24 Frontotemporal Dementia

Bradford C. Dickerson • Megan Quimby • Katherine Brandt • Diane E. Lucente • Bonnie Wong

INTRODUCTION then largely incorporated with some simplification into the fifth edition of the American Psychiatric Association Diagnostic and Professor Arnold Pick first reported, in 1892, a 71-year-old Statistical Manual in 2013. patient with progressive language and cognitive decline, and Although terminology remains confusing in this family of grossly visible anterior temporal lobe atrophy post-mortem.1 diseases, we continue to recognize the syndromes of bvFTD, This is thought to be the first report of a patient with what semantic variant PPA (svPPA), and nonfluent or agrammatic was later called semantic dementia by Professors John Hodges variant PPA (nfvPPA) to present in the context of a neuropatho- and Julie Snowden. Professor Alois Alzheimer subsequently logical family of diseases termed frontotemporal lobar degener- described the microscopic histologic abnormalities that were ation (FTLD). The third major subtype of PPA, the “logopenic” later called “Pick’s disease” by Drs. Onari and Spatz. Professor variant, is usually associated with AD pathology. FTLD is a Schneider published a detailed report on clinical course of the loosely knit group of neurodegenerative diseases that preferen- disease, highlighting the insidious early changes in behavior and tially affect the frontal and anterior temporal lobes, with relative personality and—in contrast with Alzheimer’s disease (AD)— sparing of other cortical regions in many cases, and often affect- the typical relative preservation of memory and orientation.2 ing basal ganglia and in some cases basal forebrain and brain- Through most of the rest of the century, patients with behav- stem nuclei. Largely for reasons of pathological overlap, several ioral-comportmental dementias were usually diagnosed as hav- other diseases have also now been included in this clinical and ing “Pick’s disease.” In the 1980s and 1990s, Professors Marsel pathological spectrum, including progressive supranuclear Mesulam, Sandra Weintraub, John Hodges, Julie Snowden, palsy (PSP), corticobasal degeneration (CBD), and FTD with Andrew Kertesz, and others reignited the interest of the behav- motor neuron disease or amyotrophic lateral sclerosis (FTD- ioral neurology and neuropsychiatry field in progressive apha- MND or FTD-ALS). sias.3–5 In the 1980s, the Lund6 and Manchester7 groups reported important early studies generating renewed interest in the behav- EPIDEMIOLOGY ioral phenotype of frontotemporal dementia (FTD), soon there- after proposing clinical and pathological diagnostic criteria.8 FTLD is thought to be the third most common degenerative In the late 1990s, formal international consensus diagnostic cause of dementia, after AD and Lewy body disease (LBD), criteria9 were developed for three major clinical phenotypes: accounting for 5–15% of dementias. FTLD often causes early “frontotemporal dementia,” “progressive nonfluent aphasia,” -onset dementia, typically affecting people in their mid-40s to and “semantic dementia.” In the early 2000s, interest in the syn- mid-60s. In people younger than 65 years old, it is thought to dromes we now call FTDs surged, leading to the development be the second most common cause of dementia. Nevertheless, and evolution of clinical and pathological criteria for the diag- pathologically confirmed cases have been reported with age of nosis and, more recently, an explosion in scientific understand- clinical symptom onset as young as age 2113 and as old as age ing of this family of diseases, as well as a robust international 85.14 Some epidemiologic studies raise the question of whether clinical-scientific organization devoted to the diseases (http:// it is being substantially underreported,15 suggesting that it may www.isftd.org) with biannual international conferences spark- be more common than previously thought, including in the ing tremendous collaborative energy.10 Important advances elderly.16,17 were formalized in 2011 when new consensus diagnostic crite- The incidence and prevalence rates of FTD have received lit- ria were published for primary progressive aphasia (PPA)11 and tle study with widely ranging results, from a prevalence of ~1.1 the behavioral variant of FTD (bvFTD).12 These criteria were per 100,000 cases in a study from the Netherlands18 to 15–17

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per 100,000 cases in two studies from the United Kingdom19,20 of pathologically unclassified FTLD cases were determined to and one from Northern Italy16 to 35 per 100,000 cases from a be immunoreactive to the fused in sarcoma (FUS) protein.43 door-to-door investigation in Southern Italy.21 With regard Therefore, except for a very small number of cases, the major- to incidence, an American study reported incidence rates in ity of FTLD neuropathology is now possible to classify as (1) Rochester, Minnesota of 2.2 per 100,000 between ages 40 and FTLD-tau (~40–50% of cases), (2) FTLD-TDP-43 (~40–50% of 49, 3.3 per 100,000 between ages 50 and 59, and 8.9 per 100,000 cases), or (3) FTLD-FUS (~5% of cases), and several other rare between ages 60 and 69.17 proteinopathies. Meanwhile, Professor William Seeley identified the selec- NEUROPATHOLOGY OF FTLD tive loss of the von Economo neuron (VEN), a specific cell type found in the anterior cingulate and frontoinsular cortex of The hallmark of the neuropathology of FTLD is its topographic evolutionarily advanced mammals.44 This spindle-shaped neu- distribution—which in some cases is strikingly focal—in the ron appears to be reduced substantially in these brain regions frontal and anterior temporal lobes, as well as often involv- in patients with FTLD but not in patients with AD. Remaining ing the hippocampus, amygdala, basal ganglia, diencephalon, VEN neurons showed pathologic features in FTLD, but brainstem nuclei, and sometimes cerebellum. appeared morphologically normal in AD. So-called fork cells Dr. Pick described the focal “knife-like” atrophy of ante- are also selectively vulnerable to FTLD pathology.45 Further rior temporal and frontal cortex that later came to be called research on selectively vulnerable cell types in FTLD may reveal FTLD.22,23 Using silver staining histopathologic techniques, new insights into the mechanisms of neuropathology and the Dr. Alzheimer reported two important microscopic lesions24: predilection for certain brain regions in these diseases. intraneuronal argyrophilic inclusion bodies which were later called the “Pick body” and achromatic neuronal balloon cells GENETICS OF FTLD which were called “Pick cells.”25 During the mid-20th century, 26–28 detailed reports of such cases provided further insights, Genetic Mutations Associated with FTLD describing the major features of what came to be known as “Pick’s disease,” including atrophy, neurodegeneration, and tau In the mid- to late-20th century it became clear that Pick’s disease pathology in prefrontal cortex, frontoinsula, anterior cingulate, could be observed in multiple generations.27,46–48 Approximately and anterior temporal cortex, with relative sparing of the pos- 20–40% of cases of FTLD exhibit a family history of a similar or terior third of the superior temporal gyrus and primary visual related condition, and 10–20% of cases have a family history con- cortex.29,30 It has since become clear that there is often prominent sistent with an autosomal dominant inheritance pattern.49 When white matter tau pathology as well,31 including near the cortical linkage studies identified loci on chromosomes 3, 9, and 17, gray matter-white matter junction.32 The basal ganglia, basal the hunt for specific genetic mutations was on. forebrain, and brainstem structures are prominently affected in In 1998, mutations of the microtubule-associated protein some patients and minimally affected in others.32 Drs. Kertesz tau (MAPT) gene on chromosome 17q21 were reported, with and Munoz conceptualized Pick’s disease as one of a spectrum many patients in the initially reported families also exhibiting of tauopathies that can present as PPA or bvFTD, including the parkinsonism, leading to the term FTD-parkinsonism linked to tauopathies PSP and CBD.33–36 chromosome 17 (FTDP-17).50,51 More than 44 MAPT mutations In the 1970s and 1980s, observations were made that some have been reported in over 100 families in the world.52 MAPT patients with what otherwise appeared clinically to be a frontal mutations are toxic gain-of-function abnormalities that reduce lobe-type dementia did not exhibit classical Pick’s disease neu- the ability of the tau protein to bind to and stabilize microtu- ropathology. Constantinidis and colleagues37 developed a clas- bules. The clinical phenotypes of patients with MAPT mutations sification system that recognized three major types of so-called include bvFTD, PSP syndrome, corticobasal syndrome (CBS), “Pick’s disease,” the first of which is classical Pick’s pathology, or rarely PPA. A fascinating aspect of this and other forms of the second is CBD, and the third lacked specific histological autosomal dominant FTD is that patients within the same fam- characteristics. Brun and Gustafson recognized a “frontal lobe ily with the same genetic mutation may present with distinct degeneration of non-Alzheimer type” that was neither AD nor clinical phenotypes, including PPA, CBS, or bvFTD.53 Pick’s disease, and other investigators also reported on this mys- Despite these advances in understanding, it became apparent terious disease,7,38 with one particularly memorable moniker that there were a number of families with autosomal dominant being “dementia lacking distinctive histology (DLDH).”39 FTLD with linkage to chromosome 17q21 who did not have In the early 2000s, it became clear that most DLDH cases MAPT gene mutations—none of the cases in these families that were immunoreactive to ubiquitin (FTLD-U). The break- came to autopsy had tau pathology, but instead demonstrated through came in 2006, with the demonstration that the major- what was originally described as DLDH and subsequently ity of cases showed intraneuronal inclusions of transactive DNA FTLD-U. The cause was elucidated in 2006 with reported muta- binding protein, molecular weight 43 kD (TDP-43).40 Professor tions in the progranulin (GRN) gene,54,55 which is also on 17q21 Ian Mackenzie and others41 described distinct subtypes (A, B, C, and very close to the MAPT gene. GRN mutations are associated and D) based on the intracellular localization and morphology with FTLD-TDP-43 pathology. More than 70 GRN mutations of the inclusions. This proteinaceous inclusion is also found in have been reported, which are thought to result in a degraded most cases of ALS, leading these diseases to be called TDP pro- protein whose function is lost (“loss of function”) due to haplo- teinopathies.42 Within a few years, most of the remaining ~10% insufficiency. Mutations in GRN are the second most common

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genetic cause of familial FTLD (4–26% of familial FTLD). Age Detailed clinical and clinicopathologic studies of families of symptom onset averages between ages 53 and 64, but var- in which FTLD is associated with particular genetic mutations ies widely, from as young as age 35 to as old as 88. The clinical have revealed important heterogeneity. Members of families phenotypes of GRN carriers include bvFTD (most common), with the same genetic mutation can develop pathology localized PPA, CBS, and a progressive amnesic syndrome similar to that in different brain regions, and therefore present with different associated with AD. GRN mutation carriers who present with clinical phenotypes. This was first described clearly in families bvFTD tend to exhibit apathy, executive dysfunction, and social with MAPT mutations.52,53,68 Although the major clinical pheno- withdrawal rather than disinhibition or compulsive behavior. type association with MAPT mutations is a behavioral-dysex- Those with PPA usually present with a nonfluent form, but may ecutive syndrome, some patients present with extrapyramidal have logopenic features. Parietal degeneration is common, more dysfunction, CBS, or PPA. This phenotypic heterogeneity was prominently than in most other forms of FTLD, and frequently later also observed in families with GRN mutations, with some giving rise to limb apraxia, spatial disorientation, and related patients developing bvFTD, some PPA, and some CBS or other symptoms. Extrapyramidal features are also common, and psy- phenotypes.69 Note that CBS is much more common in patients chosis is more common than in sporadic FTLD. Importantly, a with GRN mutations (~4%) than it is in patients with MAPT common variant in the gene TMEM106B modifies the expres- mutations (~2%). A few GRN cases have even presented with sion of GRN, delaying age of onset.56 a posterior cortical atrophy syndrome.70,71 Families with the Another major discovery in the genetics of FTLD was made C9orf72 mutation are now the prototypical example of mark- in 2011. Families with members affected with FTD or ALS or edly different clinical phenotypes, with some patients exhibiting both (FTD-ALS) had been reported with linkage to chromosome bvFTD, others with ALS, and others with FTD-ALS. The bvFTD 9p, but the responsible gene remained unknown until reports of phenotype associated with C9orf72 mutations is also unusual in an expanded GGGGCC hexanucleotide repeat in the chromo- that psychosis is much more prominent than in typical bvFTD; some 9 open reading frame 72 gene (C9orf72).57,58 This import- bizarre delusions are commonly a symptom very early in the ant finding brought the FTD and ALS research communities course of the C9orf72 bvFTD phenotype.72 A growing research together to investigate common biological mechanisms. It has effort is being devoted to trying to understand this genetic- since become clear that C9orf72 repeat expansions are the most clinical heterogeneity. Families such as this imply the presence common genetic cause of FTD (29% of familial FTD), ALS (38% of modifying influences on the initial localization of pathology; of familial ALS), and FTD-ALS (88% of familial FTD-ALS). In some of these are likely genetic but it is also possible that some patients without a family history of FTD or ALS, expansions in are developmental or environmental. C9orf72 are occasionally found, that is, patients with sporadic FTD or ALS are rarely determined to have this genetic abnor- Genetic Counseling and Testing in FTD mality.59 Age of symptom onset averages between ages 50 and 64, but—like GRN—also varies widely, from as young as age 27 to as The clinical practice of genetic counseling and testing in old as 83. As with GRN, variants in TMEM106B seem to protect patients and families with FTD is complex; we and other spe- against FTD due to C9orf72 but does not influence ALS in the cialty groups follow an approach similar to that summarized in same way.60 The clinical phenotypes of C9orf72 include bvFTD, several reviews.73–75 The foundation for genetic counseling is a ALS, and FTD-ALS, with bulbar symptoms appearing to be more confident diagnosis of the likely etiology of the patient’s syn- common than in sporadic ALS. Psychosis and other neuropsychi- drome, since the likely molecular pathology dictates genetic atric symptoms, including anxiety, are much more common than considerations. When we begin working with a patient and in sporadic FTD. Memory loss is common, as are language symp- family we start by evaluating our confidence in the diagno- toms, although primary amnesic or aphasic phenotypes without sis. Then, we carefully obtain a family history ideally encom- behavioral symptoms are relatively uncommon. Extrapyramidal passing three generations, recording each blood relative’s features are not any more common than in sporadic FTD. age of death, cause of death if known, and general cognitive/ Tank-binding kinase 1 (TBK1, located on chromosome 12) behavioral/neuropsychiatric status in later life (Figure 24-1). was discovered in 2015 as the third most common cause of We summarize with the family that FTD and related conditions FTLD in a large Belgian cohort, after GRN and C9orf72.61 TBK1- were often not diagnosed or may have been misdiagnosed in related disease has been noted to cause bvFTD with prominent prior generations. If the family chose to have an autopsy per- disinhibition, and, in a series of cases, with memory loss as an formed, valuable information can be obtained, but in prior important associated symptom in the initial phase of the dis- generations brain autopsy is relatively infrequent. If there is a ease.62 Some patients exhibit ALS. Neuroimaging has demon- potential family history of FTD or related disorders, we ask strated widespread frontotemporal atrophy. Neuropathology in the family to try to obtain additional information or records two patients demonstrated TDP-43 type B pathology.62 about the affected relatives, and to consider meeting with our Very rarely, familial FTLD can be associated with muta- group’s genetic counselor. If there is clearly not a family his- tions in other genes, such as CHMP2B63 and valosin-contain- tory of FTD or related disorders, and family members lived ing protein (VCP).64 In 2009, mutations in the FUS gene were past typical age of onset, there is usually a low likelihood of the discovered in association with familial ALS,65,66 but nearly all presence of a genetic mutation.76 If family history information FTLD-FUS cases examined to date do not appear to be associ- is unavailable or blood relatives died at a younger age, we sug- ated with FUS mutations or other known genetic abnormalities gest that the patient/family work with our genetic counselor to (i.e., they appear to be sporadic).67 discuss the issues involved. In a patient with FTD with age of

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of disease drops to the general population risk, and they will not pass the genetic abnormality to offspring.

CLINICAL CHARACTERISTICS OF FTLD

It is essential to try to determine the earliest clinical symptoms that were present, which may or may not be the symptoms most troublesome to the patient and/or family at the time of evalua- tion. A direct history with a spouse or adult child informant in private is essential, and it is often helpful to obtain documen- tation through medical records or other notes of concerns at the time of symptom onset. Although time-consuming, this approach facilitates an open discussion of symptoms (infor- FIGURE 24-1. Pedigree of a family with familial FTD with all cases mants may be uncomfortable discussing some issues in front presenting with behavioral variant FTD with age of onset in the of the patient) and enables the clinician to evaluate insight and late 50s or early to mid-60s. The genetic mutation identified in this concern in the patient separately from influence by informants. family was MAPT P301L. Six out of seven cases in this family were Lack of awareness or concern is often a core element of the clini- male, leading family members to believe women in the family cal presentation in patients with bvFTD. Since many of the early were at lower risk. Since this genetic abnormality is inherited with symptoms are related to changes in affect or personality, it is an autosomal dominant pattern, it was important during genetic not surprising that patients may first present to psychiatrists or counseling to emphasize the fact that each offspring has a 50% other mental health professionals. likelihood of inheriting the mutation regardless of sex. Behavioral Variant FTD onset younger than 50 years, we and others often recommend FTLD neuropathology is often associated with a clinical pheno- that the patient undergo genetic testing. In patients who are type involving the insidious development of changes in inter- older than 50, we typically do not recommend genetic testing personal and emotional behavior, commonly accompanied by when there is not a family history of FTD or related disorders executive dysfunction. This clinical syndrome has historically and family members lived past age 75, since there is such a low been referred to as “Pick’s disease” but is now called bvFTD. likelihood of an abnormality. Based on a variety of concerns regarding prior criteria,77 new When the patient’s genetic test results are returned, there are international consensus diagnostic criteria were published in three possible results: positive, negative, or variant of unknown 2011 (Table 24-1).12 BvFTD appears to be the most common significance (VUS). The interpretation of a VUS can be difficult syndrome associated with FTLD. The specific symptoms of for health professionals, and, if possible, it may be worth testing this variant depend on the particular regions of frontotempo- additional affected or unaffected family members if available. ral cortical and frontostriatal brain systems involved and their The identification of a positive test result for a known, patho- laterality. genic FTD gene mutation in a patient usually has a powerful Disinhibition is a common early symptom, and can manifest impact on the family and patient. A genetic counselor can guide as socially inappropriate behavior such as overly familiar interac- families in planning the disclosure of results to other family tions with strangers; loss of manners or violations of social nor- members. In some families, such results may provide relief in mative behavior such as public urination or changes in behavior explaining a mysterious familial condition, while in other fam- during social meals; or impulsive actions such as unnecessary ilies this kind of result may lead to fear and stigma. Genetic or excessive purchasing or shoplifting.78–80 Sometimes patients counseling plays an important role in helping family members who are very active, jocular, and making rash decisions or going with this complex and emotionally challenging medical infor- on spending sprees can be mistakenly diagnosed with mania or mation. If a patient with FTD is found to have a pathogenic hypomania. Disinhibition appears to be related particularly to mutation associated with FTD, first-degree relatives have a 50% orbitofrontal and cingulo-opercular abnormalities in FTD.81 chance of inheriting it (since they are autosomal dominant). Another very common early symptom is apathy, including loss Asymptomatic blood relatives can choose to undergo presymp- of interest in hobbies or leisure activities and social withdrawal82–84; tomatic genetic testing under the guidance of a genetic coun- these behavioral changes are often mistaken for depression. Yet selor. Most genetic counselors follow the so-called Huntington’s patients with bvFTD do not usually exhibit sadness or cry, do disease protocol for performing this kind of counseling and not talk about concerns, worries, or thoughts of worthlessness testing. Individuals who test positive for a pathogenic mutation or hopelessness, and do not usually exhibit the loss of appetite will almost certainly develop symptoms if they live long enough or sleep disturbance often seen in depression. Some investiga- and each offspring has a 50% chance of inheriting the genetic tors have suggested that bvFTD may present as a “disinhibited” abnormality. The types of symptoms and age of onset vary by or “inert” (apathetic) subtype80 while many patients present with gene and are best discussed with a genetic counselor experi- intermixed symptoms of both types.85 Atrophy in the anterior cin- enced with FTD. If individuals test negative for the pathogenic gulate cortex, dorsolateral prefrontal cortex,84 and striatum86 has FTD gene mutation that runs in their family, their lifetime risk been observed in association with apathy in bvFTD.

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TABLE 24-1 • Diagnostic Criteria for bvFTD. Compulsive, ritualistic, or repetitive behaviors are common in bvFTD, often early in the illness, and can be very distressing Evidence of neurodegenerative disease by progressive 92,93 deterioration of cognition or behavior based on observation to family members. In some cases, they may be the present- 94 or history ing symptom. Examples of these symptoms include repeti- tive “projects” (e.g., stereotyped writing of greeting cards), Possible bvFTD (at least 3 of the following must be present chores (e.g., repeated emptying of trash), or playing of card early [<3 years] in the course) or computer games or repetitive watching of a particular tele- Behavioral Socially inappropriate behavior; loss of vision show.95 Speech patterns may be stereotyped (e.g., catch disinhibition manners or decorum; impulsivity phrases, telling of stories as if by a script). Some of these symp- Apathy or inertia toms appear similar to those of obsessive-compulsive disorder Loss of sympathy or Diminished response to other people’s (OCD) but usually bvFTD patients do not describe obsessive empathy needs and feelings; diminished social thoughts or any relief of such thoughts by a compulsive activ- interest ity, as is typically described in primary OCD. Some patients Perseverative, Simple repetitive movements; complex have very rigid routines that must be performed identically stereotyped, or compulsive or ritualistic behavior; each day (often at a particular time, associated with “clock compulsive behavior stereotypy of speech watching”); if these routines are disrupted, some patients Hyperorality and Altered food preferences; binge eating become very upset. These symptoms may change as the disease dietary changes or increased consumption of alcohol or progresses, in some cases becoming simpler. Simple repetitive cigarettes; oral exploration of inedible behaviors include tapping or moving a limb, licking lips, pick- objects ing skin, grunting, or moaning. These may appear similar to Neuropsychological profile of executive dysfunction with relative choreiform movements seen in dyskinetic movement disor- sparing of episodic memory and visuospatial skills ders or tardive dyskinesia. Anatomic abnormalities associated Probable bvFTD with compulsive behaviors include striatal and anterior tem- poral atrophy.96–98 Meets criteria for possible bvFTD Changes in eating behavior are common and may include Exhibits functional decline altered food preferences (such as an increased sweet tooth or a Imaging results Frontal and/or anterior temporal rigid stereotypy in the foods eaten from day to day) or gluttonous consistent with bvFTD atrophy or hypometabolism or or binge-like eating.95,99 This may—but does not always—result perfusion in substantial weight gain. Normative social eating conventions bvFTD with definite FTLD pathology are often violated, including rapid eating or stuffing food in the Meets criteria for possible or probable bvFTD mouth, taking food from others’ plates, or belching. Patients may exhibit changes in the consumption of alcohol or ciga- Histopathological evidence of FTLD on biopsy or autopsy rettes, sometimes resulting in extreme intoxication or vomiting. Presence of a known pathogenic mutation Occasionally early, but more often later, in the course of the dis- Exclusionary criteria for bvFTD ease patients may explore inedible objects by placing them in Pattern of deficits is better accounted for by another their mouth similar to the behavior seen in Kluver-Bucy syn- neuromedical disorder drome. The neurobiological basis of changes in eating behav- Behavioral disturbance is better accounted for by a psychiatric ior in FTD appears to involve right lateralized ventral anterior disorder insula, striatum, and orbitofrontal cortex on structural MRI voxel-based morphometry,100,101 as well as degenerative changes Biomarkers strongly indicative of Alzheimer’s disease or another 102,103 neurodegenerative process in the hypothalamus. Executive dysfunction (problems with organization, plan- Source: Rascovsky et al.12 ning, sequencing, decision making, multitasking, or monitoring performance) is very common in bvFTD.95 Symptoms described by family members often include difficulty with financial man- Loss of empathy or sympathy toward the spouse, other family agement, poor decision making, inability to complete tasks members, and friends is very common and can be subtle in some (particularly novel tasks), or not recognizing or correcting mis- cases, depending in part on premorbid personality traits.87–89 These takes. Despite the report of these symptoms in daily life, patients behavioral changes may concern family members for some time may still perform within normal limits on neuropsychological before it becomes obvious that something is wrong, which often tests of executive function.104 Progressive impairment of execu- occurs when the patient exhibits a highly unusual response to an tive abilities may lead to job loss or disastrous mismanagement event that almost universally provokes a vigorous, uniform emo- of money. In many cases, it can be difficult to determine which tion in most people, such as the death of a close friend or family problems in daily life are caused by executive dysfunction as member, or the birth of a child. Even under these circumstances, opposed to apathy. This is not surprising given that constructs of the behavior is commonly attributed to depression or another the executive functions usually include initiation or “energiza- psychiatric illness or to stress or a mid-life crisis. Right anterior tion” as a component process. Although executive dysfunction temporal cortex, anterior insula, and striatal abnormalities have is typically thought of as being caused by dorsolateral prefron- been most consistently identified as related to loss of empathy.90,91 tal cortical involvement, it can originate in anterior cingulate,

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insular, parietal, or subcortical nodes of large-scale executive Psychosis has been thought unusual in bvFTD, but the dis- systems. covery of the C9orf72 expansion has highlighted the common Another important clinical feature of bvFTD is lack of insight. presence of psychosis in patients as well as non-demented fam- This symptom was considered a core element of the Neary et al.9 ily members with this genetic mutation.72,118 diagnostic criteria but was not included in the new international consensus diagnostic criteria because it was thought to be too Progressive Aphasic Subtypes of FTLD difficult to ascertain consistently. Nevertheless, it is well estab- lished that many patients with bvFTD, and some patients with The other major clinical phenotype associated with FTLD semantic dementia (SD), have a striking lack of insight105–107 involves a primary language disturbance. According to the even when confronted with obvious impairments. Clinically, Neary et al.9 diagnostic criteria, such a patient would have this can be particularly challenging when the patient refuses to been diagnosed as having a language-predominant form of make office follow-up visits because he or she is convinced there FTD (and likely FTLD), and further subtyped into progres- is not a problem. Lack of insight in FTD has been associated sive nonfluent aphasia (PNFA) or SD. At present, the approach with right-lateralized ventromedial prefrontal atrophy.108 suggested by the recent international consensus diagnostic Another core feature of bvFTD is personality change. criteria for PPA11 focuses on determining the precise clini- Alterations in personality can be prominent in bvFTD and also cal phenotype without reference to the presumed underlying in SD.109 Although questionnaire-based instruments to assess pathology. Three canonical clinical phenotypes of PPA are cur- classical dimensional personality traits are readily available, rently recognized: the nonfluent/agrammatic variant (nfvPPA, changes in personality might be best understood clinically by which likely captures most of the patients formerly diagnosed considering more specific process-oriented functions contrib- with PNFA), the semantic variant (svPPA, which likely cap- uting to personality traits. When faced with a family member tures most of the patients formerly diagnosed with SD), who says “my spouse is not the person I married, his/her per- and the logopenic variant (lvPPA). Some patients with clin- sonality is completely different,” it is incumbent upon the cli- ical phenotype consistent with SD do not meet criteria for nician to probe further to ascertain the specific changes being svPPA because they present with prosopagnosia or visual described. Some symptoms may include changes in the expres- object agnosia or with relatively prominent behavioral symp- sion or comprehension of emotion, social withdrawal or disin- toms and thus do not meet core criteria for PPA. lvPPA is most hibition, or loss of empathy. In some cases, a previously gruff frequently associated with biomarkers of underlying AD and or aggressive individual becomes docile. The patient’s insight ultimately AD pathology, and thus would not be considered into these changes is often poor. We have reported on a bvFTD a major clinical subtype of FTLD. Nevertheless, a minority of patient who developed the Geschwind syndrome of hyperreli- lvPPA patients do not demonstrate biomarkers of AD pathobi- giosity, hypergraphia, irritability, and other symptoms.110 Other ology in vivo119 and in fact have solely FTLD neuropathology symptoms that may also be described as personality changes post-mortem (usually FTLD-TDP-43).120 Thus, while lvPPA is include obsessive-compulsive behaviors, such as hoarding, and often considered nearly synonymous with an atypical language those involving changes in appetitive drives, such as sexual, eat- variant of AD, these recent observations support the inclusion ing, or drinking behaviors. of this clinical phenotype as a part—if small—of the FTLD Despite the inclusion in the 2011 bvFTD diagnostic criteria spectrum. of “the relative preservation of memory,” memory impairment As its name implies, PPA is a disorder that can only be diag- can be a prominent early feature in some cases of bvFTD,111,112 nosed when language is the sole of major dysfunction early in including those that are pathologically proven.113 In some cases, the illness, usually considered to be at least 2 years (Table 24-2); memory symptoms are reported by the patient and/or family when other cognitive dysfunction is clearly present, such as loss but test performance is normal; this may reflect executive con- of memory for daily events, visuospatial dysfunction, or behav- tributions to memory encoding or retrieval in daily life which ioral symptoms, the diagnosis of PPA cannot be made.121–123 In may be relatively controlled in the office setting.114 In other cases, some patients, language dysfunction can slowly progress and be day-to-day memory is preserved but psychometric test perfor- the principal impairment for as long as a decade, but in many mance is impaired due to the magnitude of executive or seman- patients, impairments in other cognitive functions emerge after tic deficits, thereby resulting in an overestimation of memory the first few years.124 impairment. In our clinical practice, we do not avoid the clinical Although patients with progressive aphasias may have per- diagnosis of bvFTD in a patient with well-documented amnesia sonality, comportmental, and social symptoms, they are, by if the remainder of the clinical presentation is consistent with definition, less prominent than the language impairment early bvFTD, especially if supported by neuroimaging test results. in the course of the disorder. The presence of prominent early Unlike the language-dominant types of FTLD, language neuropsychiatric or behavioral symptoms is generally consid- may be relatively intact early in the course of bvFTD. This is ered exclusionary for PPA. In spite of this distinction, which is particularly true on basic neuropsychological tests of language particularly important for clinical research on these disorders, performance. Higher-order language abilities at the level of dis- some patients whose diagnosis would be best considered as PPA course,115 as well as emotionally laden forms of communication have prominent early neuropsychiatric or behavioral symptoms including prosody , irony, sarcasm, and humor, are often abnor- (a point discussed briefly in the 2011 diagnostic criteria). Many mal early in the course of bvFTD.91,116 As the disease progresses, others have relatively mild but notable symptoms, particularly semantic and other impairments often become prominent.117 as PPA progresses to involve abilities beyond language.125

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TABLE 24-2 • Diagnostic Criteria for PPA. motor speech disorder, such as apraxia of speech (AOS) or dysar- thria. Although a strict definition of PPA requires the presence of The following three conditions must all be present. aphasia, some patients present with an isolated dysarthria and/or 1. A new and progressive language disorder (aphasia) as AOS135,136 without obvious aphasia. NfvPPA is commonly associ- documented by abnormalities in one or more of the ated with distorted sound substitutions and additions with length following domains: grammaticality of sentence production, or complexity effects, while “pure” AOS or nfvPPA with promi- word retrieval in speech, object naming, word and sentence comprehension, spelling, reading, repetition. nent AOS are characterized by syllable segmentation and length- 2. Relative preservation of episodic memory, executive ened intersegment durations. Some patients also exhibit limb functions, visuospatial skills and comportment as apraxia or other elements of an extrapyramidal (parkinsonian) documented by history, medical records, and/or syndrome.137 Many others develop these symptoms or others con- neuropsychological testing. sistent with a CBS or a PSP syndrome as the illness progresses. 3. Imaging and other pertinent neurodiagnostic test results that The localization of symptoms in nfvPPA is typically linked rule out causes other than neurodegeneration. to the prefrontal rolandic operculum, anterior insula, and pos- Nonfluent/Agrammatic variant (nfvPPA) sibly the opercular portion of Broca’s area. The diagnosis of Impaired grammatical structure of spoken or written language imaging-supported nfvPPA indeed requires focal left-sided per- in the absence of significant word comprehension impairments. isylvian regions involvement, particularly of the inferior pos- 11,138,139 Output is usually of low fluency. terior frontal gyrus and insula. The involvement of the Semantic variant (svPPA) “dorsal” language pathways appears to be responsible for syntac- tic dysfunction.140 AOS is associated with neurodegeneration in Impaired word comprehension in the absence of significant the left posterior inferior frontal lobe or supplementary motor impairment of grammar. Object naming is severely impaired. area, while orofacial apraxia is associated with neurodegener- Output is motorically fluent but often contains word-finding hesitations, semantic paraphasias, and circumlocutions. ation in the left middle frontal, premotor, and supplementary motor cortical; and limb apraxia is associated with left inferior Logopenic variant (lvPPA) parietal lobe damage.137,141 No significant grammar or word comprehension impairment. In nfvPPA, neuropsychiatric symptoms are less frequent Speech contains many word-finding hesitations and phonemic initially, but as the illness progresses it becomes increasingly paraphasias. Object naming may be impaired and may common to see apathy, depression, or irritability. In some cases constitute the only significant finding in the examination. these symptoms are present early in the illness, which may Current classification systems require repetition impairments for diagnosing this subtype. lead to misdiagnosis as a primary psychiatric disorder (often depression). Anomic subtype All features as in lvPPA except that repetition is intact. In some cases, this subtype represents a prodromal stage of svPPA.197 Semantic Variant PPA Mixed subtype Patients with svPPA develop prominent word-finding difficulty Impaired grammatical structure and word comprehension, even in spontaneous speech, maintaining fluency but with a tendency at the early stages of disease. to rely more on high (rather than specific low) frequency nouns, and exhibiting severe anomia in confrontation naming tasks. Source: Gorno-Tempini et al.11 As semantic memory loss progresses, it impairs single-word comprehension, impacting the differentiation between with- 142 Nonfluent/Agrammatic Variant PPA in-category subordinate words. As the disease progresses, between-category words are affected and concepts become The core features of nfvPPA are an impairment of grammar and, blurred, although speech may still be fluent. Impaired reading commonly, defective motor speech production. The character- of words with irregular spelling is also typical of this disorder.143 istics of nonfluent speech are typically an effortful and halting Syntactic processing is typically spared.144 Nonverbal skills are speech with sound errors and distortions, with agrammatism in usually minimally affected in the early stages.142 language production and/or comprehension.126,127 Agrammatism The dominant hemisphere anterior temporal lobe is often is characterized by omissions of grammatical words and mor- prominently atrophic even at initial presentation, with varying phemes, reduced production of verbs,128,129 incorrect argument degrees of bilateral involvement.145,146 The atrophy predom- structures, and decreased utterance length and complexity, often inantly involves inferior and middle temporal gyri, anterior with reduced mean length of utterances and fewer embedded fusiform gyrus, perirhinal cortex, amygdala, and hippocam- clauses.115,130,131 Comprehension of simple declarative sentences pus,147–149 but the most prominent atrophy appears to be at the is usually good, reflecting relatively intact single-word compre- tip of the left temporal pole.150 Preserved motor speech and syn- hension, but performance on tasks requiring the comprehen- tactic function reflect the integrity of the dorsal language regions sion of complex syntactic structures is typically impaired.132,133 and of the corresponding white matter connections.146,151 The disorder most often evolves to an aphasic picture similar to SvPPA patients commonly exhibit neuropsychiatric symp- Broca’s aphasia due to cerebrovascular disease.130,134 toms, often relatively early and in a fairly stereotypical fashion. Some patients with nfvPPA present with relatively pure Many of these symptoms are similar to those of bvFTD, includ- agrammatic language, while many present with an accompanying ing loss of empathy, changes in eating behavior, compulsive

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behavior, and disinhibition. Although these symptoms are hypothesis of a phonologic short-term memory impairment as highly consistent with FTD, depending on when they begin and the core cognitive deficit. As will be discussed below, this clini- how they are reported by informants, it may be difficult for the cal phenotype is usually associated with underlying AD pathol- clinician to be confident in assigning a subtype diagnosis (i.e., ogy rather than FTLD. bvFTD vs. svPPA vs. SD). The Neary et al.9 diagnostic criteria for In lvPPA, neuropsychiatric symptoms are relatively infre- FTD included loss of sympathy or empathy and narrowed pre- quent early but increase as the illness progresses and include occupations (mental rigidity) as diagnostic features. Aberrant agitation, anxiety, irritability, and apathy. In many cases we have motor behavior is also reported as common in some studies; seen, the clinical phenomenology of neuropsychiatric symp- in our experience this often includes elaborate kinds of move- toms appears similar to that seen in typical clinical forms of AD. ments related to repetitive or compulsive behaviors. Depression is also reported as common in svPPA in some studies; in our DIAGNOSTIC ASSESSMENT OF SUSPECTED FTLD experience, however, at least some patients say certain phrases repetitively (i.e., “catch phrases”) that appear to express nega- As with all neurodegenerative diseases, a careful clinical his- tive emotion (e.g., “I feel so stupid,” “I used to know that and tory taken from the patient and a knowledgeable informant now I just don’t know anything”), but with minimal affective is usually the single most important element of assessment. behavior consistent with depression, and a structured interview Specific FTD symptom inventories,80,95 such as the Cambridge with some of these patients’ caregivers reveals little behavior in Behavioral Inventory,155 the Frontal Behavioral Inventory,156 daily life that appears consistent with a diagnosis of depression. and the Neuropsychiatric Inventory (NPI),157 are very useful in As the degeneration progresses, both anterior temporal lobes ascertaining symptoms of FTD in a structured manner. Some of as well as the ventromedial and posterior orbital frontal corti- these instruments can be given to caregivers in advance as ques- ces, the insula, anterior cingulate cortex, and amygdala often tionnaires, or used to structure an office-based interview. We become involved, overlapping with the imaging features of have developed structured assessment scales for patients with 152 bvFTD patients. FTD and related disorders that provide semiquantitative ratings Some patients present with semantic impairment that is of the types and severity of specific languageimpairments— ­ more prominent for objects, people, or environmental sounds the Progressive Aphasia Severity Scale (PASS)139—and social rather than words, suggesting a right-lateralized syndrome that impairments—the Social Impairment Rating Scale.158 As men- is otherwise very similar to svPPA but likely best classified as tioned above, we believe it is essential to interview the patient 153 SD. SD is a broader diagnostic construct that can be consid- separately from informants. The interview with the patient ered an umbrella term for patients with svPPA and patients with should include a psychiatric evaluation of mood and affect, agnostic and/or amnesic impairments as well as semantic mem- thought content (e.g., is there evidence of psychosis?), and ory loss. insight. Some instruments, such as the Everyday Cognition 159 Logopenic Variant PPA (Ecog) scale, have both patient and informant forms which allows for an assessment of insight by comparing the two. Patients with lvPPA present with variably hesitant speech and An important step in history-taking is to try to determine typically without articulation deficits, but with many false starts whether the symptoms are interfering with independent func- and phonological errors, long word-finding pauses, impaired tion or not (i.e., does the patient have a clinical stage of impair- sentence comprehension and naming, with spared single-word ment consistent with dementia or mild cognitive impairment?). comprehension and nonverbal semantics.126 Patients with this Some patients with PPA present with no or minimal functional syndrome typically exhibit a conduction aphasia-like deficit in impairment (problems performing activities that had previously repetition that is attributed to impaired phonological loop func- been routine for the person, such as occupational activities or tions which is considered a core element of the syndrome.133,154 community or household activities). If function is impaired in Since all patients pause when they are attempting to retrieve PPA, by definition it should be attributable to compromised lan- low-frequency words, and many patients make speech-sound guage and not to impairments in other domains of cognition or errors and have difficulty understanding of grammatically com- behavior. We have seen many patients with a progressive apha- plex sentences, they may be misdiagnosed as having nfvPPA. sic multidomain syndrome, with prominent aphasia but also But in fact their unconstrained, spontaneous speech is often flu- impaired executive function, memory, or other functions. It ent, the speech-sound errors are phonologic rather than articu- may be possible to clearly document by history or through med- latory, and grammatical production and comprehension is not ical records that such a patient would have met PPA diagnostic impaired when sentences do not exceed their limited auditory- criteria previously, but they cannot be diagnosed with PPA cur- verbal working memory capacity (or when they are reading or rently if these other domains are impaired. In other patients, it writing). Thus, fluency in lvPPA has been described as “inter- may be impossible to determine whether they ever fit into the mediate”154; we prefer to describe them as “variably” fluent. construct of PPA, and they are best described as having a mul- Note that some authors have used the term anomic aphasia to tidomain dementia with prominent aphasia (we often call this describe patients who fulfill lvPPA criteria but whose repetition “aphasic dementia” to differentiate it from amnesic dementia). is normal. Because the core symptoms relate to socioaffective func- The localization of neurodegeneration in lvPPA typically tion, many patients with bvFTD present after having lost involves the left posterior superior and middle temporal gyri, social or occupational function, and therefore would be diag- and inferior parietal lobule,126,138,139,154 consistent with the nosed with dementia even if cognitive examination and/or

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neuropsychological evaluation is within normal limits. Some and colleagues166 compiled a set of previously developed tests patients have prodromal behavioral symptoms for some period emphasizing “real-life” elements of executive function as well of time without symptoms or signs of cognitive impairment. as social cognition. This test battery demonstrated higher sen- Some patients with so-called “mild behavioral impairment” sitivity to mild FTD than many standard tests included in typ- (MBI) syndromes are in fact in the earliest stages of FTD, while ical dementia neuropsychological batteries. Another similar other patients with MBI have etiologies other than FTD such as approach was taken by Funkiewiez and colleagues, who assem- AD.160,161 Since these patients do not have cognitive impairment, bled the Social Cognition and Emotion Assessment (SEA), and and it can be difficult to be sure of the etiology at this clinical ultimately found that a subset (facial emotion recognition and stage, it is reasonable to classify such patients as having MBI, faux pas identification) of the original tests were most sensitive with further description of the clinical phenotype. In some to bvFTD, deriving the mini-SEA (Funkiewiez et al., 2012). cases this clinical phenotype may be consistent with bvFTD and The combination of findings from the assessments described in other cases it may be ambiguous, or consistent with late-onset above can be used to determine whether a patient fulfills cur- bipolar illness or another kind of syndrome. rent diagnostic criteria12 for “possible” bvFTD or one of the pro- In the initial office assessment of a patient with one of the gressive aphasias. For bvFTD, the clinician’s confidence can be FTD clinical syndromes, a basic cognitive examination is essen- formally elevated to “probable” bvFTD if neuroimaging findings tial. Most commonly used cognitive screening instruments, are present as described next. A similar approach is taken by such as the Mini Mental State Examination, are insensitive to the many clinicians in diagnosing PPA, arriving at a diagnosis of cognitive and behavioral deficits of bvFTD. Office-based gen- imaging-supported PPA.11 eral cognitive testing instruments thought to be more sensitive When a patient is suspected of having PPA, or when commu- to FTD include the Montreal Cognitive Assessment (MoCA)162 nication or speech symptoms are present, it can be very helpful and Addenbrooke’s Cognitive Examination (ACE) III.163 The to obtain a consultation with a speech-language pathologist. An Frontal Assessment Battery164 is a brief (~10 minutes) cognitive evaluation by a speech-language pathologist offers an oppor- and psychomotor assessment that has demonstrated sensitiv- tunity to clarify the diagnostic formulation, may provide ideas ity to FTD. Although these tests will often identify deficits in to develop compensatory strategies, or may help identify and patients with FTD, some patients perform normally early in the monitor speech or swallowing impairments. Speech patholo- course of the disease. In contrast, some patients with language gists offer a growing array of approaches to the development of impairments have a great deal of difficulty with tests such as the treatment approaches for patients with PPA or other forms of MoCA, leading to overestimation of their impairments because FTD (Kortte & Rogalski, 2013). these tests involve many verbally mediated cognitive tests. Finally, a neurologic examination is essential, working espe- Neuroimaging and Other Diagnostic Tests cially to determine whether there are abnormalities in eye movements or gait, limb or buccofacial apraxia, extrapyramidal Neuroimaging is an important part of the diagnostic workup of signs, primitive reflexes, or evidence of motor neuron disease. FTD, and has made valuable contributions to our understand- These signs may provide important indications suggestive of ing of the specific subtype disorders. Both structural (MRI) and possible PSP or CBD pathology, and may raise concerns regard- functional (PET, SPECT) neuroimaging may be valuable for the ing motor dysfunction as a contributor to functional impair- investigation of anatomic, metabolic, or perfusion abnormali- ment. Impersistence, perseveration, and distractibility can ties in the spectrum of FTD. present challenges during the neurologic exam but are helpful MRI is critical in the diagnostic workup of suspected FTD signs suggestive of frontal systems dysfunction. for both the exclusion of other potential causes of slowly pro- Neuropsychological assessment can be invaluable in patients gressive frontal lobe syndromes, such as tumors, cerebrovascu- suspected of having an FTD-spectrum disorder. Although some lar disease, or the newly identified “sagging brain syndrome,”167 patients may perform adequately on brief office-based cogni- and for the identification of abnormalities consistent with FTD tive testing typically performed by a neurologist, psychiatrist, neurodegenerative syndromes. Frontal and/or anterior tempo- geriatrician, or other physician, the neuropsychologist may be ral atrophy is the typical finding, and is often more prominent in able to detect abnormalities on extended testing using perfor- the right hemisphere in bvFTD and the left hemisphere in PPA mance-based measures sensitive to functioning across cog- (Figure 24-2A). Metabolic or perfusion imaging can be useful nitive domains. The use of standardized neuropsychological in addition to MRI for the identification of abnormalities when tests allows for comparison of the patient’s cognitive abilities anatomic changes are subtle or undetectable (Figure 24-2B). In to that of an age- and education-matched normative sample, some cases, both structural and functional neuroimaging may providing a measurement of the magnitude of departure from be normal early in the course of what ultimately declares itself normal/intact performance, and serving as a valuable baseline over time as FTD.165 Electroencephalography is not commonly against which future evaluations can be compared. The spe- recommended in the diagnostic evaluation of suspected FTD, cific profile of spared or impaired cognitive abilities generated but may demonstrate anterior or focal slowing consistent with from neuropsychological testing also enables the clinician to frontal neurodegeneration. identify subtypes of FTD. In at least some very mild cases of Cerebrospinal fluid (CSF) biomarkers are being investigated FTD, however, performance on reasonably extensive neuropsy- in the clinical conditions thought to be due to FTLD pathol- chological assessment can be normal.165 Aiming to assemble ogy,168 but are not yet mature enough for use in clinical practice. a neuropsychological test battery tailored to bvFTD, Torralva In some cases, the exclusion of an atypical form of AD can be

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RH LH

A RH - Lateral B

FIGURE 24-2. A 58-year-old man presented with apathy, impulsive eating, and executive dysfunction. (A) MRI demonstrated bilateral (right greater than left) frontal, temporal, and parietal atrophy, quantified with a map of cortical thickness compared to controls. (B) FDG PET showed prominent bilateral (right greater than left) frontal and temporal hypometabolism. He was found to have a Q300X (premature termination) mutation in GRN. His clinical syndrome lasted 5 years from first symptoms to death. Post-mortem examination revealed the expected TDP-43 Type A pathology.

helpful by analyzing CSF for amyloid-β and tau. General CSF in light of several autopsy studies showing the presence of AD investigation may be valuable to rule out other neurologic dis- pathology in 20–30% of FTD cases, with or without the pres- orders if the patient has atypical features or a more rapid course. ence of additional FTLD-type pathology.174–177 The distribution If clinical evidence of motor neuron disease is present, espe- of PiB tracer uptake in these four cases was similar to that typ- cially if it is subtle, electromyography can provide valuable infor- ically seen in AD. Two of the cases carried clinical diagnoses of mation regarding the presence of upper or lower motor neuron bvFTD, and the other two were clinically diagnosed with SD. dysfunction, which may be critical for prognosis (Figure 24-3). Of note, some elements of the cognitive profiles and the FDG- PET metabolic deficits of these four cases showed features more In Vivo Neuroimaging of often associated with AD than FTLD. Of the two FTD patients who have come to autopsy in this series, one had a tauopathy Neuropathologic Markers and one had a ubiquitinopathy: both were PiB negative. With the advent of neuroimaging tracers that bind to specific A large multicenter study of more than 1200 patients with pathologic molecules, such as Pittsburgh compound B (PiB) PPA demonstrated that more than 85% of lvPPA patients exhib- for fibrillar beta-amyloid169 and a growing number of putative ited amyloid pathology, while only 20% of nfvPPA patients tau-binding ligands,170–173 it is possible to investigate clinico- demonstrated amyloid pathology and 16% of svPPA patients 178 pathologic relationships in vivo. Extensive efforts are underway showed amyloid pathology. At least some cases of likely to develop tracers specific for additional pathologic markers. underlying FTLD pathology in PPA patients may exhibit dual 179,180 This will surely lead to a revolution in our understanding of the pathology, and thus may have a positive amyloid PET scan. spectrum of FTD. In the first study of FTD with PiB, a compar- ison was made between PiB tracer uptake in 12 FTD cases, 7 CLINICAL COURSE OF FTD AD cases, and 8 controls. The FTD cases included five patients with behavioral FTD, two with FTD/ALS, four with SD, and The early symptoms help determine the major subtype of FTD, one with progressive aphasia. The results indicated that all AD but as the disease progresses, involvement of other frontotem- patients had “positive” PiB PET scans, 7/8 controls had negative poral and subcortical brain regions often result in the develop- PiB scans, while 8 of 12 FTD cases had negative PiB PET scans. ment of symptoms characteristic of the other subtypes of the Although this initially seemed to be a high number of amy- diseases.181 For example, patients with svPPA may develop dis- loid-positive FTD cases, it may not be particularly surprising inhibition, compulsivity, and other behavioral symptoms, while

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A B

FIGURE 24-3. A 59-year-old man presented with loss of empathy, aggression, lack of insight, executive dysfunction, and word- finding difficulties. Within 1 year of symptom onset he developed dysarthria and dysphagia and was found to have clinical evidence of motor neuron disease with bulbar predominance (tongue weakness, fasciculations, lip weakness, as well as mild shoulder weakness and fasciculations with lower extremity hyperreflexia and extensor plantar responses). Electromyography showed sharp waves, fibrillation potentials, and fasciculation potentials in cervical, thoracic, and lumbar myotomes with long duration, high amplitude, polyphasic potentials with reduced recruitment and rapid firing. (A) MRI demonstrated bilateral (left greater than right) frontal atrophy, quantified with a map of cortical thickness compared to controls. His clinical syndrome lasted 3.5 years from first symptoms to death. (B) Post-mortem examination revealed the expected TDP-43 Type B pathology (TDP-43 immunohistochemistry of dentate gyrus of hippocampus).

CASE VIGNETTE 24.1 A 50-year-old man presented with depression and left- Symptoms progressed to include episodic and semantic hand apraxia without rigidity, alien hand syndrome, or memory impairment, compulsive behavior, impulsive eat- eye movement abnormalities, followed shortly by exec- ing, and agitation. Some of these behavioral symptoms utive dysfunction, word-finding difficulty, and memory responded to antidepressant and anticonvulsant treat- loss. When he was first evaluated, the neuroimaging ex- ments, and additional behavioral strategies and educa- amination revealed markedly asymmetric dominant hemi- tion and support helped his family develop a structured sphere FDG-PET hypometabolism and atrophy extending care plan with the involvement of home health aides and from peri-Rolandic and dorsal parietal cortex into peri- companions. Along with the progression of symptoms, at- sylvian cortex and ventral temporal cortex, with relative rophy progressed over a 4-year interval to include ventral preservation of frontal cortex and striatum (Figure 24-4). and anterior temporal, insular, and posterior frontal cortex Initial clinical syndromic diagnosis was CBS. Dopaminer- (Figure 24-4). Eventually the disease progressed into a ter- gic treatments did not change symptoms, as is often the minal phase of severe rigidity with dementia lasting about case in CBS. He was treated with occupational therapy, a year, and he finally passed away in home hospice after an speech-language therapy, as well as psychosocial support 8-year clinical course. We expected to find CBD pathology, and multidisciplinary care planning with him and his fami- but neuropathological examination identified Pick’s dis- ly. Surprisingly (given his motor impairments),­ he was able ease (FTLD tau pathology, Pick’s type). Given the absence to enjoy skiing and playing pool as well as a variety of oth- of a family history and the identification of this pathology, er social and hobby-related­ activities for several years. His we counseled the family that this is typically a sporadic symptoms gradually progressed to include severe asym- condition for which other family members are not likely metrical hand apraxia with rigidity (resulting in a complete at elevated risk. To confirm this prediction, ­sequencing loss of function of his dominant hand), and he also exhib- of the MAPT gene was performed and did not reveal any ited an increasingly prominent aphasia with dysarthria. ­abnormalities.

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A D

B

E

C

FIGURE 24-4. A 50-year-old man with a clinical syndromic diagnosis of corticobasal syndrome. The first neuroimaging examination revealed markedly asymmetric dominant hemisphere FDG-PET hypometabolism (A, B, C, left column) and atrophy (A, B, C, right column) extending from peri-Rolandic and dorsal parietal cortex (A) into perisylvian cortex (B) and ventral temporal cortex (C) with relative preservation of frontal cortex and striatum. Along with the progression of symptoms, atrophy progressed from parietal and posterolateral temporal over a 4-year interval to include ventral and anterior temporal, insular, and posterior frontal cortex (D). Although this man’s clinical and imaging features pointed toward corticobasal degeneration as the likely etiology, histological examination revealed Pick bodies (E, left) and tau immunoreactive pathology (E, right) consistent with pathological Pick’s disease (frontotemporal lobar degeneration tau pathology, Pick type).

bvFTD patients may develop speech, language, and/or semantic TREATMENT OF AND CARE PLANNING FOR PATIENTS deficits. AND FAMILIES WITH FTD Overall, survival after diagnosis is typically 6–10 years, with PPA-semantic variant patients having the longest survival.182 Once a diagnosis of one of the forms of FTD is made, the cli- A more recent study suggests a slightly better prognosis for nician unfortunately needs to deliver the news that, at present, bvFTD patients, with a median survival of 4.2 years from diag- there are no disease-modifying therapies for FTD (as is the case nosis.183 The development of early motor symptoms or signs for all other major neurodegenerative diseases). Nevertheless, is a poor prognostic feature in all forms of FTD,184 as is early despite the fact that we are not yet able to reverse or slow the language impairment in bvFTD.183 Recent data suggest that SD progression of FTD and related disorders, these diseases are patients may commonly have a very slow progression, with 50% treatable if we approach the patient and family using a biopsy- of patients alive at 12.8 years after diagnosis in a large cohort of chosocial model of care plan development. Treatment includes 100 patients.185 The ultimate development of markers of the spe- empiric pharmacologic management of symptoms, nonphar- cific form of neuropathology may be important for prognosti- macologic management of symptoms, management of comor- cation, with one autopsy study of 71 patients indicating that tau bid conditions which may exacerbate cognitive-behavioral pathology was associated with shorter (3 years) survival than impairment, psychosocial support, and education of the family non-tau forms of FTLD pathology (8 years).186 and patient.187 A multidisciplinary team of specialists is instru- In our practice, we always discuss the value of autopsy with mental in caring for patients and families suffering from FTD.188 family members and with patients if possible (see the Case Pharmacologic and nonpharmacologic management depends Vignette as an illustration of the value of autopsy). Despite con- on the identification and grading of severity of specific symp- tinued improvements in the use of clinical and biomarker data for toms (including cognitive, behavioral, and motor symptoms), probabilistic prediction of FTLD or non-FTLD pathology, every followed by their prioritization and monitoring over time. specialized center continues to observe surprising cases. Not only Once this is done, judicious empiric use of medications can be is autopsy information important for providing family members tackled. At present, no medications are approved for the symp- with the greatest detail possible about the patient’s disease, it also tomatic treatment of FTD, but many medications have demon- contributes in extremely valuable ways to ongoing research efforts. strated utility in small studies or case series.189–191 For example,

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selective serotonin reuptake inhibitors or other antidepressants Ultimately, because the myriad of resources that may be can modulate disinhibition or compulsive behavior, stimulants helpful to patients and family members can be difficult to iden- or pro-dopaminergic agents can sometimes reduce apathy or tify, it is essential to dedicate time and effort toward special- attentional impairment, and anticonvulsants/mood stabilizers ized education for the patient/family through the clinician or or antipsychotic compounds can ameliorate aggression or agi- multidisciplinary team or the Association for FTD (http://www. tation.191,192 Side effects of these medications may in some cases theaftd.org/) or Alzheimer’s Association (http://www.alz.org). outweigh benefits, and patients always need close monitoring. Psychosocial support resources can also be valuable for nearly Cholinesterase inhibitors are generally not helpful in patients all families and for some patients. Evidence is accruing that with FTD, and in some cases may exacerbate problem behaviors. caregiver interventions improve quality of life in caregivers of Nonpharmacologic symptom management strategies gen- patients with FTD.196 The development of close links between erally require the expertise of an experienced specialist clini- the FTD specialty care team and the primary care physician cian or team.193,194 These include speech and language therapy is very important to assist in general management, including for communication or swallowing issues, occupational ther- monitoring comorbid conditions and considering the role of apy for problems with hand-eye coordination or planning standard prophylactic care in the context of FTD. that impacts instrumental or basic activities of daily living, Finally, it is critical late in the course of the illness to assist physical therapy for gait disorders, and in some cases psycho- patients and families with end of life care, facilitating access to therapy for the patient. A growing body of evidence supports palliative care resources and ideally obtaining nursing home the utility of speech-language therapy in PPA.195 A driv- and hospice care at the appropriate time. There continues to be a ing assessment is critical, as is the evaluation of financial or desperate need for residential or nursing facilities that have the health care decision-making capacity. Social work assistance capacity and skill to care for patients with FTD. And although with facilitating disability compensation can be very helpful. research at present focuses largely on understanding the dis- Paid or volunteer companions or home health aides to help ease and offers little if any novel putative treatment options for patients remain active yet safe can be valuable. Day programs patients with FTD, participation in studies can provide some or respite residential programs may play important roles at meaning in an otherwise entirely tragic situation. Ultimately, some point in the course of the illness. Advanced care plan- the quality of the partnership between care providers experi- ning discussions should be considered early in the course of enced with FTD and patients/families with these diseases is a the illness. critical factor that influences the experience of living with FTD.

Summary and Key Points ■■ Diagnosis can be challenging, and usually requires a compre- hensive multimodal assessment. ■■ Frontotemporal dementia (FTD) encompasses a spectrum ■■ Some cases of FTD arise as a result of an autosomal domi- of clinical dementia phenotypes including behavioral variant nant genetic abnormality; the three major genes associated FTD, primary progressive aphasias (PPA), corticobasal degen- with FTD include MAPT, GRN, and c9orf72, as well as sev- eration, progressive supranuclear palsy, and FTD with motor eral rare genes. neuron disease or FTD with amyotrophic lateral sclerosis. ■■ Management is at present focused on empirical treatment of ■■ The clinical syndromes of FTD arise from a diverse set of symptoms and supportive multidisciplinary care. pathological diseases known as frontotemporal lobar degen- ■■ The pathophysiology of FTLD is only beginning to be eration (FTLD), with two major types: FTLD tau and FTD understood, but is providing a foundation for clinical trials TDP-43, as well as several rare pathologies. of potential therapeutics. ■■ Age of onset is usually between 45 and 65, although cases as young as 21 and as old as 85 have been reported.

Multiple Choice Questions 2. The clinical presentation of FTD a. Often includes memory loss as an early feature 1. The following points are true regarding the pathophysiology b. Typically includes prominent behavioral or language of FTLD: symptoms a. FTLD involves the aggregation of proteins that have c. Often includes a prominent early motor component important cellular functions which are then disrupted d. Is usually obvious at first evaluation and easy to diagnose b. FTLD involves tau or TDP-43 pathology and possibly e. Can easily be confirmed with a blood test interactions between them in some forms of the disease c. Amyloid pathology plays a key role in FTLD d. Genetic abnormalities in some cases are illuminating FTLD pathophysiologic mechanisms e. a, b, and d

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3. The assessment of patients with FTD typically includes all of 4. Evidence supports the following treatment options for some the following except: patients with FTD: a. Detailed history a. Antidepressant medications b. Neurologic and psychiatric exam b. Speech-language therapy c. Brain MRI c. Cholinesterase inhibitors d. FDG PET d. Caregiver support e. Amyloid PET e. a, b, and d

Multiple Choice Answers 3. Answer: e Although amyloid PET may play a role in ruling out AD in 1. Answer: e some cases of FTD, it is not part of the typical clinical evalu- As discussed in the pathophysiology section, amyloid does ation at most centers in part because of availability. In many not play a role in FTLD. The other points are correct. cases, the clinician will be highly confident in the diagnosis after a, b, and c. 2. Answer: b Most patients with FTD present with behavioral or language 4. Answer: e symptoms. Although many patients have memory loss as part As discussed in the section on treatment, there is evidence of their clinical phenotype, it is not usually the most prominent for the use of each of these therapies in at least some patients early feature. Motor symptoms or signs often occur as FTD with FTD or their caregivers. Cholinesterase inhibitors are progresses, but only a minority of cases exhibit motor impair- not effective in treating FTD. ment as an early feature (i.e., PSP, CBS, or FTD-MND). There are no blood tests for pathologic markers of FTLD at present.

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