Background

Behavioral variant frontotemporal dementia (bvFTD) is a highly genetic and heterogeneous clinical syndrome characterized by early and prominent deterioration of behavior, which includes impaired social interactions, disinhibition, apathy, and impairment in adaptive functioning, and the main causal genes are mutations of the microtubule-associated protein tau (MAPT) gene, especially in China [1,2,3]. Asymptomatic carriers with autosomal dominant mutations provide an opportunity to investigate the pathophysiology of bvFTD in the earliest phases of the illness [4]. Although bvFTD is traditionally considered a frontotemporal cortical disease, there is growing evidence that subcortical brain regions, particularly the striatum, are also significantly affected and may play a role in the generation of motor, cognitive, behavioral, and psychiatric symptoms [5,6,7]. However, limited attention has been drawn toward the striatum, especially for the limbic striatum, which is specifically associated with the central features of bvFTD: behavioral and psychiatric disturbances [8, 9].

Given that the dysfunction is not solely attributable to the nature of isolated regions, neural circuits mediated by the limbic striatum are critical for the integration of information to carry out goal-directed behavior and psychiatric function [10]. The limbic striatum receives projections from the prefrontal cortex, which includes the ventromedial prefrontal cortex (vmPFC), orbitofrontal cortex (OFC), rectus gyrus, and anterior cingulate cortex (ACC), and sends projections that ultimately relay information back to the prefrontal cortex via the thalamus, which constitutes the limbic CSTC circuit [11, 12]. Multiple lines of evidence in patients with different diseases suggested that the dysfunction of this limbic CSTC circuit plays a major role in the pathogenesis of behavioral and psychiatric symptoms, with the limbic striatum serving as the key subcortical relay [9, 13, 14]. Previous neuroimaging studies have revealed that the behavioral and psychiatric disturbances in patients with bvFTD may be attributed to structural abnormalities of the relays within the limbic CSTC circuits, which includes the vmPFC, OFC, rectus gyrus, ACC, and especially the limbic striatum; moreover, these abnormalities can be detected even in asymptomatic mutation carriers [15,16,17,www.fl.ion.ucl.ac.uk/spm). Structural MRI images were normalized to standard Montreal Neurological Institute (MNI) space using diffeomorphic anatomical registration through exponentiated lie algebra normalization as implemented in SPM12. The images were then smoothed using an 8-mm full-width half-maximum isotropic Gaussian kernel for all directions.

PET/MRI image preprocessing

The [l8F]-FDG PET image processing and analyses were performed using SPM12 implemented in the Matlab software (Mathwork, Inc., Natick, MA, USA). After normalizing the structural MRI images, the transformation parameters determined by the T1-weighted image spatial normalization were applied to the co-registered PET images for PET spatial normalization. The images were then smoothed using an isotropic Gaussian kernel with an 8-mm full-width half-maximum. The FDG-PET scan intensity was normalized using a whole cerebellum reference region to generate standardized uptake value ratio (SUVR) images.

Analysis at the striatal subregion level

We used the substriatal regions of interest (ROIs) from the Oxford-GSK-Imanova Striatal Connectivity Atlas [9], which is a probabilistic atlas of substriatal regions segmented according to their white-matter connectivity to cortical regions. Based on the differential cortical connectivity patterns, the atlas subdivides the striatum into seven subregions: limbic, executive, rostral-motor, caudal-motor, parietal, occipital, and temporal subregions (Fig. 1A). We focused on the limbic striatum because it is the principal subcortical relay of the limbic CSTC circuits. Mean [18F]-FDG PET SUVRs were determined separately in the unilateral limbic portion of the striatum using ROIs provided by the atlas.

Fig. 1
figure 1

Significant correlations between the limbic striatum and neuropsychological scores in patients with bvFTD. A Striatal parcellations based on intrinsic functional connectivity with the cerebral cortex. B Scatter plots of significant correlations between the SUVR value of the limbic striatum and neuropsychiatric scores. Region and scatterplot colors, red: left limbic striatum, blue: right limbic striatum

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Metabolic connectivity analysis of the limbic CSTC circuit

We used sparse inverse covariance estimation (SICE), which is a method previously validated by Huang et al. [21] A series of nodes (N = 172) that represent brain ROIs for the connectivity analysis were selected to cover the whole brain [22, 23]. Because our hypothesis was specifically focused on the limbic CSTC circuit, we selected six ROIs for the functional connectivity analysis, which included the vmPFC, OFC, rectus gyrus, ACC, limbic striatum, and thalamus (i.e., the main components of the limbic CTSC circuitry). We performed a seed-based analysis with the six ROIs to investigate the connectivity between the frontal cortex and the limbic striatum, the limbic striatum and the thalamus, and the thalamus and the frontal cortex.

Statistical analyses

The GraphPad Prism software (version 8.3.0, GraphPad Software Inc, La Jolla, CA, USA) was used for all statistical analyses. The normality of the distribution for all numerical variables was evaluated using Shapiro-Wilk tests, and homogeneity of variance was assessed by F tests. Numerical variables are presented as means ± standard deviations or medians (Q1–Q3). Group differences were assessed using an independent t-test for normally distributed and homogeneous variance data, otherwise, the Mann-Whitney test was used. Comparisons of categorical variables were analyzed using chi-square and Fisher’s exact tests.

The structural and [18F]-FDG PET data were subjected to voxel-wised whole-brain two-sample t-tests based on the framework of a general linear model (GLM) in SPM12, with age and sex as covariates. Brain regions with significant volume and FDG changes were determined using a voxel threshold of p < 0.05 (familywise error [FWE]-corrected). We then conducted the atlas-based ROI analysis of the PET images to extract the regional SUVRs of the relays in limbic CSTC circuit for further correlation analyses. To compare metabolic connectivity between groups, we used non-parametric permutation tests with 5000 permutations to determine significance. The p-values were calculated as the fraction of the difference in distribution values that exceeded the difference value between the actual groups.

For the bvFTD group, we performed a Pearson’s correlation between the [18F]-FDG SUVR of the relays in the limbic CSTC circuit and neuropsychiatric assessment scores using a threshold of p < 0.05 (false discovery rate [FDR]-corrected). Furthermore, multivariable linear regression analyses were performed to examine whether the severity of behavior disruption (FBI total score, FBI apathy, FBI disinhibition) was associated with involvement of limbic striatum covarying out the general cognition (MMSE) or disease severity (FTLD-CDR). For all analyses, a p-value < 0.05 indicated statistical significance.

Results

Demographic features of the subjects

Demographic, cognitive, and behavioral features of the bvFTD patients, controls, asymptomatic carriers, and noncarriers are presented in Table 1. Asymptomatic MAPT carriers exhibited no symptoms or signs of any kind, including cognitive and motor impairment. In addition, none of the bvFTD patients displayed any symptoms or signs of motor disturbance. There were significant differences in MMSE, MoCA, FTLD-CDR, AVLT, BNT, and FBI scores between bvFTD patients and controls, but not between asymptomatic MAPT mutation carriers and noncarriers. The mean (standard deviation) estimated years from the symptom onset was 8.33 (1.875) in the MAPT mutation carrier group with a range of 4 to 13 years.

Table 1 Demographic and neuropsychiatric assessment data
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Alteration in each striatal subregion

Compared with controls, bvFTD patients showed a significantly lower GM volume in the striatal limbic subregion, the executive subregion, the rostral motor subregion, and the caudal motor subregion, but not in the parietal subregion, occipital subregion, or temporal subregion, as shown in Supplementary Tables 1 and 2. No gray matter loss was identified in asymptomatic MAPT carriers compared with non-carriers based on a voxel threshold of p < 0.05 (FWE-corrected).

Even though bvFTD patients did not exhibit any symptoms or signs of motor disturbance, when compared to controls, they showed gray matter loss and hypometabolism in bilateral motor subregions of the striatum, including the rostral-motor and caudal-motor subregion. Asymptomatic MAPT carriers and noncarriers did not significantly differ in GM volume and FDG uptake of bilateral motor subregions. These results are presented in Supplementary Tables 1 and 2 and Supplementary Figure 1.

[18F]-FDG uptake in the relays of the limbic CSTC circuit

Bilateral hypometabolism was significantly more pronounced in bvFTD patients than in healthy controls in the relays within the limbic CSTC circuit, which included the vmPFC, OFC, rectus gyrus, ACC, thalamus, and limbic striatum (p < 0.0001; Supplementary Table 3). However, asymptomatic MAPT carriers and noncarriers did not significantly differ in FDG uptake of the above relays within the limbic CSTC circuit.

Correlations between the limbic CSTC circuit and neuropsychological features

As shown in Fig. 1B and Supplementary Table 4, in the bvFTD group, SUVR values of the limbic striatum were negatively correlated with the FBI total score, disinhibition subscale score, apathy subscale score, and FTLD-CDR sum of boxes scale.

Similarly, significant diffusion associations were present between the SUVR values of the vmPFC, OFC, rectus gyrus, and ACC and the FBI total score, disinhibition subscale score, apathy subscale score, and FTLD-CDR sum of boxes scale score, as shown in Supplementary Table 4 and Supplementary Figures 2 and 3.

Multivariable linear regression analyses revealed that the FBI total score was significantly correlated with SUVR of the bilateral limbic striatum when the models were adjusted by MMSE. SUVR of the bilateral limbic striatum and FBI disinhibition subscale showed a trend of correlation, as did SUVR of the right limbic striatum and FBI apathy subscale. In addition, the FBI disinhibition subscale score was significantly correlated with SUVR of the bilateral limbic striatum when the models were adjusted by FTLD-CDR. The results were present in Supplementary Tables 5 and 6.

Metabolic connectivity in the limbic CSTC circuit

Compared with the controls, bvFTD patients showed the decreased metabolic connectivity within the CSTC circuit, including connectivity between the vmPFC, OFC, rectus gyrus, ACC, and the limbic striatum, between the limbic striatum and the thalamus, as well as between the thalamus and the prefrontal cortex (vmPFC, OFC, rectus gyrus, ACC), as shown in Fig. 2.

Fig. 2
figure 2

Metabolic connectivity within the limbic CSTC circuits in bvFTD patients. A Connectivity weights in bvFTD patients compared with controls. In bvFTD patients, extensively decreased metabolic connectivity between the major components of limbic CSTC circuits was observed. B Connectomes projected onto a 3D brain template. Enhanced metabolic connections are represented by red lines, and weakened metabolic connections are represented by blue lines. Abbreviations: vmPFC, ventromedial prefrontal cortex; ACC, anterior cingulate cortex

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In asymptomatic MAPT carriers, the limbic subregions of the striatum showed weakened connections with vmPFC, OFC, rectus gyrus, and ACC, but enhanced connectivity with the thalamus compared with non-carriers. Accordingly, the thalamus had enhanced connections with the vmPFC, OFC, rectus gyrus, and ACC (Fig. 3).

Fig. 3
figure 3

Metabolic connectivity within the limbic CSTC circuits in asymptomatic MAPT mutation carriers. A Connectivity weights in asymptomatic mutation carriers compared with noncarriers. Asymptomatic mutation carriers showed the decreased fronto-striatal connectivity and compensatory increased striato-thalamo and thalamo-cortical connection within limbic CSTC circuits. B Connectomes projected onto a 3D brain template. Enhanced metabolic connections are represented by red lines, and weakened metabolic connections are represented by blue lines. Abbreviations: vmPFC, ventromedial prefrontal cortex; ACC, anterior cingulate cortex

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Discussion

We found altered connectivity within the limbic CSTC circuit in the bvFTD patients and presymptomatic MAPT mutation carriers, which, to the best of our knowledge, has not been empirically demonstrated previously. Specifically, extensive decreased connections were observed in the limbic CSTC circuit, which may be associated with more severe behavioral disturbances in bvFTD patients with both apathetic and disinhibition syndromes. In contrast to the connectivity patterns observed in bvFTD patients, the asymptomatic MAPT mutation carriers showed decreased frontostriatal connectivity and compensatory increases in striato-thalamic and thalamo-cortical connections in the limbic CSTC circuits, which may contribute to the absence of the symptom.

We revealed alterations in metabolic connectivity of the CSTC circuit in presymptomatic and symptomatic bvFTD, especially at the level of the limbic striatum associated with the behavior and psychiatric function, which has not been specifically investigated to date. Instead of using anatomically defined discrete striatal regions (nucleus accumbens, caudate nucleus, and putamen) as previously employed, we use a connectivity-based (CB) functional striatum atlas based on their distinct cortical connectivity profiles, which provides optimal subdivision to investigate specific functions of the striatum. We observed reduced metabolic connectivity within these circuits in our bvFTD patients, which is consistent with previous findings of both metabolic and structural abnormalities within regions comprising the limbic CSTC circuits in frontotemporal dementia (FTD) [5, 24]. Furthermore, the functional connectivity patterns of the limbic CSTC circuits were altered during the presymptomatic stage of MAPT mutation carriers at risk of genetic bvFTD. The above findings support previous studies that suggest that FTD is a more complex disease involving the dysfunctions in the cortical and subcortical transmission rather than dysfunctions in cortico-cortical transmission alone [5, 7, 24]. Furthermore, our study highlights that dysfunctions of cortico-subcortical transmission may occur during a very early stage of the disease. Notably, our study provided an opportunity to characterize in vivo changes in the limbic CSTC circuits from the preclinical to the symptomatic stage of bvFTD, which has not yet been experimentally established in previous studies. Taken together, the aberrance of the limbic CSTC circuit may be a sensitive and useful method for recognizing the presymptomatic stage of bvFTD and tracking disease progression.

In addition to disruption in behavior, personality, and social cognition, extensive cognitive impairment, including memory, execution, and language, were detected in bvFTD patients in this study. According to the most recent bvFTD diagnostic criteria, the neuropsychological profile includes executive dysfunction in the context of relatively preserved episodic memory and visuospatial skills [19]. Interestingly, significant memory impairment was found in our bvFTD patients, which was in line with previous studies that included pathologically proven patients with bvFTD, implying that memory deficit may be associated with the disease progression or with the fact that a portion of bvFTD does have amnestic disturbance [25,26,27].

Our FDG-PET findings showed that the limbic striatum which serves as the key subcortical relay of the limbic CSTC circuit is involved in bvFTD symptomatology, particularly in the behavioral and psychiatric disturbances of both apathetic and disinhibition syndromes. The hypometabolism of the limbic striatum in bvFTD patients was associated with the severity of the disease, which is consistent with the previous studies of FTD that used morphological and diffusion imaging [5, 24]. Notably, the SUVR of the bilateral limbic striatum was correlated with behavioral disturbances, as measured by the FBI total score, disinhibition subscale score, and apathy subscale score, which has never been studied to date. Moreover, the correlation analysis revealed that the SUVR of the vmPFC, OFC, rectus gyrus, and thalamus, which were identified as relays of the limbic CSTC circuits, was linked significantly to behavioral disturbances. In summary, these findings imply that the involvement of the limbic CSTC circuits might contribute to the central features of bvFTD including behavioral and psychiatric symptoms.

In both bvFTD patients and asymptomatic MAPT carriers, the frontostriatal connectivity in the limbic CTSC circuit was shown to be reduced. This finding is partly consistent with previous research that used DTI, which reported structural hypoconnectivity between the OFC and limbic striatum in bvFTD patients [5]. Interestingly, in contrast to the decreased metabolic connectivity observed in bvFTD patients, the asymptomatic MAPT mutation carriers showed increased connectivity between the limbic striatum and the thalamus, as well as between the thalamus and the frontal cortex within the limbic CTSC circuitry. This result suggested that increased connectivity in the CTSC circuitry during the very early stages of the disease may reflect compensatory or maladaptive remodeling, which then decreases as the disease progresses. Previous research has also discovered that the regional volumes of the striatum and thalamus connected to the medial prefrontal cortex in mild bvFTD patients were significantly larger than those in controls [5]. Thus, we speculate that the frontostriatal connectivity may be the initially involved in the asymptomatic MAPT mutation carriers, and enhanced connectivity between the other relays of the limbic CTSC circuit may reflect a compensatory process to help maintain normal function. In addition, asymptomatic MAPT carriers showed altered metabolic connectivity without corresponding hypometabolism in the relays of the limbic CSTC circuit, which is consistent with recent studies that reported that intracortical transmission deficits preceded the emergence of white matter lesions, structural brain atrophy, degeneration of neuronal synapses, and cognitive impairment [18, 28, 29]. Taken together, aberrant metabolic connectivity within the limbic CSTC circuit, albeit with different patterns, was present during both the presymptomatic and symptomatic disease stages of bvFTD and was possibly related to the underlying pathophysiological process, implying that the earliest involvement in the bvFTD continuum occur in the frontostriatal connectivity within the limbic CTSC circuit.

Limitations

This study has several limitations. First, the results were limited by the small sample size, particularly for asymptomatic MAPT mutation carriers, because FTD families that carry the MAPT mutation are rare. Second, this was a cross-sectional study. We plan to conduct longitudinal studies with postmortem confirmation in the future in asymptomatic MAPT mutation carriers and symptomatic bvFTD patients. Third, the asymptomatic MAPT subjects and subjects with bvFTD were each matched to a control group, which reduced their comparability. Nevertheless, the groups were as close as possible in age, and age was included in all analyses as a covariate to minimize potential confounds. Additionally, from a connectivity perspective, the directionality of the fronto-striatum, striato-thalamic, and thalamo-frontal connectivity could not be separated by FDG-PET imaging, which may have confounded the correlations.

Conclusion

Our FDG-derived metabolic connectivity study in bvFTD patients and asymptomatic MAPT mutation carriers revealed abnormal functional connectivity within the limbic CSTC circuits. This study provided clinically relevant insights into the features of the limbic CSTC circuit in bvFTD patients, and these disrupted metabolic connectivity patterns may be eventually be used as imaging biomarkers to detect the presymptomatic stage of bvFTD and monitor disease progression. In the future, larger but foremost longitudinal studies will be needed to confirm the aberrant connectivity patterns of the limbic CSTC circuits in a continuous spectrum of bvFTD and elucidate the sequential order of these potential markers during the evolution of the disease.