Introduction. Overview

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1 Frontotemporal dementia Marissa C Natelson Love MD ( Dr. Natelson Love of the University of Alabama at Birmingham has no relevant financial relationships to disclose. ) Victor W Mark MD, editor. ( Dr. Mark of the University of Alabama at Birmingham has no relevant financial relationships to disclose.) Originally released March 8, 1996; last updated March 11, 2017; expires March 11, 2020 Introduction This article includes discussion of frontotemporal dementia, behavioral variant frontotemporal dementia, frontotemporal lobar degeneration, Pick complex, Pick's disease, primary progressive aphasia, Parkinsonian syndromes, and motor neuron disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Frontotemporal degeneration has prevalence between 15 and 22 cases per 100,000 in the 45 to 64-year-old age range (Onyike and Diehl-Schmid 2013). 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 Since 2011, revised diagnostic criteria have been published for the 3 clinical variants of frontotemporal dementia (FTD): behavioral variant frontotemporal dementia, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia. Corticobasal syndrome, progressive supranuclear palsy, and motor neuron disease/amyotrophic lateral sclerosis are considered to exist within the frontotemporal dementia disease spectrum. The most common frontotemporal dementia-causing genes and pathological proteins 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 (Pick 1892). However, it was not until 1911 that Alois Alzheimer first described the histopathology in these cases, which he termed Pick bodies (Alzheimer 1911). In the 1920s, Onari and Spatz went on to establish the clinical-pathological relationship, which was subsequently given the name Pick's disease (Onari and Spatz 1926). 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 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) (Brun et al 1994). These criteria were further refined in 1998, when Neary and colleagues published the Consensus on Frontotemporal Lobar Degeneration, which included diagnostic criteria for the 3 clinical variants of frontotemporal dementia (behavioral, progressive non-fluent aphasia, and semantic dementia) (Neary et al 1998). 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 15 years. As alluded to above, the concept and nosology of frontotemporal dementia has undergone many revisions since it was first described. Pick disease (Onari and Spatz 1926), frontal lobe degeneration (Brun 1987), dementia of the frontal

2 lobe type (Neary et al 1998), and frontotemporal dementia (Brun et al 1994) have all been used to describe the disease. The term Pick complex has also been suggested to encompass all related clinical and pathological entities of frontotemporal dementia (Kertesz et al 1994). At this time, frontotemporal dementia is used to signify the clinical manifestation of the disease, whereas frontotemporal lobar degeneration is used to describe the disease on pathological examination. Clinical manifestations Presentation and course Clinically, frontotemporal dementia is expressed as 3 variants: behavioral variant, nonfluent/agrammatic variant primary progressive aphasia, and semantic variant primary progressive aphasia (Neary et al 1998). 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 as time progresses. These symptoms can include apathy or disinhibition, impaired personal and social awareness, reduced emotional reactivity, and changes in personality or beliefs, including compulsive behavior and poor judgment (Shinagawa et al 2006). 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. Moreover, these changes, at least initially, may stand in stark contrast to patients' cognitive ability, which may remain intact for some time. Behavioral variant frontotemporal dementia accounts for more than 50% of the clinical expression of the 3 variants (Snowden 2011). The diagnostic criteria for behavioral variant frontotemporal dementia were revised in 2011 and are called the FTDC criteria (Table 1) (Rascovsky et al 2011). With these criteria, diagnosis of possible bvftd is based solely on clinical presentation, 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 2 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) (Rascovsky et al 2011). Table 1. International Consensus Criteria for Behavioral Variant Frontotemporal Dementia (FTDC) l. Neurodegenerative disease The following symptom must be present to meet criteria for bvftd: A. Shows progressive deterioration of behavior and/or cognition by observation or history (as provided by a knowledgeable informant). II. Possible bvftd 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.

3 A. Early* behavioral disinhibition [one of the following symptoms (A.1 A.3) must be present]: A.1. Socially inappropriate behavior A.2. Loss of manners or decorum A.3. Impulsive, rash or careless actions B. Early apathy or inertia [one of the following symptoms (B.1 B.2) must be present]: B.1. Apathy B.2. Inertia C. Early loss of sympathy or empathy [one of the following symptoms (C.1 C.2) must be present]: C.1. Diminished response to other people's needs and feelings C.2. Diminished social interest, interrelatedness or personal warmth D. Early perseverative, stereotyped or compulsive/ritualistic behavior [one of the following symptoms (D.1 D.3) must be present]: D.1. Simple repetitive movements D.2. Complex, compulsive or ritualistic behaviors D.3. Stereotypy of speech E. Hyperorality and dietary changes [one of the following symptoms (E.1 E.3) must be present]: E.1. Altered food preferences E.2. Binge eating, increased consumption of alcohol or cigarettes E.3. Oral exploration or consumption of inedible objects 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]: F.1. Deficits in executive tasks F.2. Relative sparing of episodic memory F.3. Relative sparing of visuospatial skills III. Probable bvftd All of the following symptoms (A C) must be present to meet criteria: A. Meets criteria for possible bvftd B. Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or Functional Activities Questionnaire scores) C. Imaging results consistent with bvftd [one of the following (C.1 C.2) must be present]: C.1. Frontal and/or anterior temporal atrophy on MRI or CT C.2. Frontal and/or anterior temporal hypoperfusion or hypometabolism on PET or SPECT IV. BvFTD with definite frontotemporal lobar degeneration (FTLD) pathology Criterion A and either criterion B or C must be present to meet criteria: A. Meets criteria for possible or probable bvftd B. Histopathological evidence of FTLD on biopsy or at post-mortem C. Presence of a known pathogenic mutation V. Exclusionary criteria for bvftd 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: A. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders B. Behavioral disturbance is better accounted for by a psychiatric diagnosis C. Biomarkers strongly indicative of Alzheimer's disease or other neurodegenerative process From (Rascovsky et al 2011). *As a general guideline early' refers to symptom presentation within the first 3 years bvftd = behavioral variant FTD. (2) Nonfluent/agrammatic variant primary progressive aphasia (nfvppa). NfvPPA is also known as progressive nonfluent aphasia or primary progressive aphasia-agrammatic. 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 (Gorno-Tempini et al 2011). These patients tend to show preservation of social graces for some time into the course of their illness. This variant accounts for approximately 10% of the phenotypic expression of the disease (Pickering-Brown 2007).

4 (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 (Gorno-Tempini et al 2011). Characteristically, patients will ask what is? questions regarding the meaning of common nouns (Kertesz et al 2010). Behavioral changes, similar to those seen in bvftd, also occur, including disinhibition, reduced empathy, compulsions, and altered food preferences (Seeley et al 2005). This variant accounts for approximately 15% of the phenotypic expression of the disease (Pickering-Brown 2007). Similar to bvftd, the criteria for diagnosis of nfvppa and svppa have undergone a significant revision in order to facilitate scientific exchange across centers. In the new International Consensus Criteria outlined for primary progressive aphasia (Gorno-Tempini et al 2011) (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 (Mesulam 2001). If the patient meets criteria for Step 1, then their language disturbance is further parcellated into 1 of 3 variants: nonfluent variant primary progressive aphasia, semantic variant primary progressive aphasia, and logopenic variant primary progressive aphasia. Note: in the majority of cases, logopenic primary progressive aphasia is pathologically linked to Alzheimer disease; as such, it will not be reviewed here. Table 2. Classification of Primary Progressive Aphasia Inclusion and exclusion criteria for the diagnosis of primary progressive aphasia (PPA). Modified from (Mesulam 2001) Inclusion: Criteria 1 through 3 must be answered positively 1. Most prominent clinical feature is difficulty with language 2. These deficits are the principal cause of impaired daily living activities 3. Aphasia should be the most prominent deficit at symptom onset and for the initial phases of the disease. Exclusion: Criteria 1 through 4 must be answered negatively for a PPA diagnosis

5 1. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders 2. Cognitive disturbance is better accounted for by a psychiatric diagnosis 3. Prominent initial episodic memory, visual memory and visuoperceptual impairments 4. Prominent, initial behavioral disturbance Nonfluent/agrammatic variant PPA I. Clinical diagnosis of nonfluent/agrammatic variant PPA At least one of the following core features must be present: 1. Agrammatism in language production 2. Effortful, halting speech with inconsistent speech sound errors (apraxia of speech) At least 2 of 3 of the following other features must be present: 1. Impaired comprehension of syntactically complex sentences 2. Spared single word comprehension 3. Spared object knowledge II. Imaging-supported nonfluent/agrammatic variant diagnosis Both of the following criteria must be present: 1. Clinical diagnosis of nonfluent/agrammatic variant PPA 2. Imaging must show one or more of the following results: a. Predominant left posterior fronto-insular atrophy on MRI or b. Predominant left posterior fronto-insular hypoperfusion or hypometabolism on SPECT or PET III. Nonfluent/agrammatic variant PPA with definite pathology: Clinical diagnosis (Criteria 1 below) and either Criterion 2 or 3 must be present: 1. Clinical diagnosis of nonfluent/agrammatic variant PPA 2. Histopathological evidence of a specific neurodegenerative pathology (eg, FTLD-tau, FTLD-TDP, AD, other) 3. Presence of a known pathogenic mutation Diagnostic criteria for the semantic variant PPA I. Clinical diagnosis of semantic variant PPA: Both of the following core features must be present: 1. Impaired confrontation naming 2. Impaired single-word comprehension At least 3 of the following other diagnostic features must be present: 1. Impaired object knowledge, particularly for low frequency or low familiarity items 2. Surface dyslexia and/or dysgraphia 3. Spared repetition 4. Spared speech production (grammar and motor speech) II. Imaging-supported semantic variant PPA diagnosis Both of the following criteria must be present: 1. Clinical diagnosis of semantic variant PPA 2. Imaging must show one or more of the following results: A. predominant anterior temporal lobe atrophy B. predominant anterior temporal hypoperfusion or hypometabolism on SPECT or PET III. Semantic variant PPA with definite pathology Clinical diagnosis (Criteria 1 below) and either Criterion 2 or 3 must be present: 1. Clinical diagnosis of semantic variant PPA 2. Histopathological evidence of a specific neurodegenerative pathology (eg, FTLD-tau, FTLD-TDP, AD, other) 3. Presence of a known pathogenic mutation From: (Gorno-Tempini et al 2011). Associated disorders. Our enhanced understanding of the genetics, pathology, and epidemiology of frontotemporal dementia has led to the recognition that the 3 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) (Seltman and Matthews 2012). Progressive supranuclear palsy (PSP). 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 (Steele et al 1964). In addition to its motor features, some symptoms resemble bvftd as well, including significant apathy and dysexecutive symptoms (Josephs et al 2011). Corticobasal syndrome (CBS). 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 (Gibb et al 1989). However, an international research committee has

6 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 presentation in life, which includes phenotypes similar to both bvftd and nfvppa (Armstrong et al 2013). Motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). MND/ALS involves degeneration of the pyramidal tract or anterior horn cell disease. Cognitive and behavioral impairment has been observed in bulbar onset amyotrophic lateral sclerosis, with estimates as high as 48% (Portet et al 2001). 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 (Rademakers et al 2012). 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 (Roberson et al 2005; Knopman and Roberts 2011). As the disease progresses, immobility due to motor symptoms and difficulties with swallowing and choking may shorten survival. Clinical vignette This 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 (which is considered to assess higher order thinking ability). 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 positive for mild frontoparietal atrophy. Over time, he started falling, which led to his use of 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. 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 (Kertesz 2006).

7 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 travel in a prion-like manner through specific neuroanatomical networks, conferring the unique clinical characteristics seen at each stage of the disease (Seeley et al 2009). The pathology is heterogeneous, though 3 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 (Seeley et al 2008). As the disease progresses, it moves towards the dorsolateral prefrontal cortex and posteriorly towards the anterior and lateral temporal lobes (Broe et al 2003). 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 (Gorno-Tempini et al 2004). 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) (Noble et al 2013). The majority of cases of frontotemporal dementia, however, are not tau-reactive. Rather, they display ubiquitinimmunopositive histology. These cases were termed dementia lacking distinctive histology for many years (Knopman et al 1990). 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 (Neumann et al 2006). It has now been shown that approximately 50% of all cases of frontotemporal dementia have TDP-43 pathology, and the vast majority of cases with amyotrophic lateral sclerosis (Neumann et al 2006). A harmonized scheme for the pathological classification of TDP-43 was proposed, which outlines 4 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 (Mackenzie et al 2011). 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 (Kwiatkowski et al 2009). FTLD-FUS includes 3 closely related entities: atypical frontotemporal dementia with ubiquitin-positive inclusions (aftld-u), neuronal intermediate filament inclusion disease (NIFID), and basophilic inclusion body disease (BIBD) (Rademakers et al 2012). 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, whereas cases of sporadic nfvppa are more likely to be FTLD-tau, 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 (Rademakers et al 2012). Genetics. In contrast to Alzheimer disease, genetic causes of frontotemporal dementia are common and occur in at least 25% to 50% of cases (depending on the variant), often with an autosomal dominant pattern of inheritance

8 (Seelaar et al 2011). 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 (Seelaar et al 2011). 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. Four 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 DNAbinding protein 43kDa (TARDBP), and fused in sarcoma (FUS) (Seelaar et al 2011). Reidl and colleagues clearly outline the molecular classification of frontotemporal lobar degeneration with its genetic and clinical correlations in Table 2 of their paper (Riedl et al 2014). Epidemiology" Frontotemporal dementia is considered to be 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. Population-based studies in both the United States and United Kingdom estimate its sporadic occurrence at around 3.3 to 3.5 out of 100,000 individuals between 45 to 65 years of age (Mercy et al 2008). Frontotemporal dementia typically presents in midlife, between the ages of 45 and 64; however, onset varies considerably from the 30s to the 90s (Ratnavalli et al 2002; Johnson et al 2005). There has been some suggestion that gender distribution varies between clinical variants (Ratnavalli et al 2002; Johnson et al 2005); however, other studies find that men and women are equally affected (Roberson et al 2005; Seelaar et al 2011). Prevention No strategies are known except genetic counseling of mutation carriers in familial frontotemporal dementia. Differential diagnosis BvFTD is commonly misdiagnosed as early-onset Alzheimer disease, given that Alzheimer disease is the most prevalent dementia syndrome, and many symptoms of the 2 diseases can overlap. Diagnostic studies, such as CSF biomarkers (eg, tau:aβ1-42 ratio) and molecular PET amyloid imaging, can be useful for differential diagnosis between these 2 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) (Woolley et al 2011). On the other hand, psychiatric symptoms, including delusions

9 and hallucinations, appear to be a common symptom in individuals who carry the C9ORF72 gene mutation (Block et al 2016). In general, late age of onset of psychiatric symptoms should be a red flag when considering whether an individual might have a neurodegenerative disease. 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 their history. As such, 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 (Folstein et al 1975) are typically insensitive to the earliest changes in cognition that occur in frontotemporal dementia. Patients frequently receive full marks, 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 (Cummings 1997) or the Frontal Systems Behavior Scale (Grace et al 1999), can also be extremely helpful. If the patient simply displays a frontal or dysexecutive syndrome without significant behavioral issues or a history of personality change, the diagnosis is more likely to be early-onset Alzheimer disease. 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. Management Management of frontotemporal dementia is achieved through both pharmacological and behavioral interventions. Currently, aside from riluzole for amyotrophic lateral sclerosis, there are no FDA-approved medications for treating symptoms in frontotemporal dementia. Serotonin-reuptake inhibitors such as paroxetine and fluvoxamine have proven most effective in treating behavioral symptoms such as irritability, disinhibition, restlessness, and compulsive behaviors. 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 (Tsai and Boxer 2014). 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 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 (Seltman and Matthews 2012). 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.

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12 Shinagawa S, Ikeda M, Fukuhara R, Tanabe H. Initial symptoms in frontotemporal dementia and semantic dementia compared with Alzheimer's disease. Dement Geriatr Cogn Disord 2006;21(2): PMID Snowden JS, Thompson JC, Stopford CL, et al. The clinical diagnosis of early-onset dementias: diagnostic accuracy and clinicopathological relationships. Brain 2011;134(Pt 9): PMID Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. Arch Neurol 1964;10: PMID Tsai RM, Boxer AL. Treatment of frontotemporal dementia. Curr Treat Options Neurol 2014;16(11):319. PMID 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): PMID **References especially recommended by the author or editor for general reading. Former authors David Knopman MD (original author), Sergio Starkstein MD, Maria Laura Garau MD, Andrew Kertesz MD, and Amanda K LaMarre PhD ICD and OMIM codes ICD codes ICD-9: Presenile dementia uncomplicated: Other frontotemporal dementia: ICD-10: Other frontotemporal dementia: G31.09 OMIM numbers Frontotemporal dementia; FTD: # Frontotemporal lobar degeneration with TDP43 inclusions, GRN-related: # Amyotrophic lateral sclerosis 10 with or without frontotemporal dementia; ALS10: # Frontotemporal dementia and/or amyotrophic lateral sclerosis 4; FTDALS4: # Profile Age range of presentation years Sex preponderance Female=male Family history Family history is positive in 25% to 50%, more common than Alzheimer disease 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

13 Occupation groups selectively affected none selectively affected Differential diagnosis list Alzheimer disease vascular disease endocrine or metabolic conditions neoplasms or paraneoplastic syndromes CNS infections dietary deficiencies dementia with Lewy Bodies dementia associated with parkinsonism mania depression bipolar disorder HIV dementia frontal or temporal brain tumors frontal or temporal trauma vascular dementia vasculitis manic-depressive illness multiple sclerosis demyelinating encephalomyelitis obsessive-compulsive disorder schizophrenia atypical encephalitis Associated disorders Alzheimer disease Argyrophilic grain disease Basophilic inclusion body disease Chronic traumatic encephalopathy Corticobasal degeneration Huntington disease Motor neuron disease Neuronal intermediate neurofilament disease Parkinson disease Parkinsonism dementia-amyotrophic lateral sclerosis of Guam Progressive subcortical gliosis Progressive supranuclear palsy Traumatic brain injury Vascular dementia Other topics to consider Corticobasal degeneration Dementia associated with amyotrophic lateral sclerosis Genetics of movement disorders Hyposmia in neurodegenerative disorders Mental status examination Progressive subcortical gliosis Progressive supranuclear palsy Tauopathies with dementia and parkinsonism

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