Fronto-temporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioral abnormalities, language impairment, and deficits in executive functions as the most typical clinical features (Seelaar et al., 2011). FTLD is clinically heterogeneous, as different clinical variants have been carefully described. On the basis of presenting clinical symptoms, behavioural variant FTD (bvFTD), agrammatic variant of Primary Progressive Aphasia (avPPA), and semantic variant of PPA (svPPA) represent the most common phenotypes (Benussi et al., 2015). Each one presents specific neuroimaging hallmarks; bvFTD is characterized by mesial and dorsolateral frontal damage, prevalent on the right side, avPPA is defined by involvement of Broca’s area and left insula, whilst svPPA usually presents left rostral temporal involvement (Lashley et al., 2015).

Moreover, FTD is chacterized also by early stages, usually named mild cognitive impairment (MCI), that are still not completely characterized. Unfortunately, the diagnosis of FTD can be difficult because of its insidious and gradual onset and can also be misdiagnosed as Alzheimer’s disease (AD) (Rankin et al., 2005; Walker et al., 2005).

The discovery of mutations in GRN as a genetic determinant for FTLD resulted in the rapid identification of a large number of families carrying GRN mutations, inherited in an autosomal dominant pattern. At present, 77 different mutations in more than 240 unrelated families have been described (Ghidoni et al., 2012a). Mutations in GRN have been associated with a broad spectrum of clinical phenotypic variability (Benussi et al., 2008; Rohrer et al., 2010a,b).

GRN null mutations cause protein haploinsufficiency, leading to a significant decrease in progranulin (PGRN) levels that can be detected in plasma, serum, and cerebrospinal fluid of mutation carriers (Ghidoni et al., 2008, 2012b; Finch et al., 2009; Sleegers et al., 2009). It has been reported that PGRN promotes neuronal survival and neurite outgrowth in cultured neurons (Van Damme et al., 2008) and enhances neuronal survival under stress conditions (Kessenbrock et al., 2008). Data from GRN knockout experimental models suggest that PGRN deficiency leads to reduced synaptic connectivity and impaired plasticity, which may be contributing factors to FTLD pathology in human patients (Tapia et al., 2011; Petkau et al., 2012). Brain activity could be widely and variously affected in FTLD patients with GRN mutations. Neuroimaging studies have shown that the topography of brain atrophy is frequently asymmetric, and predominantly involves the frontal, temporal, and parietal cortex (Whitwell et al., 2012). Nevertheless, a recent study (Caroppo et al., 2014) have demonstrated that a diffuse and bilateral white matter involvement is common in patients with GRN mutations. The presence of white matter lesions is not surprising since expression of PGRN, not only in neurons but also in activated microglia, in astrocytes and oligodendroglia, has been previously ascertained (Ahmed et al., 2010). As a consequence, cortical and subcortical loop are both implicated in the disruption of intrinsic brain networks in GRN mutations carriers.

Electroencephalography is a reliable and non-invasive tool for the study of brain networks in dementia. Relationship of the brain oscillations with intrinsic brain network like default mode network (DMN) have been extensively studied (Nishida et al., 2015). In particular, alpha and theta field potentials are deeply involved in tuning the large and local scale networks interactions in cognitive and psychiatric illnesses (Koenig et al., 2001; Tenke et al., 2011). Previous EEG studies have demonstrated peculiar modifications in brain oscillations in patients with MCI due to AD as compared to non-AD converters (Moretti et al., 2011a). Moreover, these changes in brain oscillations have been correlated with temporo-parietal and hippocampal atrophy (Moretti et al., 2007a, 2008a, 2009a,b, 2011a, 2012) as well as to white matter lesions (Moretti et al., 2007b, 2008b). In the present explorative study, we test the working hypothesis that changes in EEG oscillations could specifically detect different stages of FTLD, namely MCI-FTD versus overt FTD, as well as differences between GRN mutation carriers versus non- carriers. The search for new biomarkers is of great importance for an early diagnosis and for monitoring the effectiveness of new therapies.

Table 1 shows ANOVA significant results. As expected, the PGRN dosage was significantly different, with an impressive decrease in GRN null mutation carrier patients [F(19,77), df = 1, p < 0.001], confirming previous results (Ghidoni et al., 2012b). As about the EEG rhythms, results show: 1) a significant increase of high alpha power in GRN positive mutations carriers [F(4,22), df = 2, p = 0.003]; (2) a significant increase of theta power in GRN negative patients [F(3,14), df = 2, p = 0.002).

ANOVA analysis showed a decrease of the theta and alpha spectral power in MCI-FTD as compared to both PGRN positive and negative FTD patients. Given that the difference between PGRN positive and negative FTD patients were limited to theta and alpha power spectra, other frequency bands were not considered in the analysis.

The only significant results about neuropsychological battery were obtained in Token test, fluency for letters and working memory test. The results showed a general better performance in MCI-FTD patients as compared to both negative and positive PGRN mutations carriers (p < 0.01). No significant differences resulted between the comparison between negative and positive mutations PGRN carriers.

Our results show that FTLD patients carrying GRN mutations have different changes of EEG rhythms when compared to patients negative for GRN mutations. Specifically, GRN mutations carriers demonstrate an increment of the high alpha and a decreased of the theta power spectra. In this view, the presence of PGRN, which is a trophic factor for the nervous system, would allow a reorganization of the neural networks in a compensatory or adaptive way: accordingly, it has been reported that PGRN promotes neuronal survival and neurite outgrowth in cultured neurons (Van Damme et al., 2008) Likewise, under stress conditions it has been exhibited that PGRN improves neuronal survival (Kessenbrock et al., 2008). Data from GRN knockout experimental models suggest that PGRN deficiency leads to reduced synaptic connectivity and impaired plasticity, which may be contributing factors to FTLD pathology in human patients (Tapia et al., 2011; Xu et al., 2011). On the other hand, the white matter impairment in GRN mutation carriers has been directly proved in a recent study (Caroppo et al., 2014). In this study, four patients carrying GRN mutation were investigated and in all of them mostly confluent white matter lesions, affecting the periventricular subcortical white matter and U-fibers, were found mainly in the frontal and parietal lobes. This trophic activity could be shown by the maintenance of theta brain oscillations. Of note, fronto-parietal network are well recognized potential generators of theta oscillations (Beck et al., 2008; Ghetti et al., 2008; Whitwell et al., 2009), traveling on long pathway bundles of the white matter of fronto-parietal lobes and related subcortical structures like brainstem, and corpus callosum systems (Rohrer et al., 2010a,b). In particular, a recent study investigating the cortical generators of theta brain rhythm, through intracranial electrode recordings, have found that the higher percentage of cortical gated theta oscillations is situated in parieto-occipital regions (Raghavachari et al., 2006). So, a possible explanation of the spared maintenance of theta power in FTLD patients negative for GRN mutations as compared to GRN mutations carriers could be related to the relative integrity of parieto-occipital areas, embedded in the DMN.

Not surprisingly, in case of PGRN deficiency, the high alpha frequency spectral power increments. The alpha oscillation is the rhythm that mirrors the brain electrical signal of the parietal-occipital default system, profoundly connoted with higher cognitive abilities (Klimesch, 2012; Moretti, 2015a). Recent studies have shown that mutations in GRN are correlated with atrophy of the parietal lobes (Pickering-Brown et al., 2008; Seeley, 2008; Van Swieten and Heutink, 2008). In particular, a recent study investigating brain network connectivity with functional resting state MRI (Premi et al., 2014) utilizing three measures of both local and global connectivity (the regional homogeneity, the fractional amplitude of low frequency fluctuation and the degree centrality) has shown that parietal lobes are affected very early in GRN mutation carriers, so that the notion of fronto-parietal dementia for PGRN related disease should be considered. The parietal lobes are well-recognized core regions of the DMN (Sala-Llonch et al., 2015). Previous studies have demonstrated that high alpha rhythm synchronization (or increase) is a marker of loss of function in the default system, as exhibited in patients with prodromal or overt AD (Moretti et al., 2011b, 2013a,b, 2014a,b; Moretti, 2015b,c,d). The increase of high alpha oscillation in FTD patients, characterized by the loss of PGRN, confirms the reliability of this biomarker as a sign of DMN impairment. Moreover, the lack of PGRN is confirmed to be connected to the disruptive of the default system, determining real reverberations on cognitive capacity.

As expected, MCI-FTD have better cognitive performance, especially in frontal function assessment tests, as compare to overt FTD patients both carriers and non-carriers of GRN mutation. Moreover, in MCI-FTD the lower spectral power of theta and alpha power could be explained with an initial stage of the disease in which EEG changes are not still clear. A possible fingerprint of this stage could be the ratio between alpha and theta power spectra. The progression of disease could modify the EEG oscillations, as observed in overt FTD and more strongly in GRN mutation positive patients. Anyway, future studies will clarify if the presence or absence of PGRN mutations also in MCI-FTD could unveil more peculiar brain oscillations changes.

GRN mutations affect brain oscillatory activity. A better understanding of the complexity of PGRN biology in the brain will help guide the development of PGRN-modulating therapies for neurodegenerative disease. Further studies with a larger number of subjects are needed to confirm the present results.

DVM: Substantial contributions to the conception or design of the work. LB: substantial contribution for the acquisition, analysis, or interpretation of data for the work; and drafting the work. SF: substantial contribution for the acquisition, analysis, or interpretation of data for the work; AND drafting the work. MC: substantial contribution for the acquisition, analysis, or interpretation of data for the work; and drafting the work. GB: substantial contribution for the acquisition, analysis, or interpretation of data for the work; and drafting the work. RG: substantial contribution for the acquisition, analysis, or interpretation of data for the work; and drafting the work.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.