Cerebellar pathology in Friedreich's ataxia: atrophied dentate nuclei with normal iron content.
BACKGROUND
In Friedreich's ataxia (FA) the genetically decreased expression of the mitochondrial protein frataxin leads to disturbance of the mitochondrial iron metabolism. Within the cerebellum the dentate nuclei (DN) are primarily affected. Histopathological studies show atrophy and accumulation of mitochondrial iron in DN. Dentate iron content has been suggested as a biomarker to measure the effects of siderophores/antioxidant treatment of FA. We assessed the iron content and the volume of DN in FA patients and controls based on ultra-high-field MRI (7 Tesla) images.


METHODS
Fourteen FA patients (mean age 38.1 yrs) and 14 age- and gender-matched controls participated. Multi-echo gradient echo and susceptibility weighted imaging (SWI) sequences were acquired on a 7 T whole-body scanner. For comparison SWI images were acquired on a 1.5 T MR scanner. Volumes of the DN and cerebellum were assessed at 7 and 1.5 T, respectively. Parametric maps of T2 and T2* sequences were created and proton transverse relaxation rates were estimated as a measure of iron content.


RESULTS
In FA, the DN and the cerebellum were significantly smaller compared to controls. However, proton transverse relaxation rates of the DN were not significantly different between both groups.


CONCLUSIONS
Applying in vivo MRI methods we could demonstrate significant atrophy of the DN in the presence of normal iron content. The findings suggest that relaxation rates are not reliable biomarkers in clinical trials evaluating the potential effect of FA therapy.
Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany.
K
K
Solbach
Erwin L. Hahn Institute for Magnetic Resonance Imaging, University Duisburg-Essen, Arendahls Wiese 199, Essen 45141, Germany.
O
O
Kraff
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich 52425, Germany ; Department of Neurology, University Hospital Bonn, Sigmund-Freud-straße 25, Bonn 53127, Germany.
M
M
Minnerop
Department of Computer Sciences, University of Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany.
A
A
Beck
Department of Neurology, Eberhard Karls-University, Geschwister-Scholl-platz, Tübingen, Tübingen 72074, Germany ; Hertie Institute for Clinical Brain Research, Eberhard Karls-University Tübingen, Hoppe-Seyler-straße 3, Tübingen 72076, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-straße 27, Tübingen 72076, Germany.
L
L
Schöls
Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany.
E R
ER
Gizewski
Erwin L. Hahn Institute for Magnetic Resonance Imaging, University Duisburg-Essen, Arendahls Wiese 199, Essen 45141, Germany ; Institute of Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany.
M E
ME
Ladd
Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany.
D
D
Timmann
D000328:Adult; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D002529:Cerebellar Nuclei / Q000378:metabolism* / Q000473:pathology*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D017352:Echo-Planar Imaging / Q000379:methods; D005260:Female; D005621:Friedreich Ataxia / Q000175:diagnosis* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
D007501:Iron
Dentate iron content; Dentate nuclei; Friedreich's ataxia; Relaxometry; Ultra-high-field MRI; Volumetry