• Christelle Langley, Sarah Gregory, Katie Osborne-Crowley, Claire O'Callaghan, Paul Zeun, Jessica Lowe, Eileanoir B Johnson, Marina Papoutsi, Rachael I Scahill, Geraint Rees, Sarah J Tabrizi, Trevor W Robbins, and Barbara Jacquelyn Sahakian.
• Department of Psychiatry, University of Cambridge, Cambridge, UK cl798@medschl.cam.ac.uk.
• J. Neurol. Neurosurg. Psychiatr. 2021 Feb 1; 92 (2): 143149143-149.

ObjectivesCognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington's disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit.MethodsIn the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage.ResultsOur results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants.ConclusionWe postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

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