We report two patients diagnosed with a slowly progressive bvFTD (bvFTD-SP), or “FTD phenocopy,” who were subsequently found to carry the C9ORF72 expansion. These individuals initially fulfilled international criteria for possible bvFTD, and were later diagnosed with bvFTD-SP due to their stable clinical course over seven (Patient 1) and two (Patient 2) years of follow-up, and imaging uncharacteristic of bvFTD. These findings demonstrate that a subset of patients with bvFTD-SP may have neurodegeneration due to underlying FTLD-TDP pathology. The presence of slowly progressive forms of C9+ bvFTD may reflect a difference in the type of underlying C9ORF72 mutation (e.g., number of hexanucleotide repeats), modifying effects of genetic/epigenetic factors, or incomplete penetrance of the allele. Since the overall number of bvFTD-SP patients was small in our C9ORF72 expansion-screened FTD population, it is not possible to reliably estimate the prevalence of C9+ bvFTD-SP; however, both patients reported here had a family history of dementia. Our findings therefore suggest that C9ORF72 mutations should be entertained in patients with bvFTD-SP, particularly if there is a known family history of dementia.
To date, only a handful of bvFTD-SP patients have come to autopsy, and none were found to harbor FTLD pathology.[1
] Structural imaging changes are not mandatory for a definite bvFTD diagnosis if a known genetic cause of FTD is present,[11
] and the lack of such atrophy over longitudinal assessment makes the diagnosis of neurodegenerative disease uncertain.[6
] As assessed visually by our clinicians, neither patient had a typical bvFTD atrophy pattern on initial visit or on longitudinal structural MRIs (). Accordingly, these patients would have received a possible bvFTD diagnosis using FTDC international research criteria. Patient 1’s normal FDG-PET is consistent with reports of normal FDG-PET in other bvFTD-SP patients.[3
] Retrospectively, VBM revealed thalamic and posterior insular atrophy in Patient 1 and a nonspecific pattern of parieto-occipital and frontal and insular atrophy in Patient 2; neither of these patterns were deemed clinically significant by the treating physicians at the time of evaluation. While the full spectrum of imaging abnormalities associated with C9FTD/ALS
has not yet been described, the pattern of atrophy observed in Patient 2 is similar to what we have described in the VSM-20 C9FTD/ALS
family in whom the C9ORF72
mutation was first identified.[7
] These findings raise the possibility that C9FTD/ALS
-associated brain atrophy patterns could be used to identify slowly progressive C9ORF72
mutation carriers with a bvFTD-SP phenotype.
Prominent frontal and insular atrophy is a consistent neuroanatomical feature of bvFTD. VBM analysis of Patient 1 showed no frontal atrophy, while insular atrophy was more posterior than typically found in patients with bvFTD (). While VBM in Patient 2 revealed frontal and insular atrophy, compared to other patients with bvFTD, these changes were unrecognized on visual inspection of structural imaging and were only detected using single-subject VBM (). The lack of significant atrophy in characteristic bvFTD regions may explain why both patients maintained a level of insight into their illness. Anosognosia, or the lack of awareness into one’s deficits, has been linked to atrophy in the frontal lobes,[28
] and the lack of significant frontal atrophy in both patients may be why both patients better adapted to their deficits. Patient 1 eventually developed strategies to cope with his symptoms, and during follow-up evaluation, Patient 2 was actively engaged with questions about her disease and interest in clinical trials. Interestingly, Patient 1 generated a list of rules to guide his conduct during social situations. While this demonstrates a depth of insight into his illness, it is also reflective of the obsessive features frequently observed in bvFTD.
Similarly, although both patients showed many deficits on socioemotional testing, such as impaired emotion naming and difficulty imagining others’ thoughts and emotions, they both retained a rudimentary concern for others and themselves that is atypical of bvFTD. Greater insight and some preservation of basic emotional responding could also be the reason that both individuals developed significant depression and anxiety, consistent with reports that individuals with bvFTD-SP may have higher rates of depression compared to typical bvFTD.[2
] In fact, both patients reported more items on the GDS across longitudinal evaluations, and at the time of final evaluation had higher GDS scores than other bvFTD patients ().
Despite the lack of frontal atrophy, both patients displayed executive dysfunction on neuropsychological testing. While impaired on some neuropsychological tests, both patients outperformed individuals with typical bvFTD on many of the executive tasks (), consistent with reports that patients with bvFTD-SP can be differentiated from progressive bvFTD through such tests.[1
] Moreover, given that both patients were at least seven years into their disease course at final evaluation and that time from first symptom to death averages six years,[29
] these patients’ impairments were remarkably mild for typical bvFTD. Importantly, mild executive dysfunction is not unusual in bvFTD, and 25% of patients with typical bvFTD initially perform within normal limits on standard neuropsychological testing.[30
] Thus, normal performance on cognitive testing may be supportive of a diagnosis of bvFTD-SP, but it does not rule out typical bvFTD.
Taken together, our findings suggest that clinicians should strongly consider FTLD pathology in patients who meet criteria for bvFTD-SP, particularly when there is significant psychiatric comorbidity, as was the case in Patient 1. Up to 51% of patients with bvFTD receive erroneous diagnoses at initial evaluation due to symptoms that resemble psychiatric diseases.[31
] Patient 1 was initially diagnosed with PTSD and bipolar affective disorder due to his early symptoms. The presence of prominent psychiatric illness in the families of both patients may further indicate underlying neurodegenerative disease,[31
] yet the absence of such history in bvFTD-SP would not rule out C9+ bvFTD, since sporadic patients of C9ORF72
bvFTD are not uncommon.[7
] Notably, the limited materials available from the father’s autopsy suggest an unclassifiable form of FTLD-TDP as well as ubiquitin-positive, TDP-43-negative NCIs in the medial temporal lobe; these features strongly suggest a C9ORF72
One of the most enigmatic and diagnostically challenging features of patients with bvFTD-SP is their altered personality and behavior in light of unremarkable imaging assessments.[6
] A possible explanation for the behavioral symptoms we observed in our subjects is that these features derive from neuronal and synaptic dysfunction that is not well captured on standard neuroimaging assessments. It is possible that newer imaging techniques such as intrinsic connectivity fMRI may be more sensitive to such C9ORF72
-related brain dysfunction.[33
] It will also be of interest to continue to monitor these patients for the emergence of more typical bvFTD imaging abnormalities.
There are limitations to this report. In our cohort of 61 patients with bvFTD without comorbid motor neuron disease who were screened for the C9ORF72
variant, only four patients had been diagnosed as bvFTD-SP, which is lower than the frequency of bvFTD-SP reported by others (26 of 71 bvFTD in one series).[2
] This difference may be due to the limited longitudinal data available within our bvFTD cohort (31 out of 61 patients were followed for ≥2 years). However, we can accurately report the frequency of bvFTD-SP due to C9ORF72
expansion to be 15% in our cohort of 13 C9+ carriers. None of the other 11 carriers with bvFTD had bvFTD-SP; 7 had progressive changes on longitudinal evaluation and all had significant atrophy at first evaluation. Nevertheless, larger studies are needed to verify this estimate as our cohort of C9ORF72
carriers is small.
Here we identify a novel link between bvFTD-SP and a known FTD-causing mutation. Our findings suggest that an underlying neurodegenerative etiology should not be ruled out in patients who meet criteria for possible bvFTD but have atypical features consistent with a bvFTD “phenocopy.” We also speculate that screening larger series of bvFTD-SP will likely identify other patients with C9ORF72 mutations.