title: Cerebellar neurochemical alterations in spinocerebellar ataxia type 14 appear to include glutathione deficiency.
abstract: Autosomal dominant ataxia type 14 (SCA14) is a rare usually adult-onset progressive disorder with cerebellar neurodegeneration caused by mutations in protein kinase C gamma. We set out to examine cerebellar and extracerebellar neurochemical changes in SCA14 by MR spectroscopy. In 13 SCA14 patients and 13 healthy sex- and age-matched controls, 3-T single-voxel brain proton MR spectroscopy was performed in a cerebellar voxel of interest (VOI) at TE = 30 ms to obtain a neurochemical profile of metabolites with short relaxation times. In the cerebellum and in additional VOIs in the prefrontal cortex, motor cortex, and somatosensory cortex, a second measurement was performed at TE = 144 ms to mainly extract the total N-acetyl-aspartate (tNAA) signal besides the signals for total creatine (tCr) and total choline (tCho). The cerebellar neurochemical profile revealed a decrease in glutathione (6.12E-06 ± 2.50E-06 versus 8.91E-06 ± 3.03E-06; p = 0028) and tNAA (3.78E-05 ± 5.67E-06 versus 4.25E-05 ± 5.15E-06; p = 0023) and a trend for reduced glutamate (2.63E-05 ± 6.48E-06 versus 3.15E-05 ± 7.61E-06; p = 0062) in SCA14 compared to controls. In the tNAA-focused measurement, cerebellar tNAA (296.6 ± 42.6 versus 351.7 ± 16.5; p = 0004) and tCr (272.1 ± 25.2 versus 303.2 ± 31.4; p = 0004) were reduced, while the prefrontal, somatosensory and motor cortex remained unaffected compared to controls. Neuronal pathology in SCA14 detected by MR spectroscopy was restricted to the cerebellum and did not comprise cortical regions. In the cerebellum, we found in addition to signs of neurodegeneration a glutathione reduction, which has been associated with cellular damage by oxidative stress in other neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia.
authors.affiliation: Department of Neurology, Charité, Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany, sarah.doss@charite.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Doss
authors.forename: Jan Leo
authors.initials: JL
authors.lastname: Rinnenthal
authors.forename: Tanja
authors.initials: T
authors.lastname: Schmitz-Hübsch
authors.forename: Alexander U
authors.initials: AU
authors.lastname: Brandt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Papazoglou
authors.forename: Silke
authors.initials: S
authors.lastname: Lux
authors.forename: Stephan
authors.initials: S
authors.lastname: Maul
authors.forename: Jens
authors.initials: J
authors.lastname: Würfel
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Martina
authors.initials: M
authors.lastname: Minnerop
authors.forename: Friedemann
authors.initials: F
authors.lastname: Paul
mesh_terms: D000328:Adult; D000368:Aged; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D003401:Creatine / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*; D020754:Spinocerebellar Ataxias / Q000378:metabolism*
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; C000179:N-acetylaspartate; D005978:Glutathione; D003401:Creatine