Frontotemporal dementia

Handbook of Clinical Neurology, Vol. 165 (3rd series) Psychopharmacology of Neurologic Disease V.I. Reus and D. Lindqvist, Editors https://doi.org/10.1016/B978-0-444-64012-3.00003-4 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 3

Frontotemporal dementia BRUCE MILLER1* AND JORGE J. LLIBRE GUERRA2,3 Memory and Aging Center and Global Brain Health Institute, University of California, San Francisco, CA, United States

1

2

Cognitive and Behavior Research Unit, National Institute of Neurology and Neurosurgery, Havana, Cuba 3

Global Brain Health Institute, University of California, San Francisco, CA, United States

Abstract Recent research reveals an overlap between frontotemporal dementia (FTD) and a variety of primary psychiatric disorders, challenging the artificial divisions between psychiatry and neurology. This chapter offers an overview of the clinical syndromes associated with FTD while describing links between these syndromes and neuroimaging. This is followed by a review of the neuropathology and genetic changes in the brain. We will illustrate the syndromic overlap that exists between FTD and several primary psychiatric disorders including bipolar affective disorder and schizophrenia. Emphasis will be placed on the behavioral variant of FTD (bvFTD), which is the common clinical syndrome seen with degeneration of the frontal lobes and is the most likely to be encountered in psychiatric settings.

The frontal lobes constitute about 40% of the human cerebral cortex and are divided into three main anatomic regions: primary motor cortex, premotor cortex, and prefrontal cortex. Prefrontal cortex functions remain elusive, but this cortical region plays a central role in the control of personality, judgment, planning and multitasking, drive, motivation, eating and other reward-related behaviors, and social regulation. Hence, disorders that affect this area usually overlap with primary psychiatric conditions. Studies that probe clinical disorders of the prefrontal cortex using MRI, EEG, transcranial magnetic stimulation, and neuropathology offer a clearer understanding of frontal lobe functions and are transforming clinical practice. The term frontotemporal lobar degeneration (FTLD) is a neuropathologic designation used to identify a group of neurodegenerative diseases of the frontal and anterior temporal lobes, associated with specific pathologies (Rabinovici and Miller, 2010). The principal clinical syndromes associated with FTLD are classified under the rubric of FTD, an umbrella term for three clinical variants distinguished by early and predominant symptoms: bvFTD; semantic variant primary progressive aphasia

(svPPA); and nonfluent variant primary progressive aphasia (nfvPPA) (Lanata and Miller, 2016). The most common FTD syndrome is bvFTD, which is characterized by early and often severely disabling changes in personality and behavior that carry a huge impact on the patient, family, and society. The full-blown syndrome may be preceded by a long phase of subclinical behavioral changes and social disruption, often occurring in the absence of cognitive impairment (Pressman and Miller, 2014). bvFTD shares many symptoms with primary psychiatric disorders including schizophrenia, obsessive–compulsive disorder, borderline personality disorder and bipolar disorder (Manoochehri and Huey, 2012; Pressman and Miller, 2014). Prevalence studies on bvFTD and the other FTD syndromes are challenging because many cases are misclassified, as the disease is largely unrecognized in the communities to which these patients present, including the courts, marriage counselors, addiction specialists, and human resource departments. Furthermore, the medical community is still unable to diagnose FTD in a reliable fashion. Additionally, the related neurologic conditions that involve movement, progressive supranuclear

*Correspondence to: Bruce Miller, M.D., Memory and Aging Center, University of California, San Francisco, CA, United States. Tel: +1-415-476-5591, Fax: +1-415-353-8292, E-mail: [email protected]

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B. MILLER AND J.J. LLIBRE GUERRA

syndrome, corticobasal syndrome, and motor neuron disease (MND) often show FTLD pathology, yet are rarely considered in epidemiologic studies (Knopman and Roberts, 2011; Onyike and Diehl-Schmid, 2013). Knopman and Roberts report that the total number of cases with FTLD syndromes ranges from 15 to 22 per 100,000 person and incidence rates are between 2.7 and 4.0 per 100,000 person/years. In the United States, at the minimum, 20,000–30,000 persons live with FTD (Knopman and Roberts, 2011; Onyike and DiehlSchmid, 2013). bvFTD cases have been reported as early as the second decade and as late as the tenth decade, although the mean age at presentation for bvFTD is approximately 58 years. There appears to be a slight male preponderance, although this finding has varied between reports. It is remarkable that about 40% of FTD patients present with a positive family history for dementia. This frequency of genetic etiology is higher when we compare it with most other neurodegenerative diseases (Riedl et al., 2014).

bvFTD SYMPTOMS, ANATOMICAL CORRELATES, AND OVERLAP WITH PRIMARY PSYCHIATRIC DISORDERS Patients with bvFTD demonstrate a gradual and progressive but insidious decline in social conduct, apathy,emotional blunting, and loss of insight. Some patients present with a prodromal phase with marriage discourse, alienation of friends and family, poor financial decisions, problems at work, new addictions, and criminal activities. Furthermore, the overlap with primary psychiatric conditions is high, leading to a diagnosis of depression, bipolar disorder, or a midlife crisis (Woolley et al., 2011; Wald€ o et al., 2015). For the purpose of this chapter, we will review the core symptoms of bvFTD and its anatomical correlates.

Early behavioral disinhibition Behavioral disinhibition is one the most classic and recognized symptoms in bvFTD patients, present in nearly 76% of the patients (Rascovsky et al., 2011). Within the first years, patients tend to break social norms and rules. As the disinhibition become more evident, patients become more impulsive, addiction prone, irritable, and likely to commit antisocial behaviors. The disinhibition syndrome correlates with atrophy in the orbitofrontal cortex (Rosen et al., 2005; Pressman and Miller, 2014). Manoochehri and Huey (2012) note that one way disinhibition manifests is that individuals become overly friendly and start conversations that are inappropriately explicit or personal. Offensive jokes, comments, or sexual remarks; encroachment on the personal space of others; childish behavior; and a general lack of etiquette are common.

Early apathy In bvFTD, approximately 85% of patients show early apathy and inertia, and patients usually present with lack of spontaneity and motivation. This may progress to mutism and immobility in the end stages of the disease (Rascovsky et al., 2011; Manoochehri and Huey, 2012; Pressman and Miller, 2014). Rosen and Eslinger have related this symptom anatomically with dysfunction of brain circuits that involve the right anterior cingulate and caudate regions (Rosen et al., 2005; Eslinger et al., 2012). Sometimes, it is challenging to differentiate between apathy and depression, but the absence of sadness, hopelessness, and suicidal ideas suggest that apathy is more likely than depression.

Early loss of sympathy or empathy Patients may lose the ability to empathize with others, become insensitive to loved ones’ emotional expressions and needs (Bartchowski et al., 2018). They become distant, cold, and indifferent in relationships, even with close friends and family. Often there is little or no concern for the effect of their behavior on loved ones (Rankin, 2005). In a voxel-based morphometry analysis, Rankin and colleagues showed that the loss of empathy correlated with atrophy in the right anterior temporal and medial frontal regions (Rankin et al., 2006). Similarly, Rosen and colleagues have shown related impairment in emotion recognition with atrophy in the right lateral inferior temporal and right middle temporal gyri (Rosen et al., 2006).

Early perseverative or compulsive behavior Patients with bvFTD often display obsessive–compulsive behaviors (71%). This varies from simple motor repetitive movements, like foot tapping or pacing, to more complex movements and language rituals. Repetition of stock words or phrases becomes common. Patients tend to be ritualistic around meals without any variation in the daily diet. Hoarding is common (Pressman and Miller, 2014). Some patients become more mentally rigid and resistant to changes in scheduled routines or plans (Cerami and Cappa, 2013). Obsessive–compulsive behavior has been related with networks involving orbitofrontal and anterior cingulate cortexes, basal ganglia, and thalamus.

Hyperorality and dietary changes In bvFTD, changes in food preferences and habits are usually present. In the clinic, we have seen patients that become vegetarian or exclusively eat meat or sweets. Others eat way beyond the point of satiety (Woolley et al., 2007). Attempts to eat nondigestible objects are also seen in later stages with relative frequency. The exact anatomical correlation of this symptom is not clear,

FRONTOTEMPORAL DEMENTIA but Woolley has associated it with atrophy in the right orbitofrontal-insular-striatal brain network (Woolley et al., 2007), while Piguet has correlated abnormal eating with atrophy in the posterior hypothalamus (Piguet, 2011; Piguet et al., 2011b).

Decline in executive function In contrast to Alzheimer’s disease (AD), cognitive decline in bvFTD tends to be less dramatic in the early stages (Gregory et al., 1999). The cognitive symptoms of bvFTD are mainly related to poor judgment, inattentiveness and distractibility, loss of planning ability, and disorganization. These patients are overly trusting and become susceptible to financial scams (Rabinovici and Miller, 2010; Pressman and Miller, 2014). The executive dysfunction correlates with atrophy in the dorsolateral and medial prefrontal cortex (Rosen et al., 2005).

Pseudobulbar affect in FTD with MND Pseudobulbar affect (PBA) is a syndrome in which emotional or affective motor control becomes dysregulated as a result of brain damage from a neurologic disease or as a result of brain injury. This syndrome is often misdiagnosed as a mood disorder caused by a primary psychiatric disease. PBA among other causes may be seen in the setting of FTD with MND (FTD-MND), which must be distinguished from depression or other primary psychiatric conditions. Laughter or crying are emotions that are dysregulated with PBA (Olney et al., 2011). The cardinal feature of the PBA is the presence of episodes of laughter and/or crying, often triggered by a discrete stimulus. These episodes present with paroxysm, tend to be uncontrollable and involuntary, and may occur even in the absence of any congruent changes in the mood of the patient. The duration tends to be short. These features help in the differentiation of PBA from mood disorders, where the emotional state tends to last longer and their emotional response is primarily a reflection of a specific situation or reaction. Several scales are available to identify and characterize PBA (Newsom-Davis et al., 1999; Smith et al., 2004). However, this is a clinical diagnosis where the level of suspicion and clinical training play important roles. This syndrome is effectively treated with a combination compound of dextromethorphan and quinidine sulfate (Sauve, 2016).

Psychotic symptoms As discussed previously, bvFTD may present with prominent neuropsychiatric symptoms and shares many symptoms with primary psychiatric disorders including schizophrenia, obsessive compulsive disorder, borderline schizoid or antisocial personality disorder, and

35

bipolar disorder (Wald€o et al., 2015). For this reason, misdiagnosis is seen in two directions, with some bvFTD patients being initially misinterpreted as suffering from a psychiatric disorder, while others with a primary psychiatric disorder being misdiagnosed as bvFTD. Recent studies (Snowden et al., 2012; Shinagawa et al., 2014; Wald€o et al., 2015) have pointed out the relative frequency of psychotic symptoms in FTD patients, and the reports vary from 10% to 32%. These differences are related to the instruments used for the evaluation of psychotic symptoms and the genetic and pathology profile of the sample. A higher prevalence of psychotic symptoms in bvFTD seems to be associated with chromosome 9 open reading frame 72 (C9orf72) mutations where hallucinations and delusions are reported as high as 50% (Sharon et al., 2012; Snowden et al., 2012; Kertesz et al., 2013). Mahoney and colleagues hypothesize that thalamic and cerebellar projections could be related to the neuropsychiatric features associated with this mutation, including hallucinations and/or delusions (Takada and Sha, 2012). These brain areas also seem to be particularly affected in C9orf72 carriers, possibly explaining the higher prevalence of psychotic symptoms in patients with this genetic mutation (Mahoney et al., 2012). Recent studies have shown reduction of right medial pulvinar volume and neuron number in patients with schizophrenia, the same region affected in C9orf72 mutation carriers which may explain symptom overlap. Another bvFTD subtype in which psychosis is high is FTLD with fused in sarcoma (FUS) pathology (Snowden et al., 2012) (Table 3.1). Table 3.1 Frequent symptoms in bvFTD patients and the anatomical correlates (Galimberti et al., 2015) Symptoms

Frequency (%) Anatomical correlates

Apathy

84

Disinhibition Loss empathy

76 73

Repetitive motor/ compulsive behavior

71

Hyperorality and dietary changes

59

Right anterior cingulate, medial frontal lobe, and caudate Right orbitofrontal cortex Right anterior temporal and orbito-insular cortex Right supplementary motor area and network involving orbitofrontal and anterior cingulate cortices, basal ganglia, and thalamus Network involving orbitofrontal-insularstriatal region and the posterior hypothalamus

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B. MILLER AND J.J. LLIBRE GUERRA

The presence of overlapping symptoms between FTD and specific psychiatric disorders can pose various problems related to differential diagnosis, prognosis, and treatment, but neuropsychologic assessment may help to differentiate the FTD profile from non-FTD patients. During the neuropsychologic testing, some core symptoms of bvFTD may be evident, as some patients make inappropriate comments to their examiners, appear cold or emotionally blunted, or appear inattentive and disinterested. During the examination, these patients often make rule violations and perseverate. The magnitude of these findings is usually greater in bvFTD than in primary psychiatric disorders. Neuropsychologic testing in bvFTD also frequently reveals executive dysfunction, which often correlates with tissue loss in the dorsolateral prefrontal cortex. In bvFTD, patient memory tends to be better than in AD, but some authors have pointed out some degree of impairment in episodic memory in the early stages of FTD (Hodges et al., 2004). In comparison with AD patients, bvFTD patients tend to show higher scores of apathy, euphoria, disinhibition, aberrant motor behavior, and eating abnormalities on the Neuropsychiatric Inventory (NPI) (Levy et al., 1996; Liscic et al., 2007). On the other hand, drawing and other visuospatial functions are often relatively spared in FTD clinical subtypes (Rabinovici and Miller, 2010). With the progression of the disease, changes in language, like stereotypy of speech, semantic deficits, and progressive reduction, may occur as a result of a disruption of dominant lobar language networks (Pressman and Miller, 2014).

bvFTD DIAGNOSIS CRITERIA The diagnosis of bvFTD requires a clinical and neuropsychologic approach supported by the use of neuroimaging or genetics studies. Most of the patients with bvFTD present with lack of insight and gradual onset. For this reason, in the assessment of a patient with suspected bvFTD, it is extremely important to interview caregivers regarding changes in patient behavior and cognition (Cerami and Cappa, 2013; Pressman and Miller, 2014). Improper diagnosis prevents patients and families from planning for the future and often leads to inappropriate and potentially harmful treatments, with FTD caregivers reporting that the delay to proper diagnosis is one of the most frustrating aspects of their experience. In 2011, the International Behavioral Variant FTD Consortium (FTDC) used pathologically confirmed cases of FTLD to develop sensitive and specific clinical criteria for diagnosing bvFTD, making possible a more accurate diagnosis (see Table 3.2) (Rascovsky et al., 2011). The international research criteria for bvFTD emphasized six core symptoms for the diagnosis, and the presence of any three of these is sufficient for a diagnosis of

Table 3.2 International consensus criteria for behavioral variant FTD (Rascovsky et al., 2011) I. 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 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. Neuropsychologic 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

FRONTOTEMPORAL DEMENTIA Table 3.2 Continued 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 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. Histopathologic evidence of FTLD on biopsy or at postmortem 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 nondegenerative 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 *As a general guideline “early” refers to symptom presentation within the first 3 years.

possible bvFTD. Probable FTD will be considered in the presence of significant functional decline and imaging findings consistent with the disease or a known causal genetic mutation. The diagnosis of definite bvFTD is given if the possible and probable criteria are supported by a finding of FTLD pathology.

CLINICAL AND PATHOLOGIC CORRELATION: HISTOPATHOLOGY AND GENETICS Initially, FTLD was pathologically identified by the presence of frontotemporal atrophy and gliosis, with neurons and glial cells containing inclusions of hyperphosphorylated τ protein. This was referred to as FTLD-τ. More

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than 50% of the FTLD patients proved to be τ-negative but ubiquitin staining positive, so two main groups were identified FTLD-τ and FTLD-ubiquitin (FTLD-U) or unknown molecular pathology (Cairns et al., 2007; MacKenzie et al., 2010). Later on, 80%–95% of FTLDU inclusions were found to be composed of transactive response (TAR) DNA binding protein 43kDa (TDP-43) (Neumann et al., 2006). Most of the remaining 5% of cases, who were τ- and TDP-43-negative, had inclusions of FUS. Thus, they were referred to as FTLD-FUS. Correlations have been noted between the clinical FTLD subtypes and underlying proteinopathies, but a strict one-to-one relationship is lacking. Nearly all bvFTD cases fall within one of three histopathologic groupings: τ, TDP-43, or FUS, each with a possibly unique genetic contribution. Positive family history is observed in 40%–50% of the FTLD patients, and in the bvFTD phenotype, a positive family history could be present in 30% of the patients when symptoms of MND are present (Lashley et al., 2011; Goldman, 2012). Molecular genetic studies have identified various genes with specific pathogenic mutations in FTD: e.g., the microtubule-associated protein τ gene (MAPT), granulin (GRN), chromosome 9 open reading frame 72 (C9orf72), TARDBP, the gene encoding valosincontaining protein (VCP), and the charged multivesicular body protein 2B gene (CHMP2B) (see Table 3.3). Other genes appear to modify the susceptibility to disease, but this remains a new and active area for investigation. For the purpose of this chapter we focus our attention on C9orf72, GRN, and MAPT mutations and their pathologic correlations in bvFTD. These three genes are the most common and together explain at least 17%–40% of the familial FTLD (DeJesus-Hernandez et al., 2011; Gijselinck et al., 2012). C9orf72 and GRN mutations are associated with TDP-43 deposits and MAPT with τ deposition. τ protein is involved in maintaining the microtubular structure in the neuronal axon. Six isoforms have been described, three of which have three microtubule binding repeats (3R), and three of which have four repeats (4R). τ is important in the pathogenesis of a variety of neurodegenerative conditions, including AD and FTLD. Mutations in MAPT have been found to represent from 17% to 32% of patients with both FTD and a positive family history (Rosso et al., 2003; Pressman and Miller, 2014). MAPT mutations on chromosome 17q21 were the first to be linked to familial FTD. These mutations were identified in families with an autosomal dominant clinical syndrome of disinhibition, dementia, and Parkinsonism. Now, more than 50 different MAPT mutations have been reported in 134 FTLD families (Bang et al., 2015).

Table 3.3 Genes related with FTLD C9orf72

MAPT

GRN

TARDBP

VCP

FUS

CHMP2B

Cr. Loc Protein

9p21.2 Unknown

17q21.32 τ

17q21.32 Progranulin

1p36.22 TDP-43

9p13.3 ATP binding

16p11.2 FUS protein deposits

Function

Unknown

Intracellular transport

51 (36–68)

Growth factor, inflammation 56 (47–87)

DNA/RNA modulation

Age of onset

Microtubule stabilization 44 (21–63)

Early ALS

DNA repair/regulates transcription Early ALS

Variable 20–60 Rare 5% Paget’s with IBM, FTD, ALS, FTD, essential ALS tremor

3p11.2 Multivesicular body protein 2B ESCRT-III complex production 50–60

Frequency in FTD 20%–50% 40%–50% Syndrome FTD, ALS, FTD- FTD, PSP, CBD ALS, psychiatric symptoms Brain inclusion TDP A/B τ

5%–25% Rare FTD, CBD, PD, AD ALS, rarely FTD

TDP A

?

TDP D

Rare FTD

Unknown

FRONTOTEMPORAL DEMENTIA FTLD-τ is mainly associated with bvFTD and symptoms of MND tend to be rare. MAPT mutations present with significant variability in clinical expression even in the same family. In these families, symptoms are often present by the age of 50; however, the range for age of onset is wide and strongly overlaps with other types of FTLD. It is remarkable that many carriers of MAPT mutations present with a long psychiatric prodromal phase (Bang et al., 2015). TDP-43 protein is found in at least one half of all bvFTD cases on histologic examination and is present in nearly all cases with FTD with amyotrophic lateral sclerosis (FTD-ALS). MacKenzie et al. (2011), in the new international FTLD classification, elicited four FTLDTDP subtypes, A–D, based on the cortical distribution, intracellular location and morphology of the TDP inclusions. Based on large clinicopathologic studies (Josephs et al., 2011), the most common FTLD-TDP subtype is type A accounting for 41%–49% of the cases, followed by type B with 28%–34% and type C with 17%–25%, while type D is rare (Sieben et al., 2012). FTLD-TDP43 type A is seen in patients with bvFTD or nfvPPA, type B is typical for FTD-MND, and type C is seen with svPPA and rarely with other FTD subtypes. The two more common genetic mutations associated with TDP-43 pathology are GRN and C9orf72 (Baker et al., 2006; Cruts et al., 2006). In the case of the progranulin gene (PGRN) more than 69 different GRN mutations have been reported in 231 families (Cruts et al., 2012). GRN mutations usually present by the age of 60 years, having an age of onset that is slightly higher than for other forms of FTD. It is remarkable that variability in penetrance has been described, with 50%– 60% of the mutation carriers being affected by the age of 60 years, and 90%–95% by the age of 70 years (Sieben et al., 2012). GRN mutations are often associated with asymmetric cerebral atrophy and, in addition to bvFTD, may be associated with nfvPPA and Parkinsonism. Motor neuron symptoms are rare (Chen-Plotkin et al., 2011). C9orf72 encodes a ubiquitously expressed protein of unknown function. In the normal population, the size of the GGGGCC repeat ranges from 3 to 25 units; a noncoding GGGGCC hexanucleotide expansion in this gene of more than 400 base pairs is strongly associated with both FTD and ALS (DeJesus-Hernandez et al., 2011; Renton et al., 2011). At the University of California, San Francisco Memory and Aging Center, mutations in this gene account for roughly 50% of familial FTD, other reports give a range of 13%–26% among familial FTD cases (Majounie et al., 2012). C9orf72 hexanucleotide repeat expansion is the most common known genetic cause of FTD and ALS and most often presents with bvFTD, bvFTD with

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MND (bvFTD-MND), or ALS, usually beginning at the age of 55 (DeJesus-Hernandez et al., 2011; Sharon et al., 2012; Snowden et al., 2012). These differences in genetic and neuropathologic subtypes suggest the need for different treatment approaches based on differential target engagement in the future management of the disease. C9orf72, chromosome 9 open reading frame 72; MAPT, microtubule-associated protein τ; GRN, granulin; TARDBP, transactive response DNA binding protein 43 kDa; VCP, valosin-containing protein; FUS, fused in sarcoma; CHMP2B, charged multivesicular body protein 2B; IBM, inclusion body myositis; ESCRT, endosomal sorting complexes required for transport.

NEUROIMAGING IN bvFTD In the diagnostic evaluation of bvFTD patients, frontotemporal atrophy or hypometabolism with structural and/or functional neuroimaging transforms a diagnosis from possible bvFTD into probable bvFTD (Rascovsky et al., 2011; Pressman and Miller, 2014). Furthermore, neuroimaging studies may help exclude alternative disorders such as tumors, vascular dementia, or normal pressure hydrocephalus. FTLD is associated with diverse patterns of atrophy of frontal and anterior temporal lobes. Different patterns of atrophy have been described in correlation with the clinical phenotypes. All of them are characterized by progressive cell loss, stereotypical spread, and abnormal protein aggregation. Patterns of neuroimaging findings can differentiate bvFTD from other FTD syndromes, AD, and other dementias (Muñoz-Ruiz et al., 2012), with important results coming from Seeley and colleagues who have demonstrated that bvFTD is associated with atrophy of the orbitofrontal, anterior cingulate, anterior insular, and anterior temporal cortices, particularly within the right hemisphere (Lee et al., 2016). This group has also shown that changes in the salience network, which is comprised of the orbitofrontal cortex, anterior cingulate cortex, anterior insula, and presupplementary motor area, may underlie the selective vulnerability and the stereotypical spread of this neurodegenerative illness (Seeley et al., 2009). bvFTD is associated with frontal and temporal lobe atrophy (Fig. 3.1) but also involves other structures like the thalamus, striatum, and hypothalamus. Typically the atrophy pattern is more pronounced on the right than left frontotemporal areas (Lee et al., 2016; Muñoz-Ruiz et al., 2012). Patterns of atrophy differ slightly among the genetic forms of FTLD. Anteromedial temporal atrophy has been associated with mutations in MAPT (Rohrer et al., 2010),

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B. MILLER AND J.J. LLIBRE GUERRA

Fig. 3.1. A T1 magnetic resonance image of the brain in sagittal, axial, and coronal cuts, shown in neurologic convention, showing severe anterior predominant atrophy with hydrocephalus ex vacuo in a patient with advanced behavioral variant frontotemporal dementia (bvFTD).

Atrophy max = seed ROI

Syndrome-specific regional atrophy patterns: patients vs controls bvFTD

AD +35

SD +11

PNFA +14

L IFG

CBS +10

R FI

A

R Ang

R PMC +40

6

4.4 L TPole

Intrinsic functional connectivity networks: healthy controls 5

3.6

B Structural covariance networks: healthy controls

6

C

4.6

Fig. 3.2. Convergent syndromic atrophy, healthy intrinsic connectivity networks (ICN), and healthy structural covariance (SC) patterns (A) Five distinct clinical syndromes showed dissociable atrophy patterns, whose cortical maxima (circled) provided seed ROIs for ICN and SC analyses. (B) ICN mapping experiments identified five distinct networks anchored by the five syndromic atrophy seeds. (C) Healthy subjects further showed gray matter volume covariance patterns that recapitulated results shown in (A and B). For visualization purposes, results are shown at P < 0.00001 uncorrected (A and C) and P < 0.001 corrected height and extent thresholds (B). In (A–C), results are displayed on representative sections of the MNI template brain. In coronal and axial images, the left side of the image corresponds to the left side of the brain. ANG ¼ angular gyrus; FI ¼ frontoinsula; IFGoper ¼ inferior frontal gyrus, pars opercularis; PMC ¼ premotor cortex; TPole ¼ temporal pole (Seeley et al., 2009).

whereas mutations in GRN have been associated with asymmetric temporoparietal atrophy, and C9orf72 mutations tend to present symmetric atrophy, predominantly involving dorsolateral, medial, and orbitofrontal lobes, anterior temporal lobes, cerebellum, and medial thalamus. Sporadic forms usually present with frontal and

anterior temporal atrophy (Beck et al., 2008; Rohrer et al., 2010). Patterns of atrophy may also help in the differential diagnosis, with Seeley et al. (2009) pointing out differential neuroimaging profiles in AD, bvFTD, svPPA, nfvPPA, and CBD (Fig. 3.2). Even though these atrophy

FRONTOTEMPORAL DEMENTIA

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Table 3.4 Differential diagnosis of bvFTD

Fig. 3.3. Axial fluorodeoxyglucose positron emission tomography (FDG-PET) images of a patient with advanced bvFTD, demonstrating hypometabolism in the anterior lobes bilaterally, but right more so than left.

patterns in structural MRI are extremely helpful in the diagnostic approach, it is important to note that early in the disease, structural imaging can be normal. In these early stages, functional neuroimaging studies such as fluorodeoxyglucose positron emission tomography (FDG-PET) may be slightly more sensitive than MRI for the diagnosis (Womack et al., 2011). Characteristic patterns of regional glucose hypometabolism on FDGPET, a marker of neuronal injury and neurodegeneration, have been identified in association with the common neurodegenerative dementias and can be clinically useful with a sensitivity of 97% and a specificity of 86% for distinguishing AD from FTD (Foster et al., 2007). FDGPET reveals hypometabolism of frontal, anterior cingulate and anterior temporal regions in FTD, in contrast to temporoparietal and posterior cingulate hypometabolism in AD (Fig. 3.3). A significant problem in bvFTD is predicting the molecular subtype from the clinical syndrome. Amyloid imaging is useful for distinguishing FTLD syndromes from AD, and eventually, it is hoped that τ imaging will help predict the risk of developing the disease, assess disease progression, and measure the efficacy of therapeutics. In the last few years, the search for a sensitive and specific τ binding ligand has intensified and τ neuroimaging agents are under development.

DIFFERENTIAL DIAGNOSIS Lack of an early or clear diagnosis of bvFTD may lead to delayed and inappropriate treatment, as well as family and patient distress. bvFTD syndromes can be mistaken for other neurodegenerative or psychiatric syndromes (Table 3.4), and in early stages, the diagnosis is more challenging, as it is important to exclude treatable conditions that can mimic FTLD. A comprehensive clinical and neuropsychologic evaluation, combined with laboratory studies and neuroimaging, are essential components of the required workup. Dementias are often mistaken for psychiatric disease, and bvFTD patients are at highest risk for misdiagnosis.

Psychiatric disorders

Neurodegenerative disorders

Obsessive–compulsive disorder Bipolar disorder Depression Schizophrenia

Alzheimer’s disease Chronic traumatic encephalopathy Other FTD syndromes Movement disorders

Treatable conditions that can mimic FTD Metabolic disturbances Nutritional deficiencies CNS infections Substance abuse Heavy metal toxicity

Cerebrovascular disease CNS tumors Paraneoplastic conditions Normal pressure hydrocephalus Low intracranial pressure

bvFTD patients are often initially misdiagnosed with a major depressive disorder, bipolar affective disorder, or schizophrenia (Gálvez-Andres et al., 2007; Woolley et al., 2007, 2011; Velakoulis et al., 2009). In one study, 28% of patients had a prior psychiatric diagnosis, and the mean delay between receiving psychiatric and neurodegenerative disease diagnoses was 33 months. Women with bvFTD received a psychiatric diagnosis more often than men. This study suggests that physicians should consider a more comprehensive evaluation in patients who present with new-onset behavioral, emotional, or cognitive changes after age 40 in order to rule out bvFTD or another neurodegenerative condition (Woolley et al., 2011). Others neurodegenerative disorders can be mistaken for FTD-spectrum disorders, particularly AD, vascular dementia, and dementia with Lewy bodies. Early age of onset AD (EOAD) can be challenging to differentiate from bvFTD because frequently it does not have the classical amnestic presentation of later onset AD. In some cases, there may be a prominent executive or language dysfunction as well. It is also important to make reference to the FTD phenocopy. This term was introduced by John Hodges and Chris Kipps and may represent a diagnostic dilemma (Kipps et al., 2010), describing patients who seem to meet the bvFTD criteria but do not appear to progress clinically and do not show atrophy on MRI. FTD phenocopy pattern usually falls into four main subtypes: 1. 2. 3. 4.

FTD by proxy Self-diagnosed FTD Primary psychiatric disorder Slow FTD

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In FTD by proxy, the caregiver becomes convinced that their loved one has bvFTD. This idea is often reinforced by reading about the disease on the Internet or though discussion with someone familiar with the disease. A similar story is seen in self-diagnosed FTD. Sometimes a psychiatric syndrome is misdiagnosed as FTD. Usually, however, patients with primary psychiatric conditions like bipolar disorder have symptoms that begin earlier in life, show relatively normal neuroimaging, respond better to psychoactive compounds, and do not progress to dementia. Finally, there are gene carriers who may initially show normal imaging and progress very slowly. In particular, some patients with C9 mutations have been reported to have a very low progression rate and long prodromal phase (Bang et al., 2015).

MANAGEMENT OF BEHAVIORAL SYMPTOMS IN FTD There is no treatment available that changes the course of the bvFTD, so the focus of medical therapy is on symptomatic relief. An individualized management plan, with both nonpharmacologic and pharmacologic interventions, should be created.

Nonpharmacologic interventions Nonpharmacologic interventions should focus on the safety and well-being of the patient. Discussion with family around financial issues, such as limiting access to credit cards and bank accounts, driving safety, and achieving an environment that assures the physical safety of the patient (Talerico and Evans, 2001; Piguet et al., 2011a) and early retirement should be considered if the patient is currently employed (Pressman and Miller, 2014). Exercises and physical therapy may be also helpful in patients with impending problems with movement. Chen and colleagues (Cheng et al., 2014) have shown a benefit in mood, cognition, and overall health in patients with dementia when regular exercise routines are performed. Physical therapy may be helpful in patients with mobility problems such as Parkinsonism and may help to reduce the risk of falls. The presence of hyperorality in some patients may require special care from caregivers to prevent excessive weight gain or the dangerous placement of inedible objects in the mouth (Manoochehri and Huey, 2012).

Pharmacologic interventions Studies in the neurochemistry of bvFTD have shown a serotoninergic network disruption, with decreased serotonin levels and 5-HT1A and 5-HT2A receptors in frontotemporal regions and neuronal loss in the raphe nuclei

(Franceschi et al., 2005; Huey et al., 2006). Disruption in the dopaminergic system, with low levels of dopamine metabolites and severely reduced presynaptic dopamine transporters in the putamen and caudate of FTD patients, seems to be part of the FTD neuropharmacology (Sj€ogren et al., 1998; Rinne et al., 2002). There is no evidence supporting a deficit of acetylcholine in this disease (Hansen et al., 1988). Consequently, the pharmacologic management of neurobehavioral symptoms should ideally suit the typical changes in neurotransmitter systems occurring with the disease. In 1997 Swartz and colleagues first treated 11 FTD subjects with fluoxetine, sertraline, or paroxetine and found improvement in disinhibition, apathy, carbohydrate cravings, and compulsive behaviors. In 2005 Mendez and colleagues described decreased verbal and motor stereotypies when sertraline was used in this group of patients. A meta-analysis of studies using serotonergic drugs was conducted by Huey et al. in 2006, and significant decrease in behavioral symptoms as measured by the NPI was observed (Huey et al., 2006). In total, the evidence suggests that serotonin selective reuptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram) are effective in helping with various symptoms of FTD, including disinhibition, impulsivity, repetitive behaviors, and eating disorders (Sj€ogren et al., 1998; Huey et al., 2006; Manoochehri and Huey, 2012). Some patients with bvFTD will require the use of antipsychotic medications for the treatment of severe neurobehavioral symptoms. These compounds are usually considered if there is no success with behavioral modification or SSRIs. Diminished dopaminergic function in these patients makes them vulnerable to extrapyramidal side effects. Therefore, agents with relatively less D2 receptor antagonism, such as quetiapine, are preferred if antipsychotics are needed (Pijnenburg et al., 2003; Komossa et al., 2011; Asmal et al., 2013). Acetylcholinesterase inhibitors are not recommended in this group of patients, as they do not have a cholinergic deficit like AD or DLB, and trials have not shown a convincing benefit for cholinesterase inhibitors in cognition or behavior (Mendez et al., 2007). AChIs are incorrectly prescribed in approximately 40% of bvFTD patients (Pressman and Miller, 2014). Memantine is an NMDA receptor antagonist used for slowing cognitive decline with moderate AD, but no significant difference in behavioral or cognitive function was found in bvFTD when compared with a placebo (Diehl-Schmid et al., 2008; Boxer et al., 2009; Vercelletto et al., 2011). Several other drugs, like lithium and some anticonvulsants, have been tested in FTD with negative or inconclusive results. Risks of toxicity are generally deemed to outweigh theoretical benefits (Pressman and Miller, 2014).

FRONTOTEMPORAL DEMENTIA

CONCLUSIONS FTD is increasingly recognized as a leading cause of earlyonset dementia. bvFTD is the most common syndrome in FTD and can be associated with behavior changes mimicking manic, depressive, obsessive–compulsive, or other psychiatric syndromes, and causing social and family disruption. bvFTD can result from a number of different proteinopathies, and some cases have a genetic etiology. A comprehensive clinical and neuropsychologic evaluation, combined with laboratory studies and neuroimaging, can help in recognizing the core features of bvFTD and in avoiding misdiagnosis. The pharmacologic management of behavioral symptoms currently relies on the effect of SSRIs, with some efficacy in reducing disinhibition, repetitive behaviors, and hyperorality. Small doses of atypical antipsychotics may be required when there is no success with SSRIs. There is no evidence supporting the use of cholinesterase inhibitors or memantine. Promising areas of research include PET imaging with τ ligands, which may make it possible to identify subgroups that could benefit from future therapies targeting the underlying pathology with disease.

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