PET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17.
Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly inherited neurodegenerative disorder presenting with a variable phenotype including ataxia, dystonia, chorea, and parkinsonism, as well as cognitive impairment. We evaluated morphologic and functional imaging characteristics to elucidate evidence of neurodegeneration in SCA17, even in the presymptomatic stage of the disease.


METHODS
Nine individuals of 3 large SCA17 pedigrees, including 4 presymptomatic mutation carriers, underwent cranial 3-dimensional MRI volumetry, as well as multitracer PET with (18)F-FDG, (11)C-d-threo-methylphenidate, and (11)C-raclopride. Healthy subjects showing no signs of a neurologic or psychiatric disease served as controls.


RESULTS
MRI volumetry revealed atrophy of the cerebellum and caudate nucleus in manifesting patients (P = 0.04 and 0.05, respectively) and in presymptomatic mutation carriers (P = 0.04 and 0.01, respectively). PET demonstrated decreased glucose metabolism in the striatum, as well as in the cuneus, cingulum, and parietal lobe, in all SCA17 patients and presymptomatic mutation carriers. In addition, PET was closely correlated with motor performance as assessed by the Scale for the Assessment and Rating of Ataxia (P = 0.037) and Unified Parkinson Disease Rating Scale (P = 0.05) and with cognitive function as assessed by the Mini-Mental Status Examination (P = 0.037). Furthermore, (11)C-raclopride PET showed impairment of the postsynaptic dopaminergic compartment of the putamen and caudate nucleus not only in manifest SCA17 patients (P = 0.04 and 0.008, respectively) but also in yet-unaffected mutation carriers (P = 0.05 and 0.05, respectively). The degree of postsynaptic dopaminergic dysfunction was associated with impairment of motor performance. In contrast, significant presynaptic dopaminergic deficits assessed with (11)C-d-threo-methylphenidate PET were not detected.


CONCLUSIONS
MRI volumetry, as well as (11)C-raclopride and (18)F-FDG PET, reveal neuronal dysfunction and neurodegeneration even in the presymptomatic stage and may serve as markers for disease activity in upcoming interventional trials on SCA17.
Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Kathrin
K
Brockmann
Matthias
M
Reimold
Christoph
C
Globas
Till Karsten
TK
Hauser
Uwe
U
Walter
Hans-Jürgen
HJ
Machulla
Arndt
A
Rolfs
Ludger
L
Schöls
D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D059290:Dopaminergic Neurons / Q000000981:diagnostic imaging; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives; D008875:Middle Aged; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging* / Q000209:etiology / Q000473:pathology*; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D020891:Raclopride; D019275:Radiopharmaceuticals; D020754:Spinocerebellar Ataxias / Q000150:complications / Q000000981:diagnostic imaging* / Q000473:pathology*
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D008774:Methylphenidate; D020891:Raclopride; C033296:4-hydroxymethylphenidate; D005947:Glucose