Identifying Delay in Glymphatic Clearance of Labeled Protons Post-Acute Head Trauma Utilizing 3D ASL MRI (Arterial Spin Labeling): a Pilot Study

doi:10.21203/rs.3.pex-2581/v1

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Identifying Delay in Glymphatic Clearance of Labeled Protons Post-Acute Head Trauma Utilizing 3D ASL MRI (Arterial Spin Labeling): a Pilot Study

https://doi.org/10.21203/rs.3.pex-2581/v1

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Abstract

This study correlated mild traumatic brain injury (mTBI) cognitive changes with ASL-MRI glymphatic clearance rates (GCRs) and recovery with GCR improvement. . mTBI disrupts the blood brain barrier (BBB), reducing capillary mean transit time (cMTT) and GCRs. mTBI is clinically diagnosed utilizing history/examination findings with no physiologic biomarkers.

3D TGSE (turbo-gradient spin-echo) PASL (pulsed arterial spin-labeling) 3T MRI with 7 long TIs (inversion times) assessed the signal clearance of labeled protons 2800-4000 ms postlabeling in bifrontal, bitemporal, and biparietal regions within 7 days of mTBI and once clinically cleared to resume activities. The Sport Concussion Assessment Tool Version 5 (SKAT5) and Brief Oculomotor/Vestibular Assessment evaluated injured athletes’ cognitive function prior to MRIs.

The pilot study demonstrated significant GCRs improvement (95% [CI] -0.06 to -0.03 acute phase; to [CI] - recovery [CI] 0.0772 to -0.0497; P <0.001 in frontal lobes; and parietal lobes (95% [CI] -0.0584 to -0.0251 acute; [CI] -0.0727 to -0.0392 recovery; P = 0.024) in 9 mTBI athletes (8 female, 1 male). Six age/activity-matched controls (4 females, 2 males) were also compared.

mTBI disrupts the BBB, reducing GCR measured using the 3D ASL MRI technique. ASL MRI is a potential noninvasive biomarker of mTBI and subsequent recovery.

Introduction

Traumatic brain injury (TBI) is a major worldwide health concern affecting an estimated 369 per 100,000 people. ^1-3. Ninety percent of injuries are mild (mTBI), defined as a Glasgow Coma Scale score of 13-15/15. Sports-related injuries account for an estimated 17% of injuries; however, the number of cases is underestimated, as the epidemiologic data are derived from hospital admissions, excluding those managed conservatively ⁴. All-cause and severity indirect and direct TBI costs were estimated to be $93 billion in 2019 in the US alone, not including lost wages and unemployment. The latter predominantly affects those with moderate or severe TBI ³. The sequelae after even mild injury may include overt or subtle emotional, cognitive, and endocrinologic dysfunction ^5,6.

The diagnosis of sports-related acute mild TBI (mTBI) is reliant on cognitive and physical exam inventories such as the Sport Concussion Assessment Tool, 5th edition (SKAT5) obtained at the time of injury, and Vestibular Ocular Motor Screening (VOMS) ^7,8. If these tests are positive for a concussive injury, athletes are held out of related activity until symptoms abate and the above tests revert to baseline. Routine CT brain and anatomic MRI imaging studies are typically normal, ruling out structural injury in the vast majority of patients with mTBI but are of little value in addressing the altered physiology due to damaged blood brain barrier (BBB) ^9-10. The measurable physiological effect on BBB integrity of mild TBI in humans can be studied directly looking for presence of leaked contrast agents or indirectly by assessing perfusion and flow dynamics. Dynamic contrast enhancement (DCE) employs gadolinium contrast directly assessing BBB leak ^13,15 . Given the potential for contrast deposition within the nervous system with unknown long-term consequences, the technique is not suitable for multiple repeat studies. MRI diffusion tensor imaging (DTI) is sensitive to BBB fluid dynamics but is limited by long scan times of 1-2 hours ^10-12. Functional MRI (fMRI) measuring regional changes in O₂ utilization is an indirect measure of perfusion alterations post TBI but is limited by cost and long scan times, which make routine usage impractical ^11-15.

Our approach is to assess perfusion changes resulting from blood brain barrier (BBB) leakage inherent to acute TBI and determine if there is subsequent repair correlating with clinical recovery using noninvasive 3D ASL MRI ¹⁶ BBB leakage is a direct result of blunt force injury and subsequent inflammatory changes that may develop ^16-21. The result is local alteration in the normal vascular perfusion affecting the capillary mean transit times (cMTT), which is the measure of time blood flows through the capillaries in a given brain region ²². Glymphatic outflow is also directly reduced by BBB injury ¹⁶. The net affect is delay in inflow of capillary blood with leakage of fluid which is then trapped .

The concept of glymphatic clearance rate (GCR) measures the time-dependent slope of the reduction in labeled proton signal in the late capillary phase of perfusion²³[figure 1]. The constituent labeled proton signal in the late perfusion phase is from both labeled blood inflowing during the capillary mean transit time (cMTT) and the presence of residual labeled free fluid present in the interstitium by diffusion. Reduced GCRs (post-BBB injury) are caused by delayed cMTT and increased labeled free fluid trapped in the interstitium due to both BBB injury related leak and consequent reduced glymphatic outflow^10,16,17,22. Simply put blood is slow to arrive, leaks in and cannot get out . Blood brain barrier leak results in delayed cMTT and disruption of glymphatic flow, both of which are demonstrable in the latter portion of the perfusion cycle by ASL MRI. Measuring the signal average of labeled protons within a region of interest (ROI) within the brain parenchyma can be graphed versus time. Using linear analysis, the slope of the signal strength over time is the GCRs which is normally negative (fluid flow out) but is flat or slightly positive in BBB injury (retained fluid) ^10,16,17,22. White matter fluid flow is delayed regionally by BBB leak to a greater extent than in associated gray matter ^12,25. 3D ASL MRI is a noninvasive and available sequence on most 3T and above MRI scanners. By labeling protons in the neck, endogenous contrast is produced, and the signal can be measured at selected delay times (TI) post labeling (PLD) during the perfusion cycle ^25-29. By choosing long delay times at 2800-4000 ms, only the residual labeled protons from the delayed capillary phase of perfusion and free fluid are measured in the region of interest (ROI) [fig 1]. The ROI, although hand drawn, encompasses a large region whose volume and shape are held constant, with the same slice chosen for each of the 7 determinations. Blood brain barrier leakage results in reduced GCRs compared to normal GCRs. The GCR reduction is not specific for head injury but occurs in any disease process damaging the BBB, such as Alzheimer’s disease ^{22, 29-33}. By using this approach in a pilot study, we found reduced labeled proton clearance rates in subjects with Alzheimer’s disease (where BBB leak develops early in the process) compared to normal age-matched control subjects ²⁷. Given the presence of BBB leakage in mTBI, the possibility of extrapolating the ASL MRI technique was explored. The short scan time of under 20 minutes, low cost, and low safety risk (no gadolinium contrast) make this a potentially attractive diagnostic biomarker to investigate.

Seimens 3T Magnatom Skyra

3D TGSE PASL MRI sequences:

Our ASL sequences include: FOV 256X256, FOV phase 100%; TR 3830ms; TE 16.40ms; and TI 2800, 3000, 3200, 3400, 3600, 3800, 4000ms. Additional parameters are TE 16.4 ms. (all sequences), TR 3830 with inversion time (TI) 2800; 3200; 3400; 3600; 3800; TR 4100 for inversion time TIs 4000. Acquisition time 2 minutes, 10 seconds per sequence except for the TI of 4000 with a scan time of 2 minutes, 19 seconds. Matrix 64X64X40; Averages 1 concatenations 1; Segments 16; Four averages (pairs); Bolus labeling 700 ms, FOV 256 mm × 256 mm. Post-inversion image acquisition time was 350 ms. Bolus labeling duration was 700 ms. Turbo factor was 12, and EPI factor was 21. Q2TIPS and vendor-supplied proprietary background suppression were used. A bandwidth of 2368/pixel and echo spacing of 0.57 ms were employed. Interleaved 40–4 mm image slices were obtained per sequence and voxel size was 2 X 2 X 5.5 mm3. Additional factors include distance factor 50%, Base resolution 64, Phase resolution 98%, and FoV phase 100%.

Flair Sequence:

The flair sequence is TR 9000ms; TE 84ms; TI 2500; TI 2500ms; Pixel volume 0.7 X 0.7 X 4 mm3

Slice 4mm interleaved, Fat Sat strong Scan time 3:20.

The total scan time was 18½ minutes. The 3D images were then formatted into 4 mm contiguous axial slices from which a single slice at the same level of all ASL sequences was chosen from the index flair axial sequence. Postprocessing was completed using position locked Perfusion and Flair images transferred to PACS and selected images were studied using the elliptical ROI tool (PACS). A slice-specific constant volume and location for each brain region were studied (4 mm axial slices). The bilateral homologous temporal lobes ROI was 650 mm²individually obtained just above the temporal horn for all subjects. The bilateral homologous frontal lobes ROI was 1150 mm² individually just above the lateral ventricles. The bilateral homologous parietal lobes ROI was 760 mm² individually at the same level as the frontal lobe ROI but posterior to it (Figure 2). By choosing a large ROI in each brain region and avoiding subarachnoid and ventricular spaces, we reduced potential sources of error related to contamination with extra parenchymal fluid and signal voxel-to-voxel signal variability. Signal averages were transferred to a spreadsheet and graphed vs time (Figure 3). Since the data collection occurs in the late phase of the perfusion cycle (egress of blood and fluid), a close approximation by linear analysis can be applied with the slope of the line corresponding to the clearance of labeled protons ^14,23. The acute injury and recovery results were then pooled and compared statistically. All subjects were scanned in the midafternoon to early evening hours and had withheld alcohol and caffeine for the preceding three hours before their study

Total overall scan time was 18minutes, 30 seconds.

Given the late phase of perfusion utilized, one can use linear analysis to determine the rate of signal clearance which is prolonged with BBB leak and is restored with time and corresponds to clinical recovery.

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Identifying Delay in Glymphatic Clearance of Labeled Protons Post-Acute Head Trauma Utilizing 3D ASL MRI (Arterial Spin Labeling): a Pilot Study

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Identifying Delay in Glymphatic Clearance of Labeled Protons Post-Acute Head Trauma Utilizing 3D ASL MRI (Arterial Spin Labeling): a Pilot Study

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References

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