatments are aimed at managing the symptoms. Treatments can include medications for behavioral changes, medications for memory loss, speech therapy, physical therapy, lifestyle and environmental changes, and other therapies.
Some of the behavioral symptoms associated with frontotemporal degeneration can be treated with antidepressants such as selective serotonin reuptake inhibitors (SSRIs), although these are not successful in all cases. Sometimes doctors recommend low doses of atypical antipsychotics to treat the associated behavioral problems. Antipsychotic drugs must be used with caution, particularly in elderly individuals, because of the risk of serious complications including stroke, heart issues and increased mortality.
Individuals with speech problems or language deficits may benefit from speech therapy. There are alternative communication techniques that can be taught to individuals who experience difficulties with expressing language. Physical and occupational therapy and an exercise program may be of benefit to some people. Behavioral modification techniques are sometimes recommended.
Individuals with frontotemporal degeneration eventually require managed and supportive care. Planning must be made for many issues including handling financial matters, driving, and managing behavioral problems. Various lifestyle changes and changes in a person’s living environment can be beneficial. The scope of these interventions are not covered in this report, but the organizations listed in the Resources section can provide detailed information on supportive and coordinated management of individuals with frontotemporal degeneration.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Growdon JH. Frontotemporal Dementia. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:533-534.
JOURNAL ARTICLES
Ahmed RM, Irish M, Henning E, et al. Assessment of eating behavior disturbance and associated neural networks in frontotemporal dementia. JAMA Neurol. 2016;73:282-290. https://www.ncbi.nlm.nih.gov/pubmed/26810632
Burrell JR, Halliday GM, Krill JJ, et al. The frontotemporal dementia-motor neuron disease continuum. Lancet. 2016;[Epub ahead of print. https://www.ncbi.nlm.nih.gov/pubmed/26987909
Ferrari R, Forabosco P, Vandrovcova J, et al. Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis. Mol Neurodegener. 2016;11:21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765225/
Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015;386:1672-1682. https://www.ncbi.nlm.nih.gov/pubmed/26595641
Benussi A, Padovani A, Borroni B. Phenotypic heterogeneity of monogenic frontotemporal dementia. Front Aging Neurosci. 2015;7:171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4555036/
Gijselinck I, van Mossevelde S, van der Zee J, et al. Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. Neurology. 2015;85:2116-2125. https://www.ncbi.nlm.nih.gov/pubmed/26581300
Ferrari R, Hernandez DG, Nalls MA, et al. Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol. 2014;13:686-699. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112126/
Mesulam M-M, Rogalski E, Wieneke C, Hurley RS, Geula C, Bigio E, Thompson C. Primary progressive aphasia and the evolving neurology of the language network. Nature Reviews Neurology. 2014;10:554-569. https://www.ncbi.nlm.nih.gov/pubmed/25179257
Pressman P, Miller BL. Diagnosis and management of behavioral variant frontotemporal dementia. Biol Psychiatry. 2014;75:574-581. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194080/
Boxer AL, Gold M, Huey E, et al. Frontotemporal dementia, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development. Alzheimers Dement. 2013;9:176-188. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542408/
Funayama M, Nakagawa Y, Yamaya Y, et al. Progression of logopenic variant primary progressive aphasia to apraxia and semantic memory deficits. BMC Neurol. 2013;13:158. https://www.ncbi.nlm.nih.gov/pubmed/24176108
Knopman DS, Roberts RO. Estimating the number of persons with frontotemporal lobar degeneration in the US population. J Mol Neurosci. 2011;45:330-335. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208074/
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioral variant of frontotemporal dementia. Brain. 2011;134:2456-2477. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170532/
Lillo P, Hodges JR. Frontotemporal dementia and motor neurone disease: overlapping clinic-pathological disorders. J Clin Neurosci. 2009;16:1131-1135. https://www.ncbi.nlm.nih.gov/pubmed/19556136
INTERNET
Lee SE, Miller BL. Frontotemporal dementia: Clinical feature and diagnosis. UpToDate, Inc. Jan 6, 2016. Available at: https://www.uptodate.com/contents/frontotemporal-dementia-clinical-features-and-diagnosis Accessed June 13, 2016.
Lee SE, Miller BL. Frontotemporal dementia: Epidemiology, pathology, and pathogenesis. UpToDate, Inc. Mar 21, 2016. Available at: https://www.uptodate.com/contents/frontotemporal-dementia-epidemiology-pathology-and-pathogenesis Accessed June 13, 2016.
Lee SE, Miller BL. Frontotemporal dementia: Treatment. UpToDate, Inc. May 29, 2015. Available at: https://www.uptodate.com/contents/frontotemporal-dementia-treatment Accessed June 13, 2016.
National Institute on Aging. The Basics on Frontotemporal Disorders. January 22, 2015. Available at: https://www.nia.nih.gov/alzheimers/publication/frontotemporal-disorders/basics-frontotemporal-disorders Page Accessed June 13, 2016.
National Institute on Aging. Frontotemporal Disorders: Information for Patients, Families and Caregivers. January 22, 2015. Available at: https://www.nia.nih.gov/alzheimers/publication/frontotemporal-disorders/types-frontotemporal-disorders Accessed June 13, 2016.
Mayo Clinic for Medical Education and Research. Frontotemporal Dementia. August 5, 2014. Available at: https://www.mayoclinic.org/diseases-conditions/frontotemporal-dementia/basics/definition/con-20023876 Accessed June 13, 2016
International PPA Connection (IMPPACT)- Resources and support for primary progressive aphasia www.ppaconnection.org
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