The major finding of the present work is that patients with bvFTD and FTD-MND show similar clinical and imaging features regardless of genotype. We identified 2 notable exceptions to this general rule. First, we detected a trend toward longer survival in C9+ FTD-MND as compared to FTD-MND noncarriers. This survival difference was not apparent in bvFTD. Second, C9ORF72 mutation carriers displayed more thalamic, posterior insula, and possibly cerebellar atrophy at first assessment than noncarriers. Together, these findings suggest subtle differences in the regional degeneration pattern in C9FTD/ALS that may inform the pathologic mechanisms underlying C9ORF72-related neurodegeneration.
The longer disease course in C9+ FTD-MND reflected a longer time from symptom onset to clinical evaluation and a longer time to develop bvFTD symptoms (patients with C9+ FTD-MND took longer to meet consensus bvFTD criteria). Additionally, patients with C9+ FTD-MND more often presented with an early age at onset (<65 years). All C9+ patients developed symptoms before age 65, whereas 8% of the noncarrier cohort developed symptoms after 65. These findings suggest that C9ORF72 hexanucleotide expansion may bias toward earlier development of bvFTD symptoms.
Delusions as a presenting neuropsychiatric manifestation were more common in patients with C9+ bvFTD. Although previous studies have not associated psychotic features with a specific brain region in FTD,27
psychosis in bvFTD has been associated with FTLD-MND pathology (FTLD-TDP type B).28,29
Because carriers may be more likely to have FTD with underlying FTLD-TDP type B pathology than noncarriers, it is possible that this association may be mediated by FTLD-TDP type B pathology rather than a mutation effect. Supporting this hypothesis is the similar frequency of psychosis in our patients with FTD-MND, regardless of genotype.
The differences in brain atrophy between bvFTD carriers and noncarriers were most pronounced in the thalamus and posterior insula. Thalamic atrophy was unexpected, despite prior reports of thalamic degeneration in FTD.30
Consistent with our results, a recent study found mild to moderate p62 and TDP-43 staining in the thalamus of 4 C9+ carriers with MND.31
Thalamic atrophy has been described in FTLD-TDP type A,5,32
but not in type B, which is typically associated with FTD-MND. Although most FTD-MND cases show FTLD-TDP type B histology, an unexpected feature of C9ORF72
pathology is the frequency of FTLD-TDP type A.33,34
Greater thalamic atrophy demonstrated here could reflect an increased frequency of FTLD-TDP type A in the C9+ group. This finding may prove useful for understanding mechanisms of C9ORF72
The trend toward greater cerebellar atrophy in C9+ FTD-MND requires further study in a larger sample, although it converges with a previous imaging analysis from our group7
and the pathologic literature, which has described ubiquitin and p62-positive, TDP-43-negative neuronal cytoplasmic inclusions within cerebellar granule cells in C9+ FTD-MND.7,35
Although ataxia has been reported in a patient with chromosome 9p-linked FTD-MND10
and was observed in 1 C9+ patient in this cohort, we found no differences in ataxia by genotype. Cerebellar efferent pathways are connected to prefrontal cortex via the thalamus, and these subcortical structures likely contribute to executive control.35
We hypothesize that cerebellar dysfunction could contribute to the network dysfunction underlying the C9+ neuropsychiatric profile that includes greater disinhibition and working memory impairment.
In this specialized dementia clinic cohort, we found only 3 phenotypes associated with C9ORF72
expansions: bvFTD, FTD-MND, and ALS. It is noteworthy that there were no C9+ patients with svPPA (left or right temporal variants) or nfvPPA, differing from a recent study that described a C9+ patient with nfvPPA-MND phenotype.36
Other clinical presentations that have been associated with C9ORF72
expansions, such as AD dementia phenotype and CBS,7–10,34,37
were not observed in this cohort, suggesting they are rare presentations of the mutation; this is inconsistent with a recent report suggesting that the mutation leads to an amnestic phenotype.37
However, 1 C9+ bvFTD patient in our cohort had a positive amyloid PET scan at age 64, possibly indicative of concurrent AD pathology. Another group has also reported34
a 61-year-old patient with comorbid FTLD-MND and AD among a cohort of 20 C9+ patients, suggesting that comorbid AD pathology may be found in patients with C9ORF72
mutations which could account for amnestic symptoms.
Limitations of this study include small sample size, particularly when C9+ subgroups were divided by syndrome and matched for severity. Due to the rigorous thresholds set for statistical significance, nonsignificant trends found here may reflect true underlying differences between genotype groups and suggest further investigations with larger cohorts. Earlier reports of kindreds of chromosome 9p-linked FTD-MND families suggested that there could be motor, cognitive, or psychiatric distinguishing characteristics of the C9ORF72
The lack of these distinctive features seen in our C9+ cohort may partly be due to group analyses of a heterogeneous phenotype or may represent selection bias in our cohort.
The present findings suggest that C9ORF72 mutation carriers are likely to receive a clinical diagnosis of FTD, ALS, or FTD-MND. Future studies focused on neuropathology of the cerebellum and thalamus may elucidate the clinical implications of the present findings and identify novel biologic substrates involved in C9ORF72 dysregulation. Given the substantial contribution of this locus to genetic risk for these syndromes, testing for C9ORF72 expansions may be indicated even without a family history, especially when one of these diagnoses is associated with slow progression or atypical posterior cortical and thalamic atrophy on MRI.