Cognitive impairment is a frequent non-motorsymptom of Parkinson’s disease (PD). In early disease stage, this takes the features of dysexecutive syndrome, and is mostly dependent on derangement of frontostriatal circuitries. In advanced stages, worsening of dysexecutive symptoms is accompanied by disorientation and memory deficit leading to dementia in 30% of cases, due to multiple neurotransmitter derangement. Dysexecutive symptoms in the early stages of PD may benefit from dopamine replacement therapy (DRT). Conversely, severe cognitive symptoms in more advanced stages are frequently aggravated by DRT. In particular, pulsatile stimulation of dopaminergic receptors by orally administered levodopa (LD) plays a significant negative role on cognitive and neuropsychiatric symptoms in advanced PD. The introduction of a gel of LD-carbidopa for continuous intestinal administration (LCIG) allows marked stabilization of plasma LD concentrations and provides benefit on motor fluctuations and dyskinesia of significantly greater magnitude than conventional oral administration in advanced PD patients. The results from several preliminary studies suggest that efficacy of LCGI on motor symptoms may be accompanied by good tolerability and potential benefit on several non-motor symptoms, including cognitive impairment. Future studies with longer observation period and larger cohorts are advised to confirm these preliminary observations.
References
[1]
Hughes, A.J., Daniel, S.E., Kilford, L., et al. (1992) Accuracy of Clinical Diagnosis of Idiopathic Parkinson’s Disease: A Clinic-Pathological Study of 100 Cases. Journal of Neurology, Neurosurgery and Psychiatry, 55, 181-184.
https://doi.org/10.1136/jnnp.55.3.181
[2]
Scherfler, C., Schwarz, J., Antonini, A., et al. (2007) Role of DAT-SPECT in the Diagnostic Work up of Parkinsonism. Movement Disorders, 22, 1229-1238.
https://doi.org/10.1002/mds.21505
[3]
Aquino, C.C. and Fox, S.H. (2015) Clinical Spectrum of Levodopa-Induced Complications. Movement Disorders, 30, 80-89. https://doi.org/10.1002/mds.26125
[4]
Encarnacion, E.V. and Hauser, R.A. (2008) Levodopa-Induced Dyskinesias in Parkinson’s Disease: Etiology, Impact on Quality of Life, and Treatments. European Neurology, 60, 57-66. https://doi.org/10.1159/000131893
[5]
Stocchi, F. (2009) The Hypothesis of the Genesis of Motor Complications and Continuous Dopaminergic Stimulation in the Treatment of Parkinson’s Disease. Parkinsonism and Related Disorders, 15, S9-S15.
https://doi.org/10.1016/S1353-8020(09)70005-7
[6]
Stocchi, F., Tagliati, M. and Olanow, C.W. (2008) Treatment of Levodopa-Induced Motor Complications. Movement Disorders, 23, S599-S612.
https://doi.org/10.1002/mds.22052
[7]
Nyholm, D. (2012) Duodopa Treatment for Advanced Parkinson’s Disease: A Review of Efficacy and Safety. Parkinsonism and Related Disorders, 18, 916-929.
https://doi.org/10.1016/j.parkreldis.2012.06.022
[8]
Antonini, A., Isaias, M., Canesi, M., et al. (2007) Duodenal Levodopa Infusion for Advanced Parkinson’s Disease: 12-Month Treatment Outcome. Movement Disorders, 22, 1145-1149. https://doi.org/10.1002/mds.21500
[9]
Nyholm, D., Nilsson Remahl, A.I., Dizdar, N., et al. (2005) Duodenal Levodopa Infusion Monotherapy vs Oral Polypharmacy in Advanced Parkinson’s Disease. Neurology, 64, 216-223. https://doi.org/10.1212/01.WNL.0000149637.70961.4C
[10]
Schrempf, W., Brandt, M.D., Storch, A., et al. (2014) Sleep Disorders in Parkinson’s Disease. Journal of Parkinson’s Disease, 4, 211-221.
Cury, R.G., Galhardoni, R., Fonoff, E.T., et al. (2016) Sensory Abnormalities and Pain in Parkinson Disease and Its Modulation by Treatment of Motor Symptoms. European Journal of Pain, 20, 151-165. https://doi.org/10.1002/ejp.745
[13]
Blonder, L.X. and Slevin, J.T. (2011) Emotional Dysfunction in Parkinson’s Disease. Behavioural Neurology, 24, 201-217. https://doi.org/10.1155/2011/143857
[14]
Emre, M., Ford, P.J., Bilgic, B. and Uc, E.Y. (2014) Cognitive Impairment and Dementia in Parkinson’s Disease: Practical Issues and Management. Movement Disorders, 29, 663-672. https://doi.org/10.1002/mds.25870
[15]
Prakash, K.M., Nadkarni, N.V., Lye, W.K., Yong, M.-H. and Tan, E.-K. (2016) The Impact of Non-Motor Symptoms on the Quality of Life of Parkinson’s Disease Patients: A Longitudinal Study. European Journal of Neurology, 23, 854-860.
https://doi.org/10.1111/ene.12950
[16]
Pellicano, C., Assogna, F., Cravello, L., et al. (2015) Neuropsychiatric and Cognitive Symptoms and Body Side of Onset of Parkinsonism in Unmedicated Parkinson’s Disease Patients. Parkinsonism and Related Disorders, 21, 1096-1100.
https://doi.org/10.1016/j.parkreldis.2015.07.002
[17]
Aarsland, D. and Kurz, M.W. (2010) The Epidemiology of Dementia Associated with Parkinson’s Disease. Journal of the Neurological Sciences, 289, 18-22.
https://doi.org/10.1016/j.jns.2009.08.034
[18]
Giladi, N., Treves, T.A., Paleacu, D., et al. (2000) Risk Factors for Dementia, Depression and Psychosis in Long-Standing Parkinson’s Disease. Journal of Neural Transmission, 107, 59-71. https://doi.org/10.1007/s007020050005
[19]
Riedel, O., Klotsche, J., Spottke, A., et al. (2008) Cognitive Impairment in 873 Patients with Idiopathic Parkinson’s Disease. Results from the German Study Group on Epidemiology of Parkinson’s Disease with Dementia (GEPAD). Journal of Neurology, 255, 255-264. https://doi.org/10.1007/s00415-008-0720-2
[20]
Wang, Q., Zhang, Z., Li, L., Wen, H. and Xu, Q. (2014) Assessment of Cognitive Impairment in Patients with Parkinson’s Disease: Prevalence and Risk Factors. Clinical Intervention in Aging, 12, 275-281.
[21]
Anang, J.B., Gagnon, J.F., Bertrand, J.A., et al. (2014) Predictors of Dementia in Parkinson Disease: A Prospective Cohort Study. Neurology, 83, 1253-1260.
https://doi.org/10.1212/WNL.0000000000000842
[22]
Fanciulli, A., Strano, S., Colosimo, C., Caltagirone, C., Spalletta, G. and Pontieri, F.E. (2013) The Potential Prognostic Role of Cardiovascular Autonomic Failure in α-Synucleinopathies. European Journal of Neurology, 20, 231-235.
https://doi.org/10.1111/j.1468-1331.2012.03819.x
[23]
Amboni, M., Barone, P. and Hausdorff, J.M. (2013) Cognitive Contribution to Gait and Falls: Evidence and Implications. Movement Disorders, 28, 1520-1533.
https://doi.org/10.1002/mds.25674
[24]
Erro, R., Santangelo, G., Picillo, M., et al. (2013) Side of Onset Does Not Influence Cognition in Newly Diagnosed Untreated Parkinson’s Disease Patients. Parkinsonism and Related Disorders, 19, 256-259.
https://doi.org/10.1016/j.parkreldis.2012.10.020
[25]
Verreyt, N., Nys, G.M., Santens, P. and Vingerhoets, G. (2011) Cognitive Differences between Patients with Left-Sided and Right-Sided Parkinson’s Disease: A Review. Neuropsychological Reviews, 21, 405-424.
https://doi.org/10.1007/s11065-011-9182-x
[26]
Siepel, F.J., Bronnick, K.S., Booij, J., et al. (2014) Cognitive Executive Impairment and Dopaminergic Deficits in De Novo Parkinson’s Disease. Movement Disorders, 29, 1802-1808. https://doi.org/10.1002/mds.26051
[27]
Monchi, O., Petrides, M., Doyon, J., Postuma, R.B., Worsley, K. and Dagher A. (2004) Neural Bases of Set-Shifting Deficits in Parkinson’s Disease. Journal of Neuroscience, 24, 702-710. https://doi.org/10.1523/JNEUROSCI.4860-03.2004
[28]
Monchi, O., Petrides, M., Strafella, A.P., Worsley, K.J. and Doyon, J. (2006) Functional Role of the Basal Ganglia in the Planning and Execution of Actions. Annals of Neurology, 59, 257-264. https://doi.org/10.1002/ana.20742
[29]
Provost, J.S., Petrides, M. and Monchi, O. (2010) Dissociating the Role of the Caudate Nucleus and Dorsolateral Prefrontal Cortex in the Monitoring of Events within Human Working Memory. European Journal of Neuroscience, 32, 873-880.
https://doi.org/10.1111/j.1460-9568.2010.07333.x
[30]
Seger, C.A., Peterson, E.J., Cincotta, C.M., Lopez-Paniagua, D. and Anderson, C.W. (2010) Dissociating the Contributions of Independent Corticostriatal Systems to Visual Categorization Learning through the Use of Reinforcement Learning Modeling and Granger Causality Modeling. Neuroimage, 50, 644-656.
https://doi.org/10.1016/j.neuroimage.2009.11.083
[31]
Jellinger, K.A. (2010) Neuropathology in Parkinson’s Disease with Mild Cognitive Impairment. Acta Neuropathologica, 120, 829-830.
https://doi.org/10.1007/s00401-010-0755-1
[32]
Adler, C.H., Connor, D.J., Hentz, J.G., et al. (2010) Incidental Lewy Body Disease: Clinical Comparison to a Control Cohort. Movement Disorders, 25, 642-646.
https://doi.org/10.1002/mds.22971
[33]
MacDonald, P.A., MacDonald, A.A., Seergobin, K.N., et al. (2011) The Effects of Dopamine Therapy on the Ventral and Dorsal Striatum-Mediated Cognition in Parkinson’s Disease: Support from Functional MRI. Brain, 134, 1447-1463.
https://doi.org/10.1093/brain/awr075
[34]
Braak, H., Del Tredici, K., Rub, U., de Vos, R.A.I., Jansen Steur, E.N.H. and Braak, E. (2003) Staging of Brain Pathology Related to Sporadic Parkinson’s Disease. Neurobiology of Aging, 24, 197-211. https://doi.org/10.1016/S0197-4580(02)00065-9
[35]
Francis, P.T. and Perry, E.K. (2007) Cholinergic and Other Neurotransmitter Mechanisms in Parkinson’s Disease, Parkinson’s Disease Dementia, and Dementia with Lewy Bodies. Movement Disorders, 22, S351-S357.
https://doi.org/10.1002/mds.21683
[36]
Kehagia, A.A., Barker, R.A. and Robbins, T.W. (2010) Neuropsychological and Clinical Heterogeneity of Cognitive Impairment in Patients with Parkinson’s Disease. The Lancet Neurology, 9, 1200-1213.
https://doi.org/10.1016/S1474-4422(10)70212-X
[37]
Lewis, S.J.G., Slabosz, A., Robbins, T.W, Barker, R.A. and Owen, A.M. (2005) Dopaminergic Basis for Deficits in Working Memory but Not Attentional Set-Shifting in Parkinson’s Disease. Neuropsychologia, 43, 823-832.
https://doi.org/10.1016/j.neuropsychologia.2004.10.001
[38]
Slabosz, A., Lewis, S.J.G., Smigasiewicz, K., Szymura, B., Barker, R.A. and Owen, A.M. (2006) The Role of Learned Irrelevance in Attentional Set-Shifting Impairments in Parkinson’s Disease. Neuropsychology, 20, 578-588.
https://doi.org/10.1037/0894-4105.20.5.578
[39]
Torta, D.M.E., Castelli, L., Zibetti, M., Lopiano, L. and Geminiani, G. (2009) On the Role of Dopamine Replacement Therapy in Decision-Making, Working Memory, and Retard in Parkinson’s Disease: Does the Therapy-Dose Matter? Brain and Cognition, 71, 84-91. https://doi.org/10.1016/j.bandc.2009.04.003
[40]
Costa, A., Peppe, A., Dell’Agnello, G., et al. (2003) Dopaminergic Modulation of Visual-Spatial Working Memory in Parkinson’s Disease. Dementia and Geriatric Cognitive Disorders, 15, 55-66. https://doi.org/10.1159/000067968
[41]
Costa, A., Peppe, A., Dell’Agnello, G., Caltagirone, C. and Carlesimo, G.A. (2009) Dopamine and Cognitive Functioning in De Novo Subjects with Parkinson’s Disease: Effects of Pramipexole and Pergolide on Working Memory. Neuropsychologia, 47, 1374-1381. https://doi.org/10.1016/j.neuropsychologia.2009.01.039
[42]
Costa, A., Peppe, A., Brusa, L., Caltagiron, C., Gatto, I. and Carlesimo, G.A. (2008) Dopaminergic Modulation of Prospective Working Memory in Parkinson’s Disease. Behavioural Neurology, 19, 45-48. https://doi.org/10.1155/2008/310437
[43]
Costa, A., Peppe, A., Brusa, L., et al. (2008) Levodopa Improve Time-Based Prospective Memory in Parkinson’s Disease. Journal of the International Neuropsychological Society, 14, 601-610. https://doi.org/10.1017/S135561770808082X
[44]
Shohamy, D., Myers, C.E., Gehman, K.D., Sage, J. and Gluck, M.A. (2006) L-Dopa Impairs Learning, but Spares Generalization, in Parkinson’s Disease. Neuropsychologia, 44, 774-784. https://doi.org/10.1016/j.neuropsychologia.2005.07.013
[45]
Jahanshahi, M., Wilkinson, L., Gahir, H., Dharminda, A. and Lagnado, D.A. (2010) Medication Impairs Probabilistic Classification Learning in Parkinson’s Disease. Neuropsychologia, 48, 1096-1103.
https://doi.org/10.1016/j.neuropsychologia.2009.12.010
[46]
Feigin, A.S., Ghilardi, M.F., Carbon, M., et al. (2003) Effects f Levodopa on Motor Sequence Learning in Parkinson’s Disease. Neurology, 60, 1744-1749.
https://doi.org/10.1212/01.WNL.0000072263.03608.42
[47]
Seo, M., Beigi, M., Jahashahi, M., et al. (2010) Effects of Dopamine Medication on Sequence Learning with Stochastic Feedback in Parkinson’s Disease. Frontiers of Human Neuroscience, 4, pii: 36.
[48]
Ghilardi, M.F., Feigin, A.S., Battaglia, A., et al. (2007) L-Dopa Infusion Does Not Improve Explicit Sequence Learning in Parkinson’s Disease. Parkinsonism and Related Disorders, 13, 146-151. https://doi.org/10.1016/j.parkreldis.2006.08.006
[49]
Frank, M.J., Seeberger, L.C. and O’Reilly, R.C. (2004) By Carrot or By Stick: Cognitive Reinforcement Learning in Parkinsonism. Science, 306, 1940-1943.
https://doi.org/10.1126/science.1102941
[50]
Evans, A.H., Lawrence, A.D., Potts, J., et al. (2006) Relationship between Impulsive Sensation Seeking Traits, Smoking, Alcohol and Caffeine Intake, and Parkinson’s Disease. Journal of Neurology, Neurosurgery and Psychiatry, 77, 317-321.
https://doi.org/10.1136/jnnp.2005.065417
[51]
Sohn, M.H., Ursu, S., Anderson, J.R., Stenger, V.A. and Carter, C.S. (2000) The Role of Prefrontal Cortex and Posterior Parietal Cortex in Task Switching. Proceedings of the National Academy of Sciences USA, 97, 13448-13453.
https://doi.org/10.1073/pnas.240460497
[52]
Dias, R., Robbins, T.W. and Roberts, A.C. (1996) Dissociation in Prefrontal Cortex of Affective and Attentional Shifts. Nature, 380, 69-72.
https://doi.org/10.1038/380069a0
[53]
Graef, S., Biele, G., Krugel, L.K., et al. (2010) Differential Influence of Levodopa on Reward-Based Learning in Parkinson’s Disease. Frontiers of Human Neuroscience, 4, 169. https://doi.org/10.3389/fnhum.2010.00169
[54]
Tomer, R., Aharon-Peretz, J. and Tsitrinbaum, Z. (2007) Dopamine Asymmetry Interacts with Medication to Affect Cognition in Parkinson’s Disease. Neuropsychologia, 45, 357-367. https://doi.org/10.1016/j.neuropsychologia.2006.06.014
[55]
Kish, S.J., Shannak, K. and Ornykiewicz, O. (1988) Uneven Pattern of Dopamine Loss in the Striatum of Patients with Idiopathic Parkinson’s Disease. Pathophysiologic and Clinical Implication. New England Journal of Medicine, 318, 876-880.
https://doi.org/10.1056/NEJM198804073181402
[56]
Fearnley, J.M. and Lees, A.J. (1991) Ageing and Parkinson’s Disease: Substantia Nigra Regional Selectivity. Brain, 114, 2283-2301.
https://doi.org/10.1093/brain/114.5.2283
[57]
Djaldetti, R., Lorberboym, M., Karmon, Y., Treves, T.A., Ziv, I. and Melamed, E. (2011) Residual Striatal Dopaminergic Nerve Terminals Nerve Terminals in Very Long-Standing Parkinson’s Disease: A Single Photon Emission Computed Tomography Imaging Study. Movement Disorders, 26, 327-330.
https://doi.org/10.1002/mds.23380
[58]
MacDonald, P.A. and Monchi, O. (2011) Differential Effect of Dopaminergic Therapies on Dorsal and Ventral Striatum in Parkinson’s Disease: Implications for Cognitive Function. Parkinson’s Disease, 2011, Article ID: 522743.
[59]
Zweig, R.M., Disbrow, E.A. and Javalkar, V. (2016) Cognitive and Psychiatric Disturbances in Parkinsonian Syndromes. Neurologic Clinics, 34, 235-246.
https://doi.org/10.1016/j.ncl.2015.08.010
[60]
Wright, B.A. and Waters, C.H. (2013) Continuous Dopaminergic Delivery to Minimize Motor Complications in Parkinson’s Disease. Expert Review of Neurotherapeutics, 13, 719-729. https://doi.org/10.1586/ern.13.47
[61]
Ferreira, J.J., Katzenschlager, R., Bloem, B.R., et al. (2013) Summary of the Recommendations of the EFNS/MDS-ES Review on Therapeutic Management of Parkinson’s Disease. European Journal of Neurology, 20, 5-15.
https://doi.org/10.1111/j.1468-1331.2012.03866.x
[62]
Grandas, F. (2013) Subcutaneous Infusion of Apomorphine: A Reappraisal of Its Therapeutic Efficacy in Advanced Parkinson’s Disease. Expert Review of Neurotherapeutics, 13, 1343-1353. https://doi.org/10.1586/14737175.2013.839235
[63]
Wu, B., Han, L., Sun, B.M., Hu, X.-W. and Wang, X.-P. (2014) Influence of Deep Brain Stimulation of the Subthalamic Nucleus on Cognitive Functions in Patients with Parkinson’s Disease. Neuroscience Bullettin, 30, 153-161.
https://doi.org/10.1007/s12264-013-1389-9
[64]
Antonini, A., Yegin, A., Preda, C., Bergmann, L. and Poewe, W. (2015) Global Long-Term Study on Motor and Non-Motor Symptoms and Safety of Levodopa-Carbidopa Intestinal Gel in Routine Care of Advanced Parkinson’s Disease Patients; 12-Month Interim Outcomes. Parkinsonism and Related Disorders, 21, 231-235. https://doi.org/10.1016/j.parkreldis.2014.12.012
[65]
Devos, D. and French Duodopa Study Group (2009) Patient Profile, Indications, Efficacy, and Safety of Duodenal Levodopa Infusion in Advanced Parkinson’s Disease. Movement Disorders, 24, 993-1000. https://doi.org/10.1002/mds.22450
[66]
Busk, K. and Nyholm, D. (2012) Long-Term 24-H Levodopa/Carbidopa Gel Infusion in Parkinson’s Disease. Parkinsonism and Related Disorders, 18, 1000-1001.
https://doi.org/10.1016/j.parkreldis.2012.04.010
[67]
Sanchez-Castaneda, C., Campdelacreu, J., Mirò, J., Juncadella, M., Jaumà, S. and Calopa, M. (2010) Cognitive Improvement after Duodenal Levodopa Infusion in Cognitively Impaired Parkinson’s Disease Patients. Progress in Neuro-psychopharmacology and Biological Psychiatry, 34, 250-251.
https://doi.org/10.1016/j.pnpbp.2009.10.021
[68]
Honig, H., Antonini, A., Martinez-Martin, P., et al. (2009) Intrajejunal Levodopa Infusion in Parkinson’s Disease: A Pilot Multicenter Study of Effects on Nonmotor Symptoms and Quality of Life. Movement Disorders, 24, 1468-1474.
https://doi.org/10.1002/mds.22596
[69]
Zibetti, M., Merola, A., Ricchi, V., et al. (2013) Long-Term Duodenal Levodopa Infusion in Parkinson’s Disease: A 3-Year Motor and Cognitive Follow-Up Study. Journal of Neurology, 260, 105-114. https://doi.org/10.1007/s00415-012-6597-0
[70]
Olanow, C.W. and Shapira, A.H. (2013) Therapeutic Prospects for Parkinson’s Disease. Annals of Neurology, 74, 337-347. https://doi.org/10.1002/ana.24011
[71]
Olanow, C.W., Kieburtz, K., Odin, P., et al. (2014) Continuous Intrajejunal Infusion of Levodopa-Carbidopa Intestinal Gel for Patients with Advanced Parkinson’s Disease: A Randomized, Controlled, Double-Blind, Double-Dummy Study. The Lancet Neurology, 13, 141-149. https://doi.org/10.1016/S1474-4422(13)70293-X
[72]
Merola, A., Zibetti, M., Angrisano, S., Rizzi, L., Lanotte, M. and Lopiano, L. (2011) Comparison of Subthalamic Nucleus Deep Brain Stimulation and Duodopa in the Treatment of Advanced Parkinson’s Disease. Movement Disorders, 26, 664-670.
https://doi.org/10.1002/mds.23524
