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AG.02 The evolution of cognitive deficits and dementia in Parkinson's disease
  1. C Williams-Gray

    Caroline Williams-Gray is a Specialist Registrar in Neurology. She graduated in medicine from Oxford University in 2001 after pre-clinical training at Cambridge. She was awarded a Clinical Research Fellowship by the Patrick Berthoud Trust to support her research at the University of Cambridge's Centre for Brain Repair and obtained her PhD in 2008. She is now completing her clinical Neurology training at Addenbrooke's hospital Cambridge, the National Hospital for Neurology and Neurosurgery, and Norfolk and Norwich University Hospital. Her primary research interest is cognitive dysfunction and dementia in PD.

Abstract

Parkinson's disease is defined clinically as a syndrome of bradykinesia, rigidity, tremor and postural instability. However it has become clear in recent years that cognitive and behavioural symptoms are common, and they have a major impact on quality of life, survival and the need for nursing home placement. An understanding of the evolution and pathophysiological basis of cognitive dysfunction in PD is important prognostically and essential for the development of targeted therapeutic strategies.

We have investigated the development of cognitive deficits in PD longitudinally in a population-representative incident PD cohort (the CamPaIGN study). We have demonstrated that cognitive deficits are present in a significant proportion of patients even at the time of diagnosis, and are heterogeneous, with some patients predominantly exhibiting a dysexecutive syndrome, some having difficulty in more posterior cortically-based tasks, and some having mixed deficits. The basis for this heterogeneity seems to be, at least in part, genetic. Specifically, a common functional polymorphism in the catechol-O-methyltransferase gene, which alters the activity of this dopamine-regulating enzyme by 40%, has a significant impact on executive tasks in patients with early PD. Through functional imaging we have demonstrated that this genetic effect on executive performance in PD is mediated by altered activation within a frontoparietal network, and that dopaminergic medication and COMT genotype have an interactive effect in this context.

Longitudinal follow-up of the CamPaIGN cohort (n=122) revealed that 17% developed dementia within 5 years from diagnosis. While baseline performance on fronto-executive tasks (Tower of London, phonemic fluency) did not predict subsequent cognitive decline, two more posterior cortically-based tasks were found to be significant predictors of dementia risk (semantic fluency and pentagon copying). In addition, age ≥72 and MAPT (microtubule-associated protein τ) haplotype were identified as important independent predictors of dementia. In combination, these risk factors had an OR of 88.

This work suggests that there are at least two types of cognitive dysfunction in early PD. Posterior cortically-based deficits predict later progression to dementia, and the influence of τ genotype on this outcome supports the hypothesis that protein aggregation in the form of cortical Lewy body deposition plays a central role in the aetiology of this dementing process. Conversely, executive deficits are influenced by genetic and pharmacological influences on dopaminergic activity in frontoparietal networks, hence are liable to change with disease progression and alterations in therapy, and do not herald inexorable cognitive decline. This has important prognostic implications, and better understanding of PD dementia as a non dopaminergic, τ dependent process is potentially important for future therapeutic strategies.

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