Showing papers by "David Neary published in 2012"

Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations

Abstract: The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.

Famous People Knowledge and the Right and Left Temporal Lobes

Abstract: It is generally accepted that the anterior temporal lobes support knowledge of famous people. The specific roles of the right and left temporal lobe remain a subject of debate, with some studies suggesting differential roles based on modality (visual versus verbal information) and others category (person knowledge versus general semantics). The present study re- examined performance of semantic dementia patients with predominantly right and predominantly left temporal lobe atrophy on famous face, famous name and general semantic tasks, with the specific aim of testing the hypothesis that the right temporal lobe has a privileged role for person knowledge and the left temporal lobe for general semantic knowledge. Comparisons of performance rankings across tasks showed no evidence to support this hypothesis. By contrast, there was robust evidence from naming, identification and familiarity measures for modality effects: right-sided atrophy being associated with relatively greater impairment for faces and visual tasks and left-sided atrophy for names and verbal tasks. A double dissociation in test scores in two patients reinforced these findings. The data present a challenge for the influential 'semantic hub' model, which views the anterior temporal lobes as an area of convergence in which semantic information is represented in amodal form.

Psychosis, C9ORF72 and dementia with Lewy bodies

Abstract: 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 …

FTLD repeat expansions in C9orf72: Evidence for variability in the repeat sequence

Abstract: tent feature of these cases, in contrast to the similar frequency of p62 and TDP-43 deposition in 53 control cases with FTLD-TDP. Conclusions: These findings corroborate the clinical importance of the C9ORF72 mutation in FTLD, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.