This is the first report of rfMRI in patients with the C9ORF72
associated bvFTD. We found increased anti-correlation between the DMN and the salience network in bvFTD patients with the C9ORF72
expansion. Abnormal anatomical spread of the anti-correlation in bilateral thalamic areas with the DMN anterior sub-network was also detected. The anatomical and signal amplitude changes were detected in neighboring anatomical structures. Until now, only one rfMRI study of genetically determined and clinically affected FTLD patients with mutations in the PGRN
has been published and decreased salience network connectivity and increased DMN connectivity was found [15
]. The other studies of genetically determined bvFTD have been conducted on presymptomatic patients and the results are contradictory [16
The DMN and the salience network are considered to be anti-correlated in a healthy brain [32
]. In the present study the patients with the C9ORF72
expansion had increased anti-correlation between bilateral dorso-medial thalamic nuclei and the DMN. The dorso-medial thalamic nuclei have been suggested to represent a key node binding the salience network circuitry together [9
]. These nuclei play a role in numerous behavioral functions including motivation and drive, memory, emotional experience and expression, executive functions and attention [34
]. A gray matter atrophy of the medial thalamus has been previously detected in patients with the C9ORF72
]. We used gray matter volumes as regressors to minimize the effects of atrophy on the functional connectivity analysis and hence the present finding of increased anti-correlation is not due to atrophy. Decreased connectivity in the anterior thalamus and elevated prefrontal cortex connectivity have been shown to associate with greater levels of apathy in FTLD patients [18
]. Apathy was also a prominent neuropsychiatric symptom in our patients. Thus functional and structural changes in thalamus may explain executive dysfunction and also neuropsychiatric profile of patients.
There are only few reports available about other brain networks than the DMN and the salience network in patients with neurodegenerative diseases. When analyzing the whole brain cortex resting state networks, we found increased connectivity in the right-sided DAN in patients with the C9ORF72
expansion. The DAN appears to be responsible for voluntary (top-down) attention orienting as well as the preparation and selection for stimuli and responses [37
]. We have previously reported increased connectivity in the left DAN in a patient group that consisted of both sporadic and genetically confirmed bvFTD [17
]. However, Filippi with colleagues did not find any changes in the DAN and there are no other reports available [14
In the present study increased connectivity was also detected in the salience network; which is controversial to the hypothesis of decreased connectivity in the salience network in patients with bvFTD. However, previous findings associated with the salience network have been somewhat controversial, while both increase and decrease of connectivity have been detected [12
]. The controversial findings in functional connectivity between different mutation carriers may be explained by neuroanatomical and neuropathological differences between the genetically driven disease groups, severity of the disease and small sample size in all genetic studies. Also the variability.
BvFTD is a neuroanatomically heterogeneous group of syndromes compared with typical AD where the atrophy is more consistent. The location of brain atrophy and also clinical symptoms seem to be different between patients with the C9ORF72
- or PGRN
-mutations and in sporadic FTLD. The C9ORF72
expansion is typically associated with symmetrical and widespread atrophy predominantly in frontal lobes, with additional involvement of the anterior temporal and parietal lobes and cerebellum [39
], while patients with MAPT
mutations have shown more prominent temporal atrophy [40
]. Interestingly, the type of atrophy is not unanimous between the patients with the C9ORF72
expansion and there is substantial variability between subjects in the imaging findings of the C9ORF72
associated FTLD, which may have an effect on fMRI findings at group level even in patients with the same genetic background [36
]. In the present study gray matter atrophy was detected pre-dominantly in right frontal lobe, but also mildly in left temporo-parietal regions. Similar types of atrophy and metabolic changes have been detected in quantitative meta-analysis of voxel-based morphometry and positron emission tomography in patients with bvFTD [43
The strength of the current study is the use of ICA that is able to separate noise sources from neurophysiological signals making the analysis more sensitive. Also the gray matter volumes were used as regressors to minimize the effects of atrophy on the functional connectivity analysis. The main limitation of this study is the small sample size of patients due to rare disease. In previous reports, the number of genetically confirmed bvFTD patients has also been limited and comparable to our study [15
]. However, even in a small cohort, we found functional changes in several relevant cognitive networks which can be thought to explain the symptoms of bvFTD.
This is the first report of fMRI-changes in bvFTD patients with the C9ORF72
expansion. Our results of increased anti-correlation between the DMN and the thalamic regions of the salience network confirm previous findings of the role of these two networks also in bvFTD patients with a new genetic background. Increased functional connectivity was detected in the dorsal attention network and the salience network. These changes are suitable to explain neuropsychiatric symptoms and cognitive defects of patients with bvFTD. However, there is a lot of variation between findings in different studies and further investigations with larger patient groups are needed to clarify the balance of the main cognitive networks in this heterogeneous patient group.