O1‐05‐01: Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: Clinical, neuroanatomical and neuropathological features

Abstract

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43-68 years) and duration (1.7-22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration-TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.

Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: A 3T high angular resolution diffusion imaging (HARDI) study

“…It is worth speculating that such a pattern of predominantly frontal WM injury, also described in other cohorts of patients with ALS (50,51), may refl ect the executive and behavioural dysfunctions that characterize our patients. Along this line of evidence, our fi ndings reinforce the patterns of degeneration detected by DTI analyses in patients with ALS (13,15,52,53) or frontotemporal dementia (FTD) (53) or both (53,54), supporting the concept of a continuum between ALS and FTD not only on a pathological and genetic level, but also on a microstructural degeneration level (1). In this regard, a recent structural neuroimaging study using voxel based morphometry (VBM) and DTI in the three subtypes of the ALS-FTD continuum (i.e.…”

Altered body schema processing in frontotemporal dementia with C9ORF72 mutations

“…C9ORF72-FTD has recently been identified as a major cause of familial FTD, FTD associated with motor neuron disease and apparently sporadic FTD 2–4. Histopathologically, C9ORF72-FTD has been associated with cellular inclusions containing TAR-DNA-binding protein 43 (TDP-43) subtypes A and B and protein p62 3 5–7. The pathophysiological mechanisms of C9ORF72-FTD are of particular clinical and neurobiological interest on account of its phenotypic heterogeneity and certain specific phenotypic features.…”

“…The pathophysiological mechanisms of C9ORF72-FTD are of particular clinical and neurobiological interest on account of its phenotypic heterogeneity and certain specific phenotypic features. Approximately 40–60% of cases across series have had early, salient neuropsychiatric disturbances,4 8 9 including anxiety, agitation and psychotic symptoms of hallucinations and delusions in a substantial though variable proportion (up to around 40% of cases) 3 4 10–12. Hallucinations and delusions in C9ORF72-FTD are phenomenologically similar to those of schizophrenia, but often have a somatic focus or include prominent elements of disordered awareness of self in relation to others, including themes of paranoia, infestation, bodily distortion or invasion, pregnancy, or loss of voluntary or sphincteric muscle control 3 4 9 12.…”

“…Approximately 40–60% of cases across series have had early, salient neuropsychiatric disturbances,4 8 9 including anxiety, agitation and psychotic symptoms of hallucinations and delusions in a substantial though variable proportion (up to around 40% of cases) 3 4 10–12. Hallucinations and delusions in C9ORF72-FTD are phenomenologically similar to those of schizophrenia, but often have a somatic focus or include prominent elements of disordered awareness of self in relation to others, including themes of paranoia, infestation, bodily distortion or invasion, pregnancy, or loss of voluntary or sphincteric muscle control 3 4 9 12. A distributed profile of brain atrophy has been identified in group neuroimaging studies of C9ORF72-FTD, particularly involving frontal and parietal lobes, thalamus and cerebellum 3 6 13.…”

Alzheimer's disease: mimics and chameleons

“…In keeping with all neurodegenerative diseases, at their most extreme these conditions are phenotypically very distinct from ‘classical’ AD. However, some patients with FTLD pathologies, particularly those with mutations in the tau gene,26 and some patients with TDP-43 pathology—including individuals who go on to develop FTD/motor neurone disease either on a sporadic basis or due to mutations in the recently identified C9orf72 gene 27—can present with an insidious onset of episodic memory impairment, sometimes with focal medial temporal lobe atrophy resembling AD. We have occasionally seen the progressive anomia of early semantic dementia mistaken for episodic memory impairment, and thus AD, though the semantic dementia syndrome (in particular, the early disintegration of verbal and semantic knowledge) is highly distinctive and not a feature of typical AD.…”