Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study.
Friedreich's ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico-cerebellar dysfunctions underlying executive functioning in individuals with FRDA.



22 FRDA patients and 22 controls were clinically and neuropsychologically examined. Fifteen of each underwent structural and functional MRI using a verbal-fluency task with phonemic and semantic conditions. Gray (GM) and white matter (WM) alterations were assessed by means of voxel-based morphometry and diffusion-tensor imaging.



The neuropsychological profile demonstrated deficits in verbal fluency, working memory and social cognition. Functional MRI data showed most pronounced group-differences in phonemic fluency with patients exhibiting enhanced activity in the cerebellum (VI, Crus I), fronto-insular, premotor and temporo-occipital regions. The semantic condition only revealed reduced activity in the anterior cerebellum; for overt speech, we found increased activity in the motor cortex. Functional connectivity-analysis showed higher co-activation within cerebellar and cortical regions, respectively, and impaired interregional coupling between the cerebellum and fronto-insular cortex for phonemic processing, which was also related to poorer task performance. GM reduction in FRDA was mainly found in lobule VI, whereas WM degeneration was more pronounced including brainstem, cerebellum, and cortex. Decreased cerebellar GM was associated with enhanced activity in the fronto-insular cortex, while loss of WM integrity may translate cortico-cerebellar pathway disruptions.



The pattern of increased neural response with both cerebellar and cortical involvement underlying executive functioning indicates functional reorganization driven by disease-related structural damage in FRDA.
Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany.
Imis
I
Dogan
Department of Neurology RWTH Aachen University Aachen Germany.
Eugenie
E
Tinnemann
Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany.
Sandro
S
Romanzetti
Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany.
Shahram
S
Mirzazade
Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany; Neurocognition Unit Department of Neurology Hospital de Braga Braga Portugal.
Ana S
AS
Costa
Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany.
Cornelius J
CJ
Werner
JARA - Translational Brain Medicine Aachen and Jülich Germany; JARA BRAIN Institute IIInstitute of Neuroscience and Medicine (INM-1) Research Center Jülich GmbH Jülich Germany; Department of Psychiatry, Psychotherapy and Psychosomatics RWTH Aachen Aachen
Germany.
Stefan
S
Heim
Department of Neurology RWTH Aachen University Aachen Germany.
Kathrin
K
Fedosov
Department of Neurology RWTH Aachen University Aachen Germany.
Stefanie
S
Schulz
Department of Neurology Essen University Hospital Essen Germany.
Dagmar
D
Timmann
Department of Neurology University Hospital of Bonn Bonn Germany; German Center for Neurodegenerative Diseases (DZNE) Bonn Germany.
Ilaria A
IA
Giordano
Department of Neurology University Hospital of Bonn Bonn Germany; German Center for Neurodegenerative Diseases (DZNE) Bonn Germany.
Thomas
T
Klockgether
Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany; JARA BRAIN Institute IIInstitute of Neuroscience and Medicine (INM-1)Research Center Jülich GmbH Jülich Germany.
Jörg B
JB
Schulz
Department of Neurology RWTH Aachen University Aachen Germany; JARA - Translational Brain Medicine Aachen and Jülich Germany; JARA BRAIN Institute IIInstitute of Neuroscience and Medicine (INM-1)Research Center Jülich GmbH Jülich Germany.
Kathrin
K
Reetz