16 February 2021
New study finds CANTAB is sensitive to very early cognitive changes in premanifest Huntington’s disease
Dr. Christelle Langley, postdoctoral Research Associate at the University of Cambridge School of Clinical Medicine shared the role that CANTAB played in her latest publication: Fronto-striatal circuits for cognitive flexibility in far from onset Huntington’s Disease: Evidence from the Young Adult Study
Can you tell us more about your research group?
I am Dr Christelle Langley, a cognitive neuroscientist, and my research focuses on the neural mechanisms of cognition in neurological and psychiatric disorders. My PhD research, at the University of Bristol, focused on the neuroimaging of fatigue and cognition in Multiple Sclerosis. I am a postdoctoral research associate based in Professor Barbara Sahakian's Research Group at the Department of Psychiatry University of Cambridge School of Clinical Medicine.
This publication was a collaborative research study between Professor Tabrizi and colleagues at University College London and Professor Sahakian and Professor Robbins at the University of Cambridge.
Professor Sahakian from the Department of Psychiatry and the Behavioural and Clinical Neuroscience Institute (BCNI), is an international leader for her research in the understanding of the neural basis of cognitive, emotional and behavioural dysfunction in order to develop more effective pharmacological and psychological treatments, and is particularly focussed on early disease detection. Professor Robbins, from the Department of Psychology and the BCNI, is a world leader in cognitive neuroscience and his research focuses on the functions of the frontal lobes of the brain and their connections with other regions. They are co-inventors of the CANTAB computerised test for assessing cognition.
Professor Tabrizi is a global leader translating Huntington’s Disease (HD) research directly from the lab to patients, with the aim of preventing the neurodegenerative process. This extends from basic cellular mechanism work to systemic insights into the preclinical phase of neurodegeneration and the development and testing of new disease modifying treatments, including investigation of DNA repair pathways as possible HD therapeutic targets and was the global PI on the first gene silencing trial in HD.
What is the rationale behind your study?
Huntington’s disease (HD) is an inherited, rare, neurodegenerative disease characterised by movement, cognitive and psychiatric symptoms . HD is caused by a repeat expansion (39 plus) of the trinucleotide cytosine-adenine-guanine (CAG) in exon 1 of the Huntingtin gene (HTT) that leads to expression of a mutant form of the Huntingtin protein . The greater the number of CAG repeats the earlier HD onset . A diagnosis of HD is based on the presence of significant motor abnormalities. Premanifest HD (pre-HD) are gene-carriers with 39+ CAG repeats, but with insufficient motor symptoms for a clinical diagnosis.
It is well established that neurodegeneration in HD begins primarily in the striatum, being detectable early on in pre-HD and becoming especially severe in manifest-HD [3-6], indeed, fronto-striatal circuits are among the earliest to show degeneration in pre-HD . Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest HD (pre-HD) [8-11].
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.
Which methods did you use?
The cohort used in this study included 67 controls and 64 pre-HD participants closely matched for age, gender and IQ (measured by the National Adult Reading Test (NART)), who were recruited from across the UK as part of HD-YAS . This HD cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years= 23.89 (s.d= 5.96)).
We used resting-state functional MRI to examine the association between the functional connectivity in predefined fronto-striatal circuits [13, 14] and separate performance on the extra-dimensional (ED) shift stage of the CANTAB Intra-Extra Dimensional Set Shift Task (IED), which has been shown to be sensitive to pre-HD.
What are your key findings?
Our results demonstrated that the CANTAB Intra-Extra Dimensional Set Shift (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. This alternative fronto-striatal circuitry recruitment may potentially represent a form of functional reorganisation, which, while effective for most pre-HD participants in preserving performance is maladaptive in a small number of the pre-HD participants.
What are the implications of your study?
The study demonstrates that the CANTAB Intra-Extra Dimensional Set Shift (IED) is sensitive to pathological changes in HD even at very early stages in disease progression, which may be useful in early disease detection. Moreover, the resting-state functional connectivity may provide the potential for a neuroimaging biomarker of individual variability in cognitive flexibility in pre-HD.
Why did you choose CANTAB?
The touch-screen technology of the CANTAB tasks mean they are easily administered to our patient population. Moreover, the tasks are well-validated and provide reliable results. The CANTAB Intra-Extra Dimensional Set Shift (IED) specifically is one of the most sensitive tests for impairments in cognitive flexibility and has been shown to be so in HD. In addition, studies have demonstrated that as HD disease progression continues the impairment appears to shift from one form of cognitive flexibility to another, from deficits in attentional set-shifting to reversal learning. The multiple stages of the CANTAB Intra-Extra Dimensional Set Shift (IED) task allows us to examine these shifts in impairment.
What are the next steps for your research?
We hope to follow up the HD-YAS cohort longitudinally. Ultimately, we would hope that this knowledge will aid in our understanding of the cognitive function in the earliest stages of preHD and in the development of novel therapeutic approaches that could stop, slow down or reverse the progression of the disease.
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14. Vaghi, M.M., Vértes, P.E., Kitzbichler, M.G., et al. Specific frontostriatal circuits for impaired cognitive flexibility and goal-directed planning in obsessive-compulsive disorder: evidence from resting-state functional connectivity. Biol Psychiatry, 2017;81:708-717.
Dr. Christelle Langley, Department of Psychiatry, University of Cambridge School of Clinical Medicine