Enhanced axonal metabolism during early natalizumab treatment in relapsing-remitting multiple sclerosis.
OBJECTIVE
The considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging.


METHODS
In this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months. Additionally 18 matched patients with relapsing-remitting multiple sclerosis continuing treatment with interferon-β or glatiramer acetate were included along with 12 healthy controls. Imaging included short TE 2D-MR spectroscopic imaging with absolute metabolite quantification of total N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, and glutamate. Concentrations were determined for lesional white matter, normal-appearing white matter, and gray matter.


RESULTS
At baseline in both patient groups, lower concentrations of total N-acetylaspartate and creatine and phosphocreatine were found in lesional white matter compared with normal-appearing white matter and additionally lower glutamate in lesional white matter of patients receiving natalizumab. In those patients, a significant yearly metabolite increase was found for lesional white matter total N-acetylaspartate (7%, P < .001), creatine and phosphocreatine (6%, P = .042), and glutamate (10%, P = .028), while lesion volumes did not change. In patients receiving interferon-β/glatiramer acetate, no significant change was measured in lesional white matter for any metabolite, while whole-brain normalized lesion volumes increased.


CONCLUSIONS
Patients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism.
From the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N., M.D.S., F.B.) Anatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N., J.J.G.G.) o.wiebenga@vumc.nl.
O T
OT
Wiebenga
Anatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N., J.J.G.G.).
A M
AM
Klauser
Anatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N., J.J.G.G.).
M M
MM
Schoonheim
From the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N., M.D.S., F.B.) Anatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N., J.J.G.G.).
G J A
GJ
Nagtegaal
From the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N., M.D.S., F.B.).
M D
MD
Steenwijk
Neurology (J.A.v.R., C.H.P.).
J A
JA
van Rossum
Neurology (J.A.v.R., C.H.P.).
C H
CH
Polman
From the Departments of Radiology and Nuclear Medicine (O.T.W., G.J.A.N., M.D.S., F.B.).
F
F
Barkhof
Physics and Medical Technology (P.J.W.P.), Neuroscience Campus Amsterdam and VU University Medical Center, Amsterdam, the Netherlands.
P J W
PJ
Pouwels
Anatomy and Neurosciences (O.T.W., A.M.K., M.M.S., G.J.A.N., J.J.G.G.).
J J G
JJ
Geurts
D000328:Adult; D001369:Axons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061345:Early Medical Intervention; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D000068717:Glatiramer Acetate / Q000627:therapeutic use; D006801:Humans; D007089:Image Enhancement / Q000379:methods*; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D016899:Interferon-beta / Q000627:therapeutic use; D008137:Longitudinal Studies; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000378:metabolism*; D000069442:Natalizumab / Q000627:therapeutic use*
D000069442:Natalizumab; D000068717:Glatiramer Acetate; D016899:Interferon-beta