DEMENTIA RESEARCH IN THE NEUROPSYCHIATRY UNIT

The Neuropsychiatry Unit has historically assessed patients with atypical, often younger-onset dementias, which not infrequently present with psychiatric disturbance. The unit has particular expertise in the diagnosis and management of patients with frontotemporal dementia, or frontotemporal lobar degeneration (FTLD), an illness that often presents in patients in the fifth or sixth decade with behavioural and personality change, psychiatric illness and impairments to memory and judgement. The unit also frequently sees patients with early-onset Alzheimer's disease, particularly patients who present in their 30s, 40s and 50s. Because of our history and experience with these illnesses, particularly over the last two decades, our unit has become increasingly involved in research into these disorders.

We have worked with neuroradiology colleagues from the Royal Melbourne Hospital (Professor Patricia Desmond) to establish a database of over 200 MRI scans in patients with young onset dementia and neurodegenerative disorders, which has formed the basis of more recent publications. This has led to a successful collaboration with Professors Paul Thompson (UCLA) and Jeff Looi (ANU). This collaboration with Professor Thompson continues our highly successful work with his group in schizophrenia imaging work with Professor Pantelis and Dr Frank Sun. The collaboration with Professor Jeff Looi has seen us work and publish together with dementia imaging researchers at Lund University and the Karolinska Institute in Sweden, and with other groups in Finland and across the European Union.

A LINK BETWEEN FTD AND SCHIZOPHRENIA?

During a sabbatical in 2007 Dr. Velakoulis spent 6 months undertaking work with Professor Catriona McLean (neuropathologist at the Alfred Hospital) which led to two important papers which, for the first time, identified a link between schizophrenia and frontotemporal dementia. This work has continued with Professor Colin Masters and Dr Qiao-Xin Li with whom we have worked on the investigation of CSF and plasma tau, progranulin and TAR-DNA binding protein 43 (TDP43), one of the key types of proteins whose storage is abnormal in FTD.

A link to the publication on the relationship between FTD and psychosis can be found here, in full text. This paper examined every published case of FTD up until that point (n=751) for rates of psychosis, in addition to reviewing all patients from a brain repository presenting with FTD younger than the age of 60.

Velakoulis et al. Frontotemporal dementia presenting as schizophrenia-like psychosis: clinicopathological series and review of cases. British Journal of Psychiatry 194: 298-305, 2006.

The second paper, which looked at alterations in staining of TDP43 in 12 patients with major psychotic illness and matched controls, can be found in paywalled version here.

Velakoulis et al. Abnormal hippocampal distribution of TDP-43 in patients with late onset psychosis. Australian and New Zealand Journal of Psychiatry 43: 739-745, 2009.

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Rate of Psychosis in FTD. Patients with younger onset show a significantly higher rate of psychosis, as exemplified by the above graph: 25% of patients under 40, and 35% of patients under 30.
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Abnormal TDP43 staining in schizophrenia. Arrowhead lines point to cells in the hippocampus with normal (brown) staining of TDP43 in the nucleus of the neuron, with roundhead lines pointing towards cells with absent (blue) TDP43, suggesting alterations to the intracellular movement of this protein in schizophrenia.
FRONTOTEMPORAL DEMENTIA: A FRONTO-STRIATAL DISORDER?

With our colleague Professor Looi from ANU, Professor Lars-Olof Wahlund from the Karolinska Institute, and Assistant Professor Martin Styner from the University of North Carolina, we have examined the shape of the caudate and putamen in a well-characterised cohort of patients with FTLD and Alzheimer's disease (AD). This uses the SPHARM methodology for examining shape change in subcortical structures. We found that marked reductions in the caudate nucleus (and to the lesser extent the putamen), particularly on the left, characterised the FTLD group, but not the AD group, when compared to controls.

This paper, published in Neuroimage in 2010, can be found here.

Looi et al. Shape analysis of the neostriatum in frontotemporal lobar degeneration, Alzheimer's disease, and controls.
Neuroimage 51: 970-976, 2010.

We extended this analysis to look at different subtypes of FTLD, including semantic dementia (SD), primary non-fluent aphasia (PNFA) and behavioural-variant frontotemporal dementia (FTD). We showed that FTD patients showed bilateral striatal changes, with PNFA showing predominantly left-side changes, and SD showing little to no changes; these differential shape changes clearly differentiated these three FTLD subtypes.

This paper, published in Psychiatry Research Neuroimaging in 2011, can be found here.

Looi et al. Shape analysis of the neostriatum in subtypes of frontotemporal lobar degeneration: neuroanatomically significant regional morphologic change. Psychiatry Research Neuroimaging 191: 98-111, 2011.
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Caudate shape changes compared to controls in FTLD. Red areas show where there was significant shape deflation in the FTLD group, with blue areas where there was no significant difference. The areas of greatest change roughly correspond to those areas connecting to frontal cortical regions, detailed in the paper.
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Caudate shape changes in PNFA compared to controls. On the left are lateral and medial views of the caudate, with significance maps as in the previous figure; on the right are displacement maps, showing the degree of displacement in mm.
HIPPOCAMPAL SHAPE IN DEMENTIA SUBTYPES

With Dr Olof Lindberg and Prof Wahlund from the Karolinska Institute in Stockholm, we have examined hippocampal shape in different dementia subtypes to examine for a key shape "signature" at the level of the hippocampus.

We found distinct shape subtypes across types of dementia, with FTLD subtypes showing differential patterns of reductions but all showed focal reduction in the head of the hippocampus, whereas patients with Alzheimer's disease (AD) showed more global volume loss generally sparing the hippocampal head.

This paper, published in Journal of Alzheimer's Disease in 2012, can be found here.

Lindberg et al: Hippocampal shape analysis in Alzheimer's disease and frontotemporal lobar degeneration subtypes. Journal of Alzheimer's Disease 30: 355-365, 2012.
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Hippocampal change in semantic dementia. Changes seen across the head and body of the hippocampus, with most atrophic change occuring in the CA1 and subiculum areas.