Effects of Cholinesterase Inhibitors in Cognition on Parkinson’s Disease Dementia: A Systematic Review and Meta-Analysis
Affiliation(s)
Division of Neurology and Epidemiology, Federal University of Bahia, Salvador, Brazil.
Division of Neurology and Epidemiology, Federal University of Bahia, Salvador, Brazil.
ABSTRACT
Introduction: Dementia is frequently associated with Parkinson’s disease, especially in later stages. Efficacy of cholinesterase inhibitors (ChI) in Alzheimer’s dementia is well established. However, treatment with ChI in Parkinson’s disease dementia (PDD) remains controversial. The objective of this systematic review and meta-analysis was to assess the effects of ChI in PDD. Methods: A comprehensive literature search was performed in MEDLINE, EMBASE and Cochrane library up to March 2014 using the descriptors “Parkinson’s disease”, “dementia in Parkinson’s disease”, “cognition”, “acetylcholinesterase inhibitors”, “cholinesterase inhibitors”, “anticholinesterase agents”, “rivastigmine”, “donepezil” and “galantamine” (Pubmed search strategy). All randomized, doubleblinded, placebo-controlled trials that met the eligibility criteria and assessed the effects of ChI in PDD were considered for analysis. There were no restrictions regarding paper language. Summary effect-sizes were presented as standardized mean differences (SMD) and the pooled analysis was performed with a fixed-effects model. Outcomes considered for analysis were the Mini Mental Status Exam (MMSE) score and the cognition scale for evaluation of dementia ADAS-Cog. The degree of heterogeneity between included studies was assessed through the I2 test. Results: After a comprehensive search, 175 references were retrieved. From these, five randomized trials involving 946PDD subjects were included in the review. Four studies used donepezil and only one study used rivastigmine. The pooled analysis of five studies that assessed the effects of ChI in MMSE total score showed a SMD of 0.24 (CI 95% 0.11 - 0.38). Three studies considered the effects of ChI on Adas-Cog and the pooled results showed a SMD of 0.21 (CI 95% 0.07 - 0.35). There was no significant heterogeneity between the studies. Conclusions: The results of this systematic review and meta- analysis suggest that ChI improves cognitive impairment in PDD subjects. Despite statistically significant, the translation of these results into relevant clinical improvement should be taken with caution, as the studies did not address what would be considered a clinically significant result.
Introduction: Dementia is frequently associated with Parkinson’s disease, especially in later stages. Efficacy of cholinesterase inhibitors (ChI) in Alzheimer’s dementia is well established. However, treatment with ChI in Parkinson’s disease dementia (PDD) remains controversial. The objective of this systematic review and meta-analysis was to assess the effects of ChI in PDD. Methods: A comprehensive literature search was performed in MEDLINE, EMBASE and Cochrane library up to March 2014 using the descriptors “Parkinson’s disease”, “dementia in Parkinson’s disease”, “cognition”, “acetylcholinesterase inhibitors”, “cholinesterase inhibitors”, “anticholinesterase agents”, “rivastigmine”, “donepezil” and “galantamine” (Pubmed search strategy). All randomized, doubleblinded, placebo-controlled trials that met the eligibility criteria and assessed the effects of ChI in PDD were considered for analysis. There were no restrictions regarding paper language. Summary effect-sizes were presented as standardized mean differences (SMD) and the pooled analysis was performed with a fixed-effects model. Outcomes considered for analysis were the Mini Mental Status Exam (MMSE) score and the cognition scale for evaluation of dementia ADAS-Cog. The degree of heterogeneity between included studies was assessed through the I2 test. Results: After a comprehensive search, 175 references were retrieved. From these, five randomized trials involving 946PDD subjects were included in the review. Four studies used donepezil and only one study used rivastigmine. The pooled analysis of five studies that assessed the effects of ChI in MMSE total score showed a SMD of 0.24 (CI 95% 0.11 - 0.38). Three studies considered the effects of ChI on Adas-Cog and the pooled results showed a SMD of 0.21 (CI 95% 0.07 - 0.35). There was no significant heterogeneity between the studies. Conclusions: The results of this systematic review and meta- analysis suggest that ChI improves cognitive impairment in PDD subjects. Despite statistically significant, the translation of these results into relevant clinical improvement should be taken with caution, as the studies did not address what would be considered a clinically significant result.
KEYWORDS
Parkinson’s Disease, Dementia, Cognitive Impairment, Cholinesterase Inhibitors, Cognition, Non-Motor Symptoms
Parkinson’s Disease, Dementia, Cognitive Impairment, Cholinesterase Inhibitors, Cognition, Non-Motor Symptoms
Cite this paper
Martorelli, M. , Monteiro, L. and Melo, A. (2015) Effects of Cholinesterase Inhibitors in Cognition on Parkinson’s Disease Dementia: A Systematic Review and Meta-Analysis. Advances in Parkinson's Disease, 4, 90-96. doi: 10.4236/apd.2015.44011.
Martorelli, M. , Monteiro, L. and Melo, A. (2015) Effects of Cholinesterase Inhibitors in Cognition on Parkinson’s Disease Dementia: A Systematic Review and Meta-Analysis. Advances in Parkinson's Disease, 4, 90-96. doi: 10.4236/apd.2015.44011.
References
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http://dx.doi.org/10.1002/1531-8257(200011)15:6<1112::AID-MDS1008>3.0.CO;2-A [11] Braak, H., Del, T.K., Rub, U., de Vos, R.A., Jansen Steur, E.N. and Braak, E. (2003) Staging of Brain Pathology Related to Sporadic Parkinson’s Disease. Neurobiology of Aging, 24, 197-211.
http://dx.doi.org/10.1016/S0197-4580(02)00065-9 [12] Rektorova, I., Srovnalova, H., Kubikova, R. and Prasek, J. (2008) Striatal Dopamine Transporter Imaging Correlates with Depressive Symptoms and Tower of London Task Performance in Parkinson’s Disease. Movement Disorders, 23, 1580-1587. http://dx.doi.org/10.1002/mds.22158 [13] Dickson, D.W., Fujishiro, H., Orr, C., DelleDonne, A., Josephs, K.A., Frigerio, R., et al. (2009) Neuropathology of Non-Motor Features of Parkinson Disease. Parkinsonism & Related Disorders, 15, S1-S5. http://dx.doi.org/10.1016/S1353-8020(09)70769-2 [14] Emre, M., Aarsland, D., Albanese, A., Byrne, E.J., Deuschl, G., De Deyn, P.P., et al. (2004) Rivastigmine for Dementia Associated with Parkinson’s Disease. New England Journal of Medicine, 351, 2509-2518. http://dx.doi.org/10.1056/NEJMoa041470 [15] Oertel, W., Poewe, W., Wolters, E., De Deyn, P.P., Emre, M., Kirsch, C., et al. (2008) Effects of Rivastigmine on Tremor and Other Motor Symptoms in Patients with Parkinson’s Disease Dementia: A Retrospective Analysis of a Double-Blind Trial and an Open-Label Extension. Drug Safety, 31, 79-94.
http://dx.doi.org/10.2165/00002018-200831010-00007 [16] Jadad, A.R., Moore, R.A., Carroll, D., Jenkinson, C., Reynolds, D.J., Gavaghan, D.J., et al. (1996) Assessing the Quality of Reports of Randomized Clinical Trials: Is Blinding Necessary? Controlled Clinical Trials, 17, 1-12. http://dx.doi.org/10.1016/0197-2456(95)00134-4 [17] Cohen, J. (1988) Statistical Power Analysis for the Behavioral Sciences. 2nd Edition, Lawrence Erlbaum Associates, Hillsdale. [18] Ravina, B., Putt, M., Siderowf, A., Farrar, J.T., Gillespie, M., Crawley, A., et al. (2005) Donepezil for Dementia in Parkinson’s Disease: A Randomised, Double Blind, Placebo Controlled, Crossover Study. Journal of Neurology, Neurosurgery & Psychiatry, 76, 934-939.
http://dx.doi.org/10.1136/jnnp.2004.050682 [19] Leroi, I., Brandt, J., Reich, S.G., Lyketsos, C.G., Grill, S., Thompson, R., et al. (2004) Randomized Placebo-Controlled Trial of Donepezil in Cognitive Impairment in Parkinson’s Disease. International Journal of Geriatric Psychiatry, 19, 1-8. http://dx.doi.org/10.1002/gps.993 [20] Aarsland, D., Laake, K., Larsen, J.P. and Janvin, C. (2002) Donepezil for Cognitive Impairment in Parkinson’s Disease: A Randomised Controlled Study. Journal of Neurology, Neurosurgery & Psychiatry, 72, 708-712. http://dx.doi.org/10.1136/jnnp.72.6.708 [21] Dubois, B., Tolosa, E., Katzenschlager, R., Emre, M., Lees, A.J., et al. (2012) Donepezil in Parkinson’s Disease Dementia: A Randomized, Double-Blind Efficacy and Safety Study. Movement Disorders, 27, 1230-1238. http://dx.doi.org/10.1002/mds.25098 [22] Litvinenko, I.V., Odinak, M.M., Mogil’naya, V.I. and Emelin, A.Y. (2008) Efficacy and Safety of Galantamine (Reminyl) for Dementia in Patients with Parkinson’s Disease (An Open Controlled Trial). Neuroscience and Behavioral Physiology, 38, 937-945. http://dx.doi.org/10.1007/s11055-008-9077-3 [23] Poewe, W., Wolters, E., Emre, M., Onofrj, M., Hsu, C., Tekin, S., et al. (2006) Long-Term Benefits of Rivastigmine in Dementia Associated with Parkinson’s Disease: An Active Treatment Extension Study. Movement Disorders, 21, 456- 461. http://dx.doi.org/10.1002/mds.20700 [24] Aarsland, D., Hutchinson, M. and Larsen, J.P. (2003) Cognitive, Psychiatric and Motor Response to Galantamine in Parkinson’s Disease with Dementia. International Journal of Geriatric Psychiatry, 18, 937-941. http://dx.doi.org/10.1002/gps.949 [25] Minett, T.S., Thomas, A., Wilkinson, L.M., Daniel, S.L., Sanders, J., Richardson, J., et al. (2003) What Happens When Donepezil Is Suddenly Withdrawn? An Open Label Trial in Dementia with Lewy Bodies and Parkinson’s Disease with Dementia. International Journal of Geriatric Psychiatry, 18, 988-993.
http://dx.doi.org/10.1002/gps.995 [26] Tombaugh, T.N. and McIntyre, N.J. (1992) The Mini-Mental State Examination: A Comprehensive Review. Journal of the American Geriatrics Society, 40, 922-935.
http://dx.doi.org/10.1111/j.1532-5415.1992.tb01992.x [27] Crum, R.M., Anthony, J.C., Bassett, S.S. and Folstein, M.F. (1993) Population-Based Norms for the Mini-Mental State Examination by Age and Educational Level. The Journal of the American Medical Association, 269, 2386-2391. http://dx.doi.org/10.1001/jama.1993.03500180078038
[1] Aarsland, D., Andersen, K., Larsen, J.P., Lolk, A. and Kragh-Sorensen, P. (2003) Prevalence and Characteristics of Dementia in Parkinson Disease: An 8-Year Prospective Study. Archives of Neurology, 60, 387-392. http://dx.doi.org/10.1001/archneur.60.3.387 [2] Cummings, J.L. (1988) Intellectual Impairment in Parkinson’s Disease: Clinical, Pathologic, and Biochemical Correlates. Journal of Geriatric Psychiatry and Neurology, 1, 24-36.
http://dx.doi.org/10.1177/089198878800100106 [3] Giladi, N., Treves, T.A., Paleacu, D., Shabtai, H., Orlov, Y., Kandinov, B., et al. (2000) Risk Factors for Dementia, Depression and Psychosis in Long-Standing Parkinson’s Disease. Journal of Neural Transmission, 107, 59-71. http://dx.doi.org/10.1007/s007020050005 [4] Hobson, P. and Meara, J. (2004) Risk and Incidence of Dementia in a Cohort of Older Subjects with Parkinson’s Disease in the United Kingdom. Movement Disorders, 19, 1043-1049.
http://dx.doi.org/10.1002/mds.20216 [5] Bublak, P., Muller, U., Gron, G., Reuter, M. and von Cramon, D.Y. (2002) Manipulation of Working Memory Information Is Impaired in Parkinson’s Disease and Related to Working Memory Capacity. Neuropsychology, 16, 577-590. http://dx.doi.org/10.1037/0894-4105.16.4.577 [6] Muslimovic, D., Post, B., Speelman, J.D. and Schmand, B. (2005) Cognitive Profile of Patients with Newly Diagnosed Parkinson Disease. Neurology, 65, 1239-1245.
http://dx.doi.org/10.1212/01.wnl.0000180516.69442.95 [7] Montse, A., Pere, V., Carme, J., Francesc, V. and Eduardo, T. (2001) Visuospatial Deficits in Parkinson’s Disease Assessed by Judgment of Line Orientation Test: Error Analyses and Practice Effects. Journal of Clinical and Experimental Neuropsychology, 23, 592-598. http://dx.doi.org/10.1076/jcen.23.5.592.1248 [8] Emre, M., Aarsland, D., Brown, R., Burn, D.J., Duyckaerts, C., Mizuno, Y., et al. (2007) Clinical Diagnostic Criteria for Dementia Associated with Parkinson’s Disease. Movement Disorders, 22, 1689-1707. http://dx.doi.org/10.1002/mds.21507 [9] Aarsland, D., Larsen, J.P., Karlsen, K., Lim, N.G. and Tandberg, E. (1999) Mental Symptoms in Parkinson’s Disease Are Important Contributors to Caregiver Distress. International Journal of Geriatric Psychiatry, 14, 866-874.
http://dx.doi.org/10.1002/(SICI)1099-1166(199910)14:10<866::AID-GPS38>3.0.CO;2-Z [10] Schrag, A., Jahanshahi, M. and Quinn, N. (2000) How Does Parkinson’s Disease Affect Quality of Life? A Comparison with Quality of Life in the General Population. Movement Disorders, 15, 1112-1118.
http://dx.doi.org/10.1002/1531-8257(200011)15:6<1112::AID-MDS1008>3.0.CO;2-A [11] Braak, H., Del, T.K., Rub, U., de Vos, R.A., Jansen Steur, E.N. and Braak, E. (2003) Staging of Brain Pathology Related to Sporadic Parkinson’s Disease. Neurobiology of Aging, 24, 197-211.
http://dx.doi.org/10.1016/S0197-4580(02)00065-9 [12] Rektorova, I., Srovnalova, H., Kubikova, R. and Prasek, J. (2008) Striatal Dopamine Transporter Imaging Correlates with Depressive Symptoms and Tower of London Task Performance in Parkinson’s Disease. Movement Disorders, 23, 1580-1587. http://dx.doi.org/10.1002/mds.22158 [13] Dickson, D.W., Fujishiro, H., Orr, C., DelleDonne, A., Josephs, K.A., Frigerio, R., et al. (2009) Neuropathology of Non-Motor Features of Parkinson Disease. Parkinsonism & Related Disorders, 15, S1-S5. http://dx.doi.org/10.1016/S1353-8020(09)70769-2 [14] Emre, M., Aarsland, D., Albanese, A., Byrne, E.J., Deuschl, G., De Deyn, P.P., et al. (2004) Rivastigmine for Dementia Associated with Parkinson’s Disease. New England Journal of Medicine, 351, 2509-2518. http://dx.doi.org/10.1056/NEJMoa041470 [15] Oertel, W., Poewe, W., Wolters, E., De Deyn, P.P., Emre, M., Kirsch, C., et al. (2008) Effects of Rivastigmine on Tremor and Other Motor Symptoms in Patients with Parkinson’s Disease Dementia: A Retrospective Analysis of a Double-Blind Trial and an Open-Label Extension. Drug Safety, 31, 79-94.
http://dx.doi.org/10.2165/00002018-200831010-00007 [16] Jadad, A.R., Moore, R.A., Carroll, D., Jenkinson, C., Reynolds, D.J., Gavaghan, D.J., et al. (1996) Assessing the Quality of Reports of Randomized Clinical Trials: Is Blinding Necessary? Controlled Clinical Trials, 17, 1-12. http://dx.doi.org/10.1016/0197-2456(95)00134-4 [17] Cohen, J. (1988) Statistical Power Analysis for the Behavioral Sciences. 2nd Edition, Lawrence Erlbaum Associates, Hillsdale. [18] Ravina, B., Putt, M., Siderowf, A., Farrar, J.T., Gillespie, M., Crawley, A., et al. (2005) Donepezil for Dementia in Parkinson’s Disease: A Randomised, Double Blind, Placebo Controlled, Crossover Study. Journal of Neurology, Neurosurgery & Psychiatry, 76, 934-939.
http://dx.doi.org/10.1136/jnnp.2004.050682 [19] Leroi, I., Brandt, J., Reich, S.G., Lyketsos, C.G., Grill, S., Thompson, R., et al. (2004) Randomized Placebo-Controlled Trial of Donepezil in Cognitive Impairment in Parkinson’s Disease. International Journal of Geriatric Psychiatry, 19, 1-8. http://dx.doi.org/10.1002/gps.993 [20] Aarsland, D., Laake, K., Larsen, J.P. and Janvin, C. (2002) Donepezil for Cognitive Impairment in Parkinson’s Disease: A Randomised Controlled Study. Journal of Neurology, Neurosurgery & Psychiatry, 72, 708-712. http://dx.doi.org/10.1136/jnnp.72.6.708 [21] Dubois, B., Tolosa, E., Katzenschlager, R., Emre, M., Lees, A.J., et al. (2012) Donepezil in Parkinson’s Disease Dementia: A Randomized, Double-Blind Efficacy and Safety Study. Movement Disorders, 27, 1230-1238. http://dx.doi.org/10.1002/mds.25098 [22] Litvinenko, I.V., Odinak, M.M., Mogil’naya, V.I. and Emelin, A.Y. (2008) Efficacy and Safety of Galantamine (Reminyl) for Dementia in Patients with Parkinson’s Disease (An Open Controlled Trial). Neuroscience and Behavioral Physiology, 38, 937-945. http://dx.doi.org/10.1007/s11055-008-9077-3 [23] Poewe, W., Wolters, E., Emre, M., Onofrj, M., Hsu, C., Tekin, S., et al. (2006) Long-Term Benefits of Rivastigmine in Dementia Associated with Parkinson’s Disease: An Active Treatment Extension Study. Movement Disorders, 21, 456- 461. http://dx.doi.org/10.1002/mds.20700 [24] Aarsland, D., Hutchinson, M. and Larsen, J.P. (2003) Cognitive, Psychiatric and Motor Response to Galantamine in Parkinson’s Disease with Dementia. International Journal of Geriatric Psychiatry, 18, 937-941. http://dx.doi.org/10.1002/gps.949 [25] Minett, T.S., Thomas, A., Wilkinson, L.M., Daniel, S.L., Sanders, J., Richardson, J., et al. (2003) What Happens When Donepezil Is Suddenly Withdrawn? An Open Label Trial in Dementia with Lewy Bodies and Parkinson’s Disease with Dementia. International Journal of Geriatric Psychiatry, 18, 988-993.
http://dx.doi.org/10.1002/gps.995 [26] Tombaugh, T.N. and McIntyre, N.J. (1992) The Mini-Mental State Examination: A Comprehensive Review. Journal of the American Geriatrics Society, 40, 922-935.
http://dx.doi.org/10.1111/j.1532-5415.1992.tb01992.x [27] Crum, R.M., Anthony, J.C., Bassett, S.S. and Folstein, M.F. (1993) Population-Based Norms for the Mini-Mental State Examination by Age and Educational Level. The Journal of the American Medical Association, 269, 2386-2391. http://dx.doi.org/10.1001/jama.1993.03500180078038