Objectives Cognitive 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.
Methods In 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.
Results Our 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.
Conclusion We postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.
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Twitter @DrCLangley, @rachiscahill, @BJSahakian
Contributors JL, PZ, SG, EBJ and RS were involved in participant recruitment. Eligibility and clinical examinations were performed by PZ. Imaging assessments were conceived by SG, RS, EBJ and GR and implemented by SG, RS, EBJ and MP. Image processing was by SG and CL. Statistical analysis was performed by CL, TWR and BJS. CL, TWR and BJS led on drafting the manuscript, with the help and review of all co-authors. All authors edited the manuscript. SJT conceived and led the HD YAS study.
Funding This study was supported by a Wellcome Trust Collaborative Award 200181/Z/15/Z awarded to Professor Sarah Tabrizi, Professor Geraint Rees, Professor Gillian Bates, Professor Barbara Sahakian, Professor Trevor Robbins and Dr Hui Zhang.
Competing interests CL, SG, KOC, CO’C, PZ, JL, EBJ, MP, RS, GR and SJT have no competing interests. TWR and BJS consult for Cambridge Cognition.
Patient consent for publication Not required.
Ethics approval The study was approved by the Bloomsbury Research Ethics Committee and all participants gave written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.
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