Dementia praecox revisited: FT dementia and schizophrenia

EMIL Kraepelin (1856–1926) was a German psychiatrist who identified “dementia praecox” (now known as schizophrenia) and manic-depressive psychosis as two distinct forms of psychosis based on his observations of the clinical trajectory of patients with severe mental illness.

Based on his clinical and pathological observations, Kraepelin viewed dementia praecox as a premature early adult-onset psychosis associated with progressive neurodegenerative changes, functional and cognitive decline. Kraepelin identified “lipoid products of disintegration in brain cells” as evidence of brain degeneration and concluded that the frontal and temporal lobes of the brain were critical in the development of dementia praecox.

However, much of this work has not stood the test of time. Dementia praecox was soon renamed schizophrenia by Eugen Bleuler. We now know that a large proportion of patients with schizophrenia do not have inexorable functional and cognitive decline, and Kraepelin’s neuropathological findings have not been replicated.

Computed tomography (CT) scan findings of ventricular enlargement and brain atrophy in people with chronic schizophrenia in the late 1970s prompted researchers to return to the concept of “Kraepelinian schizophrenia”. This work identified subgroups of people with long-standing schizophrenia who exhibited poorer cognitive function, greater structural brain changes, and poorer prognostic outcome compared with other people with schizophrenia. Neuropsychological and neuroimaging studies in schizophrenia through the 1990s and 2000s affirmed Kraepelin’s observation regarding the involvement of the frontal and temporal lobes in schizophrenia (here, here, here). Longitudinal studies of people with schizophrenia have identified progressive structural and cognitive changes, but these changes appear to be restricted to the early stages of illness and there has been limited evidence to suggest an ongoing progressive or neurodegenerative process.

Behavioural variant frontotemporal dementia (bvFTD) is a disorder defined by progressive changes in personality (disinhibition, loss of social decorum, loss of empathy), behaviour (apathy, amotivation, repetitive behaviours, hyperorality) and cognition (executive deficits without episodic memory changes) together with frontal and temporal changes on structural (magnetic resonance imaging [MRI] or CT) or functional brain imaging (positron emission tomography [PET]). The clinical distinction between bvFTD and psychiatric disorders can be very difficult in the early stages of bvFTD. A key diagnostic exclusionary criterion for bvFTD is that the clinical picture is better explained by a psychiatric disorder.

The relationship between schizophrenia and frontotemporal dementia (FTD) has recently come into focus based on clinical, imaging and genetic research identifying an overlap between the two disorders. Clinically, up to 40% of younger people diagnosed with FTD will have presented with a schizophrenia-like psychosis, although genetically, about 40% of people with bvFTD who carry a mutation in the C9orf72 gene on chromosome 9 will present with schizophrenia-like symptoms.

Our recent neuroimaging study, published in JAMA Psychiatry, highlights the structural brain overlap between these two disorders. In this study, we examined a total of 1870 subjects with schizophrenia, FTD, and Alzheimer’s disease, as well as healthy individuals. Machine learning was used to identify the structural MRI “signature” of the different conditions and the relationship between brain structure and clinical outcomes. The bvFTD and schizophrenia structural imaging signatures highly overlapped, and the expression of the schizophrenia signature in patients with bvFTD was highly linked to the C9orf72 variant. Conversely, young people with early stage psychotic disorders who overexpressed bvFTD (and schizophrenia) patterns showed poorer prognostic and recovery outcomes.

Our findings add modern weight to Kraepelin’s concept of schizophrenia as a frontotemporal disorder associated with brain changes and poorer outcomes, but do not necessarily mean that schizophrenia is a form of FTD.

There are several other possible explanations to explain the overlap in clinical, cognitive, and imaging findings. The observed relationships may be due to a “frontotemporal coincidence” in that both disorders involve frontal and temporal structures and will lead to similar clinical presentations. The observed cognitive and frontotemporal structural changes may be related to the long term effects of antipsychotic medications or the impact of long term institutionalisation. The imaging changes seen in people with schizophrenia may be a consequence of the higher prevalence of risk factors for dementia (eg, cigarette use, hypertension, diabetes and hypercholesterolemia).

Finally, it may be that some patients with schizophrenia have a variant of an as yet undetermined progressive dementing illness that progresses slowly over decades. The latter possibility requires further mechanistic and longitudinal research, as we found heightened polygenic risk scores for FTD and Alzheimer’s disease in these patients.

There are important clinical implications of these findings.

Clinicians should be aware that, in rare situations, people who present with schizophrenia-like symptoms may be in the early stages of bvFTD. Red flags include a family history of dementia or motor neurone disease (for which C9orf72 mutations are now known to be the commonest genetic cause), structural brain atrophy greater than would be expected for age, or neurological signs (primitive reflexes, fasciculations).

Early diagnosis is important for prognosis and may have genetic implications for families. Secondly, there is now significant evidence that a subgroup of people with chronic schizophrenia have cognitive and imaging changes associated with significant functional impairment and are as deserving of the same services and supports as those people with dementia.

Professor Dennis Velakoulis is a consultant neuropsychiatrist and Director of the Neuropsychiatry Unit at Royal Melbourne Hospital.

Professor Christos Pantelis is an NHMRC Senior Principal Research Fellow, Foundation Professor of Neuropsychiatry and Scientific Director of the Melbourne Neuropsychiatry Centre at the University of Melbourne and Melbourne Health.

 Professor Nikolaos Koutsouleris is Research Group Leader in the Department of Psychiatry and Psychotherapy at Ludwig Maximilian University in Munich.

The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.

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