Wilson disease
Oct. 23, 2024
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Frontotemporal dementia (FTD) …
- Updated 05.23.2024
- Released 03.08.1996
- Expires For CME 05.23.2027
Frontotemporal dementia
Introduction
Overview
Frontotemporal degeneration has prevalence between 15 and 22 cases per 100,000 and incidence ranges from 2.7 to 4.1 cases per 100,000 (42). It is the second most common form of neurodegenerative dementia in younger people. The socioeconomic burden per patient exceeds that due to Alzheimer disease (15). Initial presentation can include insidious changes in a person’s personality and behavior or a slowly evolving aphasia syndrome. Parkinsonian and motor neuron symptoms may also occur, either initially or as the disease progresses. In this article, the author discusses advances in the field of frontotemporal dementia, including discoveries regarding the neuropathological and genetic causes of the disease, revisions in the diagnostic criteria for the clinical syndromes of behavioral variant frontotemporal dementia and primary progressive aphasia, current pharmacological and behavioral interventions, and emerging clinical trials.
Key points
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• Since 2011, revised diagnostic criteria have been published for the three clinical variants of frontotemporal dementia (FTD): behavioral variant frontotemporal dementia, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia. | |
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• Corticobasal syndrome, progressive supranuclear palsy, and motor neuron disease/amyotrophic lateral sclerosis exist within the frontotemporal dementia disease spectrum. | |
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• The most common genes and pathological proteins associated with frontotemporal dementia have been identified and are actively being pursued for potential disease-modifying therapies. |
Historical note and terminology
Over 100 years ago in 1892, Arnold Pick described the first case of a progressive dementia syndrome that involved atrophy of the frontal and temporal lobes (44). However, it was not until 1911 that Alois Alzheimer first described the histopathology in these cases, which he termed “Pick bodies” (01). In the 1920s, Onari and Spatz went on to establish the clinical-pathological relationship, which was subsequently given the name “Pick’s disease” (41). Over time, interest in the disease dwindled as it became apparent that many clinical cases of Pick disease did not display the typical histological signature of Pick cells and Pick bodies filled with tau protein on autopsy.
As neuroimaging techniques were developed and refined over the 1980s, frontotemporal atrophy was demonstrated with increasing frequency in vivo, and researchers once again began to take an interest in the disease. The first consensus document for diagnosis and classification of frontotemporal dementia was developed in 1994 through the collaboration of the Lund and Manchester groups (often referred to as the “Lund-Manchester” criteria for frontotemporal dementia) (07). These criteria were further refined in 1998, when Neary and colleagues published the “Consensus on Frontotemporal Lobar Degeneration,” which included diagnostic criteria for the three clinical variants of frontotemporal dementia (behavioral, progressive non-fluent aphasia, and semantic dementia) (37). These criteria laid the foundation for clinicians and researchers in the field and have greatly contributed to the proliferation of research on frontotemporal dementia in the past 20 years. The most recent diagnostic criteria for behavioral variant frontotemporal dementia were published in 2011 and are detailed below (46).
As alluded to above, the concept and nosology of frontotemporal dementia has undergone many revisions since it was first described. Pick disease (41), frontal lobe degeneration (06), dementia of the frontal lobe type (37), and frontotemporal dementia (07) have all been used to describe the disease. The term Pick disease is no longer synonymous with frontotemporal lobar degeneration because it does not include transactive response DNA-binding protein 43kDa (TDP-43) proteinopathy associated with FTLD. The term “Pick complex” has also been suggested to encompass all related clinical and pathological entities of frontotemporal dementia (25). At this time, frontotemporal dementia (FTD) is used to signify the clinical manifestation of the disease, whereas frontotemporal lobar degeneration (FTLD) is used to describe the disease on pathological examination.
Clinical manifestations
Presentation and course
Clinically, frontotemporal dementia is expressed as three variants: behavioral variant, nonfluent/agrammatic variant primary progressive aphasia, and semantic variant primary progressive aphasia (37). Consensus and nosology are consolidating around a fourth variant, the right temporal variant of frontotemporal dementia (55; 60). Each is characterized by slow, insidious changes in behavior and/or language. Many patients also go on to develop motor dysfunction.
(1) Behavioral variant frontotemporal dementia (bvFTD). The earliest signs of disease in behavioral variant frontotemporal dementia (bvFTD) are frequently subtle personality and behavioral changes that become increasingly pronounced. The six core clinical features include disinhibition, apathy, loss of empathy, compulsivity, hyperorality, and executive dysfunction (46). Childish behavior, rudeness, inappropriate sexual remarks or jokes, impatience, careless driving, excessive spending or hoarding of certain items, perseverative routines, compulsive roaming, insistence of certain foods or excessive food intake, neglect of personal hygiene, and disinterest in the immediate family are all common symptoms. The repetitive behaviors in frontotemporal dementia can take the form of compulsions, the absence of impulse control, stereotypy, hoarding, restrictive behaviors, and insistence on sameness (47). Moreover, these changes, at least initially, may stand in stark contrast to patients’ cognitive ability, which may remain intact for some time.
The diagnostic criteria for behavioral variant frontotemporal dementia were revised in 2011 and are called the FTD Criteria Consortium FTDC criteria (Table 1) (46). With these criteria, diagnosis of possible bvFTD is based solely on clinical presentation (three of six core criteria), whereas a diagnosis of probable bvFTD is based on a diagnosis of possible bvFTD with concomitant functional decline and evidence of frontal and/or temporal atrophy on neuroimaging. The diagnostic sensitivity and specificity of the FTDC criteria have been investigated via retrospective chart review of pathologically confirmed cases in two separate studies. In the first study, they found the FTDC criteria to have greater sensitivity to the diagnosis of bvFTD when compared to the previous (“Neary”) criteria (72% vs. 51%, respectively) (46).
Table 1. International Consensus Criteria for Behavioral Variant Frontotemporal Dementia (FTDC)
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l. Neurodegenerative disease | ||
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The following symptom must be present to meet criteria for bvFTD: | ||
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A. Shows progressive deterioration of behavior and/or cognition by observation or history (as provided by a knowledgeable informant). | ||
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II. Possible bvFTD | ||
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Three of the following behavioral/cognitive symptoms (A–F) must be present to meet criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single or rare events. | ||
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A. Early* behavioral disinhibition [one of the following symptoms (A.1–A.3) must be present]: | ||
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A.1. Socially inappropriate behavior | ||
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B. Early apathy or inertia [one of the following symptoms (B.1–B.2) must be present]: | ||
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B.1. Apathy | ||
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C. Early loss of sympathy or empathy [one of the following symptoms (C.1–C.2) must be present]: | ||
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C.1. Diminished response to other people’s needs and feelings | ||
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D. Early perseverative, stereotyped or compulsive/ritualistic behavior [one of the following symptoms (D.1–D.3) must be present]: | ||
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D.1. Simple repetitive movements | ||
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E. Hyperorality and dietary changes [one of the following symptoms (E.1–E.3) must be present]: | ||
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E.1. Altered food preferences | ||
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F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions [all of the following symptoms (F.1–F.3) must be present]: | ||
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F.1. Deficits in executive tasks | ||
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III. Probable bvFTD | ||
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All of the following symptoms (A–C) must be present to meet criteria: | ||
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A. Meets criteria for possible bvFTD | ||
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B. Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or Functional Activities Questionnaire scores) | ||
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C. Imaging results consistent with bvFTD [one of the following (C.1–C.2) must be present]: | ||
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C.1. Frontal and/or anterior temporal atrophy on MRI or CT | ||
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IV. BvFTD with definite frontotemporal lobar degeneration (FTLD) pathology | ||
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Criterion A and either criterion B or C must be present to meet criteria: | ||
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A. Meets criteria for possible or probable bvFTD | ||
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V. Exclusionary criteria for bvFTD | ||
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Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTD but must be negative for probable bvFTD: | ||
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A. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders | ||
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B. Behavioral disturbance is better accounted for by a psychiatric diagnosis | ||
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C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process | ||
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(2) Nonfluent/agrammatic variant primary progressive aphasia (nfvPPA). NfvPPA is also known as progressive nonfluent aphasia or primary progressive aphasia-agrammatic (PPA-G). NfvPPA is characterized by early disturbances in motor speech output and loss of syntax (ie, grammatical structure of language). Most patients with symptoms initially develop apraxic speech that results in articulatory difficulty and phonological paraphasias (19). These patients tend to show preservation of social graces for some time into the course of their illness. This variant accounts for approximately 20% of the phenotypic expression of the disease (21).
(3) Semantic variant primary progressive aphasia (svPPA). SvPPA is also referred to as semantic dementia or the temporal variant of frontotemporal dementia. Patients with svFTD display progressive loss regarding the meaning of words, but retain fluent speech. Articulation, phonology, and syntax also remain intact, but the patient does not comprehend others’ speech and has significant word-finding difficulty (19). Characteristically, patients will ask “what is ___?” questions regarding the meaning of common nouns (26). Behavioral changes, similar to those seen in bvFTD, also occur, including disinhibition, reduced empathy, compulsions, and altered food preferences (10). This variant accounts for approximately 12% of the phenotypic expression of the disease (10).
Similar to bvFTD, the criteria for diagnosis of nfvPPA and svPPA have been significantly revised to facilitate scientific exchange across centers. In the new International Consensus Criteria outlined for primary progressive aphasia (19) (see Table 2), establishing a diagnosis is based on a 2-step process. First, a patient must meet criteria for Mesulam’s guidelines for primary progressive aphasia (35). If the patient meets criteria for Step 1, then his or her language disturbance is further parcellated into one of three variants: nonfluent variant primary progressive aphasia, semantic variant primary progressive aphasia, and logopenic variant primary progressive aphasia. Because the majority of cases of logopenic primary progressive aphasia are pathologically linked to Alzheimer disease, it will not be reviewed here.
(4) Right temporal variant frontotemporal dementia (rtvFTD). Right anterior temporal lobe degeneration leads to neurobehavioral features, especially early loss of empathy, prosopagnosia, loss of place knowledge, cognitive rigidity, disinhibition, apathy, obsessive-compulsive symptoms, changes in eating habits, and depression with person-specific and socioemotional knowledge deficits (55; 09; 60). Patients are diagnosed later than the left temporal variant of frontotemporal dementia and have shorter mortality (14). Genetic risk can be familial or sporadic with multiple genes implicated (56).
Table 2. Classification of Primary Progressive Aphasia
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Inclusion and exclusion criteria for the diagnosis of primary progressive aphasia (PPA). Modified from (35) | |||||
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Inclusion: Criteria 1 through 3 must be answered positively | |||||
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1. Most prominent clinical feature is difficulty with language | |||||
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Exclusion: Criteria 1 through 4 must be answered negatively for a PPA diagnosis | |||||
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1. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders | |||||
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Nonfluent/agrammatic variant PPA | |||||
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I. Clinical diagnosis of nonfluent/agrammatic variant PPA | |||||
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At least one of the following core features must be present: | |||||
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1. Agrammatism in language production | |||||
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At least two of three of the following other features must be present: | |||||
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1. Impaired comprehension of syntactically complex sentences | |||||
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II. Imaging-supported nonfluent/agrammatic variant diagnosis | |||||
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Both of the following criteria must be present: | |||||
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1. Clinical diagnosis of nonfluent/agrammatic variant PPA | |||||
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a. Predominant left posterior fronto-insular atrophy on MRI or | |||||
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III. Nonfluent/agrammatic variant PPA with definite pathology: | |||||
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Clinical diagnosis (Criteria 1 below) and either Criterion 2 or 3 must be present: | |||||
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1. Clinical diagnosis of nonfluent/agrammatic variant PPA | |||||
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Diagnostic criteria for the semantic variant PPA | |||||
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I. Clinical diagnosis of semantic variant PPA: | |||||
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Both of the following core features must be present: | |||||
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1. Impaired confrontation naming | |||||
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At least three of the following other diagnostic features must be present: | |||||
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1. Impaired object knowledge, particularly for low frequency or low familiarity items | |||||
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II. Imaging-supported semantic variant PPA diagnosis | |||||
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Both of the following criteria must be present: | |||||
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1. Clinical diagnosis of semantic variant PPA | |||||
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A. predominant anterior temporal lobe atrophy | |||||
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III. Semantic variant PPA with definite pathology | |||||
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Clinical diagnosis (Criteria 1 below) and either Criterion 2 or 3 must be present: | |||||
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1. Clinical diagnosis of semantic variant PPA | |||||
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Associated disorders. Our enhanced understanding of the genetics, pathology, and epidemiology of frontotemporal dementia has led to recognizing that the three clinical variants of frontotemporal dementia often occur within the context of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and motor neuron disease (MND)/amyotrophic lateral sclerosis (ALS) (04).
Progressive supranuclear palsy. The motor syndrome of progressive supranuclear palsy, which includes postural instability, axial rigidity, bradykinesia, frequent falls, dysphagia, and vertical gaze palsy, was originally described by Steele and colleagues in 1964 (53). In addition to its motor features, some symptoms resemble bvFTD as well, including significant apathy and dysexecutive symptoms (04).
Corticobasal syndrome. Corticobasal syndrome has traditionally been characterized as a clinical syndrome consisting of asymmetric rigidity, prominent apraxia, cortical sensory loss, reflex myoclonus, bradykinesia, tremor, and dystonia without prominent early dementia (17). However, an international research committee has analyzed the clinical symptomatology of 267 pathologically confirmed cases of corticobasal degeneration (a term which refers specifically to pathologically confirmed corticobasal syndrome). Based on their analysis, they set forth guidelines that reflect the heterogeneity of corticobasal syndrome, which includes phenotypes similar to both bvFTD and nfvPPA (02).
Motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). MND/ALS involves degeneration of the pyramidal tract or anterior horn cell disease. Heterogeneous cognitive and behavioral impairment occurs in amyotrophic lateral sclerosis, with neuropsychological deficits affecting over 50% of people with amyotrophic lateral sclerosis (54). The discovery of the C9ORF72 and FUS gene mutations in familial frontotemporal dementia and frontotemporal dementia-amyotrophic lateral sclerosis likely account for the high reported incidence of behavioral (and sometimes aphasia) symptoms in these patients (45).
Prognosis and complications
Across all clinical variants of frontotemporal dementia, survival from time of symptom onset has been estimated to range from 6 to 11 years (29; 10). As the disease progresses, immobility due to motor symptoms and difficulties with swallowing and choking may shorten survival.
Clinical vignette
A 68-year-old male shopkeeper became ill approximately 4 years prior to his first clinical examination. His initial symptoms included errors in judgment while driving (which resulted in rear-ending another driver) and carelessness while handling money. Two years later, he began to display socially inappropriate behavior, rudeness, and a short attention span. He would often stand up during the middle of a conversation and abruptly leave. He developed a preference for salami and would eat half a pound in one sitting. He would often eat an entire bunch of bananas.
He became apathetic. For example, he stopped doing yard work and did not shovel the snow during the winter. His hygiene declined, and he wore the same clothes for a week at a time. He only showered at the YMCA after exercising. When requested, he shaved with an electric shaver but while sitting and watching television. He was often fidgety and would manipulate objects for no reason. He became emotionally distant and disinterested and only talked about what he watched on television. Later, he stopped participating in conversations, had difficulty getting words out, and talked less. Customers at his shop, which had become quite messy, noted his lack of patience and easy frustration.
On initial examination, he was impulsive and interrupted conversations with unrelated thoughts and concerns. He had trouble with some of the sequential motor tests as well as a similarities test (considered to assess complex reasoning). His gait at that time seemed rushed; at other times he shuffled with reduced stride length, and he turned stiffly, resembling patients with Parkinson disease. His upward gaze appeared markedly reduced. He was diagnosed with early frontotemporal dementia, which led to subsequent referral for neuroimaging. His CT scan was notable for mild frontoparietal atrophy. (Author’s note: the characteristic atrophy pattern in frontotemporal dementia is frontotemporal atrophy, and an MRI is considered a better modality than CT to assess for atrophy).
Over time, he started falling, which led to his using a walker. A rapid tremor developed in the right hand, especially when he was agitated. He continued to be impulsive and restless. For example, when eating at restaurants with his family, he would finish his meal and then leave to stand beside the car until the family was ready to go home. He was emotional and tearful, at times with no provocation (pseudobulbar affect). His speech became perseverative, slurred, and less intelligible. He often repeated words and only spoke in short sentences.
On a subsequent evaluation, he was noted to have festinating gait, en bloc turns, and axial rigidity. He also displayed severe vertical gaze palsy and impaired lateral pursuit. To check his watch, he had to raise his arm up in front of his eyes (the “watch salute”). He also had several bursts of disinhibited crying and laughing with no provocation (pseudobulbar palsy), and his speech was slow and slurred, with a sing-song inflection. A rapid jerky tremor was evident in the right hand. His clock drawing was very small, and the numbers were crowded together and difficult to recognize. He failed to place the hands appropriately. Language testing demonstrated nonfluent aphasia in addition to his dysarthria. Eventually, he was admitted to a nursing home.
His case is an example of the behavioral variant of frontotemporal dementia with superimposed progressive supranuclear palsy and progressive aphasia, a convergence of the behavior, language, and extrapyramidal manifestations of the disease. This case is detailed in the case-based book on frontotemporal dementia in the chapter “The Hero of Bolero” (23).
Biological basis
Etiology and pathogenesis
Frontotemporal dementia is thought to be caused by the abnormal aggregation of proteins in the brain, which begin in selective, vulnerable neuroanatomical “hubs.” As the disease progresses, the proteins disseminate through specific neuroanatomical networks, conferring the unique clinical characteristics seen at each stage of the disease (52). The pathology is heterogeneous, though three major proteins have now been shown to cause the majority of cases of frontotemporal dementia. A large proportion of cases are genetic and caused by mutations in the tau and progranulin genes on chromosome 17 and the C9ORF72 gene on chromosome 9.
Gross pathology. The gross pathology of frontotemporal dementia is asymmetric atrophy of the frontal and anterior temporal lobes.
In bvFTD, disease begins primarily in paralimbic structures such as the anterior cingulate cortex, frontoinsular region, dorsal anterior insula, and lateral orbitofrontal cortex (51). As the disease progresses, it moves towards the dorsolateral prefrontal cortex and posteriorly towards the anterior and lateral temporal lobes (05). Nonfluent variant primary progressive aphasia typically involves the left inferior frontal gyrus and insula, whereas semantic variant primary progressive aphasia typically begins in the left anterior temporal lobe, though it eventually becomes bilateral, progressing to include degeneration of the posterior insula and ventromedial frontal lobe as well (18).
Histopathology. The first protein to be identified in the pathogenesis of frontotemporal dementia was tau (FTLD-tau). Normal tau proteins contribute to axonal transport by binding to microtubular proteins. However, abnormally phosphorylated and aggregated tau proteins are biochemical markers of various forms of degenerative dementia, collectively referred to as “tauopathies,” and include Alzheimer disease, Pick disease, corticobasal degeneration, progressive supranuclear palsy, and chronic traumatic encephalopathy (amongst others) (39).
The majority of cases of frontotemporal dementia, however, are not tau-reactive. Rather, they display ubiquitin-immunopositive histology. These cases were termed dementia lacking distinctive histology for many years (28). It was eventually found that these cases displayed ubiquitinated protein inclusions (FTLD-U); however, the exact protein was unknown. This changed in 2006, when it was determined that transactive response DNA-binding protein 43kDa (TDP-43) was the protein responsible for most ubiquitin-positive cases of frontotemporal dementia (38). It has now been shown that approximately 50% of all cases of frontotemporal dementia have TDP-43 pathology, as well as the vast majority of cases with amyotrophic lateral sclerosis (38). A harmonized scheme for the pathological classification of TDP-43 was proposed, which outlines four subtypes of FTLD-TDP: type A (TDP-A), found in the majority of cases with mutations in the GRN gene; type B (TDP-B), associated with FTD-MND; type C (TDP-C) associated predominantly with semantic variant PPA; and type D (TDP-D), associated with mutations in the valosin-containing protein (VCP) gene (34). Overall, in bvFTD, tau pathology (3R > 4R) and TDP-43 (type A > type B > type D) are equally as likely (32).
In 2009, ubiquitinated FUS protein inclusions were found to be responsible for the majority of the remaining tau/TDP-43 negative frontotemporal dementia cases, constituting the third major pathological subtype of frontotemporal dementia (30). FTLD-FUS includes three closely related entities: atypical frontotemporal dementia with ubiquitin-positive inclusions (aFTLD-U), neuronal intermediate filament inclusion disease (NIFID), and basophilic inclusion body disease (BIBD) (45). Underlying FUS pathology is the least common neuropathology in bvFTD (32).
Clinicopathological correlations. Prediction of the underlying molecular pathology of clinical frontotemporal dementia is tenuous; however, some patterns have been established and can be used as guidelines. For example, svPPA is typically sporadic and associated with FTLD-TDP type C pathology, (more likely than 3R tauopathy), whereas cases of sporadic nfvPPA are more likely to be FTLD-tau, (4-repeat (4R) tau—CBD protein and PSP protein > 3-repeat (3R) tau and TDP-43 type A), especially if they also display prominent parkinsonism. BvFTD is the most difficult variant in which to predict pathology; however, certain symptoms are more likely to present with particular pathological subtypes. For example, when bvFTD is also associated with motor neuron disease, the pathological substrate is usually FTLD-TDP; if parkinsonism is present (eg, corticobasal syndrome or progressive supranuclear palsy), then pathology will likely be FTLD-tau. Should onset be very early with significant psychiatric symptoms, pathology is likely to be FTLD-FUS (45). FTD-MND is most likely to be due to underlying TDP-43 type B pathology (with TDP-43 type A and FUS being less likely). CBS is most likely to be due to 4R tauopathy (CBD), although in rare cases, CBS may be caused by Alzheimer pathology, 4R tau (PSP protein), TDP-43, or 3R tau. PSP-S (syndrome) is most often caused by underlying 4R tau pathology (PSP> CBD) (32) (see Table 1 of their paper).
Genetics. In contrast to Alzheimer disease, genetic causes of frontotemporal dementia are common and up to 40% of cases have a family history of dementia, psychiatric disease, or motor symptoms. In addition, 10% of patients with frontotemporal dementia have an autosomal dominant pattern of inheritance (40). The first genetic mutation to be linked to familial frontotemporal dementia was discovered in 1998 and was found to cause mutations in the microtubule-associated protein (“MAPT”) gene, which is located on chromosome 17 and codes for the protein tau. More than 44 tau mutations on the MAPT gene have been identified, accounting for 5% to 20% of familial frontotemporal dementia. Clinical presentation is heterogeneous, though bvFTD and extrapyramidal motor syndromes such as corticobasal syndrome and progressive supranuclear palsy tend to predominate (49).
After the discovery of the MAPT gene mutations, there remained many chromosome 17-linked families with frontotemporal dementia that did not display mutations in MAPT. The second locus was eventually discovered in 2006, in extremely close proximity to the MAPT gene. The identified mutation was found to occur in the progranulin (GRN) gene. Since 2006, 69 pathogenic mutations have been reported worldwide, which are thought to account for approximately 5% to 20% of familial cases and approximately 1% to 5% of sporadic cases of frontotemporal dementia. Mutation carriers tend to develop symptoms characteristic of bvFTD or nfvPPA.
Since 2006, increasing evidence suggested the presence of a mutation on chromosome 9, responsible for familial cases of combined frontotemporal dementia-amyotrophic lateral sclerosis. In 2011, this gene was identified as a hexanucleotide expansion mutation in a noncoding region of C9ORF72. Furthermore, this analysis demonstrated the mutation in C9ORF72 to be the most common genetic abnormality in both familial frontotemporal dementia (11.7%) and familial amyotrophic lateral sclerosis (23.5%). The clinical presentation can include bvFTD, amyotrophic lateral sclerosis, or features of both, whereas other clinical variants of frontotemporal dementia and associated disorders are rare.
Six other genes have been identified as responsible for a minority of the familial frontotemporal dementia cases and include: valosin-containing protein (VCP), chromatin-modifying protein 2B (CHMP2B), transactive response DNA-binding protein 43kDa (TARDBP), fused in sarcoma (FUS), TBK1, and TIA1 (50).
Reidl and colleagues clearly outline the molecular classification of frontotemporal lobar degeneration with its genetic and clinical correlations in Table 2 of their paper (48).
Epidemiology
Frontotemporal dementia is considered the third most common cause of dementia, behind Alzheimer disease and dementia with Lewy bodies. Estimates of its prevalence vary considerably and likely relate to challenges in identification and accurate diagnosis of the disease. Using the 2011 revised diagnostic criteria, the incidence of frontotemporal dementia in two UK counties was demonstrated as 1.57 per 100,000 person-years (10). Age of onset can range from 40 to 90, and prevalence is equivalent between male and female gender (10).
Prevention
No strategies are known except genetic counseling of mutation carriers in familial frontotemporal dementia.
Differential diagnosis
Confusing conditions
BvFTD is commonly misdiagnosed as early-onset Alzheimer disease, given that Alzheimer disease is the most prevalent dementia syndrome, and many symptoms of the two diseases can overlap. Diagnostic studies, such as CSF biomarkers (eg, Aβ1-42:tau ratio) and molecular PET amyloid imaging, can be useful to distinguish between these diseases, if available. Evidence of vascular disease, endocrine or metabolic conditions, neoplasms or paraneoplastic syndromes, CNS infections, or dietary deficiencies should be ruled out.
Many patients with bvFTD are initially diagnosed with late-onset psychiatric disturbance. Symptoms of disinhibition, euphoria, and poor judgment can mimic those of mania, whereas profound apathy and eating disturbance might be misconstrued as depression. For example, in a retrospective chart review of 252 patients with neurodegenerative disease, Woolley and colleagues found that 51% of patients with bvFTD had received a prior diagnosis of a psychiatric disorder (eg, major depression, bipolar disorder, schizophrenia), compared to 23% of patients with Alzheimer disease (eg, major depression, anxiety) (59). Psychiatric symptoms, including delusions and hallucinations, appear to be a common symptom in individuals who carry the C9ORF72 gene mutation (03). In general, late age of onset of psychiatric symptoms should be a “red flag” when considering whether an individual might have a neurodegenerative disease.
Associated or underlying disorders
Our enhanced understanding of the genetics, pathology, and epidemiology of frontotemporal dementia has led to the recognition that the four clinical variants of frontotemporal dementia often occur within the context of progressive supranuclear palsy, corticobasal syndrome, and motor neuron disease/amyotrophic lateral sclerosis (04).
Diagnostic workup
A comprehensive diagnostic evaluation for frontotemporal dementia should include a clinical interview, neurologic exam, neuropsychological assessment, and review of neuroimaging.
The clinical interview should focus on onset and progression (eg, has it been slow and insidious or abrupt and explicit?), the nature of the change, which is typically in the realm of personality, emotionality, language, and social behavior (use of the FTDC criteria as a way to frame questions is helpful), and family history (which should be probed for family members who exhibited significant changes in personality and social behavior after the fifth decade or who also may have had symptoms of a motor syndrome). It is important to remember that due to the lack of awareness and insight that typically occurs in this disease, it is unlikely that the patient will be able to give an accurate account of his or her history. Therefore, it is crucial that an informant be present to provide details of the history.
Use of global assessment measures such as the Mini-Mental State Exam (13) are typically insensitive to the earliest changes in cognition that occur in frontotemporal dementia. Patients frequently score highly, despite obvious impairment in behavior and judgment. Neuropsychological assessment should examine the relative test score pattern between measures of executive function versus episodic memory and visuospatial function (executive dysfunction > memory/visuospatial dysfunction), in conjunction with behavioral observations such as perseverative behavior, inappropriate remarks, lack of social engagement, and apathy.
Asking informants to fill out questionnaires that address changes in behavior or psychiatric symptoms, such as the Neuropsychiatric Inventory (11) or the Frontal Systems Behavior Scale (20), can also be extremely helpful. If the patient simply displays a “frontal” or “dysexecutive” syndrome without significant behavioral problems or a history of personality change, the diagnosis is more likely to be early-onset Alzheimer disease. Other useful functional and social cognition assessment tools in frontotemporal dementia include Frontal Behavioral Inventory (24), FTLD-CDR (27), Frontotemporal Dementia Rating Scale (FRS; 36), Cambridge Behavioral Inventory (57; 58), Functional Activities Questionnaire (FAQ) (43), and the Revised Self-Monitoring Scale (31).
Clinically, structural magnetic resonance imaging (MRI) is best for reviewing findings. Atrophy is often asymmetric and in the early-middle stages, confined to the medial frontal and anterior temporal lobes. Clinicians should review the MRI readings themselves because radiologists often fail to comment on atrophy patterns.
FDG-PET can be used to reveal a specific pattern of hypometabolism in the frontal and temporal lobes consistent with the synaptic dysfunction present in that region. It has been FDA approved to distinguish between frontotemporal dementia and Alzheimer disease and is particularly beneficial in the early stages of disease. FDG-PET is highly specific for neurodegeneration, even in the preclinical and prodromal phase (08). A tau-PET ligand has been FDA-approved for use in identifying the neurofibrillary tangles of Alzheimer disease, but ligands for frontotemporal dementia-associated tau and TDP-43 aggregates are still in development.
CSF analysis can exclude Alzheimer disease pathology and distinguish frontotemporal dementia from non-neurodegenerative disorders. Amyloid PET and emerging plasma biomarkers (αβ42/490, p-tau217) can also exclude Alzheimer disease. There is no current fluid biomarker that confirms frontotemporal dementia pathology, but CSF and blood-based neurofilament light chair (NfL) can differentiate frontotemporal dementia from primary psychiatric disorders (12). pNfL may be able to track progression of disease as well as predict onset in familial mutation carriers (16).
Management
Frontotemporal dementia is managed through both pharmacological and behavioral interventions. There are currently six medications approved for treatment of amyotrophic lateral sclerosis, including tofersen, edaravone, riluzole, thickened riluzole, riluzole oral film, and dextromethorphan-quinidine sulfate—the last of these is used for pseudobulbar affect, which is characterized by involuntary crying or laughing without a clear trigger (22). However, there are no FDA-approved medications for treating symptoms in frontotemporal dementia. Selective serotonin reuptake inhibitors (SSRIs) have proven most effective in treating behavioral symptoms such as apathy, depression, anxiety, agitation, delusions, self-harm, and compulsive behaviors (33). Despite widespread use, the evidence for using acetylcholinesterase inhibitors, NMDA receptor antagonists, antipsychotics, and anticonvulsants in patients with frontotemporal dementia has not been consistently demonstrated (33). Antipsychotics are often used when SSRIs are insufficient, but they have an FDA black box warning of increased mortality in patients with dementia.
Education for caregivers regarding behavioral management techniques can be extremely useful. For example, learning the “ABC”s of problem behavior (antecedent – behavior – consequence) can allow the caregiver to pinpoint what situations give rise to problem behaviors so they can anticipate and change the situation before a behavior occurs. Physical therapy for gait and balance training, home safety evaluations by occupational therapists, speech therapy for dysarthria and compensatory techniques, cognitive rehab conducted by speech therapists for patients with insight into their impairments, and swallow evaluations due to dysphagia are also important management tools. Counseling, education, and support groups are also important given the dramatic changes that occur in patients with frontotemporal dementia. These outlets provide important information regarding coping strategies (such as taking respite), resources (day programs), and information about long-term care and advanced care directives.
Efforts to develop specific, disease-modifying therapies for frontotemporal dementia are advancing rapidly (04). For example, research in tau-related therapies has led to a number of treatment strategies that have already or will soon be in the clinical trial phase. In addition, clinical trials are currently under way with agents presumed to normalize progranulin levels in individuals who bear this genetic mutation. Finally, strategies to block the expression of the C9ORF72 hexanucleotide repeat expansions are being developed for the most common genetic form of the disease. There are currently six clinical trials targeting FTD-GRN and four trials targeting FTD-C9ORF72.
Special considerations
Anesthesia
General anesthesia for elective surgeries should be avoided due to the risk of delirium leading to rapid progression of deficits.
Media
References
- 01
- Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Z Gesamte Neurol Psychiatr 1911;4:356-85.
- 02
- Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80(5):496-503. PMID 23359374
- 03
- Block NR, Sha SJ, Karydas AM, et al. Frontotemporal dementia and psychiatric illness: emerging clinical and biological links in gene carriers. Am J Geriatr Psychiatry 2016;24(2):107-16. PMID 26324540
- 04
- Boeve BF, Boxer AL, Kumfor F, Pijnenburg Y, Rohrer JD. Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol 2022;21(3):258-72.** PMID 35182511
- 05
- Broe M, Hodges JR, Schofield E, Shepherd CE, Kril JJ, Halliday GM. Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology 2003;60(6):1005-11. PMID 12654969
- 06
- Brun A. Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Arch Gerontol Geriatr 1987;6:193-208. PMID 3689053
- 07
- Brun A, Englund B, Gustafson L, et al. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416-8. PMID 8163988
- 08
- Caminiti SP, Ballarini T, Sala A, et al. FDG-PET and CSF biomarker accuracy in predication of conversion to different dementias in a large multicenter MCI cohort. Neuroimage Clin 2018;18:167-77. PMID 29254091
- 09
- Campos DF, Rocca AR, Caixeta LF. Right temporal lobe variant of frontotemporal dementia: systematic review. Alzheimer Dis Assoc Disord 2022;36(3):272-9. PMID 35867973
- 10
- Coyle-Gilchrist IT, Dick KM, Patterson K, et al. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology 2016;86(18):1736-43. PMID 27037234
- 11
- Cummings JL. The neuropsychiatric inventory: assessing psychopathology in dementia patients. Neurology 1997;48(5 Suppl 6):S10-6. PMID 9153155
- 12
- Del Campo M, Zetterberg H, Gandy S, et al. New developments of biofluid-based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia. Alzheimers Dement 2022;18(11):2292-307. PMID 35235699
- 13
- Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189-98. PMID 1202204
- 14
- Frings L, Blazhenets G, Binder R, Bormann T, Hellwig S, Meyer PT. More extensive hypometabolism and higher mortality risk in patients with right- than left-predominant neurodegeneration of the anterior temporal lobe. Alzheimers Res Ther 2023;15(1):11. PMID 36627641
- 15
- Galvin JE, Howard DH, Denny SS, Dickinson S, Tatton N. The social and economic burden of frontotemporal degeneration. Neurology 2017;89(20):2049-56. PMID 28978658
- 16
- Gendron TF, Heckman MG, White LJ, et al. Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders. Cell Rep Med 2022;3(4):100607. PMID 35492244
- 17
- Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain 1989;112:1171–92.
- 18
- Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 2004;55:335-46. PMID 14991811
- 19
- Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011;76(11):1006-14. PMID 21325651
- 20
- Grace J, Stout J, Malloy P. Assessing frontal behavior syndromes with the Frontal Lobe Personality Scale. Assessment 1999;6(3):269-84. PMID 10445964
- 21
- Grossman M. The non-fluent/agrammatic variant of primary progressive aphasia. Lancet Neurol 2012;11(6):545-55. PMID 22608668
- 22
- Ilieva H, Vullaganti M, Kwan J. Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis. BMJ 2023;383:e075037. PMID 37890889
- 23
- Kertesz A. The Banana Lady and Other Stories of Curious Behavior and Speech. Bloomington, Indiana: Trafford, 2006.
- 24
- Kertesz A, Davidson W, Fox H. Frontal behavioral inventory: diagnostic criteria for frontal lobe dementi. Canadian J Neurol Sci 1997;24(1):29-36. PMID 9043744
- 25
- Kertesz A, Hudson L, Mackenzie IR, Munoz DG. The pathology and nosology of primary progressive aphasia. Neurology 1994;44(11):2065-72. PMID 7969961
- 26
- Kertesz, A, Jesso S, Harciarek M, Blair M, McMonagle P. What is semantic dementia.: a cohort study of diagnostic features and clinical boundaries. Arch Neurol 2010;67(4):483-9. PMID 20385916
- 27
- Knopman DS, Kramer JH, Boeve BF, et al. Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. Brain 2008;131(11):2957-68. PMID 18829698
- 28
- Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T. Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 1990;40:251-6. PMID 2300243
- 29
- Knopman DS, Roberts RO. Estimating the number of persons with frontotemporal lobar degeneration in the US population. J Mol Neurosci 2011;45(3):330-5. PMID 21584654
- 30
- Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLs gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009;323(5918):1205-8. PMID 19251627
- 31
- Lennox RD, Wolfe RN. Revision of the self-monitoring scale. J Pers Soc Psychol 1984;46(6):1349-64. PMID 6737217
- 32
- Ljubenkov PA, Miller BL. A clinical guide to frontotemporal dementias. Focus (Am Psychiatr Publ) 2016;14(4):448-64. PMID 31975825
- 33
- Logroscino G, Imbimbo BP, Lozupone M, et al. Promising therapies for the treatment of frontotemporal dementia clinical phenotypes: from symptomatic to disease-modifying drugs. Expert Opin Pharmacother 2019;20(9):1091-107. PMID 31002267
- 34
- Mackenzie IR, Neumann M, Baborie A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011;122(1):111-3. PMID 21644037
- 35
- Mesulam MM. Primary progressive aphasia. Ann Neurol 2001;49(4):425-32. PMID 11310619
- 36
- Mioshi E, Hsieh S, Savage S, Hornberger M, Hodges JR. Clinical staging and disease progression in frontotemporal dementia. Neurology 2010;74(20):1591-7. PMID 20479357
- 37
- Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546-54. PMID 9855500
- 38
- Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130-3. PMID 17023659
- 39
- Noble W, Hanger DP, Miller CC, Lovestone S. The importance of tau phosphorylation for neurodegenerative disease. Front Neurol 2013;4:83. PMID 23847585
- 40
- Olney N, Spina S, Miller B. Frontotemporal dementia. Neurol Clin 2017;35(2):339-74. PMID 28410663
- 41
- Onari K, Spatz H. Anatomische Beitrage zur Lehre von der Pickschen umschriebenen Grosshirnrinden-Atrophie (‘Picksche Krankheit’). Z Neurol 1926;101:470-511.
- 42
- Onyike CU, Diehl-Schmid J. The epidemiology of frontotemporal dementia. Int Rev Psychiatry 2013;25(2):130-7. PMID 23611343
- 43
- Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol 1982;37(3):323-9. PMID 7069156
- 44
- Pick A. Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prag Med Wochenschr 1892;17:165-7.
- 45
- Rademakers R, Neumann M, Mackenzie IR. Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 2012;8(8):423-34. PMID 22732773
- 46
- Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456-77. PMID 21810890
- 47
- Restrepo-Martinez M, Ramirez-Bermudez J, Chacon-Gonzalez J, Ruiz-Garcia R, Malik R, Finger E. Defining repetitive behaviours in frontotemporal dementia. Brain 2024;147(4):1149-65. PMID 38134315
- 48
- Riedl L, Mackenzie IR, Forstl H, Kurz A, Diehl-Schmid J. Frontotemporal lobar degeneration: current perspectives. Neuropsychiatri Dis Treat 2014;10:297-310. PMID 24600223
- 49
- Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 2011;82(5):476-86. PMID 20971753
- 50
- Seeley WW. Behavioral variant frontotemporal dementia. Continuum 2019;25(1):76-100.** PMID 30707188
- 51
- Seeley WW, Crawford R, Rascovsky K, et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch Neurol 2008;65(2):249-55. PMID 18268196
- 52
- Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009;62(1):42-52. PMID 19376066
- 53
- Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. Arch Neurol 1964;10:333-59. PMID 14107684
- 54
- Strong MJ, Abrahams S, Goldstein LH, et al. Amyotrophic lateral sclerosis – frontotemporal spectrum disorder (ALS-FTD): revised diagnostic criteria. Amyotroph Laterl Scler Frontotempral Degener 2017;18(3-4):153-74. PMID 28054827
- 55
- Ulugut Erkoyun H, Groot C, Heilbron R, et al. A clinical-radiological framework of the right temporal variant of frontotemporal dementia. Brain 2020;143(9):2831-43.** PMID 32830218
- 56
- Ulugut Erkoyun H, van der Lee SJ, Nijmeijer B, et al. The right temporal variant of frontotemporal dementia is not genetically sporadic: a case series. J Alzheimers Dis 2021;79:1195-201. PMID 33427744
- 57
- Wear HJ, Wedderburn CJ, Mioshi E, et al. The Cambridge Behavioural Inventory revised. Dement Neuropsychol 2008;2(2):102-7. PMID 29213551
- 58
- Wedderburn C, Wear H, Brown J, Mason SJ, Barker RA, Hodges J, Williams-Gray C. The utility of the Cambridge Behavioural Inventory in neurodegenerative disease. J Neurol Neurosurg Psychiatry 2008;79(5):500-3. PMID 17846114
- 59
- Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP. The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry 2011;72(2):126-33. PMID 21382304
- 60
- Younes K, Borghesani V, Montembeault M, et al. Right temporal degeneration and socioemotional semantics: semantic behavioural variant frontotemporal dementia. Brain 2022;145(11):4080-96. PMID 35731122
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Irina Anna Skylar-Scott MD
Dr. Skylar-Scott of Stanford University received funding from Alector as site principal investigator and from Ashvattha Therapeutics as co-investigator.
See Profile
Editor
-
Victor W Mark MD
Dr. Mark of the University of Alabama at Birmingham has no relevant financial relationships to disclose.
See Profile
Former Authors
- David Knopman MD
- Sergio E Starkstein MD
- Maria Laura Garau MD
- Andrew Kertesz MD
- Amanda K LaMarre PhD
- Marissa Natelson Love MD
Patient Profile
- Age range of presentation
-
- 30 to 90 years
- Sex preponderance
-
- Female=male
- Heredity
-
- First-degree relatives of frontotemporal dementia patients are 3.5 times more likely to develop dementia before age 80 compared to those without a family history of frontotemporal dementia.
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Other frontotemporal dementia: G31.09
- ICD-11
-
- Frontotemporal dementia: 6D83
- OMIM
-
- Frontotemporal dementia; FTD: #600274
- Frontotemporal lobar degeneration with TDP43 inclusions, GRN-related: #607485
- Amyotrophic lateral sclerosis 10 with or without frontotemporal dementia; ALS10: #612069
- Frontotemporal dementia and/or amyotrophic lateral sclerosis 4; FTDALS4: #616439
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