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Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
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2012 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 11, no 8, 679-687 p.Article in journal (Refereed) Published
Abstract [en]

Background: Many patients with Parkinson's disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinson's disease with and without MCI.

Methods: Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinson's disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umea catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at lima University. Included patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1.5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest.

Findings: Compared with controls (n=24), patients with Parkinson's disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0.001). Within the Parkinson's disease group, patients with Parkinson's disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0.005) and the bilateral anterior cingulate cortex (p<0.001) compared with patients with Parkinson's disease without MCI (n=26). In patients with Parkinson's disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinson's disease without MCI (p=0.008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0.32, p=0.031).

Interpretation: These altered brain responses in patients with Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction.

Place, publisher, year, edition, pages
2012. Vol. 11, no 8, 679-687 p.
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-59534DOI: 10.1016/S1474-4422(12)70138-2ISI: 000307089700013OAI: oai:DiVA.org:umu-59534DiVA: diva2:552896
Available from: 2012-09-17 Created: 2012-09-17 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Functional brain imaging of cognitive status in Parkinson's disease
Open this publication in new window or tab >>Functional brain imaging of cognitive status in Parkinson's disease
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease (PD) is next to Alzheimer’s disease (AD) the second most common neurodegenerative disease. PD has traditionally been characterised as a motor disorder, but more recent research has revealed that cognitive impairments are frequent. Cognitive impairments in executive functions, attention, and working memory with reliance on dopaminergic transmission, are often described as dominating the cognitive profile in early-phase PD. However, although knowledge about the neuropathology that underlies the cognitive impairments in PD has increased, its features are complex and knowledge remains insufficient. Therefore, the aim of the current thesis was to improve the understanding of how task-evoked brain responses relate to cognitive status in patients with PD, with and without mild cognitive impairment (MCI), and to evaluate the predictive value of PD-MCI in respect of prodromal Parkinson’s disease dementia (PDD). This was conducted within the “new Parkinsonism in Umeå” (NYPUM) project, which is a prospective cohort study. Patients with idiopathic PD were included in this thesis, and the patients were examined with a comprehensive neuropsychological battery and with a functional MRI (fMRI) working memory protocol. During scanning, patients conducted a verbal two-back task in which they needed to maintain and actively update relevant information, and the primary outcome measure was blood-oxygen-level-dependent (BOLD) signal. This thesis shows that patients with PD-MCI had significantly lower BOLD signal responses than patients without MCI in frontal (anterior cingulate cortex) and striatal (right caudate) regions (Study I). The altered BOLD response in the right caudate was associated with altered presynaptic dopamine binding. The fronto-striatal alterations persisted across time but without any additional change. However, decreased posterior cortical (right fusiform gyrus) BOLD signal responses were observed in patients with PD-MCI relative to patients without MCI across time (Study II). Finally, PD-MCI at baseline examination is highly predictive for prodromal PDD with a six-fold increased risk. Cognitive tests with a posterior cortical basis, to a greater extent, are predictive for prodromal PDD than tests with a fronto-striatal basis. The observed working memory related alterations in patients with PD-MCI suggest that early cognitive impairments in PD are linked to fronto-striatal dopaminergic dysfunction. The longitudinal development of cognitive impairment in PD reflects additional posterior cortical dysfunction. This might reflect a dual syndrome, with dopamine-depleted fronto-striatal alterations that characterise PD-MCI in general, whereas additional posterior cortical cognitive alterations with a non-dopaminergic basis to a greater extent characterise prodromal PDD. If, and how, the two potential syndromes interact, is still unclear. Thus, this thesis provides information on cognitive neuropathological changes in PD that might contribute to more relevant choices of pharmacotherapy and diagnostic accuracy in respect of PDD. However, additional large-scale longitudinal imaging studies are needed to further clarify the neuropatholgogical features of PD-MCI in respect of prodromal PDD.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. 67 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1671
Keyword
Parkinson’s disease, functional MRI, Mild cognitive impairment, Working memory, Parkinson’s disease dementia, BOLD
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-96368 (URN)978-91-7601-156-0 (ISBN)
Public defence
2014-12-10, Sal BIA 201, Biologihuset, Umeå Universitet, Umeå, 13:00 (English)
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Available from: 2014-11-19 Created: 2014-11-18 Last updated: 2014-11-19Bibliographically approved

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Ekman, UrbanEriksson, JohanForsgren, LarsJakobson Mo, SusannaRiklund, KatrineNyberg, Lars
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