Brain Advance Access originally published online on October 7, 2009
Brain 2009 132(11):2958-2969; doi:10.1093/brain/awp245
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The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort
1 Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, UK 2 Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, UK 3 Laboratory for Neuroimmunology, Section for Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium 4 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, UK 5 Department of Experimental Psychology, University of Cambridge, UK 6 Department of Public Health and Primary Care, University of Cambridge, UK 7 Genes, Cognition and Psychosis Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
Correspondence to: Caroline H. Williams-Gray, Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK E-mail: chm27{at}cam.ac.uk
Cognitive abnormalities are common in Parkinson's disease, with important social and economic implications. Factors influencing their evolution remain unclear but are crucial to the development of targeted therapeutic strategies. We have investigated the development of cognitive impairment and dementia in Parkinson's disease using a longitudinal approach in a population-representative incident cohort (CamPaIGN study, n = 126) and here present the 5-year follow-up data from this study. Our previous work has implicated two genetic factors in the development of cognitive dysfunction in Parkinson's disease, namely the genes for catechol-O-methyltransferase (COMT Val158Met) and microtubule-associated protein tau (MAPT) H1/H2. Here, we have explored the influence of these genes in our incident cohort and an additional cross-sectional prevalent cohort (n = 386), and investigated the effect of MAPT H1/H2 haplotypes on tau transcription in post-mortem brain samples from patients with Lewy body disease and controls. Seventeen percent of incident patients developed dementia over 5 years [incidence 38.7 (23.9–59.3) per 1000 person-years]. We have demonstrated that three baseline measures, namely, age 
72 years, semantic fluency less than 20 words in 90 s and inability to copy an intersecting pentagons figure, are significant predictors of dementia risk, thus validating our previous findings. In combination, these factors had an odds ratio of 88 for dementia within the first 5 years from diagnosis and may reflect the syndrome of mild cognitive impairment of Parkinson's disease. Phonemic fluency and other frontally based tasks were not associated with dementia risk. MAPT H1/H1 genotype was an independent predictor of dementia risk (odds ratio = 12.1) and the H1 versus H2 haplotype was associated with a 20% increase in transcription of 4-repeat tau in Lewy body disease brains. In contrast, COMT genotype had no effect on dementia, but a significant impact on Tower of London performance, a frontostriatally based executive task, which was dynamic, such that the ability to solve this task changed with disease progression. Hence, we have identified three highly informative predictors of dementia in Parkinson's disease, which can be easily translated into the clinic, and established that MAPT H1/H1 genotype is an important risk factor with functional effects on tau transcription. Our work suggests that the dementing process in Parkinson's disease is predictable and related to tau while frontal-executive dysfunction evolves independently with a more dopaminergic basis and better prognosis.
Key Words: Parkinson's disease; dementia; cognitive deficits; microtubule-associated protein tau; catechol-O-methyltransferase
Abbreviations: COMT, the gene coding for catechol-O-methyltransferase; gDNA, genomic DNA; MAPT, the gene coding for microtubule-associated protein tau; MCI, mild cognitive impairment; OR, odds ratio; PIGD, postural instability and gait disturbance; PRM, Pattern Recognition Memory; SRM, Spatial Recognition Memory; TOL, Tower of London
Received May 20, 2009. Revised July 23, 2009. Accepted August 19, 2009.