In this study we investigated differences in CBF between SIVD and AD and further explored if CBF reduction is modulated by subcortical vascular disease as evidenced by white matter lesions. The main findings are: First, SIVD and AD are associated with substantial CBF reductions in both frontal and parietal cortex, irrespective of brain atrophy, gray/white matter partial volumes, and WML. Second, cortical CBF reductions correlate with subcortical vascular disease, consistent with the hypothesis that dementia in SIVD is induced by subcortical-cortical disconnections.
To measure cortical CBF in SIVD and AD irrespective of cortical atrophy and WML, we performed PVE corrections based on a four compartment tissue model to account for variations of CSF, white matter, gray matter, and WML using segmented volumetric MRI data co-registered to ASL-MRI. Although most PET and SPECT studies in SIVD did not account for PVE, some have reported PVE corrections (17
). However, previous PVE corrections were limited to either 2- compartment methods, accounting for diluting effect of CSF spaces or 3-compartment methods, considering partial volume averaging between gray and white matter in addition to CSF spaces, but none included partial volume averaging of WML. We further used bootstrapping to obtain unbiased estimates CBF of cortical gray matter without relying on a normal distribution of regional differences of tissue loss and WML. While our approach aimed eliminating PVE, we sacrificed resolving regional CBF variations within brain lobe since CBF needs to be regressed against many voxels with varying amounts of gray and white matter for robust estimates of CBF of pure gray or white matter. We have previously used a similar approach to obtain PVE corrected MR spectroscopic imaging data in SIVD (44
Our first finding of substantial CBF reductions in frontal and parietal cortex in SIVD is consistent with many PET and SPECT reports of respectively reduced cortical glucose metabolism and CBF reduction in SIVD. Our results further indicate that CBF reduction and gray matter atrophy co-exist in cortical regions in SIVD. A H215
O PET study of CBF patterns in SIVD and AD found regional CBF defects primarily in the frontal cortex in patients with SIVD, whereas AD patients had CBF deficits primarily in temporal and parietal lobe regions (45
). The SIVD patients in our study had substantial CBF reduction in both frontal and parietal cortical regions, potentially indicating mixed pathology. Moreover, the distribution of cortical atrophy in these patients paralleled the distribution of CBF reduction. Our data agree with imaging-autopsy correlation studies showing AD pathology and cerebrovascular disease often coexist (27
An unexpected finding in AD is that CBF reductions in the frontal cortex are similar to those in the parietal cortex. PET and SPECT find metabolic and CBF deficits typically in parietal and temporal regions in AD (4
). In a previous ASL-MRI study in a different cohort of AD patients, we also found CBF reductions primarily in parietal brain regions (25
). However, findings of frontal lobe metabolic and CBF deficits in AD are not uncommon, especially in patients with concomitant psychiatric symptoms, including depression (46
). Four of the 14 AD patients had a history of depression but the number of subjects was too small to determine with reasonable confidence whether those with depression had greater frontal involvement than the other patients. It is also possible that the AD patients presented mixed etiologies, including cerebrovascular disease and amyloid angiopathy, which are common in older AD patients (47
). Eventually, it will be necessary to obtain autopsy information to exclude concurrent cerebrovascular disease and cerebral amyloid angiopathy as potential cause of frontal lobe hypoperfusion in these AD patients.
Our second finding of a strong correlation between decreased frontal lobe CBF and WML agrees with recent PET findings in SIVD (17
). We also found a strong correlation between cortical gray matter loss and WML that involved both frontal and parietal lobe regions. There are several possible interpretations for these findings. First, subcortical infarctions may be responsible – at least in part – for cortical neurodegeneration and secondary reduction of CBF and gray matter loss. A second possibility is that WML represent generalized cerebrovascular disease, possibly causing CBF reduction due to limited blood supply, which then leads secondarily to cortical atrophy. Furthermore, this generalized cerebrovascular disease could be associated with cortical ischemia/infarction, which is not detected by structural MRI (47
). However, the regional frontal effect of WML on cortical CBF in our study may speak against this assumption since cortical microinfarctions are typically symmetrically distributed throughout frontal and posterior cortical regions (47
In contrast to our findings, several other studies failed to detect correlations between WML and cortical glucose metabolism (18
) or blood flow (14
). These studies have used global and in most cases semiquantitative measures of white matter lesions. Moreover, these studies did not account for PVE effects on PET and SPECT measures, which may have increased measurement variability and hence decreased power to detect an effect. These factors should be taken into account when looking for effects of WML on cortical deficits.
Several limitations of the study should be mentioned: We used clinical and not autopsy data for patient classification, although in two cases, one AD and another SIVD, diagnosis has been confirmed. It is generally recognized that an accurate prediction whether a patient has AD or SIVD is difficult to make antemortum. Furthermore, autopsied cases in this SIVD program project study show that many patients diagnosed with SIVD have mixed AD/SIVD pathology (27
). Thus, some SIVD patients in this study may have had concurrent AD pathology, whereas some AD patients had likely vascular disease and may have lacked AD pathology. Another limitation is that some AD patients were taking cholinesterase inhibitors and anticholonegic drugs that could have altered brain function, potentially enhancing CBF differences between AD and SIVD. Another limitation is the small sample size, which limits confidence in the statistical significance of the findings. The findings need to be replicated in a larger cohort of patients. A technical limitation is that we did not control for potential differences of perfusion transit times between the groups to deliver labeled blood water to the imaging plane, which may have increased CBF differences. New technical developments in ASL, including full volumetric acquisitions, can circumvent problems with transit times by measuring the entire inflow dynamics of the ASL signal. Finally, detection of cortical atrophy and WML was compromised, because tissue segmentation involved T2-weighted MR images with relatively low resolution (4.2 mm3
). It is possible that different results would be obtained if tissue segmentation were performed with MRI at higher resolution.
This study is the first using ASL-MRI to investigate regional CBF alterations in SIVD. As such, ASL-MRI yielded strikingly similar findings with those from PET and SPECT. ASL-MRI offers several advantages to PET and SPECT, including higher patient safety since no injection of radioactive tracers is required, greater availability because ASL can be performed on standard clinical MRI scanners. Promising new technical innovations of ASL, such as full volumetric brain coverage at high spatial resolution and with improved sensitivity will greatly facilitate future investigations of regional CBF alterations in AD and vascular dementia (49
). Future investigations with ASL-MRI also need to shed light on the extent to which altered perfusion predicts cognitive decline and dementia. As treatments for AD and vascular brain injury are under development, predictors of cognitive decline and dementia will play an important role for the assessment of effective treatment intervention.