title: The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort.
abstract: 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 Val(158)Met) 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 >or=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.
authors.affiliation: Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. chm27@cam.ac.uk
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Williams-Gray
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Evans
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.forename: Thomas
authors.initials: T
authors.lastname: Foltynie
authors.forename: Maria
authors.initials: M
authors.lastname: Ban
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.forename: Bhaskar S
authors.initials: BS
authors.lastname: Kolachana
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
mesh_terms: D000368:Aged; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D015331:Cohort Studies; D003704:Dementia / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D012044:Regression Analysis; D012307:Risk Factors; D016875:tau Proteins / Q000235:genetics
chemical_list: D016875:tau Proteins; D002394:Catechol O-Methyltransferase; D004298:Dopamine