Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: A cross-sectional study

Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
The Lancet Neurology (Impact Factor: 21.9). 06/2012; 11(8):679-87. DOI: 10.1016/S1474-4422(12)70138-2
Source: PubMed


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.
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 Umeå catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at Umeå 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.
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).
These altered brain responses in patients with Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction.
Swedish Medical Research Council, Swedish Parkinson Foundation, Swedish Parkinson's Disease Association, Umeå University, Kempe Foundation, Foundation for Clinical Neuroscience at Umeå University Hospital, Västerbotten County Council (ALF), King Gustaf V's and Queen Victoria's Freemason Foundation, Knut and Alice Wallenberg Foundation, and Swedish Brain Power.

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    • "For instance, in studies of voxel-based morphometry , individuals with Parkinson's disease with cognitive deficits or dementia but not cognitively unimpaired individuals with Parkinson's disease have reduced gray matter volume in the dorsal caudate in comparison to healthy controls [Apostolova et al., 2010; Melzer et al., 2012; Nagano-Saito et al., 2005]. fMRI studies indicate that the subset of cognitively impaired individuals with Parkinson's disease under-recruit the dorsal caudate during working memory [Ekman et al., 2012; Lewis et al., 2003] and setshifting [Nagano-Saito et al., 2014] tasks, but in the cognitively unimpaired individuals with Parkinson's disease, the caudate activated at levels close to or even above that of healthy controls. In these anatomical and functional studies, no other regions of the striatum were reported to significantly relate to cognitive impairment in Parkinson's disease. "
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    ABSTRACT: Parkinson's disease is a neurodegenerative disorder characterized by changes to dopaminergic function in the striatum and a range of cognitive and motor deficits. Neuroimaging studies have repeatedly shown differences in activation and functional connectivity patterns of the striatum between symptomatic individuals with Parkinson's disease and healthy controls. However, the presence and severity of cognitive and motor symptoms seem to differ dramatically among individuals with Parkinson's disease at the early-stages. To investigate the neural basis of such heterogeneity, we examined the resting state functional connectivity patterns of caudate and putamen subdivisions in relation to cognitive and motor impairments among 62 early-stage individuals with Parkinson's disease (21 females, 23 drug naive, ages 39-77 years, average UPDRS motor scores off medication = 18.56, average H&Y stage = 1.66). We also explored how changes in striatal connectivity relate to changes in symptomatology over a year. There are two main findings. First, higher motor deficit rating was associated with weaker coupling between anterior putamen and midbrain including substantia nigra. Intriguingly, steeper declines in functional connectivity between these regions were associated with greater declines in motor function over the course of 1 year. Second, decline in cognitive function, particularly in the memory and visuospatial domains, was associated with stronger coupling between the dorsal caudate and the rostral anterior cingulate cortex. These findings remained significant after controlling for age, medication, gender, and education. In sum, our findings suggest that cognitive decline and motor deficit are each associated with a differentiable pattern of functional connectivity of striatal subregions. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 11/2015; DOI:10.1002/hbm.23056 · 5.97 Impact Factor
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    • "2014 ) . Also , when matching following the set - shift , the PD - non - MCI group revealed significant activity in the premotor cortex but not the putamen resembling previous PD " ON " medication results ( Jubault et al . , 2009 ) . Similar results have been observed in PD - MCI and PD - non - MCI patients while performing a working memory task ( Ekman et al . , 2012 ; Monchi and Stoessl , 2012 ) . The finding of striatal activation in the WCST is consistent with the possibility that the basal ganglia are involved in selecting the relevant action among competing motor responses ( Mink and Thach , 1993 ) ."
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    ABSTRACT: In recent years a gradual shift in the definition of Parkinson's disease (PD) has been established, from a classical akinetic-rigid movement disorder to a multi-system neurodegenerative disease. While the pathophysiology of PD is complex and goes much beyond the nigro-striatal degeneration, the striatum has been shown to be responsible for many cognitive functions. Patients with PD develop impairments in multiple cognitive domains and the PD model is probably the most extensively studied regarding striatum dysfunction and its influence on cognition. Up to 40% of PD patients present cognitive impairment even in the early stages of disease development. Thus, understanding the key patterns of striatum and connecting regions' influence on cognition will help develop more specific approaches to alleviate cognitive impairment and slow down its decline. This review focuses on the contribution of neuroimaging studies in understanding how striatum impairment affects cognition in PD.
    Frontiers in Systems Neuroscience 10/2015; 9. DOI:10.3389/fnsys.2015.00138
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    • "Cognitive dysfunction in PD may present as mild cognitive impairment (PD- MCI) or dementia (PDD). PD-MCI is frequent and often associated with frontostriatal dysfunction [5] [6]. PD-MCI can be seen as a transitional state between normal cognition and dementia [7]. "
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    ABSTRACT: Existing literature on brain volumetric alterations in patients with Parkinson's disease (PD) have mainly focused on gray matter (GM) and are largely cross-sectional. Little is known about white matter (WM) volumetric features and their impact on cognitive symptoms in PD. Therefore, the present study aims to examine both GM and WM volumes of cognitively asymptomatic PD patients with a longitudinal design. A total of 42 cognitively asymptomatic patients with early stage PD were recruited and followed up for 1.5 years. At follow-up, 12 patients progressed to mild cognitive impairment (MCI) and were classified as "converters" while the remaining 30 patients remained cognitively asymptomatic and were classified as "non-converters". All patients underwent clinical and neuropsychological assessments as well as MRI scans at baseline and at follow-up. At baseline, non-converters and converters had comparable cognitive scores. At follow-up, converters showed more deficits in frontal-related cognitive function than non-converters. Volumetric analyses revealed that converters had more longitudinal reduction in WM, but not GM, volume compared to non-converters. The decreased volumes among converters were mainly localized in the frontal areas. Moreover, baseline global WM volume significantly predicted conversion to PD-MCI, while baseline GM and WM volumes of the frontal and parietal regions were associated with frontal cognitive changes across time. PD patients who develop MCI demonstrate longitudinal reduction in WM volume, especially in the frontal areas. While both regional GM and WM volumes associate with frontal cognitive decline, baseline global WM volume may be a neuroimaging marker of conversion to PD-MCI. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 02/2015; 21(5). DOI:10.1016/j.parkreldis.2015.02.014 · 3.97 Impact Factor
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