Abstract
Objectives: The aetiology of the cognitive changes seen in Parkinson's disease (PD) is multifactorial but it is likely that a significant contribution arises from the disruption of dopaminergic pathways. This study aimed to investigate the contribution of the dopaminergic system to performance on two executive tasks using 18F-6-fluorodopa positron emission tomography (18F-dopa PET) in PD subjects with early cognitive changes.
Methods: 16 non-demented, non-depressed PD subjects were evaluated with the Tower of London (TOL) spatial planning task, a verbal working memory task (VWMT) and 18F-dopa PET, all known to be affected in early PD. Statistical parametric mapping (SPM) localised brain regions in which 18F-dopa uptake covaried with performance scores. Frontal cortical resting glucose metabolism was assessed with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET.
Results: SPM localised significant covariation between right caudate 18F-dopa uptake (Ki) and TOL scores and between left anterior putamen Ki and VWMT performance. No significant covariation was found between task scores and 18F-dopa Ki values in either limbic or cortical regions. Frontal cortical glucose metabolism was preserved in all cases.
Conclusions: These findings support a causative role of striatal dopaminergic depletion in the early impairment of executive functions seen in PD. They suggest that spatial and verbal executive tasks require integrity of the right and left striatum, respectively, and imply that the pattern of cognitive changes manifest by a patient with PD may reflect differential dopamine loss in the two striatal complexes.
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- Alexander G. E., DeLong M. R., Strick P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–381. doi: 10.1146/annurev.ne.09.030186.002041. [DOI] [PubMed] [Google Scholar]
- Alivisatos B., Petrides M. Functional activation of the human brain during mental rotation. Neuropsychologia. 1997 Feb;35(2):111–118. doi: 10.1016/s0028-3932(96)00083-8. [DOI] [PubMed] [Google Scholar]
- Baker S. C., Rogers R. D., Owen A. M., Frith C. D., Dolan R. J., Frackowiak R. S., Robbins T. W. Neural systems engaged by planning: a PET study of the Tower of London task. Neuropsychologia. 1996 Jun;34(6):515–526. doi: 10.1016/0028-3932(95)00133-6. [DOI] [PubMed] [Google Scholar]
- Beauchamp M. H., Dagher A., Aston J. A. D., Doyon J. Dynamic functional changes associated with cognitive skill learning of an adapted version of the Tower of London task. Neuroimage. 2003 Nov;20(3):1649–1660. doi: 10.1016/j.neuroimage.2003.07.003. [DOI] [PubMed] [Google Scholar]
- Blonder L. X., Gur R. E., Gur R. C., Saykin A. J., Hurtig H. I. Neuropsychological functioning in hemiparkinsonism. Brain Cogn. 1989 Mar;9(2):244–257. doi: 10.1016/0278-2626(89)90034-1. [DOI] [PubMed] [Google Scholar]
- Braak Heiko, Del Tredici Kelly, Rüb Udo, de Vos Rob A. I., Jansen Steur Ernst N. H., Braak Eva. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197–211. doi: 10.1016/s0197-4580(02)00065-9. [DOI] [PubMed] [Google Scholar]
- Brooks D. J., Salmon E. P., Mathias C. J., Quinn N., Leenders K. L., Bannister R., Marsden C. D., Frackowiak R. S. The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson's disease, studied with PET. Brain. 1990 Oct;113(Pt 5):1539–1552. doi: 10.1093/brain/113.5.1539. [DOI] [PubMed] [Google Scholar]
- Brozoski T. J., Brown R. M., Rosvold H. E., Goldman P. S. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science. 1979 Aug 31;205(4409):929–932. doi: 10.1126/science.112679. [DOI] [PubMed] [Google Scholar]
- Brück A., Portin R., Lindell A., Laihinen A., Bergman J., Haaparanta M., Solin O., Rinne J. O. Positron emission tomography shows that impaired frontal lobe functioning in Parkinson's disease is related to dopaminergic hypofunction in the caudate nucleus. Neurosci Lett. 2001 Sep 28;311(2):81–84. doi: 10.1016/s0304-3940(01)02124-3. [DOI] [PubMed] [Google Scholar]
- Caplan L. R., Schmahmann J. D., Kase C. S., Feldmann E., Baquis G., Greenberg J. P., Gorelick P. B., Helgason C., Hier D. B. Caudate infarcts. Arch Neurol. 1990 Feb;47(2):133–143. doi: 10.1001/archneur.1990.00530020029011. [DOI] [PubMed] [Google Scholar]
- Cools R., Barker R. A., Sahakian B. J., Robbins T. W. Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands. Cereb Cortex. 2001 Dec;11(12):1136–1143. doi: 10.1093/cercor/11.12.1136. [DOI] [PubMed] [Google Scholar]
- Cools Roshan, Stefanova Elka, Barker Roger A., Robbins Trevor W., Owen Adrian M. Dopaminergic modulation of high-level cognition in Parkinson's disease: the role of the prefrontal cortex revealed by PET. Brain. 2002 Mar;125(Pt 3):584–594. doi: 10.1093/brain/awf052. [DOI] [PubMed] [Google Scholar]
- Dagher A., Owen A. M., Boecker H., Brooks D. J. Mapping the network for planning: a correlational PET activation study with the Tower of London task. Brain. 1999 Oct;122(Pt 10):1973–1987. doi: 10.1093/brain/122.10.1973. [DOI] [PubMed] [Google Scholar]
- Dagher A., Owen A. M., Boecker H., Brooks D. J. The role of the striatum and hippocampus in planning: a PET activation study in Parkinson's disease. Brain. 2001 May;124(Pt 5):1020–1032. doi: 10.1093/brain/124.5.1020. [DOI] [PubMed] [Google Scholar]
- Desmond J. E., Gabrieli J. D., Glover G. H. Dissociation of frontal and cerebellar activity in a cognitive task: evidence for a distinction between selection and search. Neuroimage. 1998 May;7(4 Pt 1):368–376. doi: 10.1006/nimg.1998.0340. [DOI] [PubMed] [Google Scholar]
- Direnfeld L. K., Albert M. L., Volicer L., Langlais P. J., Marquis J., Kaplan E. Parkinson's disease. The possible relationship of laterality to dementia and neurochemical findings. Arch Neurol. 1984 Sep;41(9):935–941. doi: 10.1001/archneur.1984.04050200041016. [DOI] [PubMed] [Google Scholar]
- Divac I., Rosvold H. E., Szwarcbart M. K. Behavioral effects of selective ablation of the caudate nucleus. J Comp Physiol Psychol. 1967 Apr;63(2):184–190. doi: 10.1037/h0024348. [DOI] [PubMed] [Google Scholar]
- Dong Y., Fukuyama H., Honda M., Okada T., Hanakawa T., Nakamura K., Nagahama Y., Nagamine T., Konishi J., Shibasaki H. Essential role of the right superior parietal cortex in Japanese kana mirror reading: An fMRI study. Brain. 2000 Apr;123(Pt 4):790–799. doi: 10.1093/brain/123.4.790. [DOI] [PubMed] [Google Scholar]
- Dubois B., Pillon B. Cognitive deficits in Parkinson's disease. J Neurol. 1997 Jan;244(1):2–8. doi: 10.1007/pl00007725. [DOI] [PubMed] [Google Scholar]
- Eidelberg D., Moeller J. R., Dhawan V., Spetsieris P., Takikawa S., Ishikawa T., Chaly T., Robeson W., Margouleff D., Przedborski S. The metabolic topography of parkinsonism. J Cereb Blood Flow Metab. 1994 Sep;14(5):783–801. doi: 10.1038/jcbfm.1994.99. [DOI] [PubMed] [Google Scholar]
- Foltynie Thomas, Goldberg Terry E., Lewis Simon G. J., Blackwell Andrew D., Kolachana Bhaskar S., Weinberger Daniel R., Robbins Trevor W., Barker Roger A. Planning ability in Parkinson's disease is influenced by the COMT val158met polymorphism. Mov Disord. 2004 Aug;19(8):885–891. doi: 10.1002/mds.20118. [DOI] [PubMed] [Google Scholar]
- Friederici Angela D., Rüschemeyer Shirley-Ann, Hahne Anja, Fiebach Christian J. The role of left inferior frontal and superior temporal cortex in sentence comprehension: localizing syntactic and semantic processes. Cereb Cortex. 2003 Feb;13(2):170–177. doi: 10.1093/cercor/13.2.170. [DOI] [PubMed] [Google Scholar]
- Gibb W. R., Lees A. J. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry. 1988 Jun;51(6):745–752. doi: 10.1136/jnnp.51.6.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hammers Alexander, Allom Richard, Koepp Matthias J., Free Samantha L., Myers Ralph, Lemieux Louis, Mitchell Tejal N., Brooks David J., Duncan John S. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003 Aug;19(4):224–247. doi: 10.1002/hbm.10123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoehn M. M., Yahr M. D. Parkinsonism: onset, progression and mortality. Neurology. 1967 May;17(5):427–442. doi: 10.1212/wnl.17.5.427. [DOI] [PubMed] [Google Scholar]
- Hu M. T., Taylor-Robinson S. D., Chaudhuri K. R., Bell J. D., Labbé C., Cunningham V. J., Koepp M. J., Hammers A., Morris R. G., Turjanski N. Cortical dysfunction in non-demented Parkinson's disease patients: a combined (31)P-MRS and (18)FDG-PET study. Brain. 2000 Feb;123(Pt 2):340–352. doi: 10.1093/brain/123.2.340. [DOI] [PubMed] [Google Scholar]
- Huber S. J., Miller H., Bohaska L., Christy J. A., Bornstein R. A. Asymmetrical cognitive differences associated with hemiparkinsonism. Arch Clin Neuropsychol. 1992 Nov;7(6):471–480. [PubMed] [Google Scholar]
- Kaasinen V., Nurmi E., Brück A., Eskola O., Bergman J., Solin O., Rinne J. O. Increased frontal [(18)F]fluorodopa uptake in early Parkinson's disease: sex differences in the prefrontal cortex. Brain. 2001 Jun;124(Pt 6):1125–1130. doi: 10.1093/brain/124.6.1125. [DOI] [PubMed] [Google Scholar]
- Leentjens A. F., Verhey F. R., Luijckx G. J., Troost J. The validity of the Beck Depression Inventory as a screening and diagnostic instrument for depression in patients with Parkinson's disease. Mov Disord. 2000 Nov;15(6):1221–1224. doi: 10.1002/1531-8257(200011)15:6<1221::aid-mds1024>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
- Lehéricy Stéphane, Ducros Mathieu, Van de Moortele Pierre-François, Francois Chantal, Thivard Lionel, Poupon Cyril, Swindale Nick, Ugurbil Kamil, Kim Dae-Shik. Diffusion tensor fiber tracking shows distinct corticostriatal circuits in humans. Ann Neurol. 2004 Apr;55(4):522–529. doi: 10.1002/ana.20030. [DOI] [PubMed] [Google Scholar]
- Lewis Simon J. G., Cools Roshan, Robbins Trevor W., Dove Anja, Barker Roger A., Owen Adrian M. Using executive heterogeneity to explore the nature of working memory deficits in Parkinson's disease. Neuropsychologia. 2003;41(6):645–654. doi: 10.1016/s0028-3932(02)00257-9. [DOI] [PubMed] [Google Scholar]
- Lewis Simon J. G., Dove Anja, Robbins Trevor W., Barker Roger A., Owen Adrian M. Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry. J Neurosci. 2003 Jul 16;23(15):6351–6356. doi: 10.1523/JNEUROSCI.23-15-06351.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marié R. M., Barré L., Dupuy B., Viader F., Defer G., Baron J. C. Relationships between striatal dopamine denervation and frontal executive tests in Parkinson's disease. Neurosci Lett. 1999 Jan 29;260(2):77–80. doi: 10.1016/s0304-3940(98)00928-8. [DOI] [PubMed] [Google Scholar]
- Mattay Venkata S., Tessitore Alessandro, Callicott Joseph H., Bertolino Alessandro, Goldberg Terry E., Chase Thomas N., Hyde Thomas M., Weinberger Daniel R. Dopaminergic modulation of cortical function in patients with Parkinson's disease. Ann Neurol. 2002 Feb;51(2):156–164. doi: 10.1002/ana.10078. [DOI] [PubMed] [Google Scholar]
- Mehta M. A., Sahakian B. J., McKenna P. J., Robbins T. W. Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson's disease. Psychopharmacology (Berl) 1999 Sep;146(2):162–174. doi: 10.1007/s002130051102. [DOI] [PubMed] [Google Scholar]
- Middleton F. A., Strick P. L. Basal ganglia output and cognition: evidence from anatomical, behavioral, and clinical studies. Brain Cogn. 2000 Mar;42(2):183–200. doi: 10.1006/brcg.1999.1099. [DOI] [PubMed] [Google Scholar]
- Moore Robert Y., Whone Alan L., McGowan Stephen, Brooks David J. Monoamine neuron innervation of the normal human brain: an 18F-DOPA PET study. Brain Res. 2003 Aug 29;982(2):137–145. doi: 10.1016/s0006-8993(03)02721-5. [DOI] [PubMed] [Google Scholar]
- Müller U., Wächter T., Barthel H., Reuter M., von Cramon D. Y. Striatal [123I]beta-CIT SPECT and prefrontal cognitive functions in Parkinson's disease. J Neural Transm (Vienna) 2000;107(3):303–319. doi: 10.1007/s007020050025. [DOI] [PubMed] [Google Scholar]
- Nenadic Igor, Gaser Christian, Volz Hans-Peter, Rammsayer Thomas, Häger Frank, Sauer Heinrich. Processing of temporal information and the basal ganglia: new evidence from fMRI. Exp Brain Res. 2002 Nov 27;148(2):238–246. doi: 10.1007/s00221-002-1188-4. [DOI] [PubMed] [Google Scholar]
- Newman Sharlene D., Carpenter Patricia A., Varma Sashank, Just Marcel Adam. Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception. Neuropsychologia. 2003;41(12):1668–1682. doi: 10.1016/s0028-3932(03)00091-5. [DOI] [PubMed] [Google Scholar]
- Ortiz N., Barraquer Bordas L. Delirio de localización geográfica en el cuadro clínico de un hematoma cápsulo-putaminal derecho. Contribución al conocimiento de la semiología neuropsicológica de las lesiones subcorticales del hemisferio derecho. Neurologia. 1991 Mar;6(3):103–107. [PubMed] [Google Scholar]
- Owen A. M., Beksinska M., James M., Leigh P. N., Summers B. A., Marsden C. D., Quinn N. P., Sahakian B. J., Robbins T. W. Visuospatial memory deficits at different stages of Parkinson's disease. Neuropsychologia. 1993 Jul;31(7):627–644. doi: 10.1016/0028-3932(93)90135-m. [DOI] [PubMed] [Google Scholar]
- Owen A. M., Doyon J., Dagher A., Sadikot A., Evans A. C. Abnormal basal ganglia outflow in Parkinson's disease identified with PET. Implications for higher cortical functions. Brain. 1998 May;121(Pt 5):949–965. doi: 10.1093/brain/121.5.949. [DOI] [PubMed] [Google Scholar]
- Owen A. M., James M., Leigh P. N., Summers B. A., Marsden C. D., Quinn N. P., Lange K. W., Robbins T. W. Fronto-striatal cognitive deficits at different stages of Parkinson's disease. Brain. 1992 Dec;115(Pt 6):1727–1751. doi: 10.1093/brain/115.6.1727. [DOI] [PubMed] [Google Scholar]
- Owen A. M., Sahakian B. J., Semple J., Polkey C. E., Robbins T. W. Visuo-spatial short-term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia. 1995 Jan;33(1):1–24. doi: 10.1016/0028-3932(94)00098-a. [DOI] [PubMed] [Google Scholar]
- Patlak C. S., Blasberg R. G. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985 Dec;5(4):584–590. doi: 10.1038/jcbfm.1985.87. [DOI] [PubMed] [Google Scholar]
- Piccini Paola, Pavese Nicola, Brooks David J. Endogenous dopamine release after pharmacological challenges in Parkinson's disease. Ann Neurol. 2003 May;53(5):647–653. doi: 10.1002/ana.10526. [DOI] [PubMed] [Google Scholar]
- Poldrack R. A., Gabrieli J. D. Memory and the brain: what's right and what's left? Cell. 1998 Jun 26;93(7):1091–1093. doi: 10.1016/s0092-8674(00)81451-8. [DOI] [PubMed] [Google Scholar]
- Poldrack R. A., Prabhakaran V., Seger C. A., Gabrieli J. D. Striatal activation during acquisition of a cognitive skill. Neuropsychology. 1999 Oct;13(4):564–574. doi: 10.1037//0894-4105.13.4.564. [DOI] [PubMed] [Google Scholar]
- ROSVOLD H. E., DELGADO J. M. The effect on delayed-alternation test performance of stimulating or destroying electrically structures within the frontal lobes of the monkey's brain. J Comp Physiol Psychol. 1956 Aug;49(4):365–372. doi: 10.1037/h0087991. [DOI] [PubMed] [Google Scholar]
- Rakshi J. S., Uema T., Ito K., Bailey D. L., Morrish P. K., Ashburner J., Dagher A., Jenkins I. H., Friston K. J., Brooks D. J. Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease A 3D [(18)F]dopa-PET study. Brain. 1999 Sep;122(Pt 9):1637–1650. doi: 10.1093/brain/122.9.1637. [DOI] [PubMed] [Google Scholar]
- Riklan M., Stellar S., Reynolds C. The relationship of memory and cognition in Parkinson's disease to lateralisation of motor symptoms. J Neurol Neurosurg Psychiatry. 1990 Apr;53(4):359–360. doi: 10.1136/jnnp.53.4.359-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rinne J. O., Portin R., Ruottinen H., Nurmi E., Bergman J., Haaparanta M., Solin O. Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission tomographic study. Arch Neurol. 2000 Apr;57(4):470–475. doi: 10.1001/archneur.57.4.470. [DOI] [PubMed] [Google Scholar]
- Rolls E. T. Neurophysiology and cognitive functions of the striatum. Rev Neurol (Paris) 1994 Aug-Sep;150(8-9):648–660. [PubMed] [Google Scholar]
- Sawaguchi T., Goldman-Rakic P. S. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science. 1991 Feb 22;251(4996):947–950. doi: 10.1126/science.1825731. [DOI] [PubMed] [Google Scholar]
- Schmand B., de Bie R. M., Koning-Haanstra M., de Smet J. S., Speelman J. D., van Zomeren A. H. Unilateral pallidotomy in PD: a controlled study of cognitive and behavioral effects. The Netherlands Pallidotomy Study (NEPAS) group. Neurology. 2000 Mar 14;54(5):1058–1064. doi: 10.1212/wnl.54.5.1058. [DOI] [PubMed] [Google Scholar]
- Schott J. M., Crutch S. J., Fox N. C., Warrington E. K. Development of selective verbal memory impairment secondary to a left thalamic infarct: a longitudinal case study. J Neurol Neurosurg Psychiatry. 2003 Feb;74(2):255–257. doi: 10.1136/jnnp.74.2.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spinks T. J., Jones T., Bailey D. L., Townsend D. W., Grootoonk S., Bloomfield P. M., Gilardi M. C., Casey M. E., Sipe B., Reed J. Physical performance of a positron tomograph for brain imaging with retractable septa. Phys Med Biol. 1992 Aug;37(8):1637–1655. doi: 10.1088/0031-9155/37/8/002. [DOI] [PubMed] [Google Scholar]
- Spinks T. J., Jones T., Bloomfield P. M., Bailey D. L., Miller M., Hogg D., Jones W. F., Vaigneur K., Reed J., Young J. Physical characteristics of the ECAT EXACT3D positron tomograph. Phys Med Biol. 2000 Sep;45(9):2601–2618. doi: 10.1088/0031-9155/45/9/313. [DOI] [PubMed] [Google Scholar]
- Tomer R., Levin B. E., Weiner W. J. Side of onset of motor symptoms influences cognition in Parkinson's disease. Ann Neurol. 1993 Oct;34(4):579–584. doi: 10.1002/ana.410340412. [DOI] [PubMed] [Google Scholar]
- Trépanier L. L., Saint-Cyr J. A., Lozano A. M., Lang A. E. Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson's disease. Neurology. 1998 Jul;51(1):207–215. doi: 10.1212/wnl.51.1.207. [DOI] [PubMed] [Google Scholar]
- White N. M. Mnemonic functions of the basal ganglia. Curr Opin Neurobiol. 1997 Apr;7(2):164–169. doi: 10.1016/s0959-4388(97)80004-9. [DOI] [PubMed] [Google Scholar]
- Whone Alan L., Moore Robert Y., Piccini Paola P., Brooks David J. Plasticity of the nigropallidal pathway in Parkinson's disease. Ann Neurol. 2003 Feb;53(2):206–213. doi: 10.1002/ana.10427. [DOI] [PubMed] [Google Scholar]
- van den Heuvel Odile A., Groenewegen Henk J., Barkhof Frederik, Lazeron Richard H. C., van Dyck Richard, Veltman Dick J. Frontostriatal system in planning complexity: a parametric functional magnetic resonance version of Tower of London task. Neuroimage. 2003 Feb;18(2):367–374. doi: 10.1016/s1053-8119(02)00010-1. [DOI] [PubMed] [Google Scholar]