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Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease
Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
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2018 (Engelska)Ingår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 137, nr 1, s. 91-98Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objectives: Cognitive decline is common in Parkinson's disease (PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O-methyltransferase [COMT] Val(158)Met genotype and DRD2 (CT)-T-957 genotype) affect the development of cognitive deficits in PD.

Materials and methods: One hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [PD-MCI] or dementia [PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome.

Results: Both genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT(158)Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P=.023), the DRD2(957)T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P<.001). The poorer cognitive performance in DRD2(957)T/T carriers with PD occurred mainly in episodic memory and attention.

Conclusions: The results favor the hypothesis that dopamine deficiency in PD not only relate to mild cognitive deficits in frontostriatal functions, but also to a decline in memory and attention. This could indicate that dopamine deficiency impairs a wide network of brain areas.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2018. Vol. 137, nr 1, s. 91-98
Nyckelord [en]
COMT, dementia, DRD2, mild cognitive impairment, neurodegeneration, Parkinson's disease, Parkinson's disease genetics, population-based
Nationell ämneskategori
Neurologi
Identifikatorer
URN: urn:nbn:se:umu:diva-143002DOI: 10.1111/ane.12812ISI: 000417029600014OAI: oai:DiVA.org:umu-143002DiVA, id: diva2:1166333
Tillgänglig från: 2017-12-14 Skapad: 2017-12-14 Senast uppdaterad: 2019-05-07Bibliografiskt granskad
Ingår i avhandling
1. The biology of cognitive decline and reduced survival in Parkinson disease: prognostic factors in a population-based cohort
Öppna denna publikation i ny flik eller fönster >>The biology of cognitive decline and reduced survival in Parkinson disease: prognostic factors in a population-based cohort
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2019. s. 67
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2006
Nyckelord
Parkinson disease, multiple system atrophy, progressive supranuclear palsy, natural history, cognitive impairment, dementia, predictors of mortality, cerebrospinal fluid biomarkers, prospective, population-based
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
neurologi
Identifikatorer
urn:nbn:se:umu:diva-155588 (URN)978-91-7855-022-7 (ISBN)
Disputation
2019-02-15, Sal D, byggnad 1D, våning 9, Norrlands universitetssjukhus, Umeå, 13:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2019-01-25 Skapad: 2019-01-23 Senast uppdaterad: 2019-01-24Bibliografiskt granskad

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Bäckström, DavidEriksson Domellöf, MagdalenaGranåsen, GabrielLinder, JanMayans, SofiaElgh, EvaForsgren, Lars

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Bäckström, DavidEriksson Domellöf, MagdalenaGranåsen, GabrielLinder, JanMayans, SofiaElgh, EvaForsgren, Lars
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Klinisk neurovetenskapInstitutionen för farmakologi och klinisk neurovetenskapEpidemiologi och global hälsaInstitutionen för klinisk mikrobiologiInstitutionen för psykologi
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