Metabolic changes in the Hippocampus after Spinal Cord Injury is associated with Memory Function

Poster No:

Th252 

Submission Type:

Abstract Submission 

Authors:

Eve Huber1, Dario Pfyffer1, Armin Curt1, Anke Henning2,3, Patrick Freund4,5,6,7, Patrik Wyss2,3,8

Institutions:

1Balgrist University Hospital, Zurich, Switzerland, 2Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland, 3Max Planck Institute for Biological Cybernetics, Tübingen, Germany, 4Balgrist University Hospital, Zürich, Switzerland, 5Department of Brain Repair and Rehabilitation, UCL, London, United Kingdom, 6Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, UCL, London, United Kingdom, 7Department of Neurophysics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, 8Department of Radiology, Swiss Paraplegic Centre, Nottwil, Switzerland

Introduction:

Neuroinflammation after CNS injury is a common feature. Next to its role during recovery processes after CNS injury, a higher risk to develop dementia has been also attributed to neuroinflammation after e.g. traumatic brain injury [1]. In patients with spinal cord injury (SCI), a large epidemiological study reported that patients with SCI are at higher risk of dementia than age- and sex-matched controls [2]. Experimental evidence has shown in the mice model of chronic SCI that trauma was associated with chronic neuroinflammation and also impaired neurogenesis within the dentate gyrus of the hippocampus [3] along with decreased BDNF levels [4, 5]. The magnitude of which correlated with cognitive impairments of spatial navigation, object recognition and memory function [3]. To date, structural and metabolic changes of the hippocampus after human SCI have not been explored yet. This pilot study therefore investigated whether metabolic changes in the hippocampus occur after human SCI and whether these changes are related to memory performance.

Methods:

All participants underwent MRS measurement on a 3T scanner (Philips, Netherlands) with a 8 channel SENSE coil. T1-weighted images (1x1x1mm3) were used to place the spectroscopic voxel (16x10x12mm3) at the right hippocampus and the metabolite cycling (MC) PRESS technique [6] was applied as localization sequence. Each MRS measurement contained 256 signal averages and the data were fitted using LC Model [7]. Total N-Acetyl-Aspartate (tNAA), total creatine (tCr), choline containing compound (tCho), myo-Inositol (mI), and glutamate/glutamine (Glu+Gln=Glx) were quantified (CRLB<25%). All participants were assessed with the visual and verbal working memory test [8] on immediate (time-point 1) and mid-term (recalling of approx. 2 hours after learning, time-point 2) memory function. Statistical analyses were performed using R (R Core Team, 2016, Version 3.4.3). Group differences on metabolites were assessed with the Kruskal-Wallis test and Spearman's rank correlations were used to investigate associations between metabolites and memory function.

Results:

So far we recruited 6 chronic SCI patients (4 men, age [median, (range)]: 58 (40 – 75) years, years since injury: 11.5 (4-31) years) and 10 healthy controls (7 men, age: 47.0 (35 – 68) years). All investigated metabolites in the hippocampus were numerically lower in SCI patients compared to healthy controls. Glx was significantly lower in SCI patients compared to healthy controls (p=0.045) (see Fig. 1). Additionally, Glx levels were negatively associated with visual memory scores for all participants (time-point 1: p=0.036, R2= 0.277; time-point 2: p=0.028, R2=0.30; see Fig. 2AB), but in particular for the SCI patients (time-point 1: p<0.001, R2=1; time-point 2: p=0.049, R2=0.659; see Fig. 2CD).
Supporting Image: ohbm19_hippocampus_v2_glx.png
   ·Figure 2: Association between Glx levels and points scored on the visual memory score at immediate (time point 1) and mid-term retention (time point 2).
Supporting Image: ohbm19_hippocampus_v2_figure1.png
   ·Figure 1: Investigated metabolites in the hippocampus of healthy controls (HC) and spinal cord injured patients (SCI).
 

Conclusions:

This is the first study showing that metabolite levels are lower in the hippocampus after traumatic SCI. Although the number of patients was small, insights to the metabolic profile of hippocampal areas are revealed. In particular, we found altered levels of Glx, which were associated with decreased memory function. N-methyl-d-aspartate subtype glutamate receptors (NMDA) are required for long-term potentiation and long-term depression of hippocampal CA1 synapses, the proposed cellular substrates of learning and memory [9]. Our results indicate that SCI does not only lead to degeneration and demyelination of primarily affected tracts, but it is likely that trans-neuronal complex remodeling of primarily unaffected brain regions occurs which might also affect memory function. This pilot study therefore provides unbiased, quantitative readouts of hippocampal changes after SCI relating to memory function, which might serve as future biomarkers.

Disorders of the Nervous System:

Disorders of the Nervous System Other 1

Imaging Methods:

MR Spectroscopy 2

Learning and Memory:

Neural Plasticity and Recovery of Function
Working Memory
Learning and Memory Other

Keywords:

Degenerative Disease
Demyelinating
MR SPECTROSCOPY
MRI
Neurotransmitter
Plasticity
Trauma

1|2Indicates the priority used for review

My abstract is being submitted as a Software Demonstration.

No

Please indicate below if your study was a "resting state" or "task-activation” study.

Other

Healthy subjects only or patients (note that patient studies may also involve healthy subjects):

Patients

Was any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.

Yes

Was any animal research approved by the relevant IACUC or other animal research panel? NOTE: Any animal studies without IACUC approval will be automatically rejected.

Not applicable

Please indicate which methods were used in your research:

Other, Please specify  -   MRS

For human MRI, what field strength scanner do you use?

3.0T

Which processing packages did you use for your study?

Other, Please list  -   LC Model

Provide references using author date format

1. Faden AI, Wu J, Stoica BA, Loane DJ. Progressive inflammation‐mediated neurodegeneration after traumatic brain or spinal cord injury. Br J Pharmacol. 2016;173(4):681-91.
2. Huang SW, Wang WT, Chou LC, Liou TH, Lin HW. Risk of dementia in patients with spinal cord injury: A nationwide population-based cohort study. J Neurotrauma. 2017;34(3):615-22.
3. Wu J, Zhao Z, Kumar A, Lipinski MM, Loane DJ, Stoica BA, et al. Endoplasmic reticulum stress and disrupted neurogenesis in the brain are associated with cognitive impairment and depressive-like behavior after spinal cord injury. J Neurotrauma, 2016;33(21):1919-1935.
4. Felix MS, Popa N, Djelloul M, Boucraut J, Gauthier P, Bauer S, et al. Alteration of forebrain neurogenesis after cervical spinal cord injury in the adult rat. Front Neurosci. 2012;6:45.
5. Gomez-Pinilla F, Ying Z, Zhuang Y. Brain and spinal cord interaction: protective effects of exercise prior to spinal cord injury. PLoS On. 2012;7(2):e32298.
6. Hock A, MacMillan EL, Fuchs A, Kreis R, Boesiger P, Kollias SS, Henning A. Non-water-suppressed proton MR spectroscopy improves spectral quality in the human spinal cord. Magn Reson Med. 2013;69(5):1253-60.
7. Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30(6):672-679.
8. Schellig D, Schächtele B. Visueller und Verbaler Merkfähigkeitstest (VVM). Frankfurt: Swets und Zeitlinger. Siegel, J. Clues to the function of mammalian sleep. Nature. 2005;437: 1264-1271.
9. Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng, M. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science. 2004;304(5673):1021-1024.