PT - JOURNAL ARTICLE AU - C Williams-Gray TI - AG.02 The evolution of cognitive deficits and dementia in Parkinson's disease AID - 10.1136/jnnp-2011-300504.9 DP - 2011 Aug 01 TA - Journal of Neurology, Neurosurgery & Psychiatry PG - e2--e2 VI - 82 IP - 8 4099 - http://jnnp.bmj.com/content/82/8/e2.43.short 4100 - http://jnnp.bmj.com/content/82/8/e2.43.full SO - J Neurol Neurosurg Psychiatry2011 Aug 01; 82 AB - 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.