Schizophrenia and Frontotemporal Dementia: Shared Causation?

International Review of Psychiatry, April 2013; 25(2): 168–177 Schizophrenia and frontotemporal dementia: Shared causation? MICHA Ł HARCIAREK 1 , DOLORES MALASPINA2 , TAO SUN3 & ELKHONON GOLDBERG4 1 Division of Clinical Psychology and Neuropsychology, Institute of Psychology, University of Gdansk, Poland, 2 Department of Psychiatry, New York University School of Medicine, New York, USA, 3 Department of Cell and Developmental Biology, Cornell University Weill Medical College, New York, USA, 4 Department of Neurology, New York University School of Medicine, New York, USA Abstract The relationship between specifi c 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 fi ndings from both schizophrenia and frontotemporal dementia are also discussed. As a result, we introduce the hypothesis of a shared susceptibility for certain subgroups of schizophrenia 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 specifi c 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 For personal use only. the understanding of this relationship continues to domains of psychopathology refl ect a graduated evolve, refl ecting the changes in the neuroscientifi c symptom space is increasingly embraced to replace zeitgeist. Variable expressivity, pleiotrophic effects, the traditional notions of ‘ disorders ’ that are sepa- partial penetrance, epistasis, 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) fi rst 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 fi nd major ‘ culprit ’ genes behind many process. These illness features include psychosis, neuropsychiatric conditions has forced a re-examination which entails delusions and hallucinations, disordered Correspondence: Elkhonon Goldberg, PhD, ABPP-CN, NYU School of Medicine, 315 West 57th Street, Suite 401, New York, NY 10019, USA. Tel ϩ 1 212 541 6412. Fax ϩ 1 212 246 8916. E-mail: [email protected] (Received 19 July 2012; accepted 7 January 2013) ISSN 0954–0261 print/ISSN 1369–1627 online © 2013 Institute of Psychiatry DOI: 10.3109/09540261.2013.765389 Schizophrenia and FTD 169 thinking and bizarre behaviour (defi ned as ‘ positive ’ Diffi culties with differentiating between schizo- symptoms), and defi cits in emotional expression and phrenia-related psychosis and neurodegenerative dis- volition (defi ned 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 fi rst been recently reviewed by Forstl et al. (2008). described by Arnold Pick (1892) and previously According to the royal medical report, signifi cant 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 specifi c characteristics were not recorded) and he neous, and FTD is commonly divided into two sub- became aggressive. He also became delusional with types. The fi rst 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 classifi cation, (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-fl uent/agrammatic, and logopenic der according to DMS-IV. This diagnosis is further (Gorno-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-fl uent/agrammatic PPA Otto as well as the youngest daughter of Ludwig’ s predominantly associated with frontotemporal lobar grandfather developed severe mental disorder with For personal use only. 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 specifi c 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 diffi cult to distinguish between these two con- nia and late in 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, refl ect 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

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