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The biology of cognitive decline and reduced survival in Parkinson disease: prognostic factors in a population-based cohort
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
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 [en]
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: urn:nbn:se:umu:diva-155588ISBN: 978-91-7855-022-7 (print)OAI: oai:DiVA.org:umu-155588DiVA, id: diva2:1281967
Public defence
2019-02-15, Sal D, byggnad 1D, våning 9, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2019-01-25 Created: 2019-01-23 Last updated: 2019-01-24Bibliographically approved
List of papers
1. Early predictors of mortality in parkinsonism and Parkinson disease: A population-based study
Open this publication in new window or tab >>Early predictors of mortality in parkinsonism and Parkinson disease: A population-based study
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2018 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 91, no 22, p. E2045-E2056Article in journal (Refereed) Published
Abstract [en]

Objective To examine mortality and associated risk factors, including possible effects of mild cognitive impairment, imaging, and CSF abnormalities, in a community-based population with incident parkinsonism and Parkinson disease. Methods One hundred eighty-two patients with new-onset, idiopathic parkinsonism were diagnosed from January 2004 through April 2009, in a catchment area of 142,000 inhabitants in Sweden. Patients were comprehensively investigated according to a multimodal research protocol and followed prospectively for up to 13.5 years. A total of 109 patients died. Mortality rates in the general Swedish population were used to calculate standardized mortality ratio and expected survival, and Cox proportional hazard models were used to investigate independent predictors of mortality. Results The standardized mortality ratio for all patients was 1.84 (95% confidence interval 1.50-2.22, p < 0.001). Patients with atypical parkinsonism (multiple system atrophy or progressive supranuclear palsy) had the highest mortality. In early Parkinson disease, a mild cognitive impairment diagnosis, freezing of gait, hyposmia, reduced dopamine transporter activity in the caudate, and elevated leukocytes in the CSF were significantly associated with shorter survival. Conclusion Although patients presenting with idiopathic parkinsonism have reduced survival, the survival is highly dependent on the type and characteristics of the parkinsonian disorder. Patients with Parkinson disease presenting with normal cognitive function seem to have a largely normal life expectancy. The finding of a subtle CSF leukocytosis in patients with Parkinson disease with short survival may have clinical implications.

Place, publisher, year, edition, pages
Wolters Kluwer, 2018
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-154849 (URN)10.1212/WNL.0000000000006576 (DOI)000452519500002 ()30381367 (PubMedID)
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2019-01-23Bibliographically approved
2. Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease
Open this publication in new window or tab >>Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease
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2015 (English)In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 72, no 10, p. 1175-1182Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE: Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies. OBJECTIVE: To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders. DESIGN, SETTING, AND PARTICIPANTS: Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by amovement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison. MAIN OUTCOMES AND MEASURES: Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria. RESULTS: Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders. CONCLUSIONS AND RELEVANCE: The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.

Place, publisher, year, edition, pages
American Medical Association, 2015
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-111148 (URN)10.1001/jamaneurol.2015.1449 (DOI)000362963000014 ()26258692 (PubMedID)
Available from: 2015-11-11 Created: 2015-11-06 Last updated: 2019-01-23Bibliographically approved
3. Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease
Open this publication in new window or tab >>Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease
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2018 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 137, no 1, p. 91-98Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
COMT, dementia, DRD2, mild cognitive impairment, neurodegeneration, Parkinson's disease, Parkinson's disease genetics, population-based
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-143002 (URN)10.1111/ane.12812 (DOI)000417029600014 ()
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2019-01-23Bibliographically approved
4. PITX3 genotype and risk of dementia in Parkinson's disease: A population-based study
Open this publication in new window or tab >>PITX3 genotype and risk of dementia in Parkinson's disease: A population-based study
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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
Keywords
Parkinson's disease, PITX3, Dementia, Parkinson's disease genetics, DAT scan
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-142267 (URN)10.1016/j.jns.2017.08.3259 (DOI)000414819100057 ()28991698 (PubMedID)
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2019-01-23Bibliographically approved
5. Neurofilament concentration in CSF correlates with disease severity, survival and imaging measures of neurodegeneration in incident Parkinson disease
Open this publication in new window or tab >>Neurofilament concentration in CSF correlates with disease severity, survival and imaging measures of neurodegeneration in incident Parkinson disease
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(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-155587 (URN)
Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2019-01-23

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