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PITX3 genotype and risk of dementia in Parkinson's disease: A population-based study
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.ORCID iD: 0000-0003-0081-1156
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
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2017 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 381, p. 278-284Article in journal (Refereed) Published
Abstract [en]

Dementia is a devastating manifestation of Parkinson's disease (PD). This study investigates whether a common polymorphism in the PITX3 gene (rs2281983), which is of importance for the function of dopaminergic neurons, affects the risk of developing dementia in PD and whether it affects dopamine transporter (DAT) uptake. We PITX3 genotyped 133 patients with new-onset, idiopathic PD, participating in a population-based study in Sweden. Patients were followed prospectively during 6-11 years with extensive investigations, including neuropsychology and DAT-imaging with I-123 FP-CIT. The primary outcome was the incidence of PD dementia (PDD), diagnosed according to published criteria, studied by the Kaplan-Meier method and Cox proportional hazards. Performance in individual cognitive domains, the incidence of visual hallucinations, disease progression and striatal DAT uptake on imaging was also investigated. PD patients carrying the PITX3 C allele had an increased risk of developing PDD (hazard ratio: 2.87, 95% CI: 1.42-5.81, p = 0.003), compared to the PD patients homozygous for the T-allele. Furthermore, the PITX3 C allele carriers with PD had a poorer cognitive performance in the visuospatial domain (p < 0.001) and a higher incidence of visual hallucinations. A trend towards a lower striatal DAT uptake in the PITX3 C allele carriers was suggested, but could not be confirmed. Our results show that a common polymorphism in the PITX3 gene affects the risk of developing PDD and visuospatial dysfunction in idiopathic PD. If validated, these findings can provide new insights into the neurobiology and genetics of non-motor symptoms in PD.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2017. Vol. 381, p. 278-284
Keywords [en]
Parkinson's disease, PITX3, Dementia, Parkinson's disease genetics, DAT scan
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-142267DOI: 10.1016/j.jns.2017.08.3259ISI: 000414819100057PubMedID: 28991698OAI: oai:DiVA.org:umu-142267DiVA, id: diva2:1161849
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2019-01-23Bibliographically approved
In thesis
1. The biology of cognitive decline and reduced survival in Parkinson disease: prognostic factors in a population-based cohort
Open this publication in new window or tab >>The biology of cognitive decline and reduced survival in Parkinson disease: prognostic factors in a population-based cohort
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson disease (PD) is a progressive neurodegenerative disease that affects about 1% of the population over 60 years. The cardinal symptoms are motor disabilities but cognitive decline is also common. About 50% of all persons with PD develop dementia within 10 years after disease onset. Dementia in PD account for high social costs and has large, negative effects on quality of life. 

Aims. The aim of the study was to investigate clinical, neurobiological and genetic factors of importance for progression and for the prognosis in PD and parkinsonism. First, we aimed to describe mortality and risk factors for death, including possible associations with cognitive dysfunction, in patients with idiopathic parkinsonism. Second, we aimed to study if biomarkers in the cerebrospinal fluid (CSF) are useful for the diagnosis of different forms of idiopathic parkinsonism and prediction of cognitive decline in PD. 

Methods. A population-based cohort consisting of patients with new-onset, idiopathic parkinsonism was studied prospectively. After screening in a catchment area of ~142 000 inhabitants in Sweden, 182 patients with parkinsonism were included. The patients were investigated comprehensively, including neuropsychological testing, multimodal neuroimaging and genetic and biosample analyses. During follow up, 143 patients were diagnosed with PD, 13 with multiple system atrophy (MSA), and 18 with progressive supranuclear palsy (PSP). A total of 109 patients died. 

Results. Patients with MSA and PSP had the shortest life expectancy. PD patients who presented with normal cognitive function had a largely normal life expectancy. In contrast, the mortality was increased in PD patients with cognitive impairment, freezing of gait, hyposmia, and mildly elevated leukocytes in the CSF. Of importance for the prognosis, patients with PD with an early CSF pattern of high Neurofilament light protein, low β-amyloid, and high heart fatty acid binding protein had an 11.8 times increased risk of developing PD dementia (95% CI 3.3-42.1, p <0.001), compared with PD patients with a more ”normal” CSF pattern. Variation in genes associated with dopamine function was also associated with some effects on cognitive functions in PD. 

Conclusions. PD subtypes, for instance the subtype characterized by cognitive decline, have distinguishing clinical, neurochemical and neurobiological traits, which are of importance for the prognosis and the survival. An early CSF analysis is useful for predicting cognitive decline. The finding of a low-grade immune reaction in the CSF of patients with PD may have clinical implications. In clinical practice, CSF biomarkers could be useful for improving diagnosis and prognostication.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2019. p. 67
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2006
Keywords
Parkinson disease, multiple system atrophy, progressive supranuclear palsy, natural history, cognitive impairment, dementia, predictors of mortality, cerebrospinal fluid biomarkers, prospective, population-based
National Category
Neurosciences
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-155588 (URN)978-91-7855-022-7 (ISBN)
Public defence
2019-02-15, Sal D, byggnad 1D, våning 9, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
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Available from: 2019-01-25 Created: 2019-01-23 Last updated: 2019-01-24Bibliographically approved

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Bäckström, DavidEriksson Domellöf, MagdalenaGranåsen, GabrielLinder, JanMayans, SofiaElgh, EvaJakobson Mo, SusannaForsgren, Lars

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