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.

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

“…These data reveal vulnerable neuroanatomical structures during the presymptomatic and symptomatic stages, which include ventral and dorsomedial prefrontal cortex, ventral and dorsal insula, anterior cingulate, caudate, and the medial thalamus. These regions are highly anatomically congruent with atrophy patterns found in C9orf72 ‐associated frontotemporal dementia 45, 47, 48, 49, 50. Notably, several studies confirmed that the medial thalamus is a region affected across C9orf72 expansion carriers,50 even during the presymptomatic phase 23, 36, 46.…”

“…In parallel with the ROI analysis, the voxel‐wise analysis showed that certain sparse regions of lower grey matter volumes tended to associate with higher poly(GP), which included regions in the bilateral dorsolateral prefrontal, medial frontal, and lateral temporal cortices. Although higher poly(GP) levels showed a relatively weak association with lower grey matter volumes in our analyses, the regions identified include those atrophied in C9orf72‐ associated FTD patients,45, 47, 48, 49 and show reduced volume in presymptomatic C9orf72 expansion carriers 23, 36…”

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

“…Indeed, on the rare occasions this does occur it would appear that TDP‐43 is secondarily deposited upon pre‐existing DPR [14]. Second, despite there being reports of cerebellar atrophy in some cases with C9ORF72 expansions [25, 26], the presence of p62/DPR histological changes in this region appear clinically silent, at least when assessed using conventional measures of cerebellar function. This is despite present observations that DPR pathology appeared heavier within cerebellum than either cerebral cortex or hippocampus at early stages of the illness.…”

Isoform‐specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis

“…1,2,5,6 Patients carrying the expansion can show heterogeneous clinical presentation, and the expansion has been identified in patients with other neurological diseases. 1,2,[7][8][9][10][11][12][13][14][15][16][17][18][19] Three potential pathomechanisms have been proposed to arise from the repeat expansion in C9orf72: RNAmediated toxicity through generation of RNA foci and sequestration of RNA-binding proteins from their normal targets; expression of dipeptide repeat proteins by repeatassociated non-ATG (RAN) translation; and haploinsufficiency. 1,2,[20][21][22][23] C9orf72 generates three transcripts through alternative splicing that encode 2 protein isoforms; a long isoform of approximately 54 kDa (termed C9-L), corresponding to variants 2 (V2) and 3 (V3), and a short isoform of approximately 24 kDa (termed C9-S) corresponding to variant 1 (V1).…”