Mona Adel Mohamed1, Muhammad Saleh1, Mark Mikkelsen 1, Kristen Riley2, Jeffrey Rothstein2, Lora Clawson2, Peter B Barker1, and Richard AE Edden1
1Radiology, Johns Hopkins Medical Institutions, Baltimore, MD, United States, 2Neurology, Johns Hopkins Medical Institutions, Baltimore, MD, United States
Synopsis
Amyotrophic lateral
sclerosis (ALS) is a rapidly progressive and invariably fatal motor neuron disease. The
objective of the study was to use the newly developed HERMES (Hadamard Encoding
and Reconstruction of MEGA-Edited Spectroscopy) spectral editing methodology to
simultaneously measure key compounds related to oxidative stress and
glutamatergic metabolism (GSH, GABA, and Glx) in patients with ALS and control
subjects. Using HERMES, we were able to look at different metabolic pathways in
ALS in one MRS session. Improved understanding of the various metabolic
pathways in ALS will lead to the development of new diagnostic surrogate
markers and therapeutic approaches.
INTRODUCTION:
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive
and invariably fatal motor neuron disease that affects the nerve cells along
the descending corticospinal tract
responsible for controlling voluntary muscles. There is no
definite cause or diagnostic test for ALS. 5–10% of cases are familial or
hereditary. 90–95%
of sporadic cases have an unclear etiology.
More than 5000 people are diagnosed with ALS each year in the USA. It
has a markedly heterogeneous clinical presentation and progression. Prior animal models, in vitro, post mortem 1-6 and
MRS studies 7-12
suggest that oxidative stress
and imbalance of the glutamatergic system (glutamate neurotoxicity) play major
roles in ALS pathogenesis. Furthermore, apart from riluzole’s modest benefit,
there is no effective drug to treat ALS. The objective of the study was to use
the newly developed HERMES (Hadamard Encoding and Reconstruction of MEGA-Edited
Spectroscopy) 13
spectral editing methodology to simultaneously measure key
compounds related to oxidative stress and glutamatergic metabolism (GSH, GABA, and
Glx) in patients with ALS and control subjects.Methods
Nine patients with ALS (61 ± 8
years; 5 males) and 5 healthy controls (55 ± 9 years; 2 males) underwent MRI
and HERMES MRS at 3T (Philips Achieva, 32-channel head coil). 3 brain regions
of interest along the descending motor pathway tract were evaluated: (a) the
motor area (M1), (b) corticospinal white matter (WM) and (3) the midbrain (MB)
covering the cerebral peduncles (Figure 1). HERMES was used to edit the
antioxidant glutathione (GSH), the excitatory neurotransmitter glutamate (Glu),
and the inhibitory neurotransmitter γ-aminobutyric acid (GABA+). The
editing pulse frequencies are 1.9 and 4.56 ppm for editing GABA and GSH, respectively.
Scan parameters were 320 averages (~13 minutes) per voxel, ~18 cm3 voxel
size, 20 ms editing pulse duration, TE = 80 ms, TR = 2.5 s. Total scan time ~60
minutes. The Gannet program 14 was modified to incorporate
post-processing and quantitative analysis of HERMES data (Figure 2, 3, 4). The metabolites
concentrations were quantified relative to water.RESULTS:
In M1, ALS patients showed higher mean GABA+,
GSH and Glx as compared to controls (Figure 5). When comparing controls
vs. patients, the mean (± SD) for GABA+ was 1.03 ± 0.23 vs. 1.05
± 0.37 I.U.; GSH was 0.42 ± 0.17 vs. 0.63
± 0.27;
Glx was 0.52 ± 0.11 vs. 0.56
± 0.12 I.U. respectively. None of the metabolites reached statistical
significance. In
WM, ALS patients showed lower mean GABA+ and Glx
but higher GSH than controls (Figure 5). When
comparing controls vs. patients, GABA+ was 1.29 ± 0.50 vs. 0.9 ± 0.3; GSH was
0.69 ± 0.28 vs. 0.75 ± 0.32; Glx was 0.51 ± 0.07 vs. 0.48
± 0.08 I.U. respectively. None of the metabolites
reached statistical significance. MB was unquantifiable.
Discussion:
Simultaneous measurements of GSH,
GABA+, and Glx, in vivo were feasible in ALS patients in 3 brain
regions in a total scan time of 1 hour. Good signal intensities of the 3 metabolites
in M1 and WM were observed. In agreement with other studies
10, 11, we found
increased Glx in M1 in ALS patients; however, unlike prior MRS studies
7, 12,
we found increased Glu and GSH in M1 of ALS compared to controls. None of our comparisons showed statistical
significance owing to our small sample size. Without HERMES, this study would
have required multiple scanning sessions for the same subject. Using HERMES, we were able to look at
different metabolic pathways in ALS in one MRS session. Being close to
bone and pulsations, the midbrain’s (MB) data was not quantifiable and needs future
protocol optimization.
Conclusion:
Numerous
brain metabolites participate in interdependent metabolic pathways,
which should be explored simultaneously at the same time point. Improved
understanding of the various metabolic pathways in ALS will lead to the
development of new diagnostic surrogate markers and therapeutic approaches.
Acknowledgements
This work supported in part by the Gatewood award, Yousem award, NIH grants:
R21MH087799 (MAM), P41EB015909 (PBB/RAEE) and RO1EB016089 (RAEE).References
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