Author's Accepted Manuscript
Psychiatric symptoms in Frontotemporal Dementia: epidemiology, phenotypes, differential diagnosis Daniela Galimberti PhD, Bernardo Dell’Osso MD, A. Carlo Altamura MD, Elio Scarpini MD
www.sobp.org/journal
PII: DOI: Reference:
S0006-3223(15)00282-6 http://dx.doi.org/10.1016/j.biopsych.2015.03.028 BPS12522
To appear in:
Biological Psychiatry
Cite this article as: Daniela Galimberti PhD, Bernardo Dell’Osso MD, A. Carlo Altamura MD, Elio Scarpini MD, Psychiatric symptoms in Frontotemporal Dementia: epidemiology, phenotypes, differential diagnosis, Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2015.03.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Galimberti et al.
Psychiatric symptoms in Frontotemporal Dementia: epidemiology, phenotypes, differential diagnosis Daniela Galimberti, PhD1,*, Bernardo Dell’Osso, MD1,2, A. Carlo Altamura, MD1,
Elio Scarpini, MD1
Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà
1
Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy.
Bipolar Disorders Clinic, Stanford University, CA, USA.
2
*Corresponding Author Telephone: +390255033847
Fax: +390255036580
e‐mail:
[email protected] Short title: Psychiatric symptoms in FTD
Keywords: Frontotemporal Lobar Degeneration (FTLD), Pick dementia, Frontotemporal Dementia (FTD), Schizophrenia (SZ), Bipolar Disorder (BD), psychosis 1
Galimberti et al.
Abstract word count: 176 Text (excluding abstract, financial disclosures and references) word count: 3986 Tables: 2 Figures: 1 Supplementary material: 0 References: 99
2
Galimberti et al.
ABSTRACT Frontotemporal Dementia (FTD) is the most frequent dementia in the presenile population. Despite epidemiological data demonstrated so far that patients with FTD may have suffered from previous psychiatric disorders or, on the other side, that patients with psychotic disorders may develop dementia more often than expected in the non‐affected population, the overlap between these two conditions have been underestimated. Nevertheless, the identification, in the last few years, of several genetic causes of FTD associated with heterogeneous and atypical presentations, including pure psychiatric symptoms, has shifted the scientific interest back to a better understanding of common mechanisms between FTD and psychotic disorders. Here, we review the current knowledge on FTD spectrum and its common features with some psychiatric diseases, starting from Pick clinical description of the disease, moving towards pathogenic aspects of the disease as well as genetic causes and associated phenotypes, and finishing with the analysis of crossing borders between FTD and psychiatric disorders (mainly represented by schizophrenic and bipolar spectrum disorders) in clinical practice, in terms of overlapping symptoms, differential diagnosis, comorbidity and treatment issues. 3
Galimberti et al.
“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” E. Kraepelin, 1919 Despite 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”. The very first description of a case that would be now defined under the umbrella of Frontotemporal Dementia (FTD), reported by Pick in 1892 (2), was actually not prototypical. He 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 due to a febrile disease. Autopsy revealed brain atrophy, more pronounced in the left hemisphere and particularly in the left temporal lobe. The case has been cited as the first description of Primary Progressive Aphasia (PPA) (3). Twelve years later, Pick described the first case (Anna H., 41‐year‐old) of the most common clinical presentation of the disease, consisting of behavioral abnormalities, including stereotypy and flattening of affect, now referred as behavioral variant (bv)FTD. 4
Galimberti et al.
FROM PICK’S DISEASE TO FRONTOTEMPORAL DEMENTIA Pick’s case descriptions did not include results of microscopic histopathological examination, which was carried out by Alzheimer indeed (5), who described argyrophilic intracytoplasmic inclusions and ballooned neurons, that he named Pick bodies and Pick cells, realizing that changes observed were distinct from those found in the form of cerebral degeneration later associated with his name. It was somewhat later that clinical descriptions and pathological findings were put together to form the nosological entity called Pick’s disease (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, as well as the observation that the absence of Pick pathology may occur in patients with clinical presentation consisting of FTD associated with Motor Neuron Disease (MND) (9). Research on FTD started in the eighties, when two groups from Lund (Sweden) and Manchester (UK) tried to better define this entity. They agreed on the fact that: 1) FTD is more than Pick disease 2) FTD and PPA [with its two subtypes Progressive Non Fluent Aphasia (PNFA) and Semantic Dementia (SD)] have overlapping pathogenic bases 3) a number of cases show an autosomal dominant inheritance (often with an early onset). This lead to the definition of clinical criteria for the diagnosis of FTD (10), which have been later refined (11), including three clinical syndromes: bvFTD, PNFA and SD. bvFTD, the most common clinical presentation, is characterized by behavioural changes and progressive deterioration of personality. Patients may show a wide spectrum of 5
Galimberti et al.
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 others’ mental states and maintaining insight to their own difficulties [see (12) for review]. Unfortunately, neither reviews on clinical features (13‐17), nor clinical criteria (11) and behavioral rating tools for FTD (17) included psychotic and other psychiatric symptoms, possibly due to the divergence occurred in the mid of the last century between neurology, mainly associated with organic causes, and psychiatry, focused instead on psychodynamic issues [see (18) for review]. Our understanding of the neurobiology of FTD and its relationship with clinical manifestations of the disease has dramatically increased in the last few years, when multiple autosomal dominant genetic causes of FTD have been discovered. A number of genetic cases with a 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 Schizophrenia (SZ) and Bipolar Disorder (BD). Here, we will focus on current knowledge on these disorders in terms of clinical diagnostic criteria, genetic causes, phenotype heterogeneity, and overlapping pathogenic mechanisms. 6
Galimberti et al.
FRONTOTEMPORAL DEMENTIA: CURRENT DIAGNOSTIC CRITERIA In 2011, new criteria for bvFTD were proposed (19) together with a new classification of language presentations (20). According to such criteria, bvFTD main feature is the progressive deterioration of behavior and/or cognition by 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 out of six clinically discriminating features. “Probable” bvFTD meets the criteria of “possible” bvFTD, with imaging results consistent with bvFTD (i.e., frontal and/or anterior temporal atrophy on MRI or hypometabolism on PET). “Definite” bvFTD implies the histopathological evidence of FTD hallmarks (post mortem) 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), the term PPA encompasses three presentations: nonfluent/agrammatic variant PPA (nvPPA; previously known as PNFA), semantic variant PPA (svPPA, previously known as SD) and logopenic variant PPA (lvPPA). Progressive loss of speech, with hesitant, non‐ fluent speech output with phonetic/phonological errors and distortions and/or agrammatism is typical of nvPPA (21), whereas loss of knowledge about words and objects, anomia and single‐word comprehension deficits are core features of the svPPA. lvPPA is characterized by phonological disorders, defective word retrieval and sentence repetition deficits, and seems to be associated, in the majority of cases, with underlying 7
Galimberti et al.
Alzheimer’s disease (AD) pathology (20). Patients with lvPPA and nv PPA have some deficits recognizing emotional prosody, whereas those with svPPA show more widespread deficits in social comprehension (12). In addition, other phenotypes, such as Progressive Supranuclear Palsy Syndrome (PSPS), Corticobasal Syndrome (CBS) 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 pathological 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) or FUS (FTLD‐FUS) (23,24) (Table 1). GENETICS: AUTOSOMAL DOMINANT MUTATIONS AND ASSOCIATED PHENOTYPES Despite the majority of FTD cases are sporadic, a number of cases present 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, suggesting FTD in at least one extra family member (26,28), with a percentage of autosomal dominant cases accounting for 13.4% of the total (27). At present, three major genes have been associated with the FTD, including: Microtubule Associated Tau Protein (MAPT) (29,30), Progranulin (GRN) (31, 32) and a hexanucleotide 8
Galimberti et al.
expansion in chromosome 9 (C9ORF72) (33,34), whereas Valosin Containing 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 autosomal dominantly inherited form of bvFTD with parkinsonism (29), named FTDP‐17, characterized at pathological level by the presence of Pick bodies. The gene responsible for such association, MAPT, was discovered few years later (30). MAPT encodes the microtubule associated protein Tau, which is involved in microtubule stabilization and assembly. The H1 haplotype in this gene was previously shown to be associated with Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) pathology (40, 41). To date, more than 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, while others lead to hyperphosphorylation of tau protein, which damages microtubule binding. Alternatively, the alternative splicing is affected, thus producing altered ratios of the different isoforms. 9
Galimberti et al.
Grisart and colleagues described a microduplication on chromosome 17g21.31 that was associated with behavioral problems and skills impairment (43). 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 FTD patient 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 tau‐positive 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 have been reported as well (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. GRN 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 a pathology characterized by tau‐negative, ubiquitin‐positive staining (FTLD‐U). A small region rich of genes, close to MAPT locus, had been recognized as the one 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 10
Galimberti et al.
(C31LfsX34) (31). In parallel, Cruts and colleagues found at the same time another mutation of five base pairs into the intron following the first non‐coding exon of GRN (IVS1+5G>C) (32). This mutation causes the splicing out of the intron 0, leading to the retention of mRNA 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 activating signaling cascades that control cell cycle progression and cell motility. Progranulin is expressed in neurons as well as in activated microglia (48). More than 70 different mutations have been described so far. The majority 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 hyperphosphorylated isoforms of the 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 of a proportion of Amyotrophic Lateral Sclerosis (ALS) cases (51). From a clinical point of view, mutations in GRN are associated with extremely heterogeneous phenotypes, including classical FTD presentations (bvFTD, PNFA, SD), CBS, which seems a quite common clinical presentation (52‐56), AD (57), Mild Cognitive Impairment (58), and Lewy Body Dementia (59). Notably, TDP‐43 pathology has been observed in AD and in DLB brains (60), suggesting that the phenotypic heterogeneity may 11
Galimberti et al.
be due to the presence of two actual pathologies. Age at disease onset is extremely wide, even in the same family, ranging from 47 to 79 years (58). Although rarely, 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, who had had a previous diagnosis of BD. A major contribution to achieve 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 pro‐inflammatory to an anti‐inflammatory phenotype. C9ORF72 The first evidence of linkage with a locus on chromosome 9q21‐22 comes from a study carried out in families with autosomal dominant FTD/MND (64). Additional data confirmed the linkage to chr9q21‐22 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 no more than 23‐30 repeats, whereas 12
Galimberti et al.
mutated alleles have hundred to thousand repeats. These studies demonstrated that the C9ORF72 expansion could represent a major cause of both familial FTD (12%) and ALS (22.5%) (33), reaching a prevalence of 46% of all familiar ALS, 21.1% of sporadic ALS and 29.3% of FTD in the Finnish population (34). Subsequently, in few years, a wide number of confirmatory studies were published [see (66,67) for review], 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). Moreover, a case showing mystic delusion with visual and auditory hallucinations, in the absence of neurological symptoms and brain atrophy, was recently described (71). After a 9‐year follow up, the patient still presented only with psychosis, and did not meet clinical criteria for bvFTD diagnosis. Presentation with memory impairment also occurs quite often [50‐65% according to Mahoney et al. (72)], possibly leading to a clinical diagnosis of AD (71‐73). Presentation with LBD phenotype may occur as well (74). In a study of a population of 651 patients with FTD, the pathogenic repeat expansion was detected in 39 cases (6%). Clinical phenotypes of carriers included: 29 patients with bvFTD (5.2% of all cases diagnosed with bvFTD), 8 with bvFTD/MND (32% of cases with bvFTD/MND), 2 with SD (5.9% of patients with SD). The presentation with late onset psychosis (megalomanic and mystic delusions, visual hallucinations) was significantly more frequent in carriers than non‐carriers as well as the presence of cognitive impairment 13
Galimberti et al.
at onset (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 c9FTD/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 non‐coding expansion disorders (76).. Reddy et al. (77) demonstrated that the r(GGGGCC)n RNA forms extremely stable G‐quadruplex structures, which are known to theoretically affect promoter activity, genetic instability, RNA splicing, translation and neurite mRNA localization. Another possible pathogenic mechanism has been proposed by Mori and colleagues (78), who have demonstrated that the intronic GGGGCC repeat might be aberrantly translated into dipeptides with an unconventional mechanisms of non‐ATG‐initiated translation, first described by Zu and coworkers (79). EPIDEMIOLOGY OF FTD AND PSYCHIATRIC SYMPTOMATOLOGY
The incidence of FTD peaks at 60‐70 years of age, at 2.2, 3.3, and 8.9/100,000 person‐
years at 40‐49, 50‐59 and 60‐69, respectively (80). FTD has the earliest onset, followed by SD and PNFA (81). The average survival is 7.5 years, ranging from 3 years for FTD patients with concomitant MND to 12 years in patients with SD (82). The mean age at presentation in FTD is about 58 years, but there is wide variability, with cases presenting in the second decade of life and others in the ninth decade (82,83). The former, more often, 14
Galimberti et al.
may be mistaken for non‐progressive 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). It could be, however, underestimated, as 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 case of typical SZ, who developed increasing affective and cognitive deficits. On biopsy, all the neuropathological hallmarks of Pickʹs disease were present.
Basing on the assumption that FTD and SZ might have a common aetiology 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, showing that the morbid risk for SZ was significantly higher in relatives of FTD probands than in those 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). Five out of 17 pathologic cases considered had tau deposition in the brain (FTLD‐tau); in life, 4 were diagnosed with SZ and one with BD. Eight cases had instead 15
Galimberti et al.
TDP‐43 positive staining (FTLD‐TDP). Moreover, Kerstein et al. (88) described a case of FTD mimicking BD, whereas Pose et al. (89) reported the most frequent psychiatric conditions that can simulate early FTD symptoms, including late onset BD, late onset SZ‐like psychosis, late onset depression, and attention deficit hyperactivity disorder in middle and older age. Woolley et al. (90) carried out a systematic, retrospective, blinded chart review of 252 patients with a neurodegenerative disease diagnosis, including bvFTD, SD, PNFA, AD, CBS, PSPS and ALS in order to record history of psychiatric diagnosis, family psychiatric and neurologic history, age at symptom onset, and demographic information. A total of 28.2% of patients with a neurodegenerative disease received a prior psychiatric diagnosis. Depression was the most common psychiatric diagnosis in all groups. FTD patients 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. On the other hand, it is well established that SZ is associated with cognitive impairment, including attention and executive functions, 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 patient with psychosis have been shown, particularly for connections integrating the frontal cortex [see (92) for review]. SZ is characterized by the 16
Galimberti et al.
involvement of basal ganglia and 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 FDG‐PET (19), and this could account for some similarities and differences in the symptomatology of the two diseases. Nicolas et al. (94) followed up for 20 months 96 patients with SZ, including psychiatric, neurological, and neuropsychological evaluation. At the end of the follow‐up, 14 patients fulfilled the diagnostic criteria for dementia. Four met the current criteria for bvFTD, two of AD, two were diagnosed with vascular dementia, one with inflammatory disorder of the central nervous system, whereas six could not be fully characterized. According to a large review on 122 studies (95), psychosis in FTD may occur with a prevalence of about 10%. The percentage increases in carriers of C9ORF72 and GRN mutations and in patients with a TDP‐43 pathology, demonstrating that neurodegenerative disease is often misclassified as psychiatric disease, with FTD patients at highest risk. While 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, the patient may receive delayed, inappropriate treatment and be subject to increased distress.
17
Galimberti et al.
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 a variety of differential diagnosis problems and, ultimately, modify the prognosis of the disorder(s), mainly due to delayed and incorrect diagnosis and lack of treatment effect. It is, therefore, of particular importance to early recognize clinical presentations of such kind, implementing specific algorithms that can orient clinicians in the diagnostic pathways and overall patient management.
As previously stated, bvFTD onset can resemble, mimicking or being misdiagnosed with, symptoms of different psychiatric disorders, which do not only belong to the schizophrenic/psychotic spectrum but also to the depressive, bipolar, obsessive‐ compulsive and impulse‐control spectrum disorders (71,87,89,96,97).
Crossing borders between FTD and the aforementioned psychiatric disorders do not only imply 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 18
Galimberti et al.
needs to be put forth in relation to the possible comorbidity between such conditions. FTD, mainly in its behavioral variant, and specific psychiatric disorders with overlapping symptoms, in fact, do not have to be viewed as mutually exclusive disorders but as potentially co‐occurring conditions, either in a cross‐sectional and longitudinal perspective. Indeed, comorbid FTD with psychiatric disorders and, in particular, psychiatric disorders with comorbid FTD, may represent the most difficult‐to‐recognize scenarios. On one hand, all reported psychiatric disorders (SZ, BD and Obsessive‐ Compulsive Disorder, in particular) have their onset in late adolescence/young adulthood. In such cases, their “late‐onset” variants occurring between 40 to 50 years of age, which represents the peak for FTD, seems to be clinically less probable, though reported in literature (98). For instance, cases of Major Depressive Disorder and non‐schizophrenic psychotic disorders (e.g., Delusional Disorder, Brief Psychotic Disorder, Paraphrenia) can often present their onset in that period and pose differential diagnosis or mutual comorbidity issues. On the other hand, pre‐existing psychiatric disorders can, after two or three decades of illness, evolve and be comorbid with FTD (62,69,99). In those cases, psychiatrists may get the erroneous perception of their patients having developed treatment resistant features, while it is the diagnostic picture that is changed. Ultimately, only the subsequent follow‐up will help to recognize the presence of FTD in such patients, when psychiatrists cannot recognize specific “red flags” in such regard. 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 19
Galimberti et al.
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 proposed in Figure 1).
In terms of treatment issues and prognostic aspects, while an early diagnosis of the aforementioned psychiatric disorders in mid‐age patients can bring, in most cases, to an effective treatment choice and consequent symptom improvement, the diagnosis of FTD, as sole or comorbid condition, significantly 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 undoubtedly represents the main and most important objective of clinicians, in order 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 DISCLOSURES The Authors do not report any biomedical financial interests or potential conflicts of interests.
20
Galimberti et al.
REFERENCES 1. Kraepelin E (1919): Dementia praecox and paraphrenia. Livingstone. 2. Pick A (1892): Über die Beziehungen der senilen atrophie zur aphasie. Prager Medizinische Wochenschrift 17: 165‐167. 3. Mesulam MM (1982): Slowly progressive aphasia without generalized dementia. Ann Neurol 11: 592‐598. 4. Pick A (1904): Über primäre progressive demenz bei erwachsenen. Prager Medizinische Wochenschrift (Sonderdruck) 29: 1‐10. 5. Alzheimer A (1911): Über eigenartige Krankheitsfälle des späteren Alters. Zeithschrift für die gesamte neurologie und Psychiatrie 4: 356‐385.
6. Gans A (1922): Betrachtungen über art and ausbreitung des krankhaften prozesses in einem fall von Pickscher atrophie des stirnhirns. Zeithschrift für die gesamte neurologie und Psychiatrie 80: 10‐28. 7. Onari K, Spatz H (1926): Anatomische, beiträge zur lehre von der Pickschen umschriebenen grobhirnrinden‐atrophie (“Picksche Krankheit”). Zeithschrift für die gesamte neurologie und Psychiatrie 101: 470‐511.
8. Constantinidis J, Richard J, Tissot R (1974): Pickʹs disease: Histological and clinical correlations. Eur Neurol 11(4): 208‐217.
21
Galimberti et al.
9. Horoupian DS, Thal L, Katzman R, Terry RD, Davies P, Hirano A, et al. (1984): Dementia and motor neuron disease: morphometric, biochemical, and Golgi studies. Ann Neurol 16(3): 305‐313.
10. [No authors listed] (1994): Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 57(4): 416‐ 418. 11. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. (1998): Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51(6): 1546‐1554. 12. Shany‐Ur T, Rankin KP (2011): Personality and social cognition in neurodegenerative disease. Curr Opin Neurol 24: 550‐555.
13. Snowden JS, Neary D, Mann DMA (2002): Frontotemporal dementia. Br J Psychiatry 180: 140‐143. 14. Wszolek ZK, Tsuboi Y, Ghetti B, Pickering‐Brown S, Baba Y, Cheshire WP (2006): Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17). Orphanet J Rare Dis 1:30. 15. Neary D, Snowden J, Mann D (2005): Frontotemporal dementia. Lancet Neurol 4: 771‐780. 16. Assal F, Cummings JL (2002): Neuropsychiatric symptoms in the dementias. Curr Opin Neurol 15: 445‐450. 22
Galimberti et al.
17. Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D (2001): Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 70(3): 323‐332. 18. Martin JB (2002): The integration of neurology, psychiatry, and neuroscience in the 21st century. Am J Psychiatry 159: 695‐704. 19. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. (2011): Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134: 2456‐2477. 20. Gorno‐Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006‐ 14. 21. Gorno‐Tempini ML, Dronkers NF, Rankin KP, Ogar JM, Phengrasamy L, Rosen HJ, et al. (2004): Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 55: 335‐346.
22. Kovacs GG (2015): Invited review: Neuropathology of tauopathies: principles and practice. Neuropathol Applied Neurobiol 41: 3–23.
23. Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, et al. (2011): A harmonized classification system for FTLD‐TDP pathology. Acta Neuropathol 122(1): 111‐113. 24. Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. (2010): Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar 23
Galimberti et al.
degeneration: an update. Acta Neuropathol 119(1): 1‐4. 25. Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002): The prevalence of frontotemporal dementia. Neurology 58: 1615‐1621. 26. Bird T, Knopman D, VanSwieten J, Rosso S, Feldman H, Tanabe H, et al. (2003): Epidemiology and genetics of frontotemporal dementia/Pick’s disease. Ann Neurol 54: S29‐S31. 27. Goldman JS, Farmer JS, Wood EM, Johnson JK, Boxer A, Neuhaus J, et al. (2005): Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 65: 1817‐1819. 28. Pickering‐Brown SM (2007): The complex aetiology of frontotemporal lobar degeneration. Exp Neurol 114: 39‐47. 29. Wilhelmsen KC, Lynch T, Pavlou E, Higgins M, Nygaard TG (1994): Localization of disinhibition‐dementia‐parkinsonism‐amyotrophy complex to 17q21‐22. Am J Hum Genet 55(6): 1159‐1165. 30. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. (1998): Association of missense and 5′‐splice‐site mutations in tau with the inherited dementia FTDP‐17. Nature 393: 702‐705. 31. Baker M, Mackenzie IR, Pickering‐Brown SM, Gass J, Rademakers R, Lindholm C, et al. (2006): Mutations in progranulin cause tau‐negative frontotemporal dementia linked to chromosome 17. Nature 442: 916‐919.
32. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al (2006): Null 24
Galimberti et al.
mutations in progranulin cause ubiquitin‐positive frontotemporal dementia linked to chromosome 17q21. Nature 442: 920‐924. 33. DeJesus‐Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. (2011): Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p‐linked FTD and ALS. Neuron 72: 245‐256. 34. Renton AE, Majounie E, Waite A, Simón‐Sánchez J, Rollinson S, Gibbs JR, et al. (2011): A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21‐linked ALS‐FTD. Neuron 72: 257‐268. 35. Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, et al. (2004): Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin‐containing protein. Nat Genet 36(4):377‐381.
36. Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, et al. (2005): Mutations in the endosomal ESCRTIII‐complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37(8):806‐808.
37. Kovacs GG, Murrell JR, Horvath S, Haraszti L, Majtenyi K, Molnar MJ, et al. (2009): TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov Disord 24(12):1843‐1847.
38. Yan J, Deng HX, Siddique N, Fecto F, Chen W, Yang Y, et al. (2010): Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75(9): 807‐814. 25
Galimberti et al.
39. Rubino E, Rainero I, Chiò A, Rogaeva E, Galimberti D, Fenoglio P, et al. (2012): SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology. 79(15):1556‐1562.
40. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez‐Tur J, et al. (1999): Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 8(4): 711‐715. 41. Houlden H, Baker M, Morris HR, MacDonald N, Pickering‐Brown S, Adamson J, et al., (2001): Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 56(12): 1702‐1706. 42. Rademakers R, Cruts M, van Broeckhoven C (2004): The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24: 277‐295. 43. Grisart B, Willatt L, Destrée A, Fryns JP, Rack K, de Ravel T, et al. (2009): 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. J Med Genet 46, 524‐530. 44. Lladó A, Rodríguez‐Santiago B, Antonell A, Sánchez‐Valle R, Molinuevo JL, Reñé R, Pérez‐Jurado LA (2007): MAPT gene duplications are not a cause of frontotemporal lobar degeneration. Neurosci Lett 424: 61‐65. 45. Rovelet‐Lecrux A, Lecourtois M, Thomas‐Anterion C, Le Ber I, Brice A, Frebourg T, et al. (2009): Partial deletion of the MAPT gene: a novel mechanism of FTDP‐17. Hum Mutat 30: 591‐602.
26
Galimberti et al.
46. Rovelet‐Lecrux A, Hannequin D, Guillin O, Legallic S, Jurici S, Wallon D, et al. (2010): Frontotemporal dementia phenotype associated with MAPT gene duplication. J Alzheimers Dis 21: 897‐902. 47. Villa C, Ghezzi L, Pietroboni AM, Fenoglio C, Cortini F, Serpente M, et al. (2011): A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia. J Alzheimers Dis 26: 19‐26. 48. He Z, Bateman A (2003): Progranulin (granulin‐epithelin precursor, PC‐cell‐derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 81: 600‐ 612. 49. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, et al (2011): A harmonized classification system for FTLD‐TDP pathology. Acta Neuropathol 122(1): 111‐ 113. 50. Clot F, Rovelet‐Lecrux A, Lamari F, Noël S, Keren B, Camuzat A, et al. (2014): Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration. Neurogenetics 15(2): 95‐100.
51. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. (2006): Ubiquitinated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130‐133. 52. Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, et al. (2010): The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67: 161‐70. 27
Galimberti et al.
53. Carecchio M, Fenoglio C, Cortini F, Comi C, Benussi L, Ghidoni R, et al. (2011): Cerebrospinal Fluid Biomarkers in Progranulin Mutations Carriers. J Alzheimers Dis 27(4): 781‐790. 54. Masellis M, Momeni P, Meschino W, Heffner R Jr, Elder J, Sato C, et al. (2006): Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 129(Pt 11): 3115‐3123. 55. Benussi L, Ghidoni R, Pegoiani E, Moretti DV, Zanetti O, Binetti G (2008): Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide. Neurobiol Dis 33(3): 379‐385. 56. Guerreiro RJ, Santana I, Bras JM, Revesz T, Rebelo O, Ribeiro MH, et al. (2008): Novel progranulin mutation: screening for PGRN mutations in a Portuguese series of FTD/CBS cases. Mov Disord 23(9): 1269‐1273. 57. Carecchio M, Fenoglio C, De Riz M, Guidi I, Comi C, Cortini F, et al. (2009): Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimerʹs disease. J Neurol Sci 287: 291‐293. 58. Pietroboni AM, Fumagalli GG, Ghezzi L, Fenoglio C, Cortini F, Serpente M, et al. (2011): Phenotypic Heterogeneity of the GRN Asp22fs Mutation in a Large Italian Kindred. J Alzheimers Dis 24: 253‐259. 59. Arosio B, Abbate C, Galimberti D, Rossi PD, Inglese S, Fenoglio C, et al. (2014): GRN Thr272fs Clinical Heterogeneity: A Case with Atypical Late Onset Presenting with a 28
Galimberti et al.
Dementia with Lewy Bodies Phenotype. J Alzheimers Dis 35(4): 669‐674. 60. Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, et al. (2009): Phosphorylated TDP‐43 in Alzheimerʹs disease and dementia with Lewy bodies. Acta Neuropathol 117(2): 125‐136. 61. Rainero I, Rubino E, Negro E, Gallone S, Galimberti D, Gentile S, et al. (2011): Heterosexual pedophilia in a frontotemporal dementia patient with a mutation in the progranulin gene. Biol Psychiatry 70: 43‐44. 62. Cerami C, Marcone A, Galimberti D, Villa C, Scarpini E, Cappa SF (2011): From genotype to phenotype: two cases of genetic frontotemporal lobar degeneration with premorbid bipolar disorder. J Alzheimers Dis 27(4): 791‐797. 63. Pickford F, Marcus J, Camargo LM, Xiao Q, Graham D, Mo JR, et al. (2011): Progranulin is a chemoattractant for microglia and stimulates their endocytic activity. Am J Pathol 178(1): 284‐295. 64. Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, et al. (2000): Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21–q22. JAMA 284: 1664‐1669. 65. Morita M, Al‐Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, et al. (2006): A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66: 839‐844. 66. Woollacott IO1, Mead S (2014): The C9ORF72 expansion mutation: gene structure, phenotypic and diagnostic issues. Acta Neuropathol 127(3): 319‐332. 29
Galimberti et al.
67. Rohrer JD, Isaacs AM, Mizlienska S, Mead S, Lashley T, Wray S, Sidle K, Fratta P, Orrell RW, Hardy J, Holton J, Revesz T, Rossor MN, Warren JD (2015) C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol. 2015 Jan 28. pii: S1474‐4422(14)70233‐9. 68. Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM, et al. (2012): Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135(Pt 3): 693‐708. 69. Floris G, Borghero G, Cannas A, Di Stefano F, Costantino E, Murru MR, et al. (2012): Frontotemporal dementia with psychosis, parkinsonism, visuo‐spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype? J Neurol 259(8): 1749‐1751. 70. Calvo A, Moglia C, Canosa A, Cistaro A, Valentini C, Carrara G, et al. (2012): Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive‐compulsive disorder associated to GGGGCC expansion of the c9orf72 gene. J Neurol 259(12): 2723‐2725. 71. Arighi A, Fumagalli GG, Jacini F, Fenoglio C, Ghezzi L, Pietroboni AM, et al. (2012): Early onset behavioural variant Frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations. J Alzheimers Dis 31: 447‐452. 72. Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, et al. (2012): Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, 30
Galimberti et al.
neuroanatomical and neuropathological features. Brain 135(Pt 3): 736‐750. 73. Murray ME, DeJesus‐Hernandez M, Rutherford NJ, Baker M, Duara R, Graff‐Radford NR, et al. (2011): Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122: 673‐690. 74. Snowden JS, Rollinson S, Lafon C, Harris J, Thompson J, Richardson AM, et al. (2012): Psychosis, C9ORF72 and dementia with Lewy bodies. J Neurol, Neurosurg, Psychiatry 83(19): 1031‐1032.
75. Galimberti D, Fenoglio C, Serpente M, Villa C, Bonsi R, Arighi A, et al. (2013): Autosomal Dominant Frontotemporal Lobar Degeneration Due to the C9ORF72 Hexanucleotide Repeat Expansion: Late‐Onset Psychotic Clinical Presentation. Biol Psychiatry 74: 384–91. 76. Renoux AJ, Todd PK (2012): Neurodegeneration the RNA way. Prog Neurobiol 97: 173‐ 189. 77. Reddy K, Zamiri B, Stanley SY, Macgregor RB, Pearson CE (2013): The disease‐ associated r(GGGGCC)n repeat from the C9ORF72 gene forms tract length‐dependent uni‐ and multi‐molecular RNA G‐quadruplex structures. J Biol Chem 288(14):9860‐9866. 78. Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. (2013): The C9orf72 GGGGCC repeat is translated into aggregating dipeptide‐repeat proteins in FTLD/ALS. Science 339(6125): 1335‐1338. 79. Zu T, Gibbens B, Doty NS, Gomes‐Pereira M, Huguet A, Stone MD, et al. (2011): Non‐ATG‐initiated translation directed by microsatellite expansions. Proc Natl Acad Sci 31
Galimberti et al.
USA 108: 260‐5. 80. Pressman PS, Miller BL (2014): Diagnosis and management of behavioral variant Frontotemporal Dementia. Biol Psych 75: 574‐581.
81. Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, Forman M, et al. (2005): Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Arch Neurol 62(6): 925‐930.
82. Roberson ED, Hesse JH, Rose KD, Slama H, Johnson JK, Yaffe K, et al. (2005): Frontotemporal dementia progresses to death faster than Alzheimer disease. Neurology 65(5): 719‐725.
83. Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, et al. (2003): Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population‐based study. Brain 126(Pt 9): 2016‐2022.
84. Onyike CU, Diehl‐Schmid J (2013): The epidemiology of Frontotemporal dementia. Int Rev Psychiatry 25: 130‐137.
85. Waddington JL, Youssef HA, Farrell MA, Toland J (1995): Initial ʹschizophrenia‐likeʹ psychosis in Pickʹs disease: case study with neuroimaging and neuropathology, and implications for frontotemporal dysfunction in schizophrenia. Schizophr Res 18(1): 79‐82.
86. Schoder D, Hannequin D, Martinaud O, Opolczynski G, Guyant‐Maréchal L, Le Ber I, Campion D (2010): Morbid risk for schizophrenia in first‐degree relatives of people with 32
Galimberti et al.
frontotemporal dementia. Br J Psichiatry 197: 28‐35.
87. Velakoulis D, Walterfang M, Mocellin R, Pantelis C, McLean C (2009): Frontotemporal dementia presenting as schizophrenia‐like psychosis in young people: clinicopathological series and review of cases. Br J Psychiatry 194(4): 298‐305.
88. Kerstein AH, Schroeder RW, Baade LE, Lincoln J, Khan AY (2013): Frontotemporal dementia mimicking bipolar disorder. J Psychiatr Pract 19(6): 498‐500.
89. Pose M, Cetkovich M, Gleichgerrcht E, Ibáñez A, Torralva T, Manes F (2013): The overlap of symptomatic dimensions between frontotemporal dementia and several psychiatric disorders that appear in late adulthood. Int Rev Psychiatry 25(2): 159‐167.
90. Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP (2011): 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 72: 126‐133.
91. Rund BR (1998): A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull 24: 425‐435.
92. Schmidt A, Diwadkar VA, Smieskova R, Harrisberger F, Lang UE, McGuire P, et al. (2015): Approaching a network connectivity‐driven classification of the psychosis continuum: a selective review and suggestions for future research. Front Hum Neurosci 8: 1047. 33
Galimberti et al.
93. Stevens JR (1973): An anatomy of schizophrenia? Arch Gen Psychiatry 29: 177‐189.
94. Nicolas G, Beherec L, Hannequin D, Opolczynski G, Rothärmel M, Wallon D, et al. (2014): Dementia in middle‐aged patients with schizophrenia. J Alzheimers Dis 39(4): 809‐ 822.
95. Shinigawa S, Nakajima S, Plitman E, Graff‐Guerrero A, Mimura M, Nakayama K, Miller BL (2014): Psychosis in Frontotemporal Dementia. J Alzheimers Dis 42: 485‐499.
96. Ibanez N (2012): Atypical presentation of frontotemporal dementia masquerading as bipolar disorder and substance abuse: a case report. W V Med J 108(4): 16‐17.
97. Wylie MA, Shnall A, Onyike CU, Huey ED (2013): Management of frontotemporal dementia in mental health and multidisciplinary settings. Int Rev Psychiatry 25(2): 230‐ 236.
98. Monji A, Motomura K, Mizoguchi Y, Ohara T, Baba S, Yoshiura T, Kanba S (2014): A case of late‐onset bipolar disorder with severely abnormal behavior and neuroimaging observations very similar to those of frontotemporal dementia. J Neuropsychiatry Clin Neurosci 26(1): E35.
99. Pavlovic A, Marley J, Sivakumar V (2011): Development of frontotemporal dementia in a case of bipolar affective disorder: is there a link? BMJ Case Rep 2011.
34
Galimberti et al.
Figure legends
Figure 1. Diagnostic algorithm tree describing the approach to work up of someone presenting with neuropsychiatric symptoms.
35
Galimberti et al.
TABLES Table 1. Possible critical areas in the differential diagnosis between FTD and specific psychiatric disorders suggesting further neurologic/psychiatric investigation Late onset and/or long‐lasting depressive/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)
36
Galimberti et al.
Table 2. Key aspects for differential diagnosis between FTD and some psychiatric disorders (i.e., Depressive/Bipolar Disorders) Psychiatric Disorder (i.e., Depressive/BD),
Frontotemporal Dementia (FTD), in most
in most cases
cases
Early acute/subacute onset (i.e., 15‐30 years) Later, insidious onset (> 40‐45 years) Positive family history for mood disorders Positive family history for dementia (for familial forms) History of multiple mood episodes
Progressive and continuous course
Presence of comorbidity (anxiety and
Enduring and progressive cognitive
substance use disorders) Suicidal ideation and previous suicide
impairment Genetic and neuroimaging evidence
attempts Inter‐episodic complete or partial recovery Poor response to psychiatric treatments Cognitive impairment mostly limited to
affective episodes Episodic wake‐sleep cycle alterations
37
Galimberti et al.
Fig 1
38