Xiao-Hong Zhu1, Byeong-Yeul Lee1, Katherine Ingram2, Wei Chen1, Robert Doss2,3, and Joseph Petronio2
1CMRR, Department of Radiology, University of Minnesota, Minneapolis, MN, United States, 2Children’s Minnesota Neuroscience Institute, St. Paul, MN, United States, 3Department of Neurology, University of Minnesota,, Minneapolis, MN, United States
Synopsis
Abnormal
changes in brain metabolism and its role in pediatric concussion have not been
well studied. We employed 31P MRS technique at 7T to assess the
neurometabolic alteration in children with concussion. Phosphorous metabolites
concentrations and other key physiological parameters were measured in patient
and control cohorts. Metabolic differences between healthy and concussed brains
were detected at two time points after the injury. We also found that mild head
trauma reduced the age-dependences of high-energy phosphates and NAD contents
in the developing brain, and it took much longer than clinically defined
“recovery time” to fully restore such relationship.
INTRODUCTION
Concussion
is a mild form of traumatic brain injury (TBI). Abnormal changes in cerebral function
are thought to be responsible for the cognitive impairment following concussion
acutely and possibly longer term. Specific markers of neurometabolic
derangement have been reported during post-concussion in adults, but their
manifestations are unknown in children with concussion. 1 In this
study we applied in vivo 31P
MRS technique on 7T human scanner to quantitatively assess an array of metabolic
parameters, including concentrations of major phosphorous compounds, oxidized
and reduced nicotinamide adenine dinucleotide (NAD+ and NADH), 2-3
intracellular pH and NAD redox ratio, in pediatric patients suffered from
concussion. We detected cerebral metabolic changes in the patient at sub-acute
phase as compared to age-matched controls, as well as the changes during
subsequent recovery period after the head injury.METHODS
Study Participants: Ten
pediatric concussion patients (11-17 years old, 9 males and 1 female) were recruited
from the Pediatric Concussion Program or Emergency Department at Children’s MN
with Glasgow Coma Scale (GCS) =13-15, post traumatic amnesia <24 hours, loss
of consciousness <1 minute, and normal head CT/MRI. Their symptoms were
evaluated using Post-Concussion Symptom
Inventory for Parents (PCSI-P). 4 Each patient was scanned
shortly after the initial injury and 4-6 weeks post injury. Six age-matched
children were also recruited as neurologically normal controls (12-15 years
old, 4 males and 2 females) for comparison.
In vivo 31P
MRS measurement and data analysis: The in vivo 31P MRS study was conducted on a 7T/90cm human
scanner (Siemens MAGNETOM) with a 1H/31P (Dia.≈ 5cm) surface
coil probe placed over the occipital lobe. After anatomic imaging and B0
shim, 31P spectra were acquired with following parameters: 300µs
hard pulse for excitation, TR=3s and NT=320. For absolute quantification, 3D-CSI
(FOV=12×12×9cm3, matrix=7×7×5, TR=1.2s, total NT=896) was acquired on
each brain and an ATP phantom. 5 AMARES algorithm 6 in jMRUI software and a homemade Matlab program 2 were used for
analyzing the 31P MRS spectra,
and metabolite concentrations were determined using ATP as an internal standard.
5RESULTS
The intervals between initial
injury and the time of MR scans are 6.8±1.5 days (TBI-1) and 44.0±7.1 days (TBI-2)
for the concussion patients. Their
PCSI-P scores are 3.3±4.5 (Pre-TBI), 17.7±16.6 (TBI-1) and 8.6±13.6
(TBI-2), respectively, and the mean recovery time determined based on their
symptoms is ~23 days.
Figure 1 summarizes
the key metabolic parameters, i.e., the concentrations of ATP, PCr, Pi, phosphoethanolamine
(PE), glycerophosphocholine (GPC), NAD+, NADH and total NAD ([NAD]total),
intracellular pH and NAD redox ratio (RX=[NAD+]/[NADH) measured in the brains of controls (CT) and patients at two post-injury time
points. It is clearly evident that the [ATP], [[Pi], [PE], [NAD+],
[NAD]total and RX decreased, while the [PCr] and intracellular pH increased
shortly after the injury. Except [NADH] and RX, most of the changes were partially
reversed at the second scan, at least one month later. The ratios of various
metabolites were also calculated from their concentrations and are summarized
in Figure 2, where tP represents the total pool size of the free
high-energy phosphates in the brain (tP=ATP+PCr+Pi). Interestingly, we found
strong age-dependences (p<0.05) in several phosphorous metabolites, examples
of [PCr] are shown in Figure 3; such
relationships were significantly weakened after the head injury, which only
partially recovered at the time of second scan.DISCUSSION and CONCLUSION
Little is known about the neurometabolic
derangement in children with concussion. In this pilot study, we investigated
the metabolic alterations in pediatric concussion brains using 31P
MRS at 7T. We observed PCr/ATP and pH increases in patients shortly after mild
concussion; this trend is consistent with what has been observed in adult
patients after severe TBI. 7 In addition, we quantified absolute
concentrations of seven phosphorus
metabolites as well as intracellular pH and NAD redox ratio, which is more
challenging than determining the ratio of high-energy phosphates commonly
reported in literature.
The detected metabolic changes
between CT, TBI-1 and/or TBI-2 are relatively small (<10%), but they provide
critical and previously unknown information for understanding the underlying severity
of the injury and the degree of recovery in the developing brain. So far, there
has been no report of decreased cerebral NAD+ and total NAD contents
following head injury in pediatric patient, although this is not surprising, as
initial injury likely activates the poly-ADP-ribose polymerase that consumes
NAD+ as substrate. This notion is further supported by the slow NAD+
recovery observed in this study.
We also detected strong age-dependences
in high-energy phosphates and NAD contents in normal developing brains. Such
relationships diminished after the injury, which were only partially restored
after the concussion symptoms cleared. This intriguing finding confirms that
the metabolic disturbance indeed plays an important role in the neuropathology
of the concussion injury, especially in pediatric brains. It also suggests a
possible cerebral vulnerability that exists beyond when concussion patients are
determined clinically recovered from injury.
In conclusion, the in vivo 31P MRS technique at ultrahigh field can detect
metabolic and energetic changes in healthy and mild-TBI human brains with
superior sensitivity; thus, it offers a unique tool and valuable metabolic
markers for concussion research.Acknowledgements
Education
and Research Committee’s Internal Research Grant of Children’s Hospital &
Clinic MN;
NIH Grants: R01 MH111413, R01 CA240953, R24 MH106049, U01EB026978,
P41 EB027061, P30 NS076408.
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