Amna Yasmin1, Olli Gröhn1, Asla Pitkänen1, and Riikka Immonen1
1Department of Neurobiology, A.I. Virtanen Institute University of Eastern Finland, Kuopio, Finland
Synopsis
Traumatic brain injury (TBI)
is the main cause of mortality and morbidity worldwide. Up to 53 % of TBI
patients with penetrating head injuries develop epilepsy in later part of life.
Unavailability of biomarkers for epileptogensis is a major unmet clinical need,
and is the greatest obstacle on the way of developing treatment in patients at
risk, e.g., after TBI. Objective of
this study is to
determine metabolic profile in perilesional cortical area in clinically
relevant TBI rat model and correlate MRS findings with EEG and histological
outcomes in search for biomarkers. Results:
Six out of 13 parameters showed changes at some follow point. Findings of long TBI follow up will help to investigate cellular and
molecular mechanisms underlying post-traumatic epileptogenesis and identify
reliable biomarkers that could serve as therapeutic targets for the development
of new antiepileptogenic and antiseizure compound.INTRODUCTION
Traumatic brain injury (TBI) leads to post-traumatic
epilepsy (PTE) in up to 53% of patients.
1 In many cases, epileptogenic focus
develops to the perilesional cortex. Here we hypothesized that TBI induces a
metabolic fingerprint to the perilesional cortex that predicts epileptogenesis.
To address the hypothesis we used magnetic resonance spectroscopy (1H-MRS)
to reveal metabolic alterations in the perilesional cortex
in vivo.
METHODS
Thirteen
in vivo detectable neurochemicals were
analyzed in the perilesional cortex in lateral fluid-percussion injury (LFPI) rat
model of TBI. Adult, male Spraque-Dawley rats (n=20 TBI, 10 sham) were imaged at
1, 3, and 6 months post-TBI. 1H-MRS was carried out at 9.4 Tesla high
field magnet. Spectra were obtained from single perilesional voxel (1*3*5mm) by
PRESS (TE 11ms, TR 2500ms, 320/640 averages for sham/TBI). Spectra were analyzed
by LC model and only metabolites with SD%≤ 20 were included. Metabolite
concentrations were normalized to creatine and phosphocreatine (Cr+PCr) peak to
account for the tissue atrophy. In the end, rats were monitored for 4 wk with
24/7 video-EEG to detect epileptiform activity.
RESULTS
Six out of 13 parameters showed
changes at some follow-up point. Myo-inositol
was increased up to 77% (p<0.01) at 1 month, 35 %( p<0.01) at 3 months, and
21% (p<0.01) at 6 months post-TBI as compared to corresponding controls.
There was partial recovery of elevated Myo-inositol levels among the injured
animals (p<0.01, between 1 month and 6 months post injury). At 6 months
post-TBI, NAA was increased by 14%
(p<0.05) as compared to controls, and by 16 % (p<0.01) as compared to 1 month
post injury animals. Also perilesional NAA+NAAG
levels in trauma animals elevated 14% over time (p<0.01, 1 month vs 6
months) despite the progressive atrophy of the primary lesion. Glutathione
(GSH) was increased by 17% (p<0.05) in 1 month post-TBI. Glycerophosphocholine
(GPC) alone and with phosphocholine (GPC+PCh)
both showed an increase over time in the TBI group (GPC 12%, GPC+PCh 11%,
p<0.05 from 1 to 3 months). In further analysis the MRS findings will be
correlated with the seizure susceptibility in EEG.
CONCLUSIONS
We
found markedly increased myo-inositol levels in the perilesional cortex,
indicating gliosis. The elevated glutathione may reflect potential on-going
oxidative stress. Phosphocholines are linked to membrane turnover. Whether any
of these metabolic anomalies could identify the epileptogenic animals is yet to
be examined.
Acknowledgements
No acknowledgement found.References
Hauser, W. Allen, John F. Annegers, and Leonard T. Kurland. 1991.
‘Prevalence of Epilepsy in Rochester, Minnesota: 1940–1980.’ Epilepsia 32 (4):
429–45. doi:10.1111/j.1528-1157.1991.tb04675.x.