The main finding of this study is that FTD was associated with discordant cortical atrophy in absence of significant reduction of perfusion in premotor areas whereas concordant alterations of cortical atrophy and hypoperfusion occurred predominantly in the right prefrontal cortex and bilaterally in the medial frontal lobe. The new finding in this study is the detection of concordance/discordance regions between hypoperfusion and GM atrophy in patients with FTD, compared to a previous report involving largely the same patients that showed only hypoperfusion. In addition, tests of cortical atrophy and hypoperfusion in FTD when conducted separately indicated widespread atrophy involving large aspects of the lateral and medial frontal lobe bilaterally and hypoperfusion in the medial frontal and right prefrontal cortex, consistent with previous imaging reports (Broe et al. 2003
; Diehl et al. 2004
; Du et al. 2007
; Gee et al. 2003
; Grimmer et al. 2004
; Grossman et al. 2004
; Ishii et al. 1998
; Jeong et al. 2005
; McMurtray et al. 2006
; Pickut et al. 1997
; Rosen et al. 2002
; Salmon et al. 2003
; Whitwell and Jack 2005
; Whitwell et al. 2005
We interpret the finding of discordant brain atrophy in absence of hypoperfusion in the premotor cortex as indication of brain tissue that is still functioning and connected in FTD, though other explanations are possible: First, loss of brain tissue other than neurons might contribute disproportionately to atrophy while surviving neurons still function normally as reflected by normal levels of perfusion. Indeed, some histopathological studies suggest that earliest cellular changes in FTD occur in astrocytes without frank neuron loss whereas neuronal damage is found in later stages of the disease (Broe et al. 2004
; Kersaitis et al. 2004
). This view is also supported by clinical observations that many patients with FTD do not have motor symptoms, despite apparent atrophy of the premotor cortex. Discordant MRI perfusion in presence of brain atrophy might provide an index for the condition of motor neurons in FTD which atrophy alone cannot provide. The recruited patients with FTD were all mild to moderate stage and accounting for disease severity, e.g. using MMSE, did not significantly alter the results. However, given the small number of subjects and limited power, we cannot exclude that the results might change for patients at a more advanced stage of FTLD. Further studies permitting concurrent assessment of structural and function alterations in FTD are necessary to test this conjecture.
Second, it is also possible that we lacked power with ASL-MRI to measure small alterations in hypoperfusion in presence of GM atrophy. A conservative power analysis of our data based on previous reliability tests (Jahng et al. 2005
) suggests that the minimum difference in perfusion we can expect to detect with 28 patients and controls and 80% power (alpha
0.05) is about 20%. In comparison, the minimum difference in atrophy that we can detect at the same level of power and significance is 1.5%. This may also explain why we did not observe significant discordance between hypoperfusion without GM atrophy in FTD. In another study involving AD, however, we found regions with significant hypoperfusion in absence of atrophy, indicating that it is principally possible to measure discordant alterations between atrophy and perfusion with our method. Another issue that suggests technology rather than biological effects explains discrepancies between structural and perfusion findings are the typical observation of higher SNR of the perfusion signal from the frontal cortex, where regions are more adjacent to one another, compared to SNR of the perfusion signal from parietal brain regions. Hence, differences will be more datable in frontal than parietal brain regions. We also found concordant reductions of GM volume and perfusion in the right prefrontal cortex and bilateral medial frontal lobe, regions that have been consistently implicated in the pathology of FTD. Since the perfusion data were corrected for CSF and GM/WM tissue variations, the concurrent reductions in perfusion and GM volume cannot be explained simply as an artifact of partial volume effects. One possible explanation for concordant atrophy and hypoperfusion is that the remaining brain tissue is already damaged as indicated by reduced perfusion. It is interesting that the regions showing concurrent atrophy and hypoperfusion involved the right prefrontal cortex and bilaterally the medial frontal lobe. These regions are considered particularly vulnerable to FTD, as indicated in previous imaging studies (Broe et al. 2003
). In addition, we found that concordance regions in the predominant right frontal lobe. It is consistent with several studies (Ishii et al. 1998
; McMurtray et al. 2006
; Du et al. 2006
) that showed hypoperfusion and hypometabolism in the predominant right frontal lobe. The clinical significance of the metabolic and perfusion asymmetry is unknown. One possible explanation may be caused by sampling bias. Left-dominant patients can show language disturbances even in early stages. Thus, it is more likely that these patients are brought to neurology clinics. On the other hand, right-dominant patients may present predominantly with behavioral or psychiatric abnormalities, and so are first seen as psychiatric abnormalities, and potentially are misdiagnosed as having psychiatric illnesses. It should be noted that the equivalence between structural MRI and functional imaging, i.e. FDG-PET, in FTD has been seen in multiple studies of the two techniques independently but also in studies comparing the two modalities (Kanda et al. 2008
; Kipps et al. 2009
). Therefore, our findings of concordance, which agree with these previous studies, are not surprising. Nonetheless, the results support the equivalence between ASL measured hypoperfusion and PET measured hypometabolism in FTD.
The image analysis approach used in this report was previously employed to explore the concordance/discordance between structural and perfusion changes in patients with AD and mild cognitive impairment (Hayasaka et al. 2006
). Our results demonstrate that the same concept applied to FTD provides new information, not available from testing each modality separately. The method could potentially be used to explore the relationship between various other imaging modalities, including PET and SPECT, in FTD and other neurodegenerative diseases.
Several limitations in our study ought to be mentioned. First, the patients were diagnosed clinically, without autopsy confirmation of FTD. Thus, it is possible that some of patients with FTD had other causes of dementia. Studies involving brain autopsies are needed to confirm that our findings are related to FTD pathology. The small number of patients limits power to detect significant differences in perfusion and generalization of the findings. Further studies including a larger number of patients are warranted to confirm the findings. A technical limitation is that this implementation of ASL-MRI in conjunction with the short lifetime of spin labels at 1.5 T did not permit covering more brain regions, especially the temporal lobes, which are also susceptible to FTD. Therefore, we may have missed other prominent regions with atrophy and hypoperfusion in FTD. Lack of perfusion data from the ventral prefrontal cortex and most of the temporal lobes limit, which both can be highly impacted in FTLD, limit the conclusions in this study. New volumetric ASL-MRI methods (Fernández-Seara et al. 2005
; Günther et al. 2005
) can provide more brain coverage, including the temporal lobe, especially when performed at a higher magnetic field strength than 1.5 T. Finally, another technical limitation is that the choice of combining functions is somewhat arbitrary and subjective and different choices for combining functions might alter the outcome. However, the sensitivity and robustness of the combining functions can be evaluated by simulations and permutation tests as we previously showed (Hayasaka and Nichols 2004
). In addition, the functions we chose here are identical to those we used in previous studies of Alzheimer’s disease (Hayasaka et al. 2006
) and brain aging (Zhang et al. 2008
). Another limitation is that our concordance/discordance analysis is constraint to an analysis at the group level while examinations at the single subject level might be even more informative. In theory, a potential solution to this is performing the concordance/discordance analysis using each subject’s regional z-scores (deviation from the normal mean) rather than t-scores from the group comparison, supplemented by an appropriate statistic that takes both between group and across subject variations into account.
In summary, we found concordant hypoperfusion and brain atrophy in the right prefrontal cortex and bilateral medial frontal lobe in FTD as well as discordant atrophy without significant hypoperfusion in premotor regions. These results suggest that damage of brain function in FTD may vary regionally despite widespread atrophy. Detection of discordance between brain perfusion and structure in FTD might aid diagnosis and staging of the disease.