Cognitive Impairment in Parkinson’s Disease: The Dual Syndrome HypothesisKehagia A.A.a · Barker R.A.b · Robbins T.W.c, d
aSchool of Psychology, University of St. Andrews, St. Andrews, bCambridge Centre for Brain Repair, Department of Clinical Neurosciences, cBehavioural and Clinical Neuroscience Institute, and dDepartment of Experimental Psychology, University of Cambridge, Cambridge, UK
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Research into the heterogeneous nature of cognitive impairment documented in patients with Parkinson’s disease (PD) has focused on disentangling deficits that vary between individuals, evolve and respond differentially to pharmacological treatments, and relate differentially to PD dementia (PDD). We summarise studies conducted in our laboratory over the last 2 decades, outlining the incremental development of our hypotheses, the starting point for which is our early work on executive deficits mirroring fronto-striatal dysfunction. We present subsequent findings linking these deficits to a model of dopaminergic function that conforms to an inverted curvilinear function. We review studies that investigated the range of dopamine-independent attentional and visuospatial memory deficits seen in PD, demonstrating that abnormalities in these domains more accurately predict PDD. We conclude with an exposition of the dual syndrome hypothesis, which distinguishes between dopaminergically mediated fronto-striatal executive impairments and a dementia syndrome with distinctive prodromal visuospatial deficits in which cholinergic treatments offer some clinical benefits.
© 2012 S. Karger AG, Basel
- Kish SJ, Shannak K, Hornykiewicz O: Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implications. N Engl J Med 1988;318:876–880.
- Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986;9:357–381.
- Cash R, Dennis T, L’Heureux R, Raisman R, Javoy-Agid F, Scatton B: Parkinson’s disease and dementia: norepinephrine and dopamine in locus ceruleus. Neurology 1987;37:42–46.
- Chan-Palay V, Asan E: Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson’s disease with and without dementia and depression. J Comp Neurol 1989;287:373–392.
- Zarow C, Lyness SA, Mortimer JA, Chui HC: Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 2003;60:337–341.
- Brooks DJ, Piccini P: Imaging in Parkinson’s disease: the role of monoamines in behavior. Biol Psychiatry 2006;59:908–918.
- Scatton B, Javoy-Agid F, Rouquier L, Dubois B, Agid Y: Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res 1983;275:321–328.
- Jellinger KA: Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991;14:153–197.
- Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA: Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain 2007;130(Pt 7):1787–1798.
- Levy G, Tang MX, Louis ED, Cote LJ, Alfaro B, Mejia H, et al: The association of incident dementia with mortality in PD. Neurology 2002;59:1708–1713.
- Sahakian BJ, Morris RG, Evenden JL, Heald A, Levy R, Philpot M, et al: A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson’s disease. Brain 1988;111(Pt 3):695–718.
- Loranger AW, Goodell H, McDowell FH, Lee JE, Sweet RD: Intellectual impairment in Parkinson’s syndrome. Brain 1972;95:405–412.
- Mortimer JA, Pirozzolo FJ, Hansch EC, Webster DD: Relationship of motor symptoms to intellectual deficits in Parkinson disease. Neurology 1982;32:133–137.
- Mayeux R, Stern Y, Rosen J, Leventhal J: Depression, intellectual impairment, and Parkinson disease. Neurology 1981;31:645–650.
- Taylor AE, Saint-Cyr JA, Lang AE: Frontal lobe dysfunction in Parkinson’s disease: the cortical focus of neostriatal outflow. Brain 1986;109:845–883.
- Morris RG, Downes JJ, Sahakian BJ, Evenden JL, Heald A, Robbins TW: Planning and spatial working memory in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;51:757–766.
- Robbins TW, James M, Owen AM, Lange KW, Lees AJ, Leigh PN, et al: Cognitive deficits in progressive supranuclear palsy, Parkinson’s disease, and multiple system atrophy in tests sensitive to frontal lobe dysfunction. J Neurol Neurosurg Psychiatry 1994; 57:79–88.
- Canavan AG, Passingham RE, Marsden CD, Quinn N, Wyke M, Polkey CE: Prism adaptation and other tasks involving spatial abilities in patients with Parkinson’s disease, patients with frontal lobe lesions and patients with unilateral temporal lobectomies. Neuropsychologia 1990;28:969–984.
- Cools AR: Basal ganglia and Parkinson’s disease: neurobiological and pharmacological aspects in animals and man. Clin Neurol Neurosurg 1984;86:178–195.
- Brown RG, Marsden CD: An investigation of the phenomenon of ‘set’ in Parkinson’s disease. Mov Disord 1988;3:152–161.
- Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP, et al: Fronto-striatal cognitive deficits at different stages of Parkinson’s disease. Brain 1992;115(Pt 6):1727–1751.
- Owen AM, Sahakian BJ, Hodges JR, Summers BA, Polkey CE, Robbins TW: Dopamine-dependent frontostriatal planning deficits in early Parkinson’s disease. Neuropsychology 1995;9:126–140.
- Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW: Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 1990;28:1021–1034.
- Robbins TW, James M, Owen AM, Sahakian BJ, McInnes L, Rabbitt P: Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 1994;5:266–281.
- Lange KW, Robbins TW, Marsden CD, James M, Owen AM, Paul GM: l-dopa withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology (Berl) 1992;107:394–404.
- Loranger AW, Goodell H, Lee JE, McDowell F: Levodopa treatment of Parkinson’s syndrome. Improved intellectual functioning. Arch Gen Psychiatry 1972;26:163–168.
- Bowen FP, Kamienny RS, Burns MM, Yahr M: Parkinsonism: effects of levodopa treatment on concept formation. Neurology 1975;25:701–704.
- Cools R, Barker RA, Sahakian BJ, Robbins TW: Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb Cortex 2001;11:1136–1143.
- Cools R, Barker RA, Sahakian BJ, Robbins TW: l-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson’s disease. Neuropsychologia 2003;41:1431–1441.
- Lewis SJ, Slabosz A, Robbins TW, Barker RA, Owen AM: Dopaminergic basis for deficits in working memory but not attentional set-shifting in Parkinson’s disease. Neuropsychologia 2005;43:823–832.
- Lewis SJ, Dove A, Robbins TW, Barker RA, Owen AM: Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J Neurosci 2003;23:6351–6356.
- Gotham AM, Brown RG, Marsden CD: ‘Frontal’ cognitive function in patients with Parkinson’s disease ‘on’ and ‘off’ levodopa. Brain 1988;111(Pt 2):299–321.
- Swainson R, Rogers RD, Sahakian BJ, Summers BA, Polkey CE, Robbins TW: Probabilistic learning and reversal deficits in patients with Parkinson’s disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication. Neuropsychologia 2000;38:596–612.
- Cools R, Clark L, Owen AM, Robbins TW: Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. J Neurosci 2002;22:4563–4567.
- Rogers RD, Owen AM, Middleton HC, Williams EJ, Pickard JD, Sahakian BJ, et al: Choosing between small, likely rewards and large, unlikely rewards activates inferior and orbital prefrontal cortex. J Neurosci 1999;19:9029–9038.
- Lawrence AD, Sahakian BJ, Robbins TW: Cognitive functions and corticostriatal circuits: insights from Huntington’s disease. Trends Cogn Sci 1998;2:379–388.
- Schultz W: Getting formal with dopamine and reward. Neuron 2002;36:241–263.
- Cools R, Lewis SJ, Clark L, Barker RA, Robbins TW: l-DOPA disrupts activity in the nucleus accumbens during reversal learning in Parkinson’s disease. Neuropsychopharmacology 2007;32:180–189.
- Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE: Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease. Mayo Clin Proc 2009;84:310–316.
- van Eimeren T, Ballanger B, Pellecchia G, Miyasaki JM, Lang AE, Strafella AP: Dopamine agonists diminish value sensitivity of the orbitofrontal cortex: a trigger for pathological gambling in Parkinson’s disease? Neuropsychopharmacology 2009;34:2758–2766.
- Robbins TW, Arnsten AF: The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu Rev Neurosci 2009;32:267–287.
- Cools R, Stefanova E, Barker RA, Robbins TW, Owen AM: Dopaminergic modulation of high-level cognition in Parkinson’s disease: the role of the prefrontal cortex revealed by PET. Brain 2002;125(Pt 3):584–594.
- Kaasinen V, Nurmi E, Bruck A, Eskola O, Bergman J, Solin O, et al: Increased frontal [(18)F]fluorodopa uptake in early Parkinson’s disease: sex differences in the prefrontal cortex. Brain 2001;124(Pt 6):1125–1130.
- Rakshi JS, Uema T, Ito K, Bailey DL, Morrish PK, Ashburner J, et al: Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson’s disease. A 3D [(18)F]dopa-PET study. Brain 1999;122(Pt 9):1637–1650.
- Pycock CJ, Kerwin RW, Carter CJ: Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature 1980;286:74–76.
- Roberts AC, De Salvia MA, Wilkinson LS, Collins P, Muir JL, Everitt BJ, et al: 6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine. J Neurosci 1994;14(5 Pt 1):2531–2544.
- Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, et al: Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001;98:6917–6922.
- Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, et al: Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 2003;100:6186–6191.
- Yerkes RM, Dodson JD: The relation of strength of stimulus to rapidity of habit-formation. J Comp Neurol Psychol 1908;18:459–482.
- Foltynie T, Brayne CE, Robbins TW, Barker RA: The cognitive ability of an incident cohort of Parkinson’s patients in the UK. The CamPaIGN study. Brain 2004;127(Pt 3):550–560.
- Williams-Gray CH, Hampshire A, Robbins TW, Owen AM, Barker RA: Catechol O-methyltransferase Val158Met genotype influences frontoparietal activity during planning in patients with Parkinson’s disease. J Neurosci 2007;27:4832–4838.
- Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW, et al: The distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up of the CamPaIGN cohort. Brain 2009;132(Pt 11):2958–2969.
- Downes JJ, Roberts AC, Sahakian BJ, Evenden JL, Morris RG, Robbins TW: Impaired extra-dimensional shift performance in medicated and unmedicated Parkinson’s disease: evidence for a specific attentional dysfunction. Neuropsychologia 1989;27:1329–1343.
- Slabosz A, Lewis SJ, Smigasiewicz K, Szymura B, Barker RA, Owen AM: The role of learned irrelevance in attentional set-shifting impairments in Parkinson’s disease. Neuropsychology 2006;20:578–588.
- Owen AM, Beksinska M, James M, Leigh PN, Summers BA, Marsden CD, et al: Visuospatial memory deficits at different stages of Parkinson’s disease. Neuropsychologia 1993;31:627–644.
- Owen AM, Roberts AC, Hodges JR, Summers BA, Polkey CE, Robbins TW: Contrasting mechanisms of impaired attentional set-shifting in patients with frontal lobe damage or Parkinson’s disease. Brain 1993;116(Pt 5):1159–1175.
- Kehagia AA, Cools R, Barker RA, Robbins TW: Switching between abstract rules reflects disease severity but not dopaminergic status in Parkinson’s disease. Neuropsychologia 2009;47:1117–1127.
- Collins P, Wilkinson LS, Everitt BJ, Robbins TW, Roberts AC: The effect of dopamine depletion from the caudate nucleus of the common marmoset (Callithrix jacchus) on tests of prefrontal cognitive function. Behav Neurosci 2000;114:3–17.
- Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW, Robbins TW: Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Eur J Neurosci 2007;25:3719–3724.
- McGaughy J, Ross RS, Eichenbaum H: Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 2008;153:63–71.
- Kehagia AA, Murray GK, Robbins TW: Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation. Curr Opin Neurobiol 2010;20:1–6.
- Weintraub D, Mavandadi S, Mamikonyan E, Siderowf AD, Duda JE, Hurtig HI, et al: Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology 2010;75:448–455.
- Marsh L, Biglan K, Gerstenhaber M, Williams JR: Atomoxetine for the treatment of executive dysfunction in Parkinson’s disease: a pilot open-label study. Mov Disord 2009;24:277–282.
- Flowers KA, Pearce I, Pearce JM: Recognition memory in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1984;47:1174–1181.
- Blackwell AD, Sahakian BJ, Vesey R, Semple JM, Robbins TW, Hodges JR: Detecting dementia: novel neuropsychological markers of preclinical Alzheimer’s disease. Dement Geriatr Cogn Disord 2004;17:42–48.
- Dubois B, Ruberg M, Javoy-Agid F, Ploska A, Agid Y: A subcortico-cortical cholinergic system is affected in Parkinson’s disease. Brain Res 1983;288:213–218.
- Cooper JA, Sagar HJ, Doherty SM, Jordan N, Tidswell P, Sullivan EV: Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson’s disease. A follow-up study of untreated patients. Brain 1992;115(Pt 6):1701–1725.
- Dubois B, Danze F, Pillon B, Cusimano G, Lhermitte F, Agid Y: Cholinergic-dependent cognitive deficits in Parkinson’s disease. Ann Neurol 1987;22:26–30.
- Herzallah MM, Mustafa AA, Misk AJ, Al-Dweib LH, Abdelrazeq SA, Myers CE, et al: Depression impairs learning whereas anticholinergics impair transfer generalization in Parkinson patients tested on dopaminergic medications. Cogn Behav Neurol 2010;23:98–105.
- Folstein MF, Folstein SE, McHugh PR: ‘Mini Mental State’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
- Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA: Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005;76:343–348.
- Lewis SJ, Barker RA: Understanding the dopaminergic deficits in Parkinson’s disease: insights into disease heterogeneity. J Clin Neurosci 2009;16:620–625.
- Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, et al: Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson’s disease. Ann Neurol 2007;62:145–153.
- Kehagia AA, Barker RA, Robbins TW: Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson’s disease. Lancet Neurol 2010;9:1200–1213.
- Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, et al: Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004;351:2509–2518.
- Bohnen NI, Kaufer DI, Ivanco LS, Lopresti B, Koeppe RA, Davis JG, et al: Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003;60:1745–1748.
Bentivoglio M, Morelli M: The organization and circuitry of mesencephalic dopamine neurons and the distribution of dopamine receptors in the brain; in Dunnett DB, Bjorklund A, Hokfelt T (eds): The Handbook of Chemical Neuroanatomy. Amsterdam, Elsevier, 2005, pp 1–107.
- De Keyser J, Ebinger G, Vauquelin G: Evidence for a widespread dopaminergic innervation of the human cerebral neocortex. Neurosci Lett 1989;104:281–285.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.