Altered body schema processing in frontotemporal dementia with C9ORF72 mutations

Abstract

BackgroundMutations in C9ORF72 are an important cause of frontotemporal dementia (FTD) and motor neuron disease. Accumulating evidence suggests that FTD associated with C9ORF72 mutations (C9ORF72-FTD) is distinguished clinically by early prominent neuropsychiatric features that might collectively reflect deranged body schema processing. However, the pathophysiology of C9ORF72-FTD has not been elucidated.MethodsWe undertook a detailed neurophysiological investigation of five patients with C9ORF72-FTD, in relation to patients with FTD occurring sporadically and on the basis of mutations in the microtubule-associated protein tau gene and healthy older individuals. We designed or adapted behavioural tasks systematically to assess aspects of somatosensory body schema processing (tactile discrimination, proprioceptive and body part illusions and self/non-self differentiation).ResultsPatients with C9ORF72-FTD selectively exhibited deficits at these levels of body schema processing in relation to healthy individuals and other patients with FTD.ConclusionsAltered body schema processing is a novel, generic pathophysiological mechanism that may link the distributed cortico-subcortical network previously implicated in C9ORF72-FTD with a wide range of neuropsychiatric and behavioural symptoms, and constitute a physiological marker of this neurodegenerative proteinopathy.

Clinicopathological Study of Patients With C9ORF72-Associated Frontotemporal Dementia Presenting With Delusions

“…55 Our findings corroborate their observations. In fact, their results provide a useful framework for interpreting our findings, in particular the candidate mechanism of self/non–self-regulation.…”

The neural correlates and clinical characteristics of psychosis in the frontotemporal dementia continuum and the C9orf72 expansion

“…The findings are exploratory however they do converge with the hypothesis of Downey and colleagues who showed that C9orf72 carriers have an altered body schema (Downey et al, 2014). These authors suggested that altered body schema deficits might contribute to the development of psychosis generation in C9orf72 carriers through alterations in thalamo-cortico-cerebellar networks.…”

“…As such, we have seen renewed interest in psychosis in the Frontotemporal dementia-Amyotrophic lateral sclerosis (FTD-ALS) continuum, with recent systematic reviews of the literature suggesting that the prevalence is approximately 10–25% (Hall and Finger, 2015, Shinagawa et al, 2013). Neuroimaging studies of the C9orf72 expansion in both FTD and ALS have highlighted an excess of subcortical atrophy in comparison to non-carriers, and have led researchers to postulate that perhaps subcortical structures play a role in the generation of psychotic symptoms in C9orf72 cases but up until now this theory has not been explored (Bede et al, 2013b, Downey et al, 2014, Mahoney et al, 2012). The largest body of evidence regarding psychosis and associated brain abnormalities comes from the literature in schizophrenia and related psychotic disorders, where abnormal changes in the volume, connectivity and function of the frontal and temporal cortices, thalamus and cerebellum have been reported (Andreasen et al, 1996, Byne et al, 2009, Fusar-Poli et al, 2012).…”

Toward a Molecular Profile of Self-Representation

“…Another case is the one of hemiplegic patients that can feel ownership over another person performing an action, even when the arm is in the position of the limb over which they have no control (Garbarini et al, 2015). Moreover, some dementias (e.g., frontotemporal dementia) can also affect patient's sense of ownership (measured by the rubber hand illusion) and sense of agency (using a test for the attribution of an action) (Downey et al, 2014). Interestingly, Alzheimer's patients seem to have a similar self-perception than their healthy counterparts, but with defects in the attribution of self- vs. non-self memories (Bond et al, 2016).…”

“…We have not found any reports on possible genetic factors altering the sense of embodiment in healthy individuals, but there are specific mutations in patients affected by frontotemporal dementia that correspond to self-perception alterations. For example, the presence of C9ORF72 or MAPT mutations correlate to different embodiment defects (Downey et al, 2014). In addition, we have previously mentioned that schizophrenic patients have an increased sense of agency (Garbarini et al, 2016) and several genetic factors have been associated to this condition using genome-wide association studies (GWAS) (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Sekar et al, 2016).…”