This study examined the relationship between MRI measures including hippocampal volume and fornix and posterior cingulum (PC) white matter integrity, their relation to memory, and their predictive value for cognitive decline and progression from aMCI to AD dementia. Cross-sectionally, fornix white matter integrity (FA, MD, DA, and DR) correlated more strongly with memory performance than the hippocampal/ICV ratio or PC white matter integrity. Longitudinally, both fornix FA and hippocampal/ICV ratio were predictive of decline in memory performance and progression from MCI to AD dementia over 2.5 yrs. Fornix white matter integrity (FA, MD, DA, and DR) was as good as the hippocampal volume in predicting progression from MCI to dementia. Since the fornix (FA, DA and DR) also cross-sectionally correlated with memory performance, the fornix may be a better correlate of early disease progression, and a clinically useful biomarker. Additional studies with larger sample sizes are warranted to confirm these results.
The disruption of white matter, including axonal and dendritic integrity, occurs early in the AD process, and has been demonstrated in both animal and in vivo
human studies [37
]. One evolving hypothesis is that disruption of white matter tracts reflects the susceptibility of late-myelinating regions to the effects of aging and AD. These white matter changes make individuals particularly vulnerable to the clinical manifestations of AD [39
] and occur before neuronal degradation and atrophy are detectable. DTI was developed to measure the integrity of white matter fiber bundles in the nervous system [40
]. It is thought to be especially sensitive to microstructural alterations in nerve fibers [42
], and a sensitive early indicator of Alzheimer pathology [43
]. There are multiple indices that can be measured with DTI. FA is a measure of anisotropic water diffusion and reflects the degree of directionality of cellular structures within the fiber tracts and, therefore, the structural integrity of tracts [44
]. MD, a measure of randomized mean water diffusion, represents a loss of barriers restricting the water motion, partial breakdown of tissue cytoarchitecture [44
] or demyelinating processes [39
]. However, FA and MD alterations could be due to changes of diffusion either parallel or perpendicular to the principal direction of the tensor. Thus, in the present study we also examined DA and DR. Axial diffusivity (DA) is a measure of parallel diffusivity and is thought to be an indicator of axonal damage while radial diffusivity (DR) is a measure of perpendicular diffusivity and thought to be an indicator of myelin breakdown [45
Previous DTI studies using the ROI approach have focused on hippocampal or posterior cingulum FA, MD, or apparent diffusion coefficient (ADC) (e.g. [46
]. These studies suggest that hippocampal MD and ADC is higher, and FA lower, in MCI cases compared to cognitively normal controls. One study that compared hippocampal volumetry and DTI measures reported poor correlation between the volumetry and DTI measures [48
], and that left hippocampal MD was the strongest independent correlate of poor verbal memory performance and also best separated MCI cases from normal controls. Another study reported higher hippocampal ADC values in MCI cases who converted to AD dementia compared to those who did not convert over two years [49
In contrast to these studies, we focused directly on the fornix, the predominant outflow tract of the hippocampus that connects it with the septal nuclei and mamillary bodies in the hypothalamus. The posterior fornix fibers further connect to anterior thalamic nuclei and to cingulate cortex. Prior studies have demonstrated that limbic projections and pathways (e.g. fornix) connecting to the frontal lobes are preferentially affected early in the course of AD [39
]. An initial study examining the fornix in PS1 and PS2 mutation carriers reported that, compared to non-carriers, presymptomatic mutation carriers had significantly reduced fornix FA [17
]. While the cingulum bundle FA was also reduced in the presymptomatic carriers, this finding was not significant, suggesting the fornix may be a more sensitive, early pathological marker. Our results, among MCI cases, are congruent with this finding such that the fornix, but not the PC, correlated cross-sectionally with memory performance, and predicted longitudinal decline in memory and progression to AD. While the PC MD and DR were predictive of memory decline, the fornix was a much better predictor of clinical conversion to AD dementia and is likely a more useful correlate of disease progression.
As mentioned, the majority of DTI studies to date have primarily reported on FA and MD. Of those using a ROI approach, FA has been the most sensitive [18
] although another study reported that MD was more sensitive [46
]. It has been suggested that ROI-based approaches may inflate the significance of FA over MD [52
]. Indeed, a recent cross-sectional voxel-wise analysis of 25 AD patients and 13 elderly controls using tract-based spatial statistics reported alterations in diffusivity (MD, DA and DR) were more significant and more sensitive than FA in temporo-parietal white matter, posterior cingulum, splenium and fornix [52
]. However, another recent cross-sectional study, using an atlas-based tractography approach, of 25 AD patients, 19 MCI, and 15 cognitively normal controls reported group differences that varied by DTI measurement and tract [53
]. FA was significantly different among groups only in the fornix; DA and MD in all white matter tracts except the fornix; and DR was altered in the fornix and interior longitudinal fasciculus. These data suggest that the sensitivity of the DTI measurements may vary by region and tract of interest.
In the present ROI-based study of participants with MCI, we also examined DA and DR in addition to FA and MD. While DA and DR were more strongly associated with cognitive performance cross-sectionally (), fornix FA and MD were more strongly predictive of longitudinal decline. Thus, it is also possible that the sensitivity of each DTI measures varies by diagnostic group and over time. Ultimately, a longitudinal study of normal controls, MCI and AD participants using various approaches (ROI-based, voxel-based and tract-based) are needed to better understand these conflicting results and to determine the relationship of the methodology to any differences in findings between FA, MD, DA and DR. This is particularly important in further understanding the pathology of AD in terms of whether damage to white matter is due to secondary degeneration or primary myelin damage [45
Limitations of this study warrant consideration. First, while the expected percentage (10–15%/year) of individuals with MCI converted to AD, the overall sample size was small. Second, a possible confounder in this study is that atrophy of the fornix could also contribute to decreased FA. The smaller the fornix, the more CSF could be included in a given voxel size. Since CSF has FA near 0, the partial volume effect of increased CSF in a voxel would cause the mean FA within that voxel to be decreased. While we cannot completely eliminate the partial volume effect, we did use high-resolution MPRAGE and Large Deformation Diffeomorphic Metric Mapping (LDDMM) analysis, in an attempt to reduce the likelihood of this problem.
A recently-published phase I clinical trial evaluating the effects of fornix deep brain stimulation (F-DBS) in AD patients supports the relevance of the fornix to the pathophysiology of AD [54
]. Thus, this biomarker could be a useful measure to enrich a clinical trial with those most likely to progress.