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Psychosis, C9ORF72 and dementia with Lewy bodies
  1. Julie S Snowden1,2,
  2. Sarah Rollinson2,3,
  3. Chloe Lafon1,2,
  4. Jennifer Harris1,2,
  5. Jennifer Thompson1,2,
  6. Anna M Richardson1,2,
  7. Matthew Jones1,2,
  8. Alexander Gerhard1,2,
  9. David Neary1,2,
  10. David M A Mann2,
  11. Stuart Pickering-Brown2,3
  1. 1Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford, UK
  2. 2The University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK
  3. 3Mental Health and Neurodegeneration Research Group, AV Hill Building, University of Manchester, Manchester, UK
  1. Correspondence to Professor Julie S Snowden, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford M6 8HD, UK; julie.snowden{at}

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Hexanucleotide repeat expansions in the C9ORF72 gene are an important cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis.1 ,2 Whether they have a role in other conditions remains unclear.3 ,4 We previously identified in FTD a strong association between repeat expansions in C9ORF72 and the presence of psychosis.4 This raises the question whether C9ORF72 expansions might also have a role in dementia with Lewy bodies (DLB), in which hallucinations and delusions are prevalent. The study addressed this question.


The cohort comprised 102 consecutive patients who fulfilled criteria for ‘probable DLB’, exhibiting at least two of the cardinal features: fluctuating cognition, recurrent visual hallucinations and parkinsonism, or one cardinal feature together with rapid eye movement sleep disorder. All patients gave informed written consent to blood donation, as part of an ethically approved molecular genetic study. Patients' DNA was screened for the C9ORF72 repeat expansion using the repeat primed PCR,2 an excess of 30 repeats being considered abnormal. Hallucinations and delusions were ascertained, blind to genetic results, from patients' hospital records.


Demographic and clinical findings are shown in table 1. There was a high prevalence of formed visual hallucinations, consisting of people or animals. Auditory hallucinations were relatively rare. Delusions were predominantly linked to patients' visual hallucinations, consisting of false belief of people having entered the home. However, they also comprised paranoid ideation, including the belief that someone wished to kill them, delusions of infidelity, belief that their spouse was an impostor (Capgras delusion) and that the family home was duplicated (reduplicative paramnesia). Thirty-three patients exhibited hallucinations without delusions whereas only four patients exhibited delusions without hallucinations, in two cases this constituting Capgras delusion.

Table 1

Characteristics of dementia with Lewy bodies cohort (n=102)

In 100/102 patients (98%) no repeat expansions in the C9ORF72 gene were found (median repeats 3, range 1–25). Expansions (>30) were detected in two patients (2%).

Patient 1 presented with gradual decline in memory, expressive language, calculation and visuospatial skills aged 60 years. She became lost in familiar surroundings, could no longer cook or operate household gadgets. Behaviour and affect were unchanged, aside from a false belief that neighbours were taking part in television programmes. No hallucinations were reported. Neurological examination revealed amimia, limb rigidity and resting tremor, but no weakness, wasting or fasciculations. Neuropsychological examination revealed performance fluctuations. There were impairments in language, perception, spatial skills, memory (with confabulation and interference) and executive skills. An MRI scan showed generalised atrophy, single-photon emission CT scan parietal hypoperfusion and EEG delta activity. She became increasingly parkinsonian and tremulous. Her sleep pattern was disrupted. She was prescribed cholinesterase inhibitors, leading to some improvement. There was a previous medical history of an acute onset of aphasia and limb weakness, ascribed to a stroke. These symptoms had apparently resolved prior to the onset of her progressive illness. There was no family history of dementia or other neurodegenerative disease.

Patient 2 presented with gradual mental and physical slowing aged 69 years. His gait was shuffling, his hands trembled and his voice was hypophonic. Speech content was rambling and off the point. His personality was retained and he exhibited no stereotypic behaviours or altered eating habits. During a routine hospital admission he suffered an acute confusional episode lasting several days in which he became deluded and hallucinated. He believed he was being poisoned and that there were criminal activities taking place on the ward. He saw animals and puppets. There was no relevant previous medical or family history. Neurological examination revealed parkinsonism, but no wasting or fasciculations. Neuropsychological examination revealed performance variability, with fluctuations of attention and distractibility. Mild deficits were elicited in spelling, calculation, visual perception, spatial and constructional skills. Confrontation naming, word and sentence comprehension and repetition were preserved. He had a normal span of eight digits. There was no gestural apraxia. Memory recall was poor and on story recall he misconstrued the thematic content. However, he was well oriented, recognition memory was intact with no abnormal information loss over a delay. Executive tests elicited poor sequencing and a mild perseverative tendency, but preserved abstraction and mental set shifting. Category and letter fluency performance was within normal limits. Motor responses were slowed. A CT scan showed generalised cerebral atrophy. He was lost to follow-up.


Evidence was sparse for a role in DLB of repeat expansions in the C9ORF72 gene. One hundred patients showed no repeat expansion, despite a high prevalence of psychotic features. However, expansions were detected in two patients. The clinical picture in one was compounded by a previous vascular event. In the other, clinical features were not entirely typical. Psychotic features were transient. Performance fluctuations might feasibly have been products of distractibility. Neither patient had pathological confirmation of diagnosis. The question arises whether the clinical diagnosis of DLB was correct.

Neither patient had notable personality or behavioural change to suggest FTD. The posterior hemisphere imaging changes in one patient and generalised atrophy in the other would favour DLB rather than FTD. It is unclear whether C9ORF72 repeat expansions are fully penetrant or might be unrelated to the disease process. However, attention has previously been drawn to a phenotype of FTD that mimics DLB.5 The possibility exists that the two patients are further rare examples of TDP-43 proteinopathy, presenting with a DLB rather than FTD clinical phenotype.

In this study of DLB, visual hallucinations predictably predominated over delusions. By contrast, psychotic features associated with C9ORF72 repeat expansions, consist predominantly of delusions, particularly of a paranoid and somatoform type.4 This clinical distinction might suggest a different underlying neurobiological substrate.

In conclusion, C9ORF72 repeat expansions are not a major determinant of the psychotic features of DLB. However, the findings do not rule out the possibility that C9ORF72 repeat expansions can be associated with DLB. Alternatively, FTD may occasionally present as a more ‘posterior hemisphere’ disorder than previously thought, with clinical features resembling DLB. Repeat expansions in C9ORF72 may be a predictor of such atypical forms of FTD.



  • Funding The work was supported by the Medical Research Council (MRC G0701441), the Bill Edmonds bequest and the Manchester Neurological Research Trust.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by Oldham Local Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.