Visual pathway neurodegeneration winged by mitochondrial dysfunction.
OBJECTIVE
To test for structural and functional contribution of mitochondrial dysfunction to neurodegeneration in multiple sclerosis (MS). A visual pathway model void of MS lesions was chosen in order to exclude neurodegeneration secondary to lesion related axonotmesis.


METHODS
A single-centre cohort study (230 MS patients, 63 controls). Spectral domain optical coherence tomography of the retina, 3T magnetic resonance imaging of the brain, spectrophotometric assessment of serum lactate levels. Postmortem immunohistochemistry.


RESULTS
The visual pathway was void of MS lesions in 31 patients and 31 age-matched controls. Serum lactate was higher in MS compared to controls (P = 0.029). High serum lactate was structurally related to atrophy of the retinal nerve fiber layer at the optic disc (P = 0.041), macula (P = 0.025), and the macular ganglion cell complex (P = 0.041). High serum lactate was functionally related to poor color vision (P < 0.01), Expanded Disability Status Scale score (R = 0.37, P = 0.041), Guy's Neurological disability score (R = 0.38, P = 0.037), MS walking scale (R = 0.50, P = 0.009), upper limb motor function (R = 0.53, P = 0.002). Immunohistochemistry demonstrated increased astrocytic expression of a key lactate generating enzyme in MS lesions as well as profound vascular expression of monocarboxylate transporter-1, which is involved in lactate transport.


CONCLUSIONS
This study provides structural, functional, and translational evidence for visual pathway neurodegeneration in MS related to mitochondrial dysfunction.
Department of Neurology, VU University Medical Center De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands ; Department of Ophthalmology, VU University Medical Center De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands ; Molecular Neuroscience, UCL Institute of Neurology Queen Square, London, WC1N 3BG, United Kingdom ; Moorfields Eye Hospital, Neuro-ophthalmology City Road, London, UK.
Axel
A
Petzold
Department of Pathology, VU University Medical Center Amsterdam, The Netherlands.
Philip G
PG
Nijland
Department of Neurology, VU University Medical Center De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
Lisanne J
LJ
Balk
Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome Largo F. Vito 1, 00168, Rome, Italy.
Angela Maria
AM
Amorini
Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome Largo F. Vito 1, 00168, Rome, Italy.
Giacomo
G
Lazzarino
Department of Radiology & Nuclear Medicine, VU University Medical Center Amsterdam, The Netherlands.
Mike P
MP
Wattjes
Department of Neurosciences, S Camillo Forlanini Hospital Circonvallazione Gianicolense 87, 00152, Rome, Italy.
Claudio
C
Gasperini
Department of Pathology, VU University Medical Center Amsterdam, The Netherlands.
Paul
P
van der Valk
Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome Largo F. Vito 1, 00168, Rome, Italy.
Barbara
B
Tavazzi
Division of Biochemistry and Molecular Biology, Department of Biology, Geology and Environmental Sciences, University of Catania Viale A. Doria 6, 95125, Catania, Italy.
Giuseppe
G
Lazzarino
Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, The Netherlands.
Jack
J
van Horssen