Synopsis

Impaired white matter (WM) integrity is common in Alzheimer's disease (AD), in addition to gray matter degeneration. While fMRI has been widely used in understanding the disease-associated changes, results so far have omitted the WM even though WM activation has repeatedly been reported in healthy younger adults in recent fMRI studies. Here we applied three tasks targeting interhemispheric transfer at 3.0T to extend the WM fMRI research to clinical applications in AD-dementia. The study detected fMRI activation in the corpus callosal WM in 87% individuals with early AD and normal cognitive aging (NC), and a difference between AD and NC.

Purpose

1) To detect functional MRI activation in brain's white matter (WM) for individuals with early Alzheimer's disease (AD) and normal cognition (NC).

2) To investigate potential differences in the corpus callosal WM fMRI activation between subjects with AD and NC.

Methods

Subjects: Thirty-five older adults participated in the study, including patients who were newly diagnosed as having probable or possible AD (n=10; age=74.2±4.3; women=40%; Table 1) and cognitively normal (n=25; age=70.4±5.2; women=44%; Table 1). Participants were screened to exclude any neurological and psychological conditions other than the target ones.

MRI data acquisition: Imaging data were acquired using a 3.0T whole body system (SignaHDx, General Electric), equipped with an 8-channel head coil. Blood oxygen level dependent (BOLD) fMRI data were acquired using a GRE-EPI sequence (TR=2000ms, TE=30ms, flip angle=90°). Total FOV=224mm×224mm×153mm; 34 axial slices covering the entire brain (matrix=64x64; thickness=4mm, gap=0.5mm). A high-resolution whole brain anatomical T1-weighted imaging was acquired for co-registration (3D-BRAVO; TR/TE=3000ms/min-full, flip angel=13°). FOV=270mm×270 mm, matrix=256×256, with 195 contiguous 1mm slices.

Experiments: During the fMRI session, participants performed three tasks (Figure 1), which targeted the detection of corpus callosal WM activity during information processing and involved lateralized stimulus presentation to elicit inter-hemispheric transfer across the corpus callosum.^1-3 The tasks used a block design and were performed in a counter-balanced order by the participants (Figure 1).

Data analysis: Standard pre-processing including motion correction, high-pass filtering (100Hz), spatial smoothing (5mm) used FMRIB Software Library 5.0.9.⁴ Whole brain activation was examined using a general linear model fitted with a double-gamma hemodynamic response function to predict brain activities in response to the task onset and duration. Individual functional data were registered to structural images and MNI152 space using FLIRT and FNIRT⁵ for the group mean and the between-group contrast maps. Activation threshold was set at Z>2.3 (p=0.05, cluster corrected).

Results

Widespread whole brain fMRI activations were observed in both the NC and AD groups (Figure 2). The activation topography and extent differed across tasks (p<0.05; Figure 2).

Activations in the corpus callosum were seen in the majority of NC (90%) and AD (87%) individuals (Table 2, Figure 3). WM activation clusters differed by task: while all tasks tended to involve the corpus callosum body, the first two tasks also frequently activated the splenium of corpus callosum.

AD patients showed decreased activation across both the genu and the body of the corpus callosum (30% vs. 72%, p<0.01), especially under Task 2, No participant with AD showed activation in the genu of corpus callosum with any task.

Discussion

The results suggested: 1) the whole brain GM fMRI activation was quite consistent with previous reports, as was the difference between AD and normal aging in the GM;^6-8 2) Corpus callosum activation was commonly found in both AD and NC individuals (87%), as previously suggested for healthy younger adults; ^1-2,9-12 and 3) there were less WM clusters in AD relative to NC, particularly in the genus of the corpus callosum. The study provided the initial results demonstrating functional WM impairment in AD using fMRI.

Deterioration of WM integrity, in addition to GM atrophy, has been widely reported for people with AD or those at high risk, associated with chronic ischemia and amyloid accumulation and characterized by multiple neuropathological changes.^13-15 Many of these changes can alter the task related oxygen energy demands, on which BOLD fMRI signal is based and thus detectable using fMRI.¹⁶ Our findings support the hypothesis and suggest that further AD fMRI studies should take WM activation into account.

It is worth noting that fMRI has traditionally excluded the WM, as lower perfusion and scarcity of synapses have caused researchers to discount the possibility of detecting a BOLD response in the WM.^16-18 With increases in both signal-to-noise and contrast-to-noise ratio in fMRI, WM activation has been increasingly noted, ^2,9-12 although these investigations have been restricted to healthy younger people. The current study contributes to the growing WM fMRI research by demonstrating multiple tasks eliciting interhemispheric transfer across corpus callosum in WM fMRI in aging and AD conditions.

Conclusion

Our data provide the first report of WM fMRI in older adults and the initial demonstration of functional impairment of WM integrity in individuals with AD, implying a new avenue to understanding WM changes in AD-dementia. Ongoing studies by our group are testing these preliminary findings at the group level and examining data within several key WM ROIs in a larger sample size.

Acknowledgements

References

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