Elsevier

The Lancet Neurology

Volume 11, Issue 8, August 2012, Pages 679-687
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(12)70138-2Get rights and content

Summary

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 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.

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.

Funding

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.

Introduction

Parkinson's disease is characterised by motor symptoms, but cognitive deficits are also common.1, 2, 3 Several cognitive domains are affected,1, 2, 3, 4, 5 with deficits consistently reported for measures of executive function, episodic memory, and working memory that rely on frontostriatal brain circuits5, 6, 7, 8, 9, 10 and dopaminergic neurotransmission.5, 7 Correspondingly, findings from imaging studies have shown altered functional activity in the striatum in patients with Parkinson's disease compared with that in healthy individuals during task-set shifting,6 manipulation,7 and updating.8

Between 20% and 40% of patients with Parkinson's disease have mild cognitive impairment (MCI) in the early phase of the disease.4 MCI is defined as a cognitive deficit commonly quantified as a performance level 1–2 SDs below the population mean in one or more cognitive domains.11 Patients with Parkinson's disease and MCI have an increased risk of developing dementia compared with patients without MCI.1, 5, 9 Patients with Parkinson's disease and MCI might experience more pronounced alterations in the frontostriatal circuit than those without MCI, and phasic hypoactivity has been noted in the striatum and the prefrontal cortex of patients with Parkinson's disease with impairments in executive function compared with cognitively non-impaired patients.10 However, functional brain responses have not been studied in patients with Parkinson's disease and MCI. The cognitive dysfunctions associated with Parkinson's disease are gaining clinical importance because of the relative success of therapeutic approaches in the treatment of motor symptoms, but knowledge of the neuropathology underlying cognitive impairment remains insufficient.5 We therefore examined brain responses during a working memory task and presynaptic dopamine striatal integrity during the resting state in a population-based cohort of newly diagnosed drug-naive patients with Parkinson's disease with or without MCI. We hypothesised that frontostriatal under-recruitment occurs in patients with Parkinson's disease compared with healthy individuals and in patients with Parkinson's disease with MCI compared with those without MCI.

Section snippets

Participants

Participants were recruited within the newly diagnosed parkinsonism in Umeå (NYPUM) project, which is a longitudinal population-based cohort study of incident patients with idiopathic parkinsonism, including Parkinson's disease.2 Between Jan 1, 2004, and April 30, 2009, all physicians in the Umeå catchment area (about 142 000 inhabitants) were asked to refer all patients with suspected parkinsonism to the Department of Neurology at Umeå University. All referred patients underwent a standardised

Results

77 patients with Parkinson's disease were included in the study, of whom 33 (43%) were diagnosed with MCI (figure 1). Within the Parkinson's disease and MCI group, 21 participants scored below the criteria (ie, ≥1·5 SDs below the normative age-matched test data) on at least one executive function measure. The corresponding numbers of participants for the other cognitive domains were as follows: attention or working memory, 25; episodic memory, 21; language, seven; and visuospatial function,

Discussion

The main finding of this study was the pronounced working-memory-related under-recruitment of the right dorsal caudate nucleus, the bilateral anterior cingulate cortex, and, more weakly, the right dorsolateral prefrontal cortex in patients with Parkinson's disease with MCI compared with those without MCI (panel). Furthermore, patients with Parkinson's disease and MCI had lower presynaptic 123I-FP-CIT binding in the right caudate than those without MCI, and binding correlated with caudate BOLD

References (31)

  • D Aarsland et al.

    Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis

    Neurology

    (2010)
  • O Monchi et al.

    Cortical activity in Parkinson's disease during executive processing depends on striatal involvement

    Brain

    (2007)
  • AM Owen

    Cognitive dysfunction in Parkinson's disease: the role of frontostriatal circuitry

    Neuroscientist

    (2004)
  • P Marklund et al.

    Temporal dynamics of basal ganglia under-recruitment in Parkinson's disease: transient caudate abnormalities during updating of working memory

    Brain

    (2009)
  • SJG Lewis et al.

    Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry

    J Neurosci

    (2003)
  • Cited by (127)

    View all citing articles on Scopus
    View full text