Psychiatric Symptoms in Frontotemporal Dementia: Epidemiology, Phenotypes, and Differential Diagnosis

Review

Biological Psychiatry

Psychiatric Symptoms in Frontotemporal Dementia: Epidemiology, Phenotypes, and Differential Diagnosis Daniela Galimberti, Bernardo Dell’Osso, A. Carlo Altamura, and Elio Scarpini ABSTRACT Frontotemporal dementia (FTD) is the most frequently occurring dementia in the presenile population. Despite epidemiologic data showing that patients with FTD may have experienced previous psychiatric disorders and that patients with psychotic disorders may develop dementia more often than expected in the nonaffected population, the overlap between these two conditions has been underestimated. Nevertheless, the identification in recent years of several genetic causes of FTD associated with heterogeneous and atypical presentations, including pure psychiatric symptoms, has shifted scientific interest back to obtaining a better understanding of common mechanisms between FTD and psychotic disorders. We review the current knowledge of the FTD spectrum and common features shared by FTD and some psychiatric diseases, starting from Pickʼs clinical description of the disease, moving toward pathogenic aspects of the disease and genetic causes and associated phenotypes, and finishing with analysis of crossing borders between FTD and psychiatric disorders (mainly represented by schizophrenia and bipolar spectrum disorders) in clinical practice in terms of overlapping symptoms, differential diagnosis, comorbidity, and treatment issues. Keywords: Bipolar disorder (BD), Frontotemporal dementia (FTD), Frontotemporal lobar degeneration (FTLD), Pick dementia, Psychosis, Schizophrenia (SZ) http://dx.doi.org/10.1016/j.biopsych.2015.03.028

“Dementia praecox consists of a series of states, the common characteristic of which is a peculiar destruction of the internal connections of the psychic personality. The effects of this injury predominate in the emotional and volitional spheres of mental life.”

first case (“Anna H.,” 41 years old) of the most common clinical presentation of the disease 12 years later, consisting of behavioral abnormalities, including stereotypy and flattening of affect, now referred as behavioral variant frontotemporal dementia (bvFTD).

—E. Kraepelin, 1919 Although the concept of “dementia praecox” as a frontotemporal disorder characterized by psychotic symptoms and dementia in young people was proposed by Kraepelin decades ago (1), few studies investigated the neuropathology of the so-called organic psychoses or secondary schizophrenia (SZ). The first description of a case that would be defined today under the umbrella of frontotemporal dementia (FTD), reported by Pick in 1892 (2), was actually not prototypical. Pick described a 71-year-old woman (“Auguste H.”) with marked language disorder, severe comprehension deficit, and semantic and phonemic paraphasias, but with relatively preserved repetition. In addition, she had bouts of aggressiveness. The patient died soon after presenting to Pick, as a result of a febrile disease. Autopsy revealed brain atrophy, more pronounced in the left hemisphere and particularly in the left temporal lobe. This case was cited as the first description of primary progressive aphasia (PPA) (3). Pick described the

FROM PICK’S DISEASE TO FTD Pick’s case descriptions did not include results of microscopic histopathologic examination, which was carried out later by Alzheimer (5), who described argyrophilic intracytoplasmic inclusions and ballooned neurons, which he named Pick bodies and Pick cells, realizing that the changes observed were distinct from changes found in the form of cerebral degeneration later associated with his name. The clinical descriptions and pathologic findings were put together later to form the nosologic entity called Pick’s disease (4,6,7). The concept that Pick bodies and Pick cells are not always present in patients with FTD has been recognized for a long time (8) but substantially ignored, along with the observation that no Pick pathology may be present in patients with a clinical presentation consisting of FTD associated with motor neuron disease (MND) (9).

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Research on FTD started in the 1980s, when two groups from Lund, Sweden, and Manchester, United Kingdom, respectively, tried to define this entity better. The two groups agreed on the following: 1) FTD is more than Pick disease, 2) FTD and PPA (with two subtypes, progressive nonfluent aphasia [PNFA] and semantic dementia [SD]) have overlapping pathogenic bases, and 3) many cases show autosomal dominant inheritance (often with an early onset). Clinical criteria were defined for the diagnosis of FTD (10), which were later refined (11), including three clinical syndromes: bvFTD, PNFA, and SD. The most common clinical presentation, bvFTD, is characterized by behavioral changes and progressive deterioration of personality. Patients may show a wide spectrum of symptoms, including behavioral alterations, such as disinhibition, overeating, and impulsiveness, and impairment of cognitive functions, with relative sparing of memory. Changes in social behavior, loss of empathy, and impairment of social insight are early and consistent symptoms of bvFTD. Patients perform poorly on laboratory-based tasks, including recognizing emotions, attending to salient information that guides social behavior, representing social knowledge, comprehending mental states of others, and maintaining insight to their own difficulties (12). Reviews of clinical features (13–17), clinical criteria (11), and behavioral rating tools for FTD (17) did not include psychotic and other psychiatric symptoms, possibly because of the divergence that occurred in the middle of the 20th century between neurology, which became mainly associated with organic causes, and psychiatry, which focused instead on psychodynamic issues (18). Understanding of the neurobiology of FTD and its relationship with clinical manifestations of the disease has dramatically increased in recent years, with the discovery of multiple autosomal dominant genetic causes of FTD. Numerous genetic cases with co-occurrence of typical FTD symptoms and psychosis have been described, speeding up the research on common altered mechanisms between FTD and major psychoses, including SZ and bipolar disorder (BD). The focus of this review is on current knowledge of these disorders, in terms of clinical diagnostic criteria, genetic causes, phenotype heterogeneity, and overlapping pathogenic mechanisms.

CURRENT DIAGNOSTIC CRITERIA FOR FTD In 2011, new criteria for bvFTD were proposed (19) together with a new classification of language presentations (20). According to these criteria, the main feature of bvFTD is the progressive deterioration of behavior or cognition or both based on observation or history (provided by a knowledgeable informant). If this criterion is satisfied, there are three further levels of certainty for bvFTD: possible, probable, or definite. “Possible” bvFTD requires three of six clinically discriminating features. “Probable” bvFTD meets the criteria of “possible” bvFTD with imaging results consistent with bvFTD (i.e., frontal or anterior temporal atrophy on magnetic resonance imaging or hypometabolism on positron emission tomography). “Definite” bvFTD includes histopathologic evidence of FTD hallmarks (postmortem) or the presence of a known pathogenic mutation. These new criteria have a flexible structure to account for the high heterogeneity at initial presentation.

Concerning language presentations, according to new criteria (20), PPA encompasses three presentations: nonfluent/agrammatic variant PPA (previously known as PNFA), semantic variant PPA (previously known as SD), and logopenic variant PPA. Progressive loss of speech, with hesitant, nonfluent speech output with phonetic/phonologic errors and distortions or agrammatism is typical of nonfluent/agrammatic variant PPA (21), whereas loss of knowledge about words and objects, anomia, and single-word comprehension deficits are core features of semantic variant PPA. Logopenic variant PPA is characterized by phonologic disorders, defective word retrieval, and sentence repetition deficits and seems to be associated in most cases with underlying Alzheimer’s disease (AD) pathology (20). Patients with logopenic variant PPA and nonfluent/agrammatic variant PPA have some deficits recognizing emotional prosody, whereas patients with semantic variant PPA show more widespread deficits in social comprehension (21). Other phenotypes, such as progressive supranuclear palsy syndrome, corticobasal syndrome, and FTD with MND, are part of the clinical manifestations within the FTD spectrum. Considering the heterogeneity of the pathology at the basis of clinical symptoms, the term frontotemporal lobar degeneration (FTLD) (22) is currently used to designate pathologic features of the disease, including three major subtypes, defined by inclusions containing the proteins tau, FTLD-Tau (22); TAR DNA-binding protein (TDP)-43, FTLD-TDP; and fused in sarcoma (FUS), FTLD-FUS (23,24).

GENETICS: AUTOSOMAL DOMINANT MUTATIONS AND ASSOCIATED PHENOTYPES Although most cases of FTD are sporadic, numerous cases are associated with familial aggregation and are inherited in an autosomal dominant fashion, suggesting a genetic cause (25– 27). Up to 40% of patients have a family history, with FTD present or suggested to be present in at least one family member (26,28), with autosomal dominant cases accounting for 13.4% of total cases of FTD (27). At the present time, three major genes have been associated with the FTD: microtubule-associated tau protein (MAPT) (29,30), progranulin (GRN) (31,32), and a hexanucleotide expansion in chromosome 9 (C9ORF72) (33,34). Valosincontaining protein (VCP) (35), charged multivesicular body protein 2B (CHMP2B) (36), TAR DNA-binding protein (TARDBP) (37), fused RNA binding protein (FUS) (38), and sequestosome 1 (SQSTM1) (39) are rare causes of familial FTD.

MAPT The first evidence of a genetic cause for familial FTD came from the demonstration of a linkage with chromosome 17q21.2 in a form of bvFTD with parkinsonism with autosomal dominant inheritance (29), named FTDP-17, characterized pathologically by the presence of Pick bodies. The gene responsible for this association, MAPT, was discovered a few years later (30). MAPT encodes the microtubuleassociated protein Tau, which is involved in microtubule stabilization and assembly. The H1 haplotype in this gene

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was previously shown to be associated with corticobasal degeneration and progressive supranuclear palsy pathology (40,41). To date, .40 pathogenic MAPT mutations have been described, mainly clustered in exons 9–13, which contain the microtubule-binding regions (42). The pathogenic mechanism of each different mutation depends on the type and location of the genetic defect and affects the normal function of tau (i.e., the stabilization of microtubules, promoting their assembly by binding tubulin). Some mutations increase the free cytoplasmic portion of the protein promoting tau aggregation, whereas others lead to hyperphosphorylation of tau protein, which damages microtubule binding. Alternatively, the alternative splicing is affected, producing altered ratios of the different isoforms. Grisart et al. (43) described a microduplication on chromosome 17g21.31 that was associated with behavioral problems and skills impairment. Subsequent studies failed to identify abnormal copy number variations at the genetic region encompassing MAPT (44). However, in 2009, a heterozygous deletion responsible for the removal of exons 6–9 of MAPT in one patient with FTD was described (45). The same group reported a duplication in the region encompassing MAPT in one patient affected by behavioral and amnestic disorders (46). At autopsy, patients with MAPT mutations show taupositive inclusions (FTLD-Tau). The clinical presentation in MAPT mutation carriers is mainly consistent with FTD and parkinsonism, with a mean onset in the 50s. Nevertheless, cases of PNFA also have been reported (47). Despite the heterogeneous clinical presentation in terms of symptoms and age at onset, subjects carrying MAPT mutations usually exhibit severe temporal lobe atrophy, mostly on the right side.

hyperphosphorylated isoforms of TDP-43 were recognized as main components of the ubiquitin-positive inclusions, typical of the GRN mutated families as well as of idiopathic FTLD and some cases of amyotrophic lateral sclerosis (ALS) (51). From a clinical point of view, mutations in GRN are associated with extremely heterogeneous phenotypes, including classic FTD presentations (bvFTD, PNFA, and SD); corticobasal syndrome, which seems a quite common clinical presentation (52–56); AD (57); mild cognitive impairment (58); and Lewy body dementia (59). TDP-43 pathology has been observed in AD brains and in Lewy body dementia brains (60), suggesting that the phenotypic heterogeneity may be due to the presence of two actual pathologies. Age at disease onset is extremely variable, even in the same family, with a range of 47–79 years (58). Although rare, an overlap between psychiatric disorders and genetically determined FTD can occur, as shown by Rainero et al. (61), who described a patient with heterosexual pedophilia who was a carrier of a GRN mutation and developed bvFTD over time, and by Cerami et al. (62), who reported two clinically different, apparently sporadic FTD cases, sharing the Thr272fs GRN mutation, in patients who had had a previous diagnosis of BD. A major contribution to achieving a correct diagnosis independent of the phenotypic presentation is the demonstration that progranulin plasma levels are extremely low in GRN mutation carriers, even in asymptomatic subjects (57,58). Regarding the function of progranulin, Pickford et al. (63) demonstrated that it has chemotactic properties, stimulates cytokine and chemokine secretion, and induces microglia to switch from a proinflammatory to an anti-inflammatory phenotype.

GRN

C9ORF72

After the discovery of MAPT as causal gene for FTD, there were still numerous autosomal dominant cases (with or without parkinsonism) genetically linked to the same chromosomal region of MAPT, without any mutation in MAPT, and with pathology characterized by tau-negative, ubiquitin-positive staining (FTLD-U). A small region rich in genes, close to the MAPT locus, had been recognized as containing the gene responsible for the disease in these families. The first mutation in GRN, identified in 2006, consists of a 4-bp insertion, which causes a frameshift and premature termination in progranulin (C31LfsX34) (31). At the same time, Cruts et al. (32) found another mutation of 5 bp into the intron following the first noncoding exon of GRN (IVS115G.C). This mutation causes the splicing out of the intron 0, leading to the retention of messenger RNA within the nucleus and its degradation. GRN encodes for the growth regulation factor named progranulin. It belongs to a family of proteins involved in development, wound repair, and inflammation by activation of signaling cascades that control cell cycle progression and cell motility. Progranulin is expressed in neurons and in activated microglia (48). So far .70 different mutations have been described. Most of them result in a premature stop codon, and aberrant mRNA is degraded through nonsense mediated decay, leading to haploinsufficiency (49). In addition, partial deletions of the GRN gene (one or more exons) may occur (50). Truncated and

The first evidence of linkage with a locus on chromosome 9q21-22 comes from a study carried out in families with autosomal dominant FTD with MND (64). Additional data confirmed the linkage to chromosome 9q21-22 in bvFTD/ MND families (65), until, in 2011, two international groups identified the gene responsible for the disease in this locus, C9ORF72 (33,34). The mutation consists of a large hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene, segregating with ALS or FTD/MND phenotype and FTLD-TDP pathology. Wild-type alleles contain 23–30 repeats, whereas mutated alleles have 100–1000 repeats. These studies demonstrated that the C9ORF72 expansion could represent a major cause of familial FTD (12%) and ALS (22.5%) (33), reaching a prevalence of 46% of all familial cases of ALS, 21.1% of sporadic cases of ALS, and 29.3% of cases of FTD in the Finnish population (34). Numerous confirmatory studies subsequently were published (66,67), showing that this mutation is as frequent as GRN and MAPT. Regarding the clinical phenotype, it was shown that psychosis and obsessive-compulsive disorder were common symptoms at disease onset in patients with FTD carrying the repeat expansion (68–70). A case showing mystic delusion with visual and auditory hallucinations, in the absence of neurologic symptoms and brain atrophy, was described more recently (71). After a 9-year follow-up, the patient still presented only with psychosis and did not meet clinical criteria for

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bvFTD diagnosis. Presentation with memory impairment also occurs often—50%–65% according to Mahoney et al. (72)— possibly leading to a clinical diagnosis of AD (71–73). Presentation with Lewy body dementia phenotype may occur as well (74). In a study of 651 patients with FTD, the pathogenic repeat expansion was detected in 39 cases (6%). Clinical phenotypes of carriers were as follows: 29 patients with bvFTD (5.2% of all bvFTD cases diagnosed), 8 patients with bvFTD/MND (32% of bvFTD/MND cases), and 2 patients with SD (5.9% of SD cases). Presentation with late-onset psychosis (megalomanic and mystic delusions, visual hallucinations) and the presence of cognitive impairment at onset were significantly more frequent in carriers than noncarriers (75). Regarding the function of the C9ORF72 product and the mechanisms at the basis of the pathogenesis, the accumulation of RNA transcript containing the GGGGCC repeat within nuclear foci in frontal cortex and spinal cord in chromosome 9p-linked FTD/ALS suggests a toxic RNA gain of function (33). RNA foci, which lead to the sequestration and altered activity of RNA-binding proteins, have been implicated in several neurodegenerative noncoding expansion disorders (76). Reddy et al. (77) demonstrated that r(GGGGCC)n RNA forms extremely stable G-quadruplex structures, which are known theoretically to affect promoter activity, genetic instability, RNA splicing, translation, and neurite mRNA localization. Another possible pathogenic mechanism has been proposed by Mori et al. (78), who demonstrated that the intronic GGGGCC repeat might be aberrantly translated into dipeptides with an unconventional mechanism of non–ATG-initiated translation, first described by Zu et al. (79).

EPIDEMIOLOGY OF FTD AND PSYCHIATRIC SYMPTOMS The incidence of FTD peaks at 60–70 years of age (2.2/ 100,000 person-years at 40–49, 3.3/100,000 person-years at 50–59, and 8.9/100,000 person-years at 60-69) (80). The earliest onset occurs with FTD, followed by SD and PNFA (81). The average survival is 7.5 years, ranging from 3 years for patients with FTD and concomitant MND to 12 years in patients with SD (82). The mean age at presentation for FTD is about 58 years, but there is wide variability, with patients presenting in the second decade of life and others presenting in the ninth decade (82,83). The former, earlier presentation often may be mistaken for nonprogressive psychiatric diseases of young adults, such as SZ and BD. The overall prevalence of FTD varies among different ethnic groups and from center to center on the basis of the specific setting but could be estimated to be about 15–22/100,000 (84). However, it could be underestimated because personality changes occurring at onset may be not recognized as due to a degenerative disease, directing people with such symptoms to psychiatrists, psychologists, or primary care physicians. The manifestation of psychosis in FTD is not a new concept but has been underestimated. In 1995, Waddington et al. (85) described a patient with typical SZ, who developed increasing affective and cognitive deficits. On biopsy, all the neuropathologic hallmarks of Pickʼs disease were present.

Based on the assumption that FTD and SZ might have a common etiology in some families in which both syndromes coexist, Schoder et al. (86) analyzed the morbid risk for SZ in first-degree relatives of 100 FTD probands and compared it with first-degree relatives of 100 AD probands, showing that the morbid risk for SZ was significantly higher in relatives of FTD probands than in relatives of AD probands. In support of the hypothesis that FTD and psychotic disorders share common pathogenic mechanisms, there is the evidence of tau or TDP-43 deposition in brains from patients diagnosed in life with SZ and BD (87). Of 17 pathologic cases considered, 5 had tau deposition in the brain (FTLD-Tau); in life, SZ was diagnosed in 4, and BD was diagnosed in 1. Eight cases had TDP-43-positive staining (FTLD-TDP). Kerstein et al. (88) described a case of FTD mimicking BD. Pose et al. (89) reported the most frequent psychiatric conditions that can simulate early FTD symptoms, including late-onset BD, lateonset SZ-like psychosis, late-onset depression, and attentiondeficit/hyperactivity disorder in middle and older age. Woolley et al. (90) performed a systematic, retrospective, blinded chart review of 252 patients with a neurodegenerative disease diagnosis, including bvFTD, SD, PNFA, AD, corticobasal syndrome, progressive supranuclear palsy syndrome, and ALS, and recorded history of psychiatric diagnosis, family psychiatric and neurologic history, age at symptom onset, and demographic information. Of patients with a neurodegenerative disease, 28.2% received a prior psychiatric diagnosis. Depression was the most common psychiatric diagnosis in all groups. Patients with FTD received a prior psychiatric diagnosis significantly more often (50.7%) than patients with AD (23.1%), SD (24.4%), or PNFA (11.8%) and were more likely to receive diagnoses of BD or SZ than patients with other neurodegenerative diseases. It is well established that SZ is associated with cognitive impairment, including attention and executive functions and working and declarative memory deficits, which is present from the onset of the disease and remains stable over time (91). In line with these observations, a broad spectrum of abnormalities in brain connectivity in patients with psychosis has been shown, particularly for connections integrating the frontal cortex (92). The involvement of basal ganglia characterizes SZ as well as dopaminergic projections to the nucleus accumbens and orbital and medial prefrontal cortices, which are hyperactive in this disease (93). Some of these circuits, mainly the prefrontal cortex, are involved in FTD, but probably with a functional hypoactivity, as demonstrated by metabolic fluorodeoxyglucose positron emission tomography (19), and this could account for some similarities and differences in the symptoms of the two diseases. Nicolas et al. (94) reported 20-month follow-up of 96 patients with SZ, including psychiatric, neurologic, and neuropsychological evaluation. At the end of the follow-up period, 14 patients fulfilled the diagnostic criteria for dementia. Four patients met the current criteria for bvFTD, two met the criteria for AD, two were given a diagnosis of vascular dementia, and one was given a diagnosis of inflammatory disorder of the central nervous system. Six patients could not be fully characterized. According to a large review of 122 studies (95), psychosis in FTD may occur with a prevalence of about 10%. The percentage increases in carriers of C9ORF72 and GRN

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Table 1. Possible Critical Areas in Differential Diagnosis between FTD and Specific Psychiatric Disorders Warranting Further Neurologic/Psychiatric Investigation Late-onset and/or long-lasting depressive disorder/BD with progressive (not episodic) course, prominent cognitive impairment, and poor antidepressant/mood stabilizer response Late-onset psychotic spectrum disorder (e.g., delusional disorder, brief psychotic disorder, paraphrenia) with prominent cognitive impairment and poor antipsychotic response Late-onset obsessive/compulsive and impulsive behaviors with cognitive alterations and poor treatment response Early-onset sporadic FTD with prominent behavioral alterations mimicking symptoms characteristic of other psychiatric disorders Cases of real cross-sectional and longitudinal comorbidity (e.g., patient with previous BD who subsequently develops FTD)

BD, bipolar disorder; FTD, frontotemporal dementia.

mutations and in patients with a TDP-43 pathology, demonstrating that neurodegenerative disease is often misclassified as psychiatric disease, with patients with FTD at highest risk. Although the possibility that psychiatric disorders represent an independent risk factor for neurodegenerative disease cannot be ruled out, when patients with neurodegenerative disease are initially classified with psychiatric disease, they may receive delayed or inappropriate treatment and be subject to increased distress.

CROSSING BORDERS BETWEEN FTD AND PSYCHIATRIC DISORDERS IN CLINICAL PRACTICE: OVERLAPPING SYMPTOMS, DIFFERENTIAL DIAGNOSIS, COMORBIDITY, AND TREATMENT From a clinical point of view, the presence of overlapping symptoms between FTD and specific psychiatric disorders can pose various problems related to differential diagnosis and ultimately modify the prognosis of the disorders, mainly secondary to delayed and incorrect diagnosis and lack of treatment effect. It is particularly important to recognize clinical presentations with such overlapping symptoms early, implementing specific algorithms that can orient clinicians in the diagnostic pathways and overall patient management. As previously stated, onset of bvFTD can resemble, mimick, or be misdiagnosed with symptoms of different psychiatric disorders not only belonging to the schizophrenic/psychotic spectrum but also including depressive, bipolar, obsessivecompulsive, and impulse-control disorders (71,87,89,96,97). Crossing borders between FTD and the aforementioned psychiatric disorders implies not only the presence of cognitive

impairment, in terms of social cognition and executive functions, but also behavioral aspects, including (but not restricted to) anhedonia, apathy, disinhibition, stereotyped and perseverative behaviors, mood alterations, emotional blunting, sleep and appetite modifications, and psychotic symptoms (88,89). When approaching the two distinct clinical areas (bvFTD and psychiatric disorders) from different perspectives (neurologic and psychiatric), a preliminary, pivotal consideration needs to be put forth in relation to the possible comorbidity between such conditions. Specific psychiatric disorders and FTD, mainly bvFTD, with overlapping symptoms do not have to be viewed as mutually exclusive disorders but can be viewed as potentially co-occurring conditions, from either a cross-sectional or a longitudinal perspective. Comorbid FTD with psychiatric disorders and, in particular, psychiatric disorders with comorbid FTD may represent the most difficult-torecognize scenarios. On one hand, all reported psychiatric disorders (in particular, SZ, BD, and obsessive-compulsive disorder) have their onset in late adolescence and young adulthood. In such cases, “late-onset” variants occurring between 40 and 50 years of age, which represents the peak age of onset for FTD, seems to be clinically less probable, although reported in the literature (98). For instance, cases of major depressive disorder and nonschizophrenic psychotic disorders (e.g., delusional disorder, brief psychotic disorder, paraphrenia) often can have their onset in that period and pose differential diagnosis or mutual comorbidity issues. On the other hand, pre-existing psychiatric disorders can evolve after 2 or 3 decades of illness and be comorbid with FTD (62,69,99). In those cases, psychiatrists may erroneously perceive that their patients have developed treatment-resistant features, whereas it is the diagnostic picture that is changed. Ultimately, when psychiatrists cannot recognize specific “red flags,” only subsequent follow-up evaluation will help to recognize the presence of FTD in such patients. Nevertheless, a specific sensitization to these aspects and a close collaboration between neurologists and psychiatrists can lead to an earlier diagnosis of familial variants of FTD, through genetic tests and neuroimaging procedures. Key aspects for differential diagnosis between FTD and specific psychiatric disorders are summarized in Tables 1 and 2, and a diagnostic algorithm is presented in Figure 1. In terms of treatment and prognosis, although an early diagnosis of the aforementioned psychiatric disorders in younger patients in most cases can result in effective treatment choices and consequent symptom improvement, the diagnosis of FTD as a sole or comorbid condition significantly

Table 2. Differential Diagnosis between FTD and Depressive Disorder/BD Likely Psychiatric Disorder (i.e., Depressive/BD)

2 2 2 2 2 2 2 2

Early acute/subacute onset (i.e., 15-30 years) Positive family history for mood disorders History of multiple mood episodes Presence of comorbidity (anxiety and substance use disorders) Suicidal ideation and previous suicide attempts Inter-episodic complete or partial recovery Cognitive impairment mostly limited to affective episodes Episodic wake-sleep cycle alterations

BD, bipolar disorder; FTD, frontotemporal dementia.

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Likely Frontotemporal Dementia (FTD)

2 2 2 2 2 2

Later, insidious onset (. 40-45 years) Positive family history for dementia (for familial forms) Progressive and continuous course Enduring and progressive cognitive impairment Genetics and neuroimaging evidence Poor response to psychiatric treatments

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Figure 1. Diagnostic algorithm describing the approach to the workup of a patient presenting with neuropsychiatric symptoms. bvFTD, behavioral variant frontotemporal dementia; FDG-PET, fluorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging.

worsens the overall prognosis, making the effect of eventual psychiatric treatments merely symptomatic and short-acting. Nevertheless, an early diagnosis of FTD in patients with or without pre-existing psychiatric disorders is the main and most important objective of clinicians to help families to implement more specific caregiving strategies and provide more informed and overall better management to their patients.

“We hold the opinion that Pick’s disease does not belong to the extreme rarities, but that it remains often unrecognized by the clinician as well as the anatomist because not enough attention is directed to it.” —K. Onari and H. Spatz, 1926

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ACKNOWLEDGMENTS AND DISCLOSURES

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The authors report no biomedical financial interests or potential conflicts of interest.

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ARTICLE INFORMATION From the Department of Pathophysiology and Transplantation (DG, BD, ACA, ES), University of Milan, Milan, Italy; and Bipolar Disorders Clinic (BD), Stanford University, Stanford, California. Address correspondence to Daniela Galimberti, Ph.D., Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Via F. Sforza 35, Milan 20122, Italy; E-mail: daniela. [email protected]. Received Dec 12, 2014; revised Feb 24, 2015; accepted Mar 24, 2015.

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