We have described longitudinal neuropsychological and neuroimaging features in a cohort of patients with FTD due to a C9ORF72 expansion. Considering the mutation group as a whole, impaired executive function and also episodic memory were early and prominent neuropsychological features. Over follow-up intervals of some 18 months, there was a significant decline in general intellect and a further decline in visual memory, naming and parietal skills, whereas nondominant parietal (visuoperceptual) functions remained relatively intact. Mean brain atrophy and ventricular expansion rates were increased compared with healthy controls and broadly in line with rates of change in previous longitudinal imaging studies of FTD [29, 30], although there was substantial diversity across the group. Increased rates of ventricular expansion were consistently observed and may be a candidate biomarker of disease evolution associated with the C9ORF72 mutation. Cerebellar atrophy was also a relatively prominent feature in the C9ORF72 mutation group, with an approximately 10-fold increase in mean atrophy rate compared with controls. Notably, no specific cortical region appeared disproportionately affected; however, subcortical structures including the thalamus and globus pallidus showed mean rates of atrophy around three times greater than controls. Unlike certain other genetic variants of FTD, notably GRN , hemispheric atrophy remained largely symmetrical. In further contrast to previous neuroimaging findings in association with mutations of GRN (asymmetric fronto-temporo-parietal atrophy) and MAPT (antero-medial temporal lobe atrophy) , individual atrophy profiles in this C9ORF72 mutation cohort were highly variable (Figure 2) - some patients showing chiefly frontal volume loss, whilst others showed relatively more posterior volume loss. Cerebellar atrophy was a relatively consistent feature in individual cases here, although whether this is truly a signature of C9ORF72-associated FTD requires substantiation in larger patient cohorts from different centres.
The evolution of cognitive deficits here suggests a distributed disease process implicating frontal, temporal and parietal cortices, particularly in the dominant hemisphere. Degeneration of a distributed subcortical network might reconcile this neuropsychological profile with the rather variable and diffuse profiles of brain atrophy observed here. Degeneration of thalamus, cerebellum and thalamic and frontal white matter tracts has been identified previously in cross-sectional imaging studies of C9ORF72 expansions [6, 8, 9]. In the present study, we provide further evidence that the pathophysiological mechanisms of C9ORF72-associated FTD target subcortical networks: rates of thalamic and cerebellar atrophy and ventricular expansion were disproportionately increased relative to whole brain atrophy rates, consistent with involvement of subcortical structures and pathways . The involvement of the globus pallidus observed here is in line with the development of extrapyramidal symptoms in a substantial proportion of C9ORF72 cases in other series , although our patients did not manifest clear-cut features of Parkinsonism. The thalamus, globus pallidus and cerebellum together act as key hubs coordinating distributed cortico-subcortical circuits and the cognitive operations they mediate [34, 35]. Early involvement of such hub regions and projections could facilitate diffusive spread of the molecular pathology responsible for the brain degeneration associated with C9ORF72 expansions [36–38] and might be anticipated to lead to rapid clinical evolution, although the very wide range of clinical disease durations among individual patients with a C9ORF72 mutation remains an important unsolved problem. Both the thalamus and cerebellum have been previously implicated in cross-sectional neuroimaging work in C9ORF72-associated FTD . The increased prevalence of cerebellar p62 inclusions with C9ORF72 expansions compared with other pathologically proven cases of FTD further supports the role of the cerebellum as an important anatomical nidus of C9ORF72-associated pathology [6, 39].
This study has a number of limitations. Case numbers here were relatively small and individual variation was substantial; larger (ideally, multicentre) longitudinal studies are required to establish the true range of cognitive and neuroimaging features associated with C9ORF72-associated FTD and to evaluate candidate biomarkers. The historical nature of the present cohort was a particular limitation on the systematic analysis of behavioural deficits; for example, the nature of the naming impairment here remains ill-defined, and this could in principle reflect primary word retrieval, semantic or mixed deficits. Inclusion of presymptomatic carriers in future studies may allow the earliest behavioural and neuroimaging markers of disease onset to be determined. The specificity of any candidate biomarkers will only be established by comparisons with other genetic and sporadic forms of FTD. We argue that future work should particularly target subcortical (including cerebellar) structures and cognitive functions in the C9ORF72 mutation group, incorporating neuroimaging modalities that capture white matter disintegration: although any synthesis must be preliminary, we interpret the present findings as further circumstantial evidence that a distributed cortico-subcortical network is integral to the phenotypic expression of C9ORF72-associated FTD.