Clinical Approach to the Differential Diagnosis Between Behavioral ...

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Clinical Approach to the Differential Diagnosis Between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders Simon Ducharme, M.D., M.Sc., Bruce H. Price, M.D., Mykol Larvie, M.D., Ph.D., Darin D. Dougherty, M.D., M.Sc., Bradford C. Dickerson, M.D.

A middle-aged woman with obsessive-compulsive symptoms with atypical features is seen for a diagnostic neuropsychiatric assessment.

“Ms. A,” a 46-year-old woman, was referred for inpatient treatment at the Obsessive-Compulsive Disorder Institute (OCDI) of McLean Hospital (Belmont, Mass.). She had no prior history of psychiatric disorders. Two years earlier she had developed cleaning and checking rituals that gradually became severe and intrusive to the point of losing her longterm employment. She had been diagnosed with obsessivecompulsive disorder (OCD) by a community psychiatrist. Sertraline was prescribed, but she soon stopped taking it because of side effects. After a few days at the OCDI, a diagnostic neuropsychiatric assessment was requested because of atypical features for OCD, including a late age at onset and an inability to engage in therapy. Ms. A denied obsessions or anxiety. She felt well and had no concerns about having lost her job. Collateral history was obtained from her husband. After the onset of compulsions, he noticed major changes in her personality. Ms. A had previously been caring, organized, and reliable, but over the past 2 years she had become emotionally detached and apathetic, and she now had poor judgment and neglected her daughter. She also exhibited odd eating behaviors, such as eating butter by the spoonful. Most recently she had developed bilateral hand-rubbing stereotypies. There was no family history of psychiatric disorders, dementia, or amyotrophic lateral sclerosis. On examination, the patient was superficially cooperative, but without insight, awareness, or concern about her behavior. Her affect was jovial and shallow. She was indifferent to her family’s concerns. There were no psychotic symptoms or language abnormalities. Her score on the Montreal Cognitive Assessment was 25/30 (3/5 in the visuospatial and executive tasks, 4/5 on the serial 7s task, 3/5 on the recall task, 12 words with cues), and her score on the Frontal Assessment Battery was 17/18. On phonemic

fluency testing, she listed 12 words, reciting more words in the first 15 seconds than in the last 45 seconds (generation deficit). A brief social cognition battery was administered. She made no mistakes on faux-pas vignettes, but identified only 17/36 emotions on the Reading the Mind in the Eyes test. Her elemental neurological examination was normal except for inextinguishable bilateral palmomental reflexes. While Ms. A’s compulsions were typical of OCD, the clinical profile was not compatible with this diagnosis because of the absence of anxiety or distress related to the rituals. Given the history of loss of empathy, apathy, careless actions, dietary changes, hand-rubbing stereotypies, generation deficits, and impaired facial emotion recognition, she met clinical criteria for possible behavioral variant frontotemporal dementia (bvFTD). A recent brain MRI performed at a private facility was reported as normal (images were not available for review). However, another brain MRI, at our hospital, showed moderate to severe circumscribed ventromedial prefrontal and orbitofrontal cortical atrophy bilaterally. A [18F]fluorodeoxyglucose positron emission tomography study demonstrated marked cortical hypometabolism within the medial aspects of the anterior frontal lobes. Hematology, biochemistry, and EEG results were within normal limits. The final diagnosis was probable bvFTD. A genetic evaluation revealed none of the autosomal dominant mutations associated with frontotemporal dementia (C9ORF72, progranulin, and MAPT). Over the next few months, aggressive behaviors at home became more prominent. Divalproex sodium was initiated for behavioral management. Despite the medication, Ms. A’s behavior continued to deteriorate, and she was admitted to a psychiatric ward after biting her daughter. She was placed in an assisted-living facility 30 months after the onset of symptoms.

See related features: Clinical Guidance (Table of Contents) and AJP Audio (online)

Am J Psychiatry 172:9, September 2015

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Frontotemporal dementia (FTD) describes a heterogeneous group of neurodegenerative diseases featuring various combinations of behavioral changes, language abnormalities, social cognitive impairment, and executive function deficits. FTD is divided into two major clinical syndromes: the behavioral variant (bvFTD) (1) and the language variants referred to as primary progressive aphasias (2). Identifying bvFTD is challenging because symptoms can be subtle in the early stages, and they may combine features that are traditionally within the realm of psychiatry (e.g., personality changes, lack of empathy, compulsions) and others usually seen by neurologists (e.g., aphasia, cognitive impairments). Patients are often first evaluated in general psychiatric settings, and about 50% are initially diagnosed with a primary psychiatric illness (3). Knowledge about FTD has grown exponentially over the past 10 years, and it is crucial for psychiatrists to include bvFTD as part of their differential diagnosis in a wide range of adult psychiatric disorders. In this article, we review the clinical approach to bvFTD, focusing in particular on the differential diagnosis between bvFTD and primary psychiatric disorders. DEFINITIONS AND DIAGNOSTIC CRITERIA Diagnostic criteria for bvFTD were last revised in 2011 (1) and are included in DSM-5 (major frontotemporal neurocognitive disorder). A DSM-5 diagnosis of bvFTD requires the insidious onset and gradual progression of a neurocognitive disorder combined with at least three behavioral symptoms and a prominent decline in social cognition and/or executive abilities. Behavioral symptoms include disinhibition, apathy or inertia, loss of sympathy or empathy, perseverative, stereotyped, or compulsive/ritualistic behaviors, and hyperorality and dietary changes (which can lead to weight gain). The clinical phenotype sometimes includes features of the Kluver-Bucy syndrome (e.g., docility, oral exploration of inedible objects) (4). Current diagnostic criteria state that there should be relative sparing of learning and memory and visuospatial (perceptual-motor) function. However, multiple studies have challenged the validity of this criterion by showing significant impairment of memory functions in bvFTD (5, 6) and parietal lobe deficits in FTD due to progranulin (GRN) mutations (7). Consequently, the presence of such deficits should not be viewed as an absolute exclusion criterion in clinical practice (although in research studies they are usedinpartto exclude patientswithatypicalAlzheimer’sdisease). The diagnosis of bvFTD is referred to as possible bvFTD when it is based solely on clinical criteria. Supportive neuroimaging or genetic findings can increase the degree of certainty of the diagnosis (see the Neuroimaging and Genetics sections below). One exclusion criterion is that symptoms should not be better explained by another mental disorder, which is often challenging to determine. In this article, we use the term “primary psychiatric disorder” to describe emotional and behavioral syndromes for which there are no currently identified diagnostic pathology correlates (e.g., major depressive disorder, schizophrenia). We consider bvFTD to be 828


a quintessential neuropsychiatric disease, and we recommend abandoning the false dichotomy of bvFTD being “neurological” as opposed to “psychiatric.” In our opinion, conceptualizing bvFTD as not being “psychiatric” because pathological correlates have been identified is neither clinically helpful nor scientifically valid. Both psychiatrists and neurologists need to have basic competence in identifying patients who are potentially suffering from this disease. EPIDEMIOLOGY The estimated incidence of FTD is 2.7–4.1 per 100,000 people, and the prevalence is 15–22 per 100,000 (8). There are reports of a higher incidence of bvFTD in males, but overall there is no consistent gender disparity across studies (8). FTD represents about 5% of all cases of dementia in unselected autopsies. Although onset is typically between ages 40 and 70, up to 25% of FTD cases occur after age 65 (8). Late-onset bvFTD is probably underrecognized because of the clinical overlap with Alzheimer’s disease (9). Onset as early as the 20s has also been described. The median life expectancy is 7–8 years after the onset of symptoms, but the rate of progression varies significantly among patients (10). PATHOPHYSIOLOGY bvFTD is characterized by bilateral (often asymmetric) atrophy of the frontal lobes and the anterior temporal lobes, reflecting neuronal loss, microvacuolation, and a variable degree of astrocytic gliosis, referred to as frontotemporal lobar degeneration (11). Neuronal dysfunction is thought to be caused by the accumulation of one of several protein aggregates, including tau, 43-kDa TAR DNA-binding protein (TDP-43), RNA-binding protein fused in sarcoma (FUS), and ubiquitin-positive proteins (11, 12). Most cases of bvFTD are due to tau or TDP-43 (in equal proportion), but a small proportion are caused by FUS or a predominantly frontal variant of Alzheimer’s disease (12). Of note, Pick bodies are a specific cellular morphologic subtype of tau accumulation that is not present in all cases. Consequently, “Pick’s disease” should no longer be used as a clinical diagnostic term. There are three main causative autosomal dominant genetic mutations with almost complete penetrance: microtubuleassociated protein tau (MAPT; 17q21), progranulin (GRN; 17q21), and the recently discovered chromosome 9 hexanucleotide repeat expansion in C9ORF72 (12). MAPT is also related to parkinsonian syndromes, and C9ORF72 to amyotrophic lateral sclerosis (ALS). Approximately 10%220% of FTD cases have an autosomal dominant inheritance pattern (13, 14); therefore, most cases are sporadic. There are no known replicated nongenetic risk factors (8). OVERLAP AND DIFFERENCES BETWEEN BVFTD AND PRIMARY PSYCHIATRIC DISORDERS In this section, we review the overlap and differences between bvFTD and primary psychiatric disorders in terms of Am J Psychiatry 172:9, September 2015


clinical symptomatology. A schematized summary is provided in Figure 1. Differentiating factors in neuroimaging and other biomarkers are covered afterward, in the Clinical Approach section. Major Depressive Disorder Major depressive disorder and bvFTD share common symptoms, including lack of interest, decreased motivation, low energy, and impaired concentration. Diagnostic confusion can occur between bvFTD and severe major depression that is causing impaired cognitive processing. However, sustained depressed mood, which is a hallmark of depression, is usually not present in bvFTD. Other symptoms of major depression rarely seen in bvFTD include guilty ruminations, feelings of worthlessness, and suicidal thoughts. Patients with bvFTD sometimes report mood changes (e.g., inability to feel normally), but their descriptions tend to be shallow (15). Major depression can also present with diminished interest or pleasure (anhedonia) without pervasive sadness, which can be difficult to distinguish from apathy. Apathy is a deficit in motivation, manifested by a reduction in selfinitiated or environment-responsive goal-directed behaviors, cognitive activity, and emotional responsiveness. A core distinction is that apathy is not experienced as distressing or accompanied by dysphoria. Geriatric major depression can be challenging, as elderly patients tend to have less subjective sadness, more cognitive symptoms, and less insight (16). Strategies to distinguish depression-related cognitive impairment from bvFTD include a structured clinical history (17), social cognition batteries (18), and neuroimaging studies (see the Clinical Approach section). Bipolar Disorder In bipolar depression there is a higher prevalence of atypical features, including hypersomnia and hyperphagia, symptoms that may be observed in bvFTD. In addition, bvFTD and mania share symptoms such as disinhibition, irritability, distractibility, risk taking, impaired social judgment, and excessive involvement in pleasurable activities with potentially harmful consequences (19). Although patients with bvFTD can be inappropriately jocular (20), euphoric mania is accompanied by a qualitatively distinct elevated and expansive mood, with a sense of grandiosity and invulnerability that is uncommon in bvFTD. In addition, in mania irritability is combined with increased energy and decreased need for sleep, a clinical feature not seen in bvFTD. Most importantly, bvFTD involves an inexorable deterioration of cognitive and behavioral functions, while bipolar disorder is usually an episodic syndrome with waxing and waning symptoms. Severe cases of bipolar disorder can evolve toward a chronic state, but cognitive impairment is not as profound or progressive (21). Am J Psychiatry 172:9, September 2015

Obsessive-Compulsive Disorder (OCD) Stereotyped and compulsive/ritualistic behaviors due to bvFTD range from simple stereotypies (e.g., rubbing) to more elaborate rituals mimicking compulsions of OCD (e.g., checking, washing) (22). Compulsions can be the initial manifestation of bvFTD (23). Compulsive/ritualistic behaviors can be phenotypically identical in bvFTD and OCD, but there are key distinguishing factors. In OCD, the patients engage in repetitive rituals as a response to obsessions to reduce distress or to “prevent” an adverse outcome. Although the behavior in bvFTD appears seemingly driven by a specific worry, patients usually deny or are unable to describe obsessions (15). It remains unclear whether there are no obsessions, or whether the loss of neuronal function causes an inability to consciously identify obsessions. Importantly, rituals in bvFTD are not typically accompanied by apparent anxiety, which is a core feature of OCD. Most people suffering from OCD have insight that their compulsions are excessive and do not logically prevent dreaded consequences, although some hold on to this possibility. Patients with FTD usually exhibit an almost complete absence of insight. Hoarding can be a prominent feature of bvFTD (24), but it can also manifest as an idiopathic OCD-related disorder. Idiopathic hoarding tends to start in early life and get worse over the years, while in bvFTD it usually follows the onset of cognitive decline. In some cases hoarding may have been present before the onset of bvFTD symptoms and subsequently intensified. Patients with idiopathic hoarding usually accumulate objects with some theoretical value (e.g., paperwork) and endorse weak rationalization about the potential need for future use. In bvFTD, hoarded items can be unsanitary (e.g., rotten food), and hoarding is attributable to impaired decision making rather than anxiety (25). Schizophrenia Negative symptoms of schizophrenia strikingly overlap with the predominantly apathetic variant of bvFTD. Moreover, schizophrenia is associated with mild cognitive deficits in attention, working memory, executive function, declarative memory, and processing speed, which can mimic early deficits of bvFTD (26). The two diseases also share similar social cognitive deficits (27) and limited insight. The clinical distinction is informed by the presence of positive psychotic symptoms, which are relatively rare in FTD (28), and longitudinal history. Schizophrenia usually starts with a prodrome beginning in the late teens to mid-30s, followed by episodic exacerbations and a variable level of residual deficits. Onset of symptoms before age 30–35 is supportive of a primary psychotic disorder; onset of bvFTD before age 30–35 is unusual although possible (29). Most importantly, the course of primary psychotic disorder with periodic exacerbations intertwined with more stable phases is incompatible with bvFTD, which follows a course of progressive neurodegeneration without remission of deficits. ajp.psychiatryonline.org

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FIGURE 1. Algorithm to Determine Whether Behavioral Symptoms Are More Compatible With Behavioral Variant Frontotemporal Dementia (bvFTD) or Primary Psychiatric Disordersa

Possible bvFTD Symptoms

Compulsions

Apathy

Is it due to low mood and/or anhedonia?

YES

Major depression more likely

NO Is it associated with decreased appetite, guilt, or suicidal thoughts?

OCD more likely

YES

Is the compulsion a long-term hoarding pattern?

YES

Consider primary hoarding disorder

YES

YES

Schizophrenia more likely

Is it associated with elevation of affect and grandiosity?

YES

Bipolar I or II disorder more likely

Is there increased energy and decreased need for sleep?

Symptom compatible with bvFTD

YES

NO



Simple Stereotypies

Are they associated with delusions and/or hallucinations?

Loss of Empathy

YES

NO Symptom compatible with bvFTD

a

YES

Assess for substance use disorder

NO NO

NO

Is this a long-standing pattern as opposed to an acute change?

Is it secondary to substance intoxication?

NO

NO

NO Is it associated with delusions and/or hallucinations?

Are compulsions related to obsessions and anxiety?

Disinhibition

Neurodevelopmental or personality disorder more likely

YES

Psychotic disorder more likely

NO Are there ≥2 other catatonia symptoms?


YES

Assess for causes of catatonia

Hyperorality

Are there other symptoms of atypical depression

YES

Assess for major depression and bipolar disorder


This figure is intended as a guide to determining the most likely diagnosis and should not be interpreted as an absolute division between disorders.

Differentiating bvFTD from late-onset schizophrenia (i.e., after age 40) can be more challenging. Late-onset schizophrenia presents with variable combinations of symptoms, including hallucinations (auditory and sometimes other types) and 830


systematized delusions, typically with a lesser degree of negative and cognitive symptoms than is seen in younger patients. Clinical presentations with prominent positive psychotic symptoms unaccompanied by apathy and/or cognitive decline Am J Psychiatry 172:9, September 2015


are more likely to be caused by a primary psychotic disorder. One notable exception is the strikingly higher prevalence of psychosis as the initial presentation of bvFTD secondary to C9ORF72 mutations (30, 31) (see the Psychiatric Disorders as a Prodrome of bvFTD section below). Catatonia Catatonic syndromes and bvFTD share symptoms, including stereotypies, echophenomena, decreased verbal output, and negativism (32). When amenable to cognitive examination, patients with catatonia often show frontal network types of dysfunction such as perseveration and environmental dependency. These syndromes are not mutually exclusive, as catatonia can be a manifestation of bvFTD (33). The diagnosis of catatonia is based on DSM-5 criteria, and it can be supported by a “lorazepam challenge.” Rapid improvement of cognitive and behavioral symptoms after the administration of a short-acting benzodiazepine (or ECT) strongly suggests catatonia. Of note, there have been anecdotal reports of persisting cognitive deficits after remission of a catatonic episode (32, 34), which could potentially mimic bvFTD. Neurodevelopmental Disorders Deficits in communication and interpersonal interactions are the core features of autism spectrum disorder (ASD). Similar acquired social cognition deficits are produced by bvFTD, suggesting some degree of shared neuroanatomical circuits (27). Obtaining a collateral developmental history is crucial to differentiate bvFTD from ASD given that symptoms of the latter must be present during early development. It can occasionally be challenging to determine whether distractibility, inattentiveness, and organization deficits are due to long-standing adult attention deficit hyperactivity disorder (ADHD) or to a neurodegenerative process. As with ASD, the key is to elicit a history of similar or more severe ADHD symptoms in childhood. Clinical improvement with psychostimulants is expected to be much more significant in ADHD than in bvFTD (35). While distractibility due to early-stage bvFTD can overlap with symptoms of ADHD, over time the progression of bvFTD will inexorably lead to symptoms that cannot be explained by ADHD, such as loss of empathy or apathy. Personality Traits and Personality Disorders Early symptoms of bvFTD involve subtle changes in personality and values (36). Relatives often perceive the initial phase as a psychosocial crisis, which can lead to major life changes (e.g., divorce) or legal repercussions (37). In practice, clinicians need to determine whether unusual behaviors reported by relatives should be considered a symptom of an illness or within the realm of normative experience. Indeed, patients with bvFTD often rationalize pathological behaviors as being a normal reaction to events or blame relatives for overreacting. The best strategy, in our experience, is to develop a general sense of premorbid personality by questioning the patient and Am J Psychiatry 172:9, September 2015

the family. Reported behaviors can then be analyzed as a function of how much they deviate from the patient’s own norms. A particular action might be deemed worrisome in one individual but normal in others. For example, impulsively investing a significant sum of money in a risky venture might be a symptom of disinhibition in someone with a conscientious temperament, but not in a risk-taking entrepreneur. Conversely, patients with bvFTD can exhibit an unusual calmness or ease (38) that can be normal in certain individuals, but pathological in previously dynamic or anxious individuals. If the patient has a psychotherapist, it can be useful to discuss the reported symptoms with the therapist. Longitudinal observations in therapy can provide valuable information that can favor (e.g., inability to engage with therapist) or lead away (e.g., capacity for introspection) from a diagnosis of bvFTD. While it is often difficult to determine whether or not an isolated behavior is pathological, patients with bvFTD will, over time, exhibit multiple unusual behaviors across symptomatic domains (e.g., impulse control, lack of empathy, and so on). Therefore, even if each individual symptom is subtle, bvFTD should be suspected when a patient exhibits multiple types of abnormal behaviors along the lines of bvFTD diagnostic criteria. Of note, with increased public awareness, we have also encountered situations in which families have erroneously interpreted interpersonal conflicts as being symptoms of bvFTD. Diagnosing bvFTD in patients with preexisting personality disorders can be challenging (39, 40). The key diagnostic clue for all personality disorders is their longitudinal nature, with symptoms of maladaptive traits present since early adulthood. Borderline personality disorder and bvFTD can both present with impulsivity, impaired judgment, and anger outbursts. The fear of abandonment, high degree of selfconcerns, self-harm, and unstable sense of self differentiate borderline personality disorder from bvFTD. Narcissistic personalities and bvFTD can both have selfishness, disregard for others, and lack of empathy. However, it is not typical for patients with bvFTD to have an excessive sense of selfgrandiosity. Patients with bvFTD can exhibit acquired antisocial behaviors, but they usually consist of impulsive actions resulting from disinhibition rather than instrumental aggression (41). Nonprogressive bvFTD A subgroup of patients who meet criteria for possible bvFTD do not show clear deterioration over time (42). These “bvFTD phenocopies” are predominantly men and are less impaired in executive functions, social cognition, and activities of daily living. They do not show supportive features of FTD on neuroimaging (42). Their lifespan is normal, and in many such individuals autopsy has not shown frontotemporal lobar degeneration. While some of these individuals have very slowly progressive forms of bvFTD secondary to C9ORF72 (43), it is generally assumed that many of them do not have bvFTD (42). Some authors have suggested that this phenotype ajp.psychiatryonline.org

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could be a late deterioration of unidentified ASD (Asperger’s syndrome) (42, 44). This seems unlikely given the long-standing nature of deficits in ASD. Atypical residual mood disorders, low-grade psychotic disorders, and catatonic syndromes are diagnostic alternatives, but there is much uncertainty as to the nature of this disorder. Psychiatric Disorders as a Prodrome of bvFTD Primary psychiatric disorders are often diagnosed in the few years preceding a diagnosis of bvFTD (3). While this is in part related to missing the bvFTD diagnosis because of complex symptomatic overlap (45), recent studies (especially related to the C9ORF72 mutation) have highlighted the possibility of bone fide primary psychiatric disorders representing the initial (or prodromal) stage of bvFTD. Among patients with C9ORF72 mutations, a relatively high proportion have lateonset positive psychotic symptoms as the initial presentation (30, 31). Various other neuropsychiatric presentations have been reported, including mania/bipolar disorder (46, 47) and “depressive pseudodementia” (48). However, C9ORF72 mutations are rare (,1%) in cohorts of patients with a clinical diagnosis of schizophrenia (49, 50) or bipolar disorder (46, 51). Based on these findings, patients presenting with lateonset psychiatric disorders should have a careful clinical assessment for bvFTD symptoms and a detailed family history to identify autosomal-dominant disease inheritance patterns. CLINICAL APPROACH In addition to the psychiatric interview, the clinical assessment should include a family history, a mental status examination, a screening cognitive examination, and a neurological examination. The nature and time course of symptoms should be established, including features that are atypical of primary psychiatric disorders. An atypically late onset age for psychiatric disorders should raise suspicion for a broader differential diagnosis, including neurodegenerative diseases. Behavioral symptoms of bvFTD should be explored with both the patient and at least one informant. The assessment should include screening for cognitive and functional decline. A detailed family history of first- and second-degree relatives for neurological and psychiatric disorders (with particular attention to dementia, ALS, and parkinsonism) is a crucial component of the assessment. A positive family history of mental illness congruent with current psychiatric symptoms supports the diagnosis of a primary psychiatric disorder (52). However, clinicians should be aware that a positive family psychiatric history has been shown to bias toward missing FTD diagnoses (3). Based on the report that primary progressive aphasias are associated with a more frequent family history of developmental language disabilities (53) and our clinical observations, we hypothesize that bvFTD may be associated with an elevated family history of psychiatric disorders. This has not yet been formally investigated, but a recent study showed a higher proportion of psychiatric 832


disorders in relatives of patients with C9ORF72 mutations (54). A family history of early-onset dementia, ALS, lateonset psychiatric syndromes, and unexplained institutionalization in psychiatric hospitals raises suspicion for familial bvFTD. Any late-onset psychiatric presentation in patients with a family history of autosomal-dominant dementia should be assessed for the possibility of a neurodegenerative disorder. In this situation, it is helpful to ask family members to obtain medical records of relatives. Cognitive Testing Specialized evaluation for neurodegenerative diseases should be pursued aggressively when a patient presents with progressive cognitive impairment in parallel with the new onset of a neuropsychiatric syndrome (55, 56). The first step is to disentangle cognitive weaknesses that can be satisfactorily explained by an acute mental illness from those that cannot. During acute episodes of depression, mania, psychosis, or delirium, attentional disturbances often severely interfere with cognitive performance for a temporary period (57). Persistent and especially progressive executive dysfunction despite improvement in psychiatric symptoms raises the index of suspicion for bvFTD. It is important to keep in mind that severe chronic mental illnesses are associated with multidomain cognitive deficits even between acute exacerbations, but with limited progression over time (26). Deficits due to schizophrenia have been documented prior to the first psychotic episode and can involve multiple cognitive domains, including attention, working memory, verbal learning, verbal memory, and executive functions (performance across testing on average 0.5–2 standard deviations below the mean of age- and educationmatched controls) (26, 58). In bipolar disorder, there can be mild and generally stable weaknesses in attention, working memory, lexical fluency, and verbal learning and memory (21, 59). Patients suffering from major depressive episodes and anxiety disorders often express subjective memory concerns. These are usually secondary to primary deficits in attention and working memory, which can have a negative impact on other cognitive domains (e.g., executive functions) and lead to inefficient encoding and retrieval of information (57). Cognitive symptoms are expected to improve in parallel with mood with treatment (60). High antipsychotic dosages and polypharmacy can contribute to cognitive impairment (26, 59); if possible, clinicians should attempt to reduce use of antipsychotics, mood stabilizers, benzodiazepines, and any medication with anticholinergic effects. In the initial stages of bvFTD, the magnitude of cognitive weaknesses can be similar to symptoms observed in primary psychiatric disorders, including major depression (61). The relative specificity of deficits in executive function and language and their progressive nature are characteristics that can help distinguish cognitive impairments in bvFTD from those of severe and persistent mental illnesses (61). Performance on standard screening tests can be within normal limits in early bvFTD (62), and a referral for more in-depth neuropsychological testing is often helpful to identify subtle Am J Psychiatry 172:9, September 2015


deficits. Deficits in social cognition are among the earliest impairments in bvFTD and are not captured adequately by standard cognitive tests. Social cognition refers to a cluster of cognitive skills that are required for interpersonal interactions, such as theory of mind, self-knowledge, and perception of others (27). Social cognition batteries, including tests such as identification of interpersonal faux-pas and facial emotion recognition, have been shown to be potentially more sensitive than standard neuropsychological testing for the early diagnosis of bvFTD and to distinguish bvFTD from mood disorders (18, 62). Neuroimaging Neuroimaging plays a crucial role in the diagnosis of bvFTD. The degree of certainty increases from possible to probable if either frontal or anterior temporal atrophy is identified in CT or MRI studies, or if a pattern of frontal or temporal lobe abnormality is identified in positron emission tomography (PET) or single-photon emission computed tomography (SPECT) (1) (Figure 2). Positive neuroimaging biomarkers increase the diagnostic specificity from 82% to 95% (63). Brain imaging should be obtained for the evaluation of any late-onset psychiatric syndrome for which bvFTD is in the differential diagnosis. Structural imaging with CT or MRI is a reasonable first examination, ideally including coronal and sagittal images if available. MRI offers the advantage of more accurate definition of boundaries between CSF and brain parenchyma, thus permitting more sensitive evaluation for patterns of atrophy. Since neuroimaging findings in early FTD can be subtle, a specialist with expertise in the imaging of neurodegenerative disorders should review the examination, ideally in close collaboration with the treating physicians. If the initial brain MRI is unremarkable, obtaining a [18F]fluorodeoxyglucose (FDG)-PET (or perfusion SPECT if FDG-PET is not available) is an appropriate next step. A principal advantage of FDG-PET relative to structural imaging is increased sensitivity that may allow diagnosis at an earlier stage (64). Normal imaging results argue against bvFTD but do not entirely exclude the diagnosis, especially in the early phases. Of note, schizophrenia and bipolar disorder have been statistically associated with cortical thinning compared with healthy subjects (52, 65), but this finding is usually very subtle and is not a reliable diagnostic feature at the individual level. Similarly, structural and functional abnormalities that have been identified in specific networks in major depression (66) and OCD (67) are based on small differences detected by group statistics and are not reliable diagnostic indicators in individual patients. Although MRI and PET findings are generally expected to be within normal limits, some patients with primary psychiatric disorders, including bipolar disorder and major depression, may exhibit frontal hypometabolism on FDG scans (68); thus, a radiologic finding of isolated frontal hypometabolism should be considered within the clinical context and may not necessarily indicate bvFTD. Am J Psychiatry 172:9, September 2015

Genetics Genetic testing for MAPT, GRN, and C9ORF72 should be considered when a patient with bvFTD symptoms has a family history positive for at least one first-degree relative with early-onset dementia (13, 14). As previously mentioned, C9ORF72 testing should be considered in late-onset psychosis or mania if there is at least one first-degree relative with FTD or ALS (30, 31, 47). A referral for genetic counseling prior to testing is recommended. Other Biomarkers No reliable diagnostic CSF biomarker pattern has yet emerged for bvFTD. CSF analysis can be helpful when Alzheimer’s disease is also a possible diagnosis, in appropriately selected cases given the invasive nature of the test. There are numerous other, relatively rare neurological disorders that should be considered when symptoms are atypical for bvFTD or are rapidly progressive, and the diagnostic evaluation of many of these conditions should include CSF analysis (56). EEG findings are usually normal in early bvFTD, and EEG is generally not useful in distinguishing bvFTD from primary psychiatric disorders. TREATMENT In diagnostically ambiguous cases, an evidence-based pharmacological or psychotherapeutic treatment trial targeting the putative primary psychiatric disorder is a rational step. Major improvement of symptoms with medications or psychotherapy argues against a neurodegenerative process. In contrast, progressive deterioration despite optimized psychiatric treatment is expected in bvFTD. No disease-modifying treatment has been developed for FTD, but there is active research on compounds acting on tau accumulation and granulin deficiency. Current pharmacological treatments aim to improve specific symptoms, but most of these are used empirically on the basis of small or open-label clinical trials (69). Selective serotonin reuptake inhibitors are sometimes helpful for compulsive/ritualistic behavior (22). Trazodone can decrease irritability, agitation, and hyperorality (70). Mood stabilizers and second-generation antipsychotics are often used to minimize agitation, aggression, and impulsivity, but there are limited data to support this practice. Psychostimulants are sometimes prescribed for apathy, with limited evidence of benefit (35). Cholinesterase inhibitors and memantine have been found in randomized controlled trials to be ineffective (71, 72). Nonpharmacologic symptom management strategies generally require the expertise of an experienced clinician and team (73, 74). These include speech and language therapy for communication or swallowing issues, occupational therapy for problems with hand-eye coordination or planning that affect activities of daily living, physical therapy for gait disorders, and in some cases psychotherapy (for patient or family or both). A driving assessment is critical, as is determination of financial and health care competency. Other helpful interventions include ajp.psychiatryonline.org

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FIGURE 2. Imaging Features of Behavioral Variant Frontotemporal Dementia (bvFTD)a

a

MRI, [18F]fluorodeoxyglucose positron emission tomography (FDG-PET), and fused PET-MRI images from a 64-year-old woman with a clinical diagnosis of bvFTD. The patient had undergone psychiatric treatment for several years with a diagnosis of major depressive disorder. Subsequently, on further evaluation, suspicion was raised of a possible neurodegenerative disorder. At the time of imaging, the principal symptoms consisted of behavior changes (increased irritability, apathy, and inability to complete tasks), depressed mood, memory complaints, and lack of insight into her problems. She was independent in her activities of daily living with modest spousal assistance. The MRI (top row) shows atrophy that is most pronounced in the frontal lobes, most prominently involving the ventromedial and dorsomedial cortices. There is asymmetrically greater involvement in the right cerebral hemisphere compared with the left. FDG-PET (middle row) shows a corresponding pattern of cerebral cortical hypometabolism, most pronounced in the medial frontal lobe cortex. The fused PET-MRI images (bottom row) demonstrate the correspondence between PET and MRI findings, with the PET hypometabolism significantly more conspicuous than the atrophy depicted on the MRI, reflecting the greater sensitivity of the FDG-PET examination compared with the MRI.

social work assistance with disability compensation, paid or volunteer companions or home health aides to help patients remain active yet safe, and day programs or respite residential programs. It is essential for health care providers to dedicate time and effort to specialized education of the patient and family, including referral to the Association for Frontotemporal Degeneration (http://www.theaftd.org) and the Alzheimer’s Association (http://www.alz.org). Psychosocial support resources can be helpful for nearly all families and for some patients. The development of close links between the FTD specialty care team and the primary care physician is important 834


to assist in general management, including monitoring comorbid conditions and reviewing the role of prophylactic care in the context of FTD. LONGITUDINAL CARE Despite investigations, diagnostic ambiguity between bvFTD and primary psychiatric disorders sometimes persists. Clinicians should openly share their uncertainties with patients and caregivers and provide longitudinal follow-up, as the lack of a clear diagnosis can be quite distressing. If there is clinical progression of behavioral symptoms or cognitive deficits, Am J Psychiatry 172:9, September 2015


repeating a thorough assessment with neuropsychological testing and imaging on a yearly basis is a reasonable approach until a final diagnosis is established. Permanent measures such as enacting a power of attorney or guardianship should be discussed, but deferred until a diagnosis of bvFTD or a related neurodegenerative disease is confirmed. If the diagnosis is ultimately determined to be bvFTD, it is important for the clinician to provide ongoing monitoring and care through the course of the illness, or to refer the patient to a specialty center. Various clinical rating scales have been developed to track symptom progression, such as the Frontotemporal Lobar Degeneration-Modified Clinical Dementia Rating scale (known as the FTLD-modified CDR) (75) or the Frontotemporal Dementia Rating Scale (the FRS) (76). Finally, it is critical late in the course of the illness to assist patients and families with end-of-life care, facilitating access to palliative care resources and ideally to nursing home and hospice care at the appropriate times. There continues to be a desperate need for residential or nursing facilities that have the capacity and skills to care for patients with bvFTD. Although research at present focuses largely on understanding the disease and offers few potential treatment options, participation can provide some meaning in an otherwise entirely tragic situation. Ultimately, the quality of the partnership between care providers and families is a critical factor that influences the experience of living with bvFTD. CONCLUSIONS Behavioral variant frontotemporal dementia is a complex neurodegenerative disease that presents with neuropsychiatric symptoms overlapping with mood disorders, psychotic disorders, catatonia, OCD, personality disorders, ASD, and ADHD. Psychiatrists have a crucial role to play in recognizing the early symptoms of bvFTD, initiating diagnostic investigations, managing symptoms, and referring patients to specialized neurocognitive clinics. Although there are currently no disease-modifying treatments, an early and accurate diagnosis is important to help patients and families prepare for this devastating disease. Future developments such as improved clinical methodology, cognitive tests (including social cognition), quantitative analysis of MRI and FDG-PET data for detection of subtle abnormalities, tauPET ligands, and CSF biomarkers will hopefully provide much-needed improvement in the early diagnosis of bvFTD. AUTHOR AND ARTICLE INFORMATION From the Frontotemporal Disorders Unit, Massachusetts General Hospital, Boston; the Montreal Neurological Institute and Hospital, the McGill University Health Centre, and the Departments of Psychiatry and of Neurology and Neurosurgery, McGill University, Montreal; and the Departments of Neurology, Radiology, and Psychiatry, Harvard Medical School, Boston. Address correspondence to Dr. Ducharme ([email protected]). Dr. Ducharme’s fellowship was supported by the Sidney R. Baer, Jr., Foundation, the Fonds de Recherche du Québec–Santé, and the Am J Psychiatry 172:9, September 2015

McGill University Health Centre Research Institute (Frank McGill Travel Fellowship). Dr. Dougherty has received research support from Cyberonics, Eli Lilly, Medtronic, and Roche and honoraria or travel support from Insys, Johnson & Johnson, Medtronic, and Roche. Dr. Dickerson has served as a consultant for Best Doctors, Forum, Isis, Inc., Haymarket Media, and Piramal, has served on a data safety monitoring board for Merck, and receives royalties from Oxford University Press. The other authors report no financial relationships with commercial interests. Received Oct. 8, 2014; revision received Feb. 18, 2015; accepted Feb. 27, 2015. Am J Psychiatry 2015; 172:827–837; doi: 10.1176/appi.ajp.2015.14101248

REFERENCES 1. Rascovsky K, Hodges JR, Knopman D, et al: Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011; 134:2456–2477 2. Gorno-Tempini ML, Hillis AE, Weintraub S, et al: Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–1014 3. Woolley JD, Khan BK, Murthy NK, et al: The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry 2011; 72:126–133 4. Cummings JL, Duchen LW: Kluver-Bucy syndrome in Pick disease: clinical and pathologic correlations. Neurology 1981; 31:1415–1422 5. Bertoux M, de Souza LC, Corlier F, et al: Two distinct amnesic profiles in behavioral variant frontotemporal dementia. Biol Psychiatry 2014; 75:582–588 6. Mansoor Y, Jastrzab L, Dutt S, et al: Memory profiles in pathology or biomarker confirmed Alzheimer disease and frontotemporal dementia. Alzheimer Dis Assoc Disord 2015; 29:135–140 7. Rohrer JD, Warren JD, Omar R, et al: Parietal lobe deficits in frontotemporal lobar degeneration caused by a mutation in the progranulin gene. Arch Neurol 2008; 65:506–513 8. Onyike CU, Diehl-Schmid J: The epidemiology of frontotemporal dementia. Int Rev Psychiatry 2013; 25:130–137 9. Baborie A, Griffiths TD, Jaros E, et al: Frontotemporal dementia in elderly individuals. Arch Neurol 2012; 69:1052–1060 10. Garcin B, Lillo P, Hornberger M, et al: Determinants of survival in behavioral variant frontotemporal dementia. Neurology 2009; 73: 1656–1661 11. Cairns NJ, Bigio EH, Mackenzie IR, et al: Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007; 114:5–22 12. Rademakers R, Neumann M, Mackenzie IR: Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 2012; 8:423–434 13. Wood EM, Falcone D, Suh E, et al: Development and validation of pedigree classification criteria for frontotemporal lobar degeneration. JAMA Neurol 2013; 70:1411–1417 14. Goldman JS, Rademakers R, Huey ED, et al: An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology 2011; 76: 475–483 15. Gregory CA: Frontal variant of frontotemporal dementia: a crosssectional and longitudinal study of neuropsychiatric features. Psychol Med 1999; 29:1205–1217 16. Alexopoulos GS: Depression in the elderly. Lancet 2005; 365:1961–1970 17. Bickart KC, Brickhouse M, Negreira A, et al: Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale. J Neurol Neurosurg Psychiatry 2014; 85:438–448 18. Bertoux M, Delavest M, de Souza LC, et al: Social Cognition and Emotional Assessment differentiates frontotemporal dementia from depression. J Neurol Neurosurg Psychiatry 2012; 83:411–416 ajp.psychiatryonline.org

835


19. Woolley JD, Wilson MR, Hung E, et al: Frontotemporal dementia and mania. Am J Psychiatry 2007; 164:1811–1816 20. Perry RJ, Miller BL: Behavior and treatment in frontotemporal dementia. Neurology 2001; 56(suppl 4):S46–S51 21. Mann-Wrobel MC, Carreno JT, Dickinson D: Meta-analysis of neuropsychological functioning in euthymic bipolar disorder: an update and investigation of moderator variables. Bipolar Disord 2011; 13:334–342 22. Mendez MF, Shapira JS, Miller BL: Stereotypical movements and frontotemporal dementia. Mov Disord 2005; 20:742–745 23. Mendez MF, Perryman KM, Miller BL, et al: Compulsive behaviors as presenting symptoms of frontotemporal dementia. J Geriatr Psychiatry Neurol 1997; 10:154–157 24. Mendez MF, Shapira JS: The spectrum of recurrent thoughts and behaviors in frontotemporal dementia. CNS Spectr 2008; 13: 202–208 25. Nakaaki S, Murata Y, Sato J, et al: Impairment of decision-making cognition in a case of frontotemporal lobar degeneration (FTLD) presenting with pathologic gambling and hoarding as the initial symptoms. Cogn Behav Neurol 2007; 20:121–125 26. Lewandowski KE, Cohen BM, Öngur D: Evolution of neuropsychological dysfunction during the course of schizophrenia and bipolar disorder. Psychol Med 2011; 41:225–241 27. Amodio DM, Frith CD: Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci 2006; 7:268–277 28. Mendez MF, Shapira JS, Woods RJ, et al: Psychotic symptoms in frontotemporal dementia: prevalence and review. Dement Geriatr Cogn Disord 2008; 25:206–211 29. Velakoulis D, Walterfang M, Mocellin R, et al: Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases. Br J Psychiatry 2009; 194:298–305 30. Snowden JS, Rollinson S, Thompson JC, et al: Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012; 135:693–708 31. Galimberti D, Fenoglio C, Serpente M, et al: Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation. Biol Psychiatry 2013; 74:384–391 32. Ducharme S, Dickerson BC, Larvie M, et al: Differentiating frontotemporal dementia from catatonia: a complex neuropsychiatric challenge. J Neuropsychiatry Clin Neurosci 2015; 27:e174–e176 33. Holm AC: Neurodegenerative and psychiatric overlap in frontotemporal lobar degeneration: a case of familial frontotemporal dementia presenting with catatonia. Int Psychogeriatr 2014; 26:345–347 34. Baker IW, Jackson M, Bass C: Catatonia causing permanent cognitive impairment: a case study. Cogn Behav Neurol 2005; 18:141–143 35. Huey ED, Garcia C, Wassermann EM, et al: Stimulant treatment of frontotemporal dementia in 8 patients. J Clin Psychiatry 2008; 69: 1981–1982 36. Miller BL, Seeley WW, Mychack P, et al: Neuroanatomy of the self: evidence from patients with frontotemporal dementia. Neurology 2001; 57:817–821 37. Liljegren M, Naasan G, Temlett J, et al: Criminal behavior in frontotemporal dementia and Alzheimer disease. JAMA Neurol 2015; 72:295–300 38. Rankin KP, Santos-Modesitt W, Kramer JH, et al: Spontaneous social behaviors discriminate behavioral dementias from psychiatric disorders and other dementias. J Clin Psychiatry 2008; 69:60–73 39. Salzbrenner LS, Brown J, Hart G, et al: Frontotemporal dementia complicated by comorbid borderline personality disorder: a case report. Psychiatry (Edgmont) 2009; 6:28–31 40. Poletti M, Bonuccelli U: From narcissistic personality disorder to frontotemporal dementia: a case report. Behav Neurol 2011; 24: 173–176 41. Mendez MF, Shapira JS, Saul RE: The spectrum of sociopathy in dementia. J Neuropsychiatry Clin Neurosci 2011; 23:132–140 836


42. Kipps CM, Hodges JR, Hornberger M: Nonprogressive behavioural frontotemporal dementia: recent developments and clinical implications of the “bvFTD phenocopy syndrome”. Curr Opin Neurol 2010; 23:628–632 43. Khan BK, Yokoyama JS, Takada LT, et al: Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J Neurol Neurosurg Psychiatry 2012; 83:358–364 44. Midorikawa A, Kawamura M: The relationship between subclinical Asperger’s syndrome and frontotemporal lobar degeneration. Dement Geriatr Cogn Dis Extra 2012; 2:180–186 45. Arciniegas DB: New-onset bipolar disorder in late life: a case of mistaken identity. Am J Psychiatry 2006; 163:198–203 46. Meisler MH, Grant AE, Jones JM, et al: C9ORF72 expansion in a family with bipolar disorder. Bipolar Disord 2013; 15:326–332 47. Floris G, Borghero G, Cannas A, et al: Bipolar affective disorder preceding frontotemporal dementia in a patient with C9ORF72 mutation: is there a genetic link between these two disorders? J Neurol 2013; 260:1155–1157 48. Bieniek KF, van Blitterswijk M, Baker MC, et al: Expanded C9ORF72 hexanucleotide repeat in depressive pseudodementia. JAMA Neurol 2014; 71:775–781 49. Huey ED, Nagy PL, Rodriguez-Murillo L, et al: C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. Neurobiol Aging 2013; 34:e9–e10 50. Galimberti D, Reif A, Dell’Osso B, et al: The C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia. Neurobiol Aging 2014; 35:1214.e1217–1214.e1210 51. Floris G, Di Stefano F, Pisanu C, et al: C9ORF72 repeat expansion and bipolar disorder: is there a link? No mutation detected in a Sardinian cohort of patients with bipolar disorder. Bipolar Disord 2014; 16: 667–668 52. Panegyres PK, Graves A, Frencham KA: The clinical differentiation of fronto-temporal dementia from psychiatric disease. Neuropsychiatr Dis Treat 2007; 3:637–645 53. Rogalski E, Johnson N, Weintraub S, et al: Increased frequency of learning disability in patients with primary progressive aphasia and their first-degree relatives. Arch Neurol 2008; 65:244–248 54. Devenney E, Hornberger M, Irish M, et al: Frontotemporal dementia associated with the C9ORF72 mutation: a unique clinical profile. JAMA Neurol 2014; 71:331–339 55. Dickerson B: Frontotemporal dementia, in Dementia: Comprehensive Principles and Practice. Edited by Dickerson B, Atri A. New York, Oxford University Press, 2014, pp 176–197 56. Schmahmann J: The differential diagnosis of rapidly progressive and rare dementia: a clinical approach, in Dementia: Comprehensive Principles and Practice. Edited by Dickerson B, Atri A. New York, Oxford University Press, 2014, pp 291–359 57. Landrø NI, Stiles TC, Sletvold H: Neuropsychological function in nonpsychotic unipolar major depression. Neuropsychiatry Neuropsychol Behav Neurol 2001; 14:233–240 58. Bilder RM, Goldman RS, Robinson D, et al: Neuropsychology of firstepisode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 2000; 157:549–559 59. Kurtz MM, Gerraty RT: A meta-analytic investigation of neurocognitive deficits in bipolar illness: profile and effects of clinical state. Neuropsychology 2009; 23:551–562 60. Douglas KM, Porter RJ: Longitudinal assessment of neuropsychological function in major depression. Aust N Z J Psychiatry 2009; 43:1105–1117 61. Elderkin-Thompson V, Boone KB, Hwang S, et al: Neurocognitive profiles in elderly patients with frontotemporal degeneration or major depressive disorder. J Int Neuropsychol Soc 2004; 10: 753–771 62. Torralva T, Roca M, Gleichgerrcht E, et al: A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia. Brain 2009; 132:1299–1309 Am J Psychiatry 172:9, September 2015


63. Harris JM, Gall C, Thompson JC, et al: Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia. Neurology 2013; 80:1881–1887 64. Jeong Y, Cho SS, Park JM, et al: 18F-FDG PET findings in frontotemporal dementia: an SPM analysis of 29 patients. J Nucl Med 2005; 46: 233–239 65. Rimol LM, Hartberg CB, Nesvåg R, et al: Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder. Biol Psychiatry 2010; 68:41–50 66. Price JL, Drevets WC: Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn Sci 2012; 16:61–71 67. Milad MR, Rauch SL: Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci 2012; 16:43–51 68. Hosokawa T, Momose T, Kasai K: Brain glucose metabolism difference between bipolar and unipolar mood disorders in depressed and euthymic states. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:243–250 69. Wylie MA, Shnall A, Onyike CU, et al: Management of frontotemporal dementia in mental health and multidisciplinary settings. Int Rev Psychiatry 2013; 25:230–236

Am J Psychiatry 172:9, September 2015

70. Lebert F, Stekke W, Hasenbroekx C, et al: Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004; 17:355–359 71. Boxer AL, Knopman DS, Kaufer DI, et al: Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013; 12:149–156 72. Kertesz A, Morlog D, Light M, et al: Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord 2008; 25:178–185 73. Gitlin LN, Kales HC, Lyketsos CG: Nonpharmacologic management of behavioral symptoms in dementia. JAMA 2012; 308:2020–2029 74. Shnall A, Agate A, Grinberg A, et al: Development of supportive services for frontotemporal dementias through community engagement. Int Rev Psychiatry 2013; 25:246–252 75. Knopman DS, Kramer JH, Boeve BF, et al: Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. Brain 2008; 131:2957–2968 76. Mioshi E, Hsieh S, Savage S, et al: Clinical staging and disease progression in frontotemporal dementia. Neurology 2010; 74:1591– 1597


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