This study generated two major findings: First, using multimodality jICA we found two behavioral variant frontotemporal dementia-related joint components of structural and physiological alterations in the brain. The 1st
joint component revealed an association between brain tissue loss and reduced rCBF* predominantly in the right brain hemisphere in behavioral variant frontotemporal dementia, and the 2nd
joint component revealed greater atrophy relative to reduced rCBF* affecting predominantly the left hemisphere in behavioral variant frontotemporal dementia. The difference in the mixing coefficients between behavioral variant frontotemporal dementia and controls, reflecting an atrophy/rCBF association, was largest for the 1st
joint component. The result is consistent with the fact that behavioral variant frontotemporal dementia tends to affect the right hemisphere more severely than the left, leading to problems with socioemotional behavior early in the disease course (Rosen et al., 2005
). Moreover, the joint components revealed that structural alterations can be associated with physiological alterations in spatially separated but potentially connected regions. The second, and perhaps most important finding is that identification of joint components across structural and perfusion-weighted MRI resulted in a significant increase in effect size separating behavioral variant frontotemporal dementia patients from controls compared to the effect size derived using a conventional univariate analysis separately for each modality. Taken together, the results demonstrate the benefit of using multimodality MRI in conjunction with jICA for mapping neurodegeneration. This may lead ultimately to an improved diagnosis of behavioral variant frontotemporal dementia and other forms of dementia.
Our first finding with multimodality jICA extends our earlier MRI findings of partially dissociated structural and physiological alteration in behavioral variant frontotemporal dementia based on simply combining the statistics from structural and perfusion MRI (Shimizu et al., 2010
). The observed dissociations involved substantial atrophy in absence of rCBF* reduction in some brain regions in behavioral variant frontotemporal dementia while other brain regions showed concordant levels of atrophy and rCBF* reductions. However, the previous approach was limited to observations of local relationships between structural and physiological alterations while relationships across brain regions were not accessible. Multimodality jICA can eloquently overcome this restriction, yielding a wealth of new information of structural and physiological relationships not only at a local level but across distal brain regions as well. Especially the evaluation of all brain regions simultaneous provides a powerful tool for new discoveries, as the findings from the 1st
jICA components demonstrate.
The findings of associated structural and physiological brain alterations with multimodality jICA are worth more discussion and clinical interpretation. The joint component with the strongest behavioral variant frontotemporal dementia related alterations relative to the control group (i.e., 1st
joint component) identified significant brain atrophy in the right frontal and limbic lobes, insular, and caudate regions as well as marked ventricular enlargement in the patients. These brain structure changes were linked to a concurrent reduction in rCBF* of the same anatomical regions in the right cortical hemisphere and subcortical regions including the thalamus and caudate. The findings suggest that certain effects of neurodegenerative disease serve as a substrate both for morphological and physiological changes in behavioral variant frontotemporal dementia. The findings in the ventromedial frontal, dorsolateral prefrontal, insula, and anterior cingulate brain regions can be related to the apathy and stereotypic behaviors, which are the most common initial symptoms among patients with behavioral variant frontotemporal dementia (Rosen et al., 2005
; Shinagawa et al., 2006
jICA analysis also found a second joint component whose expression differed with diagnosis, providing complementary information to the first component. Specifically, the 2nd
joint component showed behavioral variant frontotemporal dementia related alterations relative to alterations in the control group that involved greater brain atrophy in the left hemisphere. The affected regions included the frontal, temporal, limbic, and parietal lobes, motor cortex, and hippocampus in addition to ventricular enlargement prominently in the posterior horns in behavioral variant frontotemporal dementia compared to controls. These regional brain tissue losses were linked to reduced rCBF* in similar anatomical regions again prominently in the left hemisphere. The finding of two distinct joint components of linked structural and physiological alterations implies that the pathology in behavioral variant frontotemporal dementia underlying these changes spreads heterogeneously across the right and left hemispheres. While the majority of frontal and limbic lobe regions are affected early in behavioral variant frontotemporal dementia, the temporal and parietal lobe regions are affected later in the disease process (Kril and Halliday, 2004
). Accordingly, one can hypothesize that while the 1st
joint component identified the brain regions affected during the early disease stage, the 2nd
joint component identified the atrophy and reduced rCBF* occurring in the middle and later stages. The group of behavioral variant frontotemporal dementia patients studied in this work is very heterogeneous in terms of the duration of symptoms (i.e., standard deviation of 4.7 years). The outcome measures (i.e., local brain atrophy and perfusion) in behavioral variant frontotemporal dementia group may be affected by the duration of symptoms; hence, treating this set of subjects as a single group may not be adequate. Future longitudinal studies are warranted to elucidate a possible link between multimodality jICA components and temporal ordering of the behavioral variant frontotemporal dementia-related neuropathology. It is also possible that the components could represent different anatomical variants of behavioral variant frontotemporal dementia. The interpretation of these components would be greatly improved by a future investigation on whether the two components correlate with clinical/behavioral deficits in these patients.
Involvement of parietal, pre- and postcentral, cerebellar, and occipital region suggests that the patients in this study cohort were more demented than they appeared based on their widely used CDR scores, which may underrate disease severity in behavioral variant frontotemporal dementia. This phenomeon was also reported in other studies (Knopman et al., 2008
; Mioshi et al., 2010
). The length of symptoms might be a better proxy for disease severity. Given the long disease history of the behavioral variant frontotemporal dementia patients in this study, these patients most likely fell into the severe to very severe disease categories. Based on clinicopathological staging of FTD severity (Kril and Halliday, 2004
), we therefore find the involvement of these regions not surprising, especially since they show much weaker effects than the more prominently affected regions, including the frontal, temporal, and limbic lobes. Behavioral variant frontotemporal dementia is heterogeneous in terms of underlying pathology; peri-rolandic and parietal involvement might suggest underlying corticobasal degeneration (CBD), a common cause of behavioral variant frontotemporal dementia. Cerebellum might be seen in progressive supranuclear palsy (PSP), which can present clinically as behavioral variant frontotemporal dementia. Occipital findings were surprising to us too. Although our clinical accuracy is around 93% compare to autopsy, it is possible that some cases have additional Alzheimer's disease pathology. bvFTD shares many clinical and radiological features with CBD and PSP (Kitagaki et al., 2000; Cordato et al., 2005). Without a histopathological exam, these common features could make both clinical and radiological diagnosis difficult to distinguish these neurodegenerative disorders (Kertesz et al., 2000; Mathuranath et al., 2000).
Another interesting observation is the right- and left-sided asymmetry in 1st
joint components, respectively. Patients with behavioral variant frontotemporal dementia often present impaired behavioral symptoms that are consistent with an asymmetric left or right-sided structural and physiological abnormalities. For example, it has been shown that patients with primarily right versus left behavioral variant frontotemporal dementia have unique neuropsychological characteristics (Boone et al., 1999
). More studies are warranted to further investigate the link between asymmetry in imaging findings and neuropsychological characteristics.
Our findings of morphometric and physiological alterations in behavioral variant frontotemporal dementia based on conventional voxel-by-voxel unimodal analysis yields two interesting aspects. First, the unimodal analysis of Jac-map and rCBF* maps, showing frontal and anterior temporal predominant but widespread structural atrophy and rCBF* reduction in the behavioral variant frontotemporal dementia patients compared to the controls, is consistent with findings from previous studies including PET and SPECT studies (Cardenas et al., 2007
; Du et al., 2006
; Gorno-Tempini et al., 2004
; Grimmer et al., 2004
; Ishii et al., 1998
; Kril and Halliday, 2004
; Mummery et al., 2000
; Rabinovici et al., 2008
; Rosen et al., 2002
; Varma et al., 2002
), implying that our patient group is a representative sample of behavioral variant frontotemporal dementia. Second, although the conventional analysis approach yielded large clusters of brain alterations in behavioral variant frontotemporal dementia, it largely missed the inherent hemispheric asymmetry of deficits in behavioral variant frontotemporal dementia that jICA revealed. The shortfall in sensitivity with the conventional method is not surprising given that each region is tested separately and associations across regions cannot be inferred. Although our anatomical localizations of regional atrophy and decreased perfusion findings in behavioral variant frontotemporal dementia compared to healthy elderly controls using multimodality jICA are in conformity with findings reported in the literature, the joint components were identified by simultaneously evaluating the imaging measures from both imaging modalities as well as across all brain regions thereby taking intrinsic relationships between these imaging measures into consideration. Therefore our multimodality jICA findings provide deeper insight into the biology of the disease than the methods, which evaluate the modalities as well as each brain region separately.
The second and perhaps most important finding of the study is the gain in effect size using jICA. The results imply that joint analysis of multimodality MRI data provides unique morphological and physiological signatures with significantly larger effect sizes than a conventional approach. For diagnostic purposes, an important question is to what extent imaging modalities other than structural MRI provide “added value”. Although the current study does not explicitly address this question, comparisons based on effect sizes to separate behavioral variant frontotemporal dementia patients from controls suggest that a joint analysis of structural and perfusion-weighted MRI using multimodality jICA is more powerful than other analytical methods, especially those that evaluate structural and perfusion-weighted MRI separately. The improvement with multimodality jICA in identifying behavioral variant frontotemporal dementia likely derives from the ability to detect joint structural and physiological variations in behavioral variant frontotemporal dementia across brain regions that are involved in the neuronal network impacted by the disease (Schroeter et al., 2009
). Whether this feature of multimodality jICA improves differential diagnosis between behavioral variant frontotemporal dementia and other forms of dementia causing neurodegenerative diseases, such as AD, which impacts other neuronal networks, warrants further investigation. The fact that it is not necessary to predefine these regions a-priori for multimodality jICA is another advantage of this approach. Identifying the multimodality imaging biomarkers (e.g., patterns of anatomical and physiological abnormalities) with predictive value for the development and progression of the disease could enhance the differential diagnosis accuracy for neurodegenerative diseases.
To our knowledge, our study is the first using jICA for the joint analysis of structural and perfusion-weighted MRI data. Furthermore, we incorporated jICA into a framework of integrated multimodality MR image-processing. The present study demonstrates that more information for the characterization and classification of behavioral variant frontotemporal dementia can be gained with this new approach. The application of jICA of multimodality imaging data is not limited to classification problems but can also be employed in principle to regression issues, such as identifying the correlates between structural and physiological changes and clinical and cognitive measures such as socioemotional or cognitive abilities.
The present study has several limitations. First, behavioral variant frontotemporal dementia was identified by clinical diagnosis but was not autopsy-confirmed. Therefore, to the extent that the diagnosis was inaccurate, the structural and physiological features from multimodality jICA may reflect other pathologies than behavioral variant frontotemporal dementia. We have autopsy confirmed pathology for three of the behavioral variant frontotemporal dementia patients. An additional five of the patients, plus another one who also had behavioral variant frontotemporal dementia confirmed by autopsy, went through PiB-PET imaging and had amyloid-negative results, implying no Alzheimer's disease pathology. In addition, two of these amyloid-negative behavioral variant frontotemporal dementia patients had lumbar Tau/Aβ ratio of 0.2 and 0.36, which do not fall into the Alzheimer's disease range. Although we cannot warrant that no Alzheimer's pathology was involved, 8 out of 12 behavioral variant frontotemporal dementia patients had no signs of Alzheimer's disease pathology and therefore our observations cannot be explained by presence of Alzheimer's disease alone. Second, the behavioral variant frontotemporal dementia patient sample is relatively small owing to difficulties in recruiting these patients, who often have behavioral and emotional disturbances, and compliance issues with participating in MRI. Therefore, generalization of our findings is limited. Further studies, including more subjects as well as behavioral variant frontotemporal dementia patients with a greater range of cognitive deficits, are warranted to validate the findings. There are additional study limitations related to the jICA technique. The current framework assumes that both image voxels and measures from each modality (i.e., Jac-map and rCBF*) are independent and identically distributed. A priori spatial correlation information and flexible distribution for each imaging measure could be incorporated to multimodality jICA to further improve the detection of multimodality imaging signatures. The inherent spatial smoothness of the data due to the point spread function of MRI, as well as the Gaussian kernel-based smoothing used for image processing introduce spurious dependencies among the samples, thereby violating to some extent the rules of component selection that are based on the assumption of independent and identically distributed samples. Thus, both smoothing factors may have caused an overestimation of the number of independent components and therefore the results should be interpreted with caution. Another study limitation is that rCBF* measurements with cASL-MRI are susceptible to age-related variations in physiological conditions, such as arterial transit delays, altered T1 relaxation, and bolus dispersion, which are complicated to account for. In particular, age associated changes in relaxation times of blood water (Cho et al., 1997
) and prolonged arterial transit time has been observed in behavioral variant frontotemporal dementia patients (Hunter et al., 1989
). Therefore, we cannot rule out that some variations in rCBF* are simply measurement artifacts that are unrelated to differences in brain function between behavioral variant frontotemporal dementia patients and controls. In addition, nine out of 12 behavioral variant frontotemporal dementia patients were receiving various drugs known to impact the cardiovascular system. Due to the small sample size of this study and limited statistical power, we couldn't control for effects of medication on arterial blood flow. Furthermore, in integrated multimodality MR image processing, the accuracy of the intra-subject inter-modality co-registration is limited since cASL-MRI is more prone to geometric distortion and imaging artifacts compared to structural MRI. The partial volume correction and anatomical localization in rCBF* measure is also limited by the differences in point spread function of structural and perfusion-weighted MRIs. In addition, structural spatial normalization accuracy and consequently accurate partial-volume correction might be compromised in behavioral variant frontotemporal dementia patients as a result of averaging across dissimilar structures. Thus, changes in brain morphology may have biased rCBF* measurements. Taken together, errors in image registration and localization may result in diminished power to detect intrinsic relationships between structural and physiological alterations in behavioral variant frontotemporal dementia at a local level. Lastly, this study was cross-sectional and cannot conclusively establish causality between structural and physiological alterations. Longitudinal studies will be necessary to further understand the synergistic effects of anatomical and physiological changes in behavioral variant frontotemporal dementia patients.
Despite these limitations, our results specifically demonstrate the benefit of jICA of multimodality MRI and to enhance the description of pathophysiological changes in neurodegenerative disease, which may ultimately lead to improved diagnostic methods. Beyond the study of neurodegenerative diseases, integrated multimodality image analysis methods could be useful in the evaluation of other brain disorders as well as pathology in other body systems.