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High-resolution Fluid-suppressed Diffusion Tractography Shows Altered Fornix Volume and Diffusion Metrics in Pediatric Multiple Sclerosis
Carly Weber1, Colin Wilbur2, and Christian Beaulieu1,3
1Biomedical Engineering, University of Alberta, Edmonton, AB, Canada, 2Pediatric Neurology, University of Alberta, Edmonton, AB, Canada, 3Radiology and Diagnostic Imaging, University of Alberta, Edmonton, AB, Canada

Synopsis

Keywords: Tractography, White Matter, microstructure, brain, adolescents, MS

Motivation: It is unknown if the fornix (main output tract of the hippocampus) is affected in pediatric multiple sclerosis (MS), which would suggest its early involvement.

Goal(s): Are the volume and diffusion metrics of the fornix affected in pediatric MS as it is in adult MS, and does fornix injury precede damage to the hippocampus?

Approach: Fornix diffusion tensor imaging and whole-brain MPRAGE were acquired from pediatric MS patients and controls. The fornix was identified with tractography.

Results: Pediatric MS showed a much (29%) smaller fornix with abnormal diffusion metrics indicative of early injury, but had no difference in hippocampus volume, compared to controls.

Impact: Diffusion tractography identifies marked injury to the fornix, a small white matter tract important for cognition, in children and adolescents with multiple sclerosis, while the hippocampus volume is unaffected, implicating the fornix as an early brain target in this disease.

Introduction

The fornix is a small white matter tract that interconnects the hippocampus and other structures of the limbic system, playing an important role in episodic memory and other cognitive functions1,2. Diffusion tensor imaging (DTI) has shown lower volume and altered diffusion metrics of the fornix in adults with multiple sclerosis (MS)3-7. The fornix is difficult to identify and measure with diffusion tractography, but it can be improved by using high-resolution fluid-attenuated inversion recovery (FLAIR) DTI which suppresses confounding cerebrospinal fluid (CSF)8. FLAIR-DTI showed marked abnormalities of the fornix in adult MS, which were greater than losses in white or gray matter volume and were most affected in those with cognitive impairment9. DTI of pediatric-onset MS (POMS) individuals scanned as children/adolescents have identified altered diffusion metrics in normal-appearing white matter10-13. Only one POMS study mentioned the fornix with elevated mean diffusivity (MD)12, but it used low spatial resolution and a voxel-based analysis not ideal for this structure14. The goal here was to use CSF-suppressed, high-resolution FLAIR-DTI tractography to determine if the fornix is affected in POMS, which would provide evidence for its early involvement.

Methods

Participants were scanned on a 3T Siemens Prisma with a 64 channel head/neck RF coil and included POMS (n=5, all female, all RRMS, age=16.2±1.9 years, age range=13-19 years, EDSS=1.5±1.3, total lesion volume=11.8±9.7 cm3, time since diagnosis=2.5±1.5 years), as well as controls (n=9, all female, age=16.7±4.0 years, age range=13-19 years). The FLAIR-DTI protocol was the same as used in a previous adult MS study9: 2D single-shot EPI, 35 2 mm transverse slices centered for fornix coverage, 1.2x1.2 mm2 zero-filled to 0.6x0.6 mm2 in-plane resolution, GRAPPA R=2, phase partial Fourier 6/8, TI 2300 ms, TR 9000 ms, TE 70 ms, 5 b=0 and 20 b=1000 s/mm2, total scan time 4.2 minutes. A 0.9 mm isotropic 3D T1-weighted MPRAGE scan of the whole brain was acquired in 3.7 min. DTI processing and deterministic tractography of the fornix (FA threshold 0.15, maximum turning angle 65°, step size 0.64 mm, minimum fiber length 10 mm)9 was performed in MRtrix3. This tract yielded a whole fornix volume, as well as average fractional anisotropy (FA), MD, axial (AD) and radial diffusivity (RD) with left and right sides combined. Hippocampus volume (sum of left and right) was measured using volBrain on the 3D T1-weighted images. These metrics were compared between POMS and controls using a two-sample unpaired t-test (p<0.05).

Results

Tractography using high-resolution and CSF suppression depicted the full fornix in all 5 POMS and 9 control participants, showing visibly thinner fornix with bilateral regions of lower FA and elevated diffusivities (MD, AD, RD) along the crus and body in POMS (Figure 1). Relative to controls, the fornix in POMS had 29% lower volume (3.1±0.2 vs 2.4±0.3 cm3, p=0.0002), 7% lower FA (0.45±0.01 vs 0.42±0.03, p=0.01), 11% higher MD (1.05±0.05 vs 1.16±0.05 x10-3 mm2/s, p=0.002), 6% higher AD (1.63±0.05 vs 1.73±0.09 x10-3 mm2/s, p=0.015) and 15% higher RD (0.76±0.04 vs 0.87±0.05 x10-3 mm2/s, p=0.001) (Figure 2A-E). However, hippocampus volume was not significantly different (controls 7.9±0.8 vs POMS 7.5±0.9 cm3, p=0.43) (Figure 2F).

Discussion and Conclusions

Tractography enables the virtual identification of the fornix, which can be used to output volume, something not possible in voxel-based DTI analyses. This identified that the fornix volume was markedly reduced by 29% in POMS children/adolescents, which is comparable to the 26% volume reduction in adult MS using the same high-resolution, FLAIR-DTI protocol9. Fornix DTI metrics in POMS were also similarly affected relative to controls as in the previously published adult MS study using the same protocol: FA -7% vs -7%, MD +11% vs +9%, AD +6% vs +6%, and RD +15% vs +12%9. The largest percent change in RD of the fornix is suggestive of demyelination and axonal loss15. The fornix may be especially susceptible to injury in MS as it is a small tract bathed in CSF that may contain soluble inflammatory factors16. The observation that the fornix is affected early on in POMS, but the hippocampus volume is not different between POMS and controls (similar to adult MS9) supports the hypothesis that white matter injury precedes damage to connected gray matter17. The limited sample size of 5 POMS prevented the assessment of correlations with cognitive or clinical disability. CSF-suppressed, high-resolution FLAIR-DTI has identified fornix injury as an early hallmark of MS.

Acknowledgements

No acknowledgement found.

References

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Figures

Figure 1. Examples of FLAIR-DTI fornix tractography (as seen from superior view) in a 16 year old female control and a 16 year old pediatric onset multiple sclerosis (POMS) participant. The fornix in POMS appears thinner and has a 29% smaller overall volume compared to the age/sex matched control. Further, the fornix in POMS shows bilateral regions with lower FA and higher MD, AD, and RD.

Figure 2. Group comparisons of controls (n=9) and POMS (n=5) are shown for entire fornix (Fx) (A) volume, (B) FA, (C) MD, (D) AD, and (E) RD, as well as (F) hippocampus volume (sum of left and right). The POMS group showed a much smaller volume (29%) as the largest change in the fornix, in addition to significant differences in FA (7% reduction), MD (11% increase), AD (6% increase), and RD (15% increase). In contrast, the volume of the hippocampus was not different in POMS.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
0117
DOI: https://doi.org/10.58530/2024/0117