Elsevier

NeuroImage

Volume 22, Issue 2, June 2004, Pages 553-561
NeuroImage

Cognitive- and motor-related regions in Parkinson's disease: FDOPA and FDG PET studies

https://doi.org/10.1016/j.neuroimage.2004.01.030Get rights and content

Abstract

Objective: Using 6-[18F]fluoro-l-dopa (FDOPA) and [18F]fluorodeoxyglucoce (FDG) positron emission tomography (PET), multiple regression analyses were performed to determine the specific brain regions that are related to cognitive and motor symptoms in nondemented patients with Parkinson's disease. Methods: Spatially normalized images of FDOPA influx rate constant (Ki) values and relative regional cerebral metabolic rates for glucose (rrCMRglc) were created. Raven's Coloured Progressive Matrices (RCPM) scores and the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were used to determine the patients' cognitive and motor functions, respectively. Multiple correlation analyses between the FDOPA and FDG images and the cognitive and motor scores were performed for each voxel. Results: RCPM score was significantly positively correlated with the FDOPA Ki in the left hippocampus and with the rrCMRglc in the left middle frontal gyrus and right retrosplenial cortex. Motor function was significantly positively correlated with the FDOPA Ki in the bilateral striatum and with the rrCMRglc in association areas and primary visual cortex. The level of motor function was significantly inversely correlated with the FDOPA Ki in the anterior cingulate gyrus and with the rrCMRglc in bilateral primary motor cortex and right putamen. Conclusions: Changes of striatal FDOPA uptake and rrCMRglc in the primary motor cortex likely represent dysfunction in the motor system involving the corticobasal ganglia-thalamocortical loop. Change of FDOPA uptake in the anterior cingulate gyrus may be related to up-regulation of dopamine synthesis in surviving dopamine neurons. The regions where correlation with cognitive function was observed belong to a cognitive frontoparietal–hippocampal network.

Introduction

Parkinson's disease (PD) is a progressive degenerative disorder characterized clinically by tremor, rigidity, and bradykinesia and pathologically by dopamine deficiency in the striatum. Cognitive impairment is also a common symptom observed among PD patients, especially at an advanced stage. The prevalence rate of dementia is estimated at 20–40% of PD patients Aarsland et al., 1996, Giladi et al., 2000, and even in PD patients without dementia, specific impairments in executive function, visual memory, and/or visuospatial abilities are prevalent Dubois and Pillon, 1997, Janvin et al., 2003.

The target cells of the projection from the dopaminergic neurons in the substantia nigra are located in the striatum, a component of parallel corticobasal ganglia-thalamocortical (CBGTC) loops. This neural system includes functionally distinct loops, including a “motor loop,” and an “associative loop,” which is involved in cognitive functions. At the level of the striatum, the motor loop is largely centered on the putamen and the associative loop mostly on the caudate Alexander et al., 1986, Middleton and Strick, 1996, Parent and Hazrati, 1995.

6-[18F]fluoro-l-dopa (FDOPA) positron emission tomography (PET) has been used to investigate the activity of aromatic l-amino acid decarboxylase in the striatum and to assess the integrity of the dopaminergic system in vivo (Garnett et al., 1983). In patients with PD, FDOPA uptake in the striatum is decreased Brooks et al., 1990, Garnett et al., 1984, Nahmias et al., 1985 and there is an inverse correlation between the degree of motor deficit and FDOPA uptake in the striatum, especially in the putamen Holthoff-Detto et al., 1997, Leenders et al., 1990, Rinne et al., 2000, Vingerhoets et al., 1997. Meanwhile, correlations between FDOPA uptake in the caudate and cognitive function have been shown in groups of demented and nondemented PD patients Ito et al., 2002, Rinne et al., 2000. In nondemented PD patients, there have been reports of a positive correlation between FDOPA uptake in the caudate and memory performance (Holthoff-Detto et al., 1997) and impairment of tactile object discrimination in patients with low caudal dopaminergic function (Weder et al., 1999). The findings of these FDOPA PET studies are consistent with the parallel CBGTC loop model. However, the following findings are less consistent with this model: no correlation between FDOPA uptake in the caudate and cognitive functions (Broussolle et al., 1999), a relationship between motor function and FDOPA uptake in the caudate, as well as in the putamen Brooks et al., 1990, Broussolle et al., 1999, Vingerhoets et al., 1997, and a correlation between a cognitive function and the FDOPA uptake in the putamen (Holthoff et al., 1994).

The results of measurement of local cerebral metabolic rate for glucose in the resting state using [18F]fluorodeoxyglucoce (FDG) PET (Phelps et al., 1979) are more complex. Because the main output target of the basal ganglia is the frontal lobe, frontal hypometabolism might have been predicted (Carbon and Marie, 2003). However, it is the parietal cortex that displays hypometabolism in PD patients, a finding that has been frequently linked to the presence of dementia Karbe et al., 1992, Kuhl et al., 1984, Peppard et al., 1992, Piert et al., 1996. Moreover, even in nondemented PD patients, parietal hypometabolism compared to normal controls has been frequently reported Arahata et al., 1999, Bohnen et al., 1999, Eberling et al., 1994, Hu et al., 2000, Peppard et al., 1992, Piert et al., 1996. In addition, positive correlations between parietal hypometabolism and motor dysfunction Eidelberg et al., 1994, Moeller and Eidelberg, 1997 and cognitive impairment Mentis et al., 2002, Wu et al., 2000 have also been observed.

These results indicate that FDOPA uptake both in the putamen and the caudate nucleus and parietal hypometabolism may both be related to motor and, in some cases, cognitive function may be attributed to parallel progression of motor and cognitive damage in PD patients. Alternatively, the same neural population in the caudate, putamen, and parietal area may subserve both cognitive and motor function in PD patients. Whether parietal hypometabolism is related to impairment of nigrostriatal dopaminergic system or to alternative neuropathological processes that occur relatively parallel with but not perfectly simultaneously to the impairment in PD is unclear. To clarify these points, we undertook a double tracer study with FDOPA and FDG PET in the same group of PD patients.

We employed FDOPA PET, FDG PET, and multiple regression analysis using measures of cognitive and motor function in the same PD patients. To avoid using a priori regions of interest (ROI), SPM99 (Friston et al., 1995) was used for these analyses. Motor function was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores (Note: higher scores denote greater parkinsonian disability). Cognitive function was assessed with Raven's Coloured Progressive Matrices (RCPM) because it is sensitive to cognitive deficits in PD (Farina et al., 2000). This test was initially developed as a nonverbal intellectual test Raven, 1962, Sugishita and Yamasaki, 1993 and can be considered to rely on at least two cognitive factors: visuospatial and executive functions. Higher RCPM scores indicate better performance, and performance does not correlate significantly with severity of PD motor symptoms (Cronin-Golomb and Braun, 1997).

Section snippets

Subjects

Twenty-eight patients with PD (males 12, females 16; mean age ± SD: 62.6 ± 7.7 years; 12 with predominantly left PD signs, 15 with predominantly right PD signs, and 1 case with bilateral signs) were enrolled in this study. The mean duration of disease was 3.8 years (SD: 2.6 years; range: 1–10 years). All patients were examined by a neurologist at Chubu National Hospital and fulfilled the clinical criteria for the diagnosis of PD (Calne et al., 1992). The mean of the Hoehn and Yahr score (Hoehn

Results

The mean RCPM score was 30.4 (SD: 5.0; range: 21–36), and the mean UPDRS motor score was 29.2 (SD: 18.8; range: 5–65). There was no significant correlation between the UPDRS motor scores and the RCPM scores (correlation coefficient of these scores was −0.005, P = 0.98).

Discussion

FDOPA PET, FDG PET, and multiple regression analysis were performed with the RCPM and UPDRS motor scores of a group of PD patients using SPM99 to identify the functional neuroanatomy of cognitive and motor impairment in PD. The correlation coefficient of the RCPM and UPRDS motor scores was close to zero, which allows us to separate motor and cognitive effects.

Conclusion

The FDOPA Ki value in the striatum was inversely, and the rrCMRglc level in the motor areas was positively, correlated with the UPDRS motor score. These regions belong to a motor CBGTC loop. Meanwhile, the FDOPA Ki value in the left hippocampus and the rrCMRglc level in the left middle frontal gyrus and the right retrosplenial cortex were positively correlated with the RCPM score, and these regions belong to a cognitive frontoparietal–hippocampal network. The UPDRS motor score was significantly

Acknowledgements

The abstract form of this report was shown in Journal of Nuclear Medicine; 43(Suppl): 244 pp., 2002. The authors thank Dr. Dale Bailey, MRC Cyclotron Unit, Hammersmith Hospital, for allowing us to use the software, ‘kronos.’ This study was supported by funds for Research on Longevity Science and for Comprehensive Research of Aging and Health from the Ministry and Welfare of Japan.

References (93)

  • R.J Schwartzman et al.

    Cerebral metabolism of parkinsonian primates 21 days after MPTP

    Exp. Neurol.

    (1988)
  • A.P Strafella et al.

    Effects of chronic levodopa and pergolide treatment on cortical excitability in patients with Parkinson's disease: a transcranial magnetic stimulation study

    Clin. Neurophysiol.

    (2000)
  • H Umegaki et al.

    Involvement of dopamine D(2) receptors in complex maze learning and acetylcholine release in ventral hippocampus of rats

    Neuroscience

    (2001)
  • G.W Van Hoesen

    The parahippocampal gyrus new observations regarding its cortical connection in the monkey

    Trends Neurosci.

    (1982)
  • A Wilkerson et al.

    Ventral hippocampal dopamine D1 and D2 systems and spatial working memory in rats

    Neuroscience

    (1999)
  • D Aarsland et al.

    Frequency of dementia in Parkinson disease

    Arch. Neurol.

    (1996)
  • Y Abe et al.

    Occipital hypoperfusion in Parkinson's disease without dementia: correlation to impaired cortical visual processing

    J. Neurol. Neurosurg. Psychiatry

    (2003)
  • G.E Alexander et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Annu. Rev. Neurosci.

    (1986)
  • A Antonini et al.

    Complementary positron emission tomographic studies of the striatal dopaminergic system in Parkinson's disease

    Arch. Neurol.

    (1995)
  • N.I Bohnen et al.

    Motor correlates of occipital glucose hypometabolism in Parkinson's disease without dementia

    Neurology

    (1999)
  • D.J Brooks et al.

    Differing patterns of striatal 18F-Dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy

    Ann. Neurol.

    (1990)
  • R Cabeza et al.

    Imaging cognition II: an empirical review of 275 PET and fMRI studies

    J. Cogn. Neurosci.

    (2000)
  • D.B Calne et al.

    Criteria for diagnosing Parkinson's disease

    Ann. Neurol.

    (1992)
  • M Carbon et al.

    Modulation of regional brain function by deep brain stimulation: studies with positron emission tomography

    Curr. Opin. Neurol.

    (2002)
  • M Carbon et al.

    Functional imaging of cognition in Parkinson's disease

    Curr. Opin. Neurol.

    (2003)
  • M.J Catalan et al.

    A PET study of sequential finger movement of varying length in patients with Parkinson's disease

    Brain

    (1999)
  • C Cavada et al.

    Posterior parietal cortex in rhesus monkey: I. Parcellation of areas based on distinctive limbic and sensory corticocortical connections

    J. Comp. Neurol.

    (1989)
  • C Cavada et al.

    Posterior parietal cortex in rhesus monkey: II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe

    J. Comp. Neurol.

    (1989)
  • A Cronin-Golomb et al.

    Visuospatial dysfunction and problem solving in Parkinson's disease

    Neuropsychology

    (1997)
  • A Dagher et al.

    The role of the striatum and hippocampus in planning: a PET activation study in Parkinson's disease

    Brain

    (2001)
  • M D'Esposito et al.

    The neural basis of the central executive system of working memory

    Nature

    (1995)
  • V Della-Maggiore et al.

    Corticolimbic interactions associated with performance on a short-term memory task are modified by age

    J. Neurosci.

    (2000)
  • B Dubois et al.

    Cognitive deficits in Parkinson's disease

    J. Neurol.

    (1997)
  • D Eidelberg et al.

    The metabolic topography of parkinsonism

    J. Cereb. Blood Flow Metab.

    (1994)
  • G Esposito et al.

    Context-dependent, neural system-specific neurophysiological concomitants of ageing: mapping PET correlates during cognitive activation

    Brain

    (1999)
  • E Farina et al.

    Researching a differential impairment of frontal functions and explicit memory in early Parkinson's disease

    Eur. J. Neurol.

    (2000)
  • A Feigin et al.

    Metabolic correlates of levodopa response in Parkinson's disease

    Neurology

    (2001)
  • P.C Fletcher et al.

    Frontal lobes and human memory insights from functional neuroimaging

    Brain

    (2001)
  • K.J Friston et al.

    Statistical parametric maps in functional imaging: a general linear approach

    Hum. Brain Mapp.

    (1995)
  • E.S Garnett et al.

    Dopamine visualized in the basal ganglia of living man

    Nature

    (1983)
  • E.S Garnett et al.

    Central dopaminergic pathways in hemiparkinsonism examined by positron emission tomography

    Can. J. Neurol. Sci.

    (1984)
  • N Giladi et al.

    Risk factors for dementia, depression and psychosis in long-standing Parkinson's disease

    J. Neural Transm.

    (2000)
  • P Gloor
  • J.A Goldberg et al.

    Enhanced synchrony among primary motor cortex neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease

    J. Neurosci.

    (2002)
  • R Hilker et al.

    Deep brain stimulation of the subthalamic nucleus versus levodopa challenge in Parkinson's disease: measuring the on- and off-conditions with FDG-PET

    J. Neural Transm.

    (2002)
  • M.M Hoehn et al.

    Parkinsonism: onset, progression and mortality

    Neurology

    (1967)
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