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International Review ofPsychiatry, April 2013; 25(2): 168-177 informa healthcare Schizophrenia and frontotemporal dementia: Shared causation? MICHAL HARCIAREKI, DOLORES MALASPINA2, TAO SUN' & ELKHONON GOLDBERG' 'Division of Clinical Psydtokgy and Neuropsydrology, Institute ofPsychology, University of Gdansk, Poland, 2Depar:ment ofPsychiatry, New York University School ofMedicine, Newlbrk, USA, 3Department of Cell and Developmental Biology, Cornell University Will Medical College, New York, USA, 4Depanmmt ofNeurology, New York University School ofMedicine, New York, USA Abstract The relationship between specific genes and particular diseases in neuropsychiatry is unclear, and newer studies focus on shared domains of neurobiological and cognitive pathology across different disorders. This paper reviews the evidence for an association between schizophrenia and frontotemporal dementia, including symptom similarity, familial co-morbidity, and neuroanatomical changes. Genetic as well as epigenetic findings from both schizophrenia and frontotemporal demen- tia are also discussed. As a result, we introduce the hypothesis of a shared susceptibility for certain subgroups of schizo- phrenia and frontotemporal dementia.This common causation may involve the same gene(s) at different stages of life: early in schizophrenia and late in frontotemporal dementia. Additionally, we provide a rationale for future research that should emphasize both genetic and cognitive parallels between certain forms of schizophrenia and frontotemporal dementia in a synergistic, coordinated way, placing both in the context of aberrant lateralization patterns. Introduction of what constitutes a 'disorder' in neuropsychiatry, The relationship between specific genes and particu- and invited the revision of, and departure from, tra- lar diseases in neuropsychiatry remains unclear, and ditional diagnostic taxonomies. The notion that the understanding of this relationship continues to domains of psychopathology reflect a graduated evolve, reflecting the changes in the neuroscientific symptom space is increasingly embraced to replace zeitgeist. Variable expressivity, plciotrophic effects, the traditional notions of 'disorders' that are sepa- partial penetrancc, cpistasis, and gene—environment rated by inherently discrete boundaries. This para- interactions have been proposed to explain different digm shift has made it conceptually feasible to draw disease presentations related to the same genes over parallels between disorders that were traditionally time and between affected individuals. This relation- regarded as taxonomically distant and unrelated. ship is made particularly elusive when cognitive and Thus, schizophrenias and dementias would seem to affective symptoms are used to construct the diag- be particularly distant taxonomically — the former nostic entities, since the nature of such symptoms is have been recently envisioned as neurodevelopmen- determined primarily by the neuroanatomy that is tal disorders characterized by psychotic symptoms, involved, and only secondarily by pathophysiology. whereas the others are disorders of cognition and Also, the same neuroanatomical structure is under affect as a consequence of pathological ageing. Yet control of numerous other regions and genes, many similar degenerative factors may be at play behind or most of which may change in expression over these conditions. Emil Kraepelin (1919) first recog- development and as a consequence of life exposures. nized the similarity of these disorders, describing This absence of one-to-one (isomorphic), or even of schizophrenia as a dementia that emerges in young many-to-one (homomorphic) relationship between adults (dementia praecox). Subsequent nosologies genes and disorders has made the investigation of any focused on other symptoms that Kraepelin consid- relationship between them particularly daunting. ered to be only secondary to the neurodegenerative The failure to fmd major 'culprit' genes behind many process. These illness features include psychosis, neuropsychiatric conditions has forced a re-examination which entails delusions and hallucinations, disordered iriat allifiginfilkaalai N *dicing, 315 West 57th Street. Suite 401. NewYork, NY 10019, USA. Tel (Received 19 jay 20:2; gasped 7 January 2013) ISSN 0954-0261 prior/ISSN 1369-1627 online t' 2013 Institute of Psychiatry DOI: 10.3109/09540261.2013.765389 RIONTS EFTA_R1_01956830 EFTA02674718  Schizophrenia and FTD 169 thinking and bizarre behaviour (defined as 'positive' Difficulties with differentiating between schizo- symptoms), and deficits in emotional expression and phrenia-related psychosis and neurodegenerative dis- volition (defined as 'negative' symptoms). orders suggestive of certain common underlying Frontotemporal dementia (FTD) is a particularly factors are not new, and they predate the original good example of a neurodegenerative disorder char- work by Kraepelin (1919) and Pick (1892). One such acterized by shared properties and perhaps even ambiguous case was the case of Ludwig II, King of shared underlying causal factors with schizophrenias. Bavaria (1845-1886), whose medical history has FTD is a midlife onset clinical condition first been recently reviewed by Forstl et al. (2008). described by Arnold Pick (1892) and previously According to the royal medical report, significant known as Pick's disease (Kertesz, 2008). It is char- and rather progressive changes in the personality and acterized by progressive behavioural and personality behaviour of Ludwig II were noted when he reached abnormalities and/or language impairment that have the age of about 25. He became withdrawn and, as been associated with the degeneration of frontal and/ with many patients with FTD became obsessed with or temporal regions of the brain (Harciarek & Jodzio, irrelevant details. His speech became odd (although 2005). The clinical presentation of FTD is heteroge- its specific characteristics were not recorded) and he neous, and FTD is commonly divided into two sub- became aggressive. He also became delusional with types. The first subtype of FTD is its behavioural frequent hallucinations, this bringing his clinical pic- variant, with impaired social conduct, disinhibition, ture towards schizophrenia-like psychosis. Interest- stereotypic behaviours, loss of empathy, as well as ingly, however, he seemed to be well aware of his apathy among its most prominent features (Rask- abnormal behaviour but did not attempt to alter it, ovsky et al., 2011). The second subtype of FTD is despite the apparent insight. With age, certain motor its language variant, also often described as primary symptoms developed, which are common in both progressive aphasia (PPA) (Hodges, 2007; Mesulam, schizophrenia and FTD. According to Forstl et al. 2003). According to the most recent classification, (2008), the description of Ludwig's symptoms is PPA can be further divided into three variants: congruent with the diagnosis of schizophrenia disor- semantic, non-fluent/agrammatic, and logopenic der according to DMS-IV. This diagnosis is further (Gomo-Tempini et al., 2011; Harciarek & Kertesz, supported by a positive family history for schizophre- 2011; Mesulam et al., 2008). Of note, in comparison nia-like psychosis; both Ludwig's younger brother to the semantic and the non-fluent/agrammatic PPA Otto as well as the youngest daughter of Ludwig's predominantly associated with ftontotemporal lobar grandfather developed severe mental disorder with degeneration (FTLD), the logopenic variant has inappropriate affect, catatonic behaviour and apathy been more often linked to the pathology of Alzheim- from an early age until death. At the same time, a er's disease (Grossman, 2010; Mesulam et al., 2008; post-mortem examination of Ludwig II, who died in Rabinovici et al., 2008). unclear circumstances (possibly drowning), revealed Although schizophrenia and FTD have been typi- extensive frontal atrophy in both hemispheres sug- cally described in terms of specific feature constella- gestive of a neurodegenerative disease. tions characteristic for each disorder (e.g. younger In this paper we review the evidence for a relation- onset and more pronounced delusions as well as hal- ship between schizophrenia and FTD and introduce lucinations in schizophrenia), it has been also shown the hypothesis that their respective causations could that there is a great deal of clinical, neuroimaging, be manifestations of the abnormalities involving the genetic, and pathological overlap, making it some- same genes at different life stages: early in schizophre- times difficult to distinguish between these two con- nia and late m FTD. Of course, both schizophrenia ditions (Momeni et al., 2010a). The association and FTD are syndromes consisting of heterogeneous between schizophrenia and FTD has been rarely and components, so any hypothesis pertaining to the sim- only recently studied, however, despite Kraepelin's ilarity of underlying mechanisms is likely to be appli- early observations. This may, at least in part, reflect cable only to certain subtypes of schizophrenia and the diagnostic criteria applied for schizophrenia and subtypes of FTD. We will examine several sources of FTD, as well as the traditional dominance of rigid evidence pertaining to the relationship between diagnostic taxonomies. For example, subjects with a schizophrenia and FTD: (1) symptom similarity, history of neurological conditions are typically not (2) familial co-morbidity, (3) neuroanatomy, (4) included in studies of schizophrenia. Also, widely genetics, and (5) epigenetics. used diagnostic criteria for FTD (McKhann et al., 2001; Neary et al., 1998) do not encompass assess- Shared symptomatology in schizophrenia ment of psychotic symptoms, although these have and Fit been known to appear in FTD (Chow et al., 1999; Le Ber et al., 2006, 2008; Mendez et al., 2008; The concept of negative and positive symptoms was Schoder et al., 2010). first introduced by John Russell Reynolds (1858) to RIGHTS .4, EFTA_R1_01956831 EFTA02674719 170 M. Harciarek a al. illuminate the features of epilepsy. In his view, nega- remains an open question. It is possible that whereas tive symptoms were the loss of vital properties that positive symptoms are related to an increase in dop- could cause conditions such as paralysis or anaesthe- amine in the mesolimbic pathway, a defective dop- sia, while positive symptoms were the excess of vital amine function in the mesocortical pathway may properties resulting in conditions such as spasms, contribute to the development of negative symptoms pain or convulsions. Although both could be observed (Weinberger & Berman, 1988). Further, it has been at the same time, Reynolds believed that positive and proposed that negative symptoms represent a conse- negative symptoms were independent of each other quence of impaired frontal lobe function (Berge (Berrios, 1985). Expanding on Reynolds idea, et al., 2011; Frith, 1992; Liddle, 1987; Weinberger, Hughlings Jackson (1958) conceptualized positive 1988). In fact, when Kraepelin (1919) introduced symptoms as the result of the loss ofhigher inhibitory the concept of 'dementia praecox', he suggested that, mechanisms that permitted excitation or the dis- based on the symptomatology of schizophrenia, it charge of lower neural systems and negative symp- should be considered a frontotemporal disorder. toms as the result of reduced neural function. Unlike Also, many authors have noted that the affective flat- Reynolds, Jackson believed that positive and negative tening, lack of volition, poor judgement, personal symptoms were different manifestations of a single neglect and social withdrawal seen in many patients process. Kraepelin (1919) and Bleuler (1908) with schizophrenia are among symptoms typically adopted Jackson's theory of positive and negative seen in subjects with disease of the frontal lobe (Frith, symptoms in their conceptualizations of schizophre- 1992; Levin, 1984; Liddle, 1987; Pantelis et al., nia. A shared aetiopathophysiology for cases of 1992; Weinberger, 1988; Winograd-Gurvich et al., schizophrenia and FTD would be most consistent 2006). Additionally, it has been shown that such with Jackson's model. Deterioration of frontal lobes negative symptoms are related to defective perfor- with secondary release of positive symptoms would mance on neuropsychological tests sensitive to fron- fit this view. tal lobe function, on tests of attention and executive As already suggested, similarity of symptomatol- abilities in particular (Dibben et al., 2009; Donohoe ogy of schizophrenia and FTD and the potential for et al., 2006). diagnostic confusion between them has been noted Although clinical signs of schizophrenia are by several authors (Duggal & Singh, 2009; Vander- similar to those seen in frontal dysfunction, and zeypen et al., 2003; Velakoulis et al., 2009; Wadding- thus, may overlap with symptoms of FTD, only few ton et al., 1995). This seems to be a serious clinical recent studies directly compared the symptomatol- problem, especially since both the therapeutic inter- ogy of schizophrenia and FTD (Kosmidis et al., ventions and prognosis of these disorders are quite 2008; Weickert et al., 2011; Velakoulis et al., 2009; different. Ziauddeen et al., 2011). Ziauddeen et al. (2011) Schizophrenia is normally characterized by the compared a small group of negative-symptom onset of so-called positive symptoms (e.g. delusions, schizophrenic patients and patients with the behav- hallucinations) during adolescence or young adult- ioural variant FTD and found that both groups hood. Nonetheless, similarly to FTD, the clinical displayed negative symptoms typically seen after presentation of schizophrenia is heterogeneous, frontal lobe injury. Specifically, high rate of apathy, encompassing also a variety of negative symptoms, loss of empathy and stereotypic behaviours were such as lack of volition, personal neglect, social with- noted in both conditions. Also, patients with drawal, and such cognitive symptoms as executive schizophrenia presented with a relatively similar deficit and/or language impairment. The neuropsy- neuropsychological profile to those with FTD on chological profile identified in schizophrenic patients neuropsychological tests, both groups particularly is usually characterized by executive deficits (Ber- impaired on tests of executive functions, although man et al., 1986), although they are often less severe this impairment was greater in FTD. Further, than seen in FTD. Although dementia is not typically speech abnormalities were seen in both disorders, considered to occur in schizophrenia, nor is it clearly although they were more common in patients with recognized as an obligatory complication of this dis- schizophrenia (the latter finding being inconclu- order, many subjects with schizophrenia develop dis- sive, since subjects with the language variant FTD orientation and cognitive impairment (de Vries et al., were not included in the study). Kosmidis et al. 2001). Furthermore, later-life cognitive deterioration (2008) compared patients with schizophrenia with in a subset of schizophrenic patients is well described those suffering from FTD and found impaired per- (Harvey, 2012); such schizophrenia cases have some- formance on measures of theory of mind in both times been called 'Kraepelinian subtypes' in the groups. Weickert et al. (2011) showed that impaired research literature. probabilistic association learning is equally impaired The exact mechanism or mechanisms underlying in schizophrenia and in FTD (particularly in the positive and negative symptoms in schizophrenia behavioural variant). RIONTS -- • el EFTA_R1_01956832 EFTA02674720  Schizophrenia and FTD 171 Whereas numerous studies have provided good for schizophrenia and schizoaffective disorder in the evidence for a significant overlap in negative symp- first-degree relatives of 100 FTD probands to that in toms between schizophrenia and FTD, positive a group of first-degree relatives of 100 Alzheimer's symptoms in FTD have been relatively rarely stud- disease (AD) probands. They noted that schizophre- ied. In the few reported studies only a small subset nia-related psychosis was seen significantly more of patients with FTD (up to 13.3%) were found to often in relatives of the FTD than AD probands. have psychotic episodes either at onset or during the Also, the occurrence of psychosis in FTD was sig- course of illness (Ibach et al., 2004; Lindau et al., nificantly higher in subjects with relatives suffering 2000; Mendez et al., 2008; Piguet et al., 2004; Seeley from schizophrenia or schizoaffective disorder (Chow et al., 2005; Velakoulis et al., 2009). The occurrence et al., 1999). of psychosis in FTD seems to be significantly higher Additionally, 10 mixed families (with both FTD in subjects with relatives suffering from schizophre- and schizophrenic family members) were identified, nia or schizoaffective disorder (Schoder et al., 2010). and in three of them an ETD causal mutation was Thus, although the percentage of positive symptoms determined (Schoder et al., 2010). This mutation in FTD seems to be rather small, psychotic symp- was also present in the schizophrenic family mem- toms do appear in this particular neurodegenerative bers, suggesting a common aetiology for both disor- condition, even in subjects with causal FTD muta- ders in some families. In this particular cohort tion (Momeni et al., 2010a, 2010b; Schoder et al., schizophrenia was diagnosed in young individuals 2010; Snowden et al., 2012). This implies that their (before age 40), the diagnosis remained stable for presence should not necessarily exclude the diagno- approximately 17 years, and all of the participants sis of FTD (Duggal & Singh, 2009). diagnosed with schizophrenia experienced positive The clear overlap between negative symptoms in symptoms rarely seen in FTD (Mendez et al., 2008). psychiatry and many behaviour abnormalities seen Moreover, the psychotic symptoms in patients with after frontal lobe injury (e.g. emotional indifference) schizophrenia were effectively treated with antipsy- or dementias suggests that they may represent the chotic medication, whereas subjects with FTD usu- same clinical phenomenon (Kleist, 1960). Hence, ally do not benefit from such treatment, have more lack of volition in schizophrenia could be the same motor side effects and may even experience an earlier phenomenon as apathy in FTD, as posited by Ziaud- death with these treatments (Kerchner et al., 2011). deen et al. (2011). Similarly, the poverty of speech Thus, the possibility of misdiagnosis of FTD for and its content in schizophrenia could mirror logope- schizophrenia in the study by Schoder et al. (2010) nia, semantic and pragmatic language disturbances, seems unlikely. High familial co-morbidity of schizo- as well as speech perseverations often seen in patients phrenia and FTD has been shown also by Momeni with FTD. Indeed, perseveration and field-depen- et al. (2010a, 2010b). dent behaviour (i.e. behaviour driven by incidental Nonetheless, the clinical overlap between schizo- task-irrelevant external or internal stimuli), com- phrenia and FTD may sometimes contribute to mis- monly seen after frontal-lobe damage, accounts diagnosing FTD as schizophrenia, particularly in the for much of the language disorder in schizophrenia less common cases of early onset FTD (Momeni (Barr et al., 1989). Likewise, motor perseveration et al., 2010a;Velakoulis et al., 2009), or in cases where characteristic of patients with frontal-lobe damage late onset schizophrenia is a differential diagnosis (Goldberg &Tucker, 1979) is also observed in schizo- (Lagodka 8c Robert, 2009; Reischle et al., 2003). For phrenia, and they may be practically indistinguish- example, Momeni et al. (2010a) described two mem- able in the two populations (Bader & Goldberg, bers of the same family diagnosed with FTD and 1987). Also, behaviours associated with delusional Parkinsonism linked to chromosome 17 (FTDP-17), beliefs (e.g. repeated phone calls to the police) may, here due to a novel exon 12 mutation in tau pathol- to some extent, overlap with abnormal behaviour of ogy. The review of medical records of these individu- patients with FTD and, thus, influence the diagnosis als revealed that both the proband and her father were (Snowden et al., 2012). Future systematic studies are initially diagnosed with schizophrenia. needed in order to better understand the relationship A possibility also exists that an early-adulthood between the cognitive symptoms in schizophrenia schizophrenic syndrome may represent a genuine and FTD. prodromal phase of FTD indicating an individual co-morbidity. This hypothesis is supported by the study by Waddington et al. (1995), who reported a Familial and individual co-morbidity in woman initially diagnosed with paranoid schizophre- schizophrenia and FTD nia due to auditory hallucinations and persecutory 1b date, only a few studies have addressed the ques- delusions. Nonetheless, a few years after the onset of tion of familial co-morbidity in schizophrenia and psychosis, her clinical picture changed and she devel- FTD. Schoder et al. (2010) compared morbid risk oped affective abnormalities as well as cognitive RIGHTS .4, EFTA_R1_01956833 EFTA02674721 172 M. Harciarek et al. deficits suggestive of FTD. Neuroimaging revealed In fact, neuropsychological, neuroimaging and path- frontotemporal atrophy and brain biopsy revealed ological studies have provided extensive support for neuropathological evidence of Pick's disease; i.e. the notion that in both schizophrenia and FTD neg- numerous neurons were found to contain spherical ative symptoms as well as other critical behavioural intracytoplasmic inclusion tau-positive bodies. Also, and cognitive changes (e.g. perseverations) are related immunohistochemistry for glial fibrillary acidic pro- to abnormalities in the prefrontal cortex (Bonilha tein revealed dense pancortical astrogliosis with et al., 2008; Frith, 1992; Liddle, 1987; Weinberger, additional subcortical gliosis. Based on these obser- 1988). By contrast, psychotic symptoms (e.g. audi- vations, Waddington et al. concluded that although tory hallucinations) may be predominantly related to it could not be ruled out that the patient was unfor- pathology in the temporal cortex (Sumich et al., tunate enough to develop two independent disease 2002), although in a recent study by Snowden et al. processes, it was more likely that 'some specific (2012) no differences in terms of frontal or temporal aspect of the pathology of Pick's disease in this atrophy as well as hemispheric asymmetries were patient has, early in its course, disrupted brain func- found between FTD patients with and without psy- tion in a manner that reproduces some fundamental chosis. Furthermore, specific subdivisions within the aspects of the pathophysiology of schizophrenia.' frontal and the temporal cortex are often implicated Similar cases of early-adulthood schizophrenic both in schizophrenia and in FTD - orbital subdivi- syndrome prodromal to FTD have been reported sions of the prefrontal cortex and anterior subdivi- (Kitabayashi et al., 2005;Vanderzeypen et al., 2003). sions of the temporal lobe (Hodges, 2007; Seeley Velakoulis et al. (2009) described four patients with et al., 2005; Shenton et al., 2001). In both disorders, FTD who at a young age developed psychotic symp- functional and structural pathology may additionally toms and received the diagnosis of schizophrenia. In encompass the thalamus and the basal ganglia contrast to the reports of initial schizophrenia-like (Rosenberg, 1983). Finally, the involvement of these psychosis with pathologically confirmed FTD- structures appears to be lateralized in both disorders; tauopathy (Waddington et al., 1995), the above cases they are more impacted in the left than in the right reported by Velakoulis et al. exhibited pathological hemisphere both in schizophrenia (Berge et al., 2011; changes characteristic of FTD with motor neuron Chance et al., 2008; Honer et al., 1996; Luaute et al., disease (FTD-MND) (i.e. TAR DNA-binding pro- 1994; Puri et al., 1994; Schobel et al., 2009; Spiro- tein 43 neuronal inclusions; TDP-43 positive). The nelli et al., 2011; van den Heuvel et al., 2010; van association between FTD, TDP-43, and psychosis Haren et al., 2011; Waddington et al., 1995; Wolf has also been suggested by Snowden et al. (2012). et al., 2008) and in FTD (Boccardi et al., 2003; Still, not enough is known about the neuropathology Jeong et al., 2005; Kanda et al., 2008; Rohrer et al., of FTD cases initially presenting as psychotic disorder, 2012; Whitwell et al., 2005, 2012). and future studies are necessary. Of note, orbitofrontal and anterior temporal Just as the true cases of FTD may be mistaken for regions are characterized by shared morphometric schizophrenia, the opposite may also occur. Namely, properties also in the normal brain: both are larger in some individuals a clinical picture mirroring that in the left than in the right hemisphere (Goldberg of FTD may in fact be due to a later onset psychiat- et al., 2013; Luders et al., 2006). The fact that these ric disorder. Nonetheless, recent studies have shown two structures are characterized by the same direc- that such cases, often referred to as FTD-pheno- tion of lateralization both in the healthy brain and in copy' (Hornberger et al., 2008, 2009, 2010; Irish the two disorders of interest raises the question of et al., 2011), rarely present with cognitive impair- certain shared factors (generic, epigenetic, or others) ment. Furthermore, their behavioural changes do controlling certain aspects of their development. Is it not typically progress, and these patients do not show possible, for instance, that these disorders are caused the characteristic frontotemporal atrophy on neu- by an aberrant expression of the same gene(s) but at roimaging (Davies et al., 2006; Kipps et al., 2007; different stages of life: early in schizophrenia and late Pennington et al., 2011). in FED? Neuroanatomy of schizophrenia and Fro Aetiology and pathogenesis in FTD and psychosis Cumulative evidence implicates similar structures in schizophrenia and FED, namely the prefrontal cor- Some studies have shown that 30-50% of FTD is tex and anterior temporal lobes (Brewer et al., 2005; familial, suggesting a genetic root for FTD (Seelaar Buckley et al., 1999; Hill et al., 2004; Lawrie & et al., 2011; Ferrari et al., 2011). Mutations of pro- Abukmeil, 1998; Raskovsky et al., 2011; Shenton granulin (GRN) and microtubule associated protein et al., 2001; de Vries et al., 2000;Waddington, 1995). tau (MAP?) account for about 50% of the familial RIONTS -- • 41:e EFTA_R1_01956834 EFTA02674722  Schizophrenia and FTD 173 FTD cases. GRN is involved in cell cycle progres- associated with a hexanucleotide repeat expansion in sion, growth control, wound healing and in many C9ORF72 gene, a mutation found in approximately other biological processes. It also displays abundant 6% of sporadic, and 25% of familial cases with amy- expression in the brain. By comparison, MAPT binds otrophic lateral sclerosis (ALS; a very common form and stabilizes microtubules and plays an important of MND) and FTD (Rademakers, 2012). In fact, the role in neuronal polarity and signal transduction. presence of psychosis increased the odds of having Hyperphosphorylation of tau may be also associated the C9ORF72 gene mutation by 15-fold. Thus, it is with schizophrenia, and it has been suggested that possible that mutation in the C9ORF72 gene may be dysregulation of reelin contributes to hyperphospho- a major cause not only of FTD and MND (Dejesus- rylation of tau in schizophrenia (Deutsch et al., Hernandez a al., 2011; Renton et at, 2011), but also 2006). Thus, tau pathology may be associated with of late onset psychosis (Ferrari et al., 2012; Murray both FTD and schizophrenia, and reelin may be one et al., 2011). Of note, aside from FTD-MND, a of the regulators of tau function. Future studies are relatively high prevalence of psychosis has been noted needed, however, to test these hypotheses. in rare cases with fused-in-sarcoma (FUS), a pathol- Magnetic resonance imaging studies have shown ogy also associated with MND (Seelaar et al., 2010; strikingly asymmetric atrophy in brains of FTD Snowden et al., 2011). However, despite the above, patients, particularly in the GREY carriers (Beck there is a phenotypic variability in regard to the et al., 2008; Rohrer et al., 2011; Whitwell et al., C9ORF72 repeat expansions. For example, cases 2012). This asymmetry is often detected in the fron- with behavioural variant FTD without MND as well tal, temporal and parietal regions. Moreover, the rate as PPAs without psychosis have been documented of atrophy in the left hemisphere is higher than that (Renton a al., 2011; Snowden et al., 2012).The neu- in the right (Rohrer et al., 2012). However, FTD ropathology may be also heterogeneous (Murray patients carrying MAPT mutations normally don't et al., 2011; Snowden, 2012). Further, in a recent show asymmetric atrophy (Rohrer & Warren, 2011). study, Huey et al. (2012) screened DNA samples These studies suggest an association of specific FTD from a large cohort of unrelated subjects with schizo- gene mutations with asymmetric atrophy during dis- phrenia for mutation in the C9ORF72 gene. Interest- ease progression. ingly, none of these subjects had the C9ORF72 Intriguing questions then arise, whether genes repeat expansions, suggesting this mutation is unlikely mutated in FTD and/or schizophrenia are asym- to cause schizophrenia. Thus, caution needs to be metrically expressed in the normal human brain, and exercised when determining the association between whether their mutations are associated with abnor- mutation in C9ORF72 gene, FTD phenotype, the mal brain laterality and pathogenesis of FTD and presence of psychosis, and schizophrenia. schizophrenia. Previous studies have shown that cer- tain genes are asymmetrically expressed in human foetal brains (Sun et al., 2005, Sun & Walsh, 2006). Shared causation and future research Among these genes, MAPT has higher expression directions levels in the left than in the right hemisphere (more The possibility of a shared causation between schizo- than two-fold) in human foetal 14-week-old brains phrenia and certain dementias has been raised before (Sun et al., 2005). In human embryonic 10-week-old (DeLisi, 2008; Schoder, 2010). The present review brains Reelin is also more highly expressed in the left provides additional rationale for pursuing this line of than in the right hemisphere (about 1.6-fold) (t research further. Such future research will emphasize Sun, unpublished data). Although a larger sample both genetic and cognitive parallels between certain size is required to draw a comprehensive gene expres- forms of schizophrenia and FTD in a synergistic, sion profile, these studies suggest that at least Reelin coordinated way. It is also increasingly possible to and MAPT may participate in the process of estab- envision genetic research provide incrementally pre- lishing normal brain laterality. Mutations of Reelin cise answers to the following questions: and MAP7'may disrupt normal asymmetry and con- tribute to the pathology of FTD and schizophrenia. 1. Are the genes particularly strongly expressed in It is yet to be understood why FTD patients with the two regions most commonly implicated in MAPT mutations mostly show symmetric brain atro- FTD and schizophrenia - orbitofrontal cortex phy patterns, whereas patients with GRN mutations and anterior temporal regions - characterized by show asymmetric atrophy in the brain. Nevertheless, asymmetric expression? investigating the molecular regulation of brain asym- 2. Are some of such asymmetrically expressed metry will likely provide insights into the aetiology genes the same in the orbitofrontal cortex and of FM and schizophrenia. the anterior temporal regions? Interestingly, Snowden et al. (2012) have recently 3. Are some of these genes implicated both in schiz- noted that psychosis in patients with FTD is strongly ophrenia and in FTD? RIGHTS 4, EFTA_R1_01956835 EFTA02674723 174 M. Harciarek et al. Inquiry into shared genetic mechanisms of diverse direct parallels with human cognition and with diseases should be conducted in parallel with the human clinical pathology. Experimental cognitive inquiry into the cognitive ramifications of altered paradigms that permit the assessment of novelty- gene expression. Advances in research methodology seeking versus propensity toward routinized behav- make it increasingly possible to manipulate gene iours, perseveration versus field dependency in expression in living animal models and to study the parallel human and animal experiments already exist, behavioural and cognitive consequences of such and new experiments can be readily designed. The manipulations. In particular, it is increasingly possi- same may be true for other cognitive constructs ble to manipulate the degrees and direction of their meaningful across species and relevant to character- asymmetric expression in the two hemispheres. izing human psychopathology. The use of such para- At the same time, the conceptual understanding of digms will permit the drawing of parallels between hemispheric specialization has advanced in ways that the cognitive effects of select gene manipulation in make parallels between animal models and human animal models on one hand, and clinical profiles in cognition (both normal and clinically aberrant) more disorders such as certain forms of schizophrenia and feasible. The traditional understanding of hemi- FTD on the other hand. Such a research programme spheric specialization emphasized the complemen- will hold the promise of advancing our understanding tary roles of the two cerebral hemispheres in language of the causation of major neuropsychiatric disorders, versus visuo-spatial functions. Clearly, such concep- including the patterns of shared causation. tual framework has no meaning outside the human species, and thus precludes any parallels between Take-home points animal and human cognition. More recently, very different approaches to hemi- Discrete taxonomies of neuropsychiatric disorders spheric specialization have been gaining prominence. may be outdated, and aberrant lateralization of gene One of them emphasizes the differential roles of the expression may be an important causal factor in neu- two hemispheres in novelty seeking (the right hemi- ropsychiatric disorders. sphere) versus exercise of established routinized behaviours (the left hemisphere) (Goldberg & Costa, 1981; Goldberg & Podell, 1995; Goldberg et al., Acknowledgements 1994b). Within this general framework, the lateral- ized nature of the effects of frontal-lobe damage in We thank Dmitri Bougakov for his assistance with humans has been demonstrated. Damage to the left literature reviews in preparation of this paper. prefrontal regions results in an extremely field-inde- pendent (rigid perseverative) response selection, Declaration of interest: While preparing this man- whereas damage to the right prefrontal regions results uscript, M.H. was receiving a scholarship from the in an extremely field-dependent (unstable, exces- Polish Ministry of Science and Higher Education; and sively variable) response selection in humans (Gold- DM was supported by NIH RC I MH088843 and berg & Podell, 1995; Goldberg et al., 1994a, 1994b). K24 MH01699 (DM). The authors alone are respon- Furthermore, sex differences in the consequences of sible for the content and writing of the paper. lateralized prefrontal damage in humans have been described (Goldberg et al., 1994a, 1994b). Unlike the classic language-visuospatial distinc- References tion, the contrasts between novelty-seeking and rou- tinized stereotypical behaviours and between "'Barr, W., Bilder, R., Goldberg, E., Kaplan, E. & Mukhergee, S. perseverative and field-dependent behaviours are (1989). Neuropsychology of schizophrenic language. Journal of Communication Disorders, 22, 327-349. meaningful across species and can be examined in lobfleck, J., Rohrer, J.D., Campbell, T., Isaacs, A., Morrison, K.E., animal models. In humans, these dimensions of cog- Goodall, F..F., ... Mead, S. (2008). A distinct clinical, neuropsy- nition are critical both in characterizing individual chological and radiological phenotype is associated with pro- differences between normal cognitive styles, and in gnnulin gene mutations in a large UK series. Brain, 13!, characterizing cognitive pathology. Perseverative 706-720. 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