Parametric fMRI of paced motor responses uncovers novel whole-brain imaging biomarkers in spinocerebellar ataxia type 3.
Machado-Joseph Disease, inherited type 3 spinocerebellar ataxia (SCA3), is the most common form worldwide. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we aimed to discover whole-brain functional biomarkers, based on parametric performance-level-dependent signals. We assessed 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel-based morphometry. Functional magnetic resonance imaging (fMRI) was designed to parametrically analyze behavior and neural responses to audio-paced bilateral thumb movements at temporal frequencies of 1, 3, and 5 Hz. Our performance-level-based design probing neuronal correlates of motor coordination enabled the discovery that neural activation and behavior show critical loss of parametric modulation specifically in SCA3, associated with frequency-dependent cortico/subcortical activation/deactivation patterns. Cerebellar/cortical rate-dependent dissociation patterns could clearly differentiate between groups irrespective of grey matter loss. Our findings suggest functional reorganization of the motor network and indicate a possible role of fMRI as a tool to monitor disease progression in SCA3. Accordingly, fMRI patterns proved to be potential biomarkers in early SCA3, as tested by receiver operating characteristic analysis of both behavior and neural activation at different frequencies. Discrimination analysis based on BOLD signal in response to the applied parametric finger-tapping task significantly often reached >80% sensitivity and specificity in single regions-of-interest.Functional fingerprints based on cerebellar and cortical BOLD performance dependent signal modulation can thus be combined as diagnostic and/or therapeutic targets in hereditary ataxia. Hum Brain Mapp 37:3656-3668, 2016. © 2016 Wiley Periodicals, Inc.
Institute for Biomedical Imaging and Life Sciences (IBILI) - Faculty of Medicine, University of Coimbra, Portugal.|Institute of Nuclear Sciences Applied to Health (ICNAS) - University of Coimbra, Brain Imaging Network of Portugal, Portugal.
João Valente
JV
Duarte
Institute for Biomedical Imaging and Life Sciences (IBILI) - Faculty of Medicine, University of Coimbra, Portugal.|Institute of Nuclear Sciences Applied to Health (ICNAS) - University of Coimbra, Brain Imaging Network of Portugal, Portugal.
Ricardo
R
Faustino
Institute for Biomedical Imaging and Life Sciences (IBILI) - Faculty of Medicine, University of Coimbra, Portugal.|Institute of Nuclear Sciences Applied to Health (ICNAS) - University of Coimbra, Brain Imaging Network of Portugal, Portugal.
Mercês
M
Lobo
Institute of Nuclear Sciences Applied to Health (ICNAS) - University of Coimbra, Brain Imaging Network of Portugal, Portugal.|Department of Neuroradiology, Hospital of Coimbra University, Portugal.
Gil
G
Cunha
Department of Neuroradiology, Hospital of Coimbra University, Portugal.
César
C
Nunes
Institute for Biomedical Imaging and Life Sciences (IBILI) - Faculty of Medicine, University of Coimbra, Portugal.|Institute of Nuclear Sciences Applied to Health (ICNAS) - University of Coimbra, Brain Imaging Network of Portugal, Portugal.
Carlos
C
Ferreira
Department of Neurology, Hospital of Coimbra University, Portugal.
Cristina
C
Januário
Institute for Biomedical Imaging and Life Sciences (IBILI) - Faculty of Medicine, University of Coimbra, Portugal.|Institute of Nuclear Sciences Applied to Health (ICNAS) - University of Coimbra, Brain Imaging Network of Portugal, Portugal.
Miguel
M
Castelo-Branco
D000328:Adult; D000367:Age Factors; D001931:Brain Mapping / Q000379:methods; D002560:Cerebrovascular Circulation / Q000502:physiology; D005260:Female; D005385:Fingers / Q000502:physiology; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D017827:Machado-Joseph Disease / Q000000981:diagnostic imaging* / Q000235:genetics / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology*; D009929:Organ Size; D010100:Oxygen / Q000097:blood; D012680:Sensitivity and Specificity; D055815:Young Adult
D010100:Oxygen
cerebellar degeneration; imaging biomarker; movement disorder; parametric functional MRI; spinocerebellar ataxia type 3; voxel-based morphometry