A comparison of the effectiveness of three drug regimens on cognitive performance of patients with Parkinson's disease.
The impaired abilities are those that based on frontal lobe functions'abilities such as executive functions, attention, visuo-spatial skills, and memory functions (Bassett, 2005; Cooper, et al., 1991; Pagonabarraga, et al., 2008; Rowe, et al., 2008). The impaired functions can interfere with occupational functioning and familial relationships, and may lead to loss of employment and family conflict (Bassett, 2005).
Depletion of dopamine supplies, in the lateral orbitofrontal and dorsolateral prefrontal circuits in PD is thought to be responsible for cognitive impairments in the disease (York & Alvarez, 2008).
It has been shown that cognitive functions can be influenced by various medications, either by worsening or improving those functions (Bassett, 2005). Two main classes of drugs, which are usually prescribed for PD are dopamine agonists and anticholinergic agents. Different studies have found different results on the effectiveness of these drugs on cognitive performance (e.g, Brusa, et al., 2003; Brusa, et al., 2005; Campbell, et al., 2010; Drag, et al., 2010; Ehrt, et al., 2010; Hamidovic, et. al, 2008; Konishi, et al., 2010; Levin, et al., 1995).
Levodopa and amantadine are two common drugs that are usually prescribed for PD patients. Different results are also found about their effectiveness on cognitive performance (De Letter, et al., 2012.; Graham, et al., 2009; Kobayashi, et al., 2004; Saletu, et al., 1992; Sanchez-Castaneda, et al., 2010).
Parkinson's disease patients usually don't treat with a single drug. Usually a drug regimen is prescribed for them. The combination of different drugs may lead to different results in cognitive performance of PD patients than a single drug. So it is essential to investigate the effectiveness of different drug regimen on cognitive functions.
In the present study it is intended to compare the effectiveness of one selected drug from each of the two classes on cognitive performance in PD patients in combination with levodopa and amantadine. For this purpose pramipexole, a D2/D3 agonist and trihexiphenidyle, an antimuscarinic agent were selected respectively.
Participants. 35 Patients who entered the study were firstly diagnosed as having PD by a neurologist. They have been all administered a specific dose of medication for at least one month before the study. For one group (3 women, 9 men) pramipexole, levodopa and amantadine, and for another group (4 women, 8 men) trihexiphenidyle, levodopa and amantadine were prescribed respectively by the physician. Also there was a control group including 11 patients (3 women, 8 men) for them only levodopa and amantadine were prescribed. All 3 groups were matched for dosage of levodopa and amantadine. The exclusion criteria were M.R, severe psychiatric disorders, commorbid neurological illness, and using either psychoactive or benzodiazepine drugs. Tables 1 and 2 show a summary of the patient's demographic information.
Montreal Cognitive Assessment (MoCA)
This test was developed by Nasreddin, et al., (2005) and assesses cognitive functions including executive functions (by an alternative trail making task, verbal fluency and abstraction), visuospatial function (by drawing a clock and copying a cube), short term memory (by learning 5 items and remember them after about 5 minutes), attention (by vigilance, subtracting serial 7s from 100, and backward and forward digit span), language (by naming 3 animals, sentence repetition and verbal fluency) and orientation (time and place). This scale use more and harder tasks for executive function, linguistic abilities, memory and visiospatial processing (Zadikoff, et al., 2008). Montreal Cognitive Assessment is more sensitive than MMSE in recognizing mild cognitive impairment and it takes only 10 to 15 minutes to administer (Gill, et al., 2008).
Its internal consistency, concurrent validity, specificity and sensitivity were reported to be acceptable in various research (Athilingam, 2007; Smith, et al., 2007; Wittich, et al., 2010; Wong, et al., 2009).
We have translated it to Farsi for the first time and we found a Cronbach alpha of 0.77 and a concurrent validity of 0.79 with MMSE for this test (Emsaki, et al., 2011).
Unified Parkinson's Disease Rating Scale (UPDRS)
This scale was developed in 1817 as a scale for incorporating elements of existing scales and providing a comprehensive scale for assessing PD related disabilities. UPDRS has four components: part I: mentation, behavior and mood; part II: activities of daily living; part III: motor; part IV: complications (Goetz, et al., 2003). Part III which was administered in this study assesses 14 motor abilities include: speech, facial expression, tremor at rest, action or postural tremor of hands, rigidity, finger taps, hand movements, rapid alternating movements of hands, leg agility, arising from chair, posture, gait, postural stability, body bradykinesia and hypokinesia. Each ability is scored on a likert scale from 0 to 4. UPDRS internal and test retest reliability and facial and concurrent validity were reported to be acceptable in different studies (Goetz, et al., 2003; Siderowf, et al., 2002).
Beck Depression Scale (BDI)
This 21--item questionnaire was developed by Aeron T. Beck in 1967 for the assessment of depression (Shaver & Brennan, 1991). Its reliability and validity is reported agreeable in many researches (Marnat, 2009; Shaver & Brennan, 1991).
Beck Anxiety Inventory (BAI)
This self report 21- item questionnaire was also developed by Beck, et al., in 1988 to assess the severity of anxiety symptoms (Wilson, et al., 2004). Its internal consistency, test retest reliability, and concurrent validity were reported to be good in various studies (Beck, et al., 1988; Martin, et al., 2001).
Patients were referred to the researchers by neurologist, according to inclusion and exclusion criteria. They were visited individually by one of the researchers. After the initial interview and explaining the aim and the qualification of the research, those patients who were volunteer to attend the study, were asked to answer Montreal Cognitive Assessment (MoCA) twice, once when they entered the study for the first time, and then 3 days later when they have stopped using pramipexole or trihexiphenidyle. Since depression, anxiety and motor disabilities can interfere with cognitive performance, BDI, BAI, and the motor part of the UPDRS were also administered to control their scores if there was a significant correlation with MoCA scores and cognitive functions.
It was necessary to test normality and homogeneity of variance, before applying the data to ANOVA. Shapiro-Wilk test of normality and Levene test of homogeneity of variance were not rejected and accordingly we were permitted to use this parametric test. To determine those variables that must be controlled, Pearson and Spearman correlation tests were administered. The results showed that only the correlation between education (r=0.39, p<0.05) and MoCA pretest (r=0.91, p<0.05) and the total score of MoCA post test were significant. The results of ANCOVA showed that even after controlling the effect of pre test and education, there is a significant difference among 3 groups in total score of MoCA F(2,30)=7.817, p<0.05. The observed power of 0.93 showed that the sample size was enough for this conclusion. Table 3 shows ANCOVA results for investigating the difference in the total scores of MoCA among 3 groups.
ANCOVA was also administered to know in which subscales of MoCA this difference is significant. It showed that there is only a significant difference in executive function among 3 groups F(2,29)=1.902, p<0.05 and there was no significant difference in any other of the subscales. The power estimation of 0.98 showed that the sample size was enough for this conclusion.
The results of pairwise comparison of estimated marginal means in executive function showed that there is a significant difference between estimated marginal means of control and pramipexole groups (p= 0.001) and trihexiphenidyle and pramipexole groups (p= 0.004). But there is no difference between estimated marginal means of control and trihexiphenidyle groups (p=0.13). Table 4 and Figure 1 can better show these differences (table 4 shows pairwise comparison of estimated marginal means in executive function).
The results showed that compared to control group and patients who were treated by trihexiphenidyle, those who used pramipexole had better performance in executive function in off treatment with this drug. This result is in agreement with those of Brusa, et al., (2003) who found that pramipexole leads to impairment in short term verbal memory, verbal fluency and executive function and Hamidovic, et al., (2008), who investigated the effect of pramipexole on cognition of healthy volunteers and concluded that this drug leads to impairment in several subtests of the Automated Neuropsychological Assessment Metrics. But Levin, et al., (2009) in a 3 month study of influence of pramipexole in PD patients found that this drug leads to improvement in verbal fluency, but doesn't have any effect on other cognitive functions. Since the pathology of cognitive dysfunction in PD is related to dopamine depletion in nigrostriatal pathway and even the frontal cortex (Bosboom, et al., 2004; Leh, et al., 2010; Sawamoto, et al., 2008), a better performance in cognitive function was expected after using dopaminergic drugs. It is worth noting that none of these studies investigated the effect of pramipexole in combination with other drugs. But because of ethical issues we were not allowed to asked patients to quit all drugs, so patients in this experimental group used levodopa and amantadine in addition to pramipexole. According to Rowe, et al., (2008), "executive functions are mediated by distinct cortico- striatothalamo- cortical circuits. In each circuit there is an optimal level of dopaminergic innervations, leading to a Yerkes-Dodson type U shape relationship between dopaminergic state and neural function". It can predict the impaired performance after dopaminergic treatment away from this optimum. Since levodopa, amantadine and pramipexole, all lead to dopamine enhancement, it may explain the worsened executive function after using these drugs.
The results also showed that there is no difference in cognitive functions of patients who had used trihexiphenidyle and control group. This result is in agreement with that of Drag and et al., (2010) who found that anticholinergic drugs was not associated with lower performance in cognitive functions. But most recent researches have shown that anticholinergic drugs lead to worsened cognitive performance including cognitive functions of PD patients (Campbell, et al., 2010; Ehrt, et al., 2010; Konishi, et al., 2010). Our results can be explained by pharmacokinetic and pharmacodynamic interaction with two other drugs. Considering that patients in this group of our research used levodopa and amantadine in addition to trihexiphenidyle, it could be said that concurrent using of these drugs that affect dopamine, reduce the undesirable effect of an anticholinergic agent on cognitive performance.
In conclusion, it is obvious that one of the drug regimens -pramipexole, levodopa and amantadine- can worsened the executive function of Parkinson's disease patients. But one of the limitations of our study was that we were not allowed to ask patients to cease all their drugs because of ethical issues and so we cannot conclude that worsening of executive function is just due to pramipexole or trihexiphenidyle alone. This result can have some important implications. Informing patients and their families that the deficiency in some aspects of cognitive performance may occur due to the usage of these drugs, will help them not to panic when they finally encounter such disabilities. Another limitation of our study was that we couldn't have a follow up stage because patient's leakage. Comparing the results after one month could help us to understand whether this worsening will maintain after that period of using this regimen.
(Manuscript received: 3 September 2012; accepted: 17 January 2013)
Athilingam, P.(2007). Validation of an Instrument to Measure Cognitive Function in Patients with Heartl Failure. Unpublished Doctoral Dissertation. University of Rochester
Bassett, S. S. (2005). Cognitive impairment in parkinson disease. Primary Psychiatry, 12 (7), 50-55
Beck, A. T., Epstein, N., Brown, G., & Steer, R. A. (1988). An inventory for measuring clinical anxiety. Psychometric properties. Journal of Consulting and Clinical Psychology, 56, 893-897.
Bosboom, J. W., Stoffers, D., & Wolters, E. C. (2004). Cognitive dysfunction and dementia in Parkinson's disease. Journal of Neural Transmission, 111, 1303-1315
Brusa, L., Bassi, A. Stefani, A., Pierantozzi, M., Peppe, A., Caramia, M. D., and et al. (2003). Pramipexole in comparison to l-dopa: A neuropsychological study. Journal of Neural Transmission, 110, 373-380.
Brusa, L., Tiraboschi, P., Koch, G., Peppe, A., Pierantozzi, M., Ruggieri, S., & Stanzione, P. (2005). Pergolide effect on cognitive functions in early-mild Parkinson's disease. Journal of Neural Transmission, 112, 231-237.
Campbell, N. L., Boustani, M. A., Lane, K. A., Gao, S., Hendrie, H., Khan, B. A., et al. (2010). Use of anticholinergics and the risk of cognitive impairment in an African American population. Neurology, 75 (2), 152-159.
Caviness, J.N., Driver-Dunckley, E., Connor, D.J., Sabbagh, M.N., Hentz, J.G., Noble, B., et al. (2007). Defining Mild Cognitive Impairment in parkinson's Disease. Movement Disorders, 22(9), 1272-1277.
Cooper, J. A., Harvey, J. S., Nigel, J., Norman, S. H., Sullivan, E. V. (1991). Cognitive impairment in early untreated parkinson's disease and its relationship to motor disability. Brain, 114, 2095-2122.
Dcamp, E., & Schneider, J. S. (2009). Interaction between nicotinic and dopaminergic therapies on cognition in a chronic Parkinson model. Brain Research, 12, 109-114.
De Letter, M., Van Borsel, J., & Santens, P. (2012). An electrophysiological investigation of the effects of levodopa on semantic comprehension of action words in Parkinson's disease. Journal of Neurolinguistics, 25 (2), 95-103.
Drag, L. L., Wright, S. L., & Bieliauskas, L. A. (2010). Prescribing Practices of Anticholinergic Medications and Their Association With Cognition in an Extended Care Setting. Journal of Applied Gerontology, published online, doi: 10.1177/0733464810384592
Ehrt, U., Broich, K., Larsen, J. P., Ballard, C., & Aarsland, D. (2010). Use of drugs with anticholinergic effect and impact on cognition in Parkinson's disease: a cohort study. Journal of Neurology, Neurosurgery and Psychiatry, 81, 160-165.
Emsaki, G., Molavi, H., Chitsaz, A., & Asgari, K. (2011). Psychometric Properties of the Montreal Cognitive Assessment (MoCA) in Parkinson's Disease Patients in Isfahan. Journal of Isfahan Medical School, 29, 1606-1615.
Gill, D. J., Freshman, A., Blender, J. A., & Ravina, B. (2008). The montreal cognitive assessment as a screening tool for cognitive impairment in Parkinson's disease. Movement Disorders, 23, 1043-1046.
Goetz, C. G., Poewe, W., Rascol, O., Sampaio, C., Stebbins, G.T., Counsell, C., et. al. (2003). The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Movement Disorders, 18, 738-750.
Graham, C. F., MacAskill, M. R., Dalrymple-Alford, J. C., L Livingston, L., & Anderson, T. J. (2009). The effects of amantadine on memory and cognition in early Parkinson's disease. Journal of Clinical Neuroscience, 16, 1514-1546.
Hamidovic, A., Kang J. U., and Wit, H. D. (2008). Effects of low to moderate acute doses of pramipexole on impulsivity and cognition in healthy volunteers. Journal of Clinical Psychopharmacology, 28(1), 45-51.
Jankovic, J. (2008). Parkinson's disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery and Psychiatry, 79, 368-376.
Kobayashi, Y, Hozumi, A., Tanaka, H., Arai, M., & Hirata, K. (2004). The efficacy of the levodopa on cognitive function in patients with de novo Parkinson's disease. International Congress Series, 1259, 357-361.
Koerts, J., Leenders, K. L., and Brouwer, W. H. (2009). Cognitive dysfunction in non-demented Parkinson's disease patients: Controlled and automatic behavior. Cortex, 45, 922-929.
Konishi, K., Hori, K., Uchida, H., Watanabe, K., Tominaga, I., Kimura, M., et al. (2010). Adverse effects of anticholinergic activity on cognitive functions in Alzheimer's disease. Psychogeriat, 10 (1), 34-38.
Lees, A. J., Smith, E. (1983). Cognitive deficits in the early stages of Parkinson's disease. Brain, 106, 257-270.
Leh, E. S., Petrides, M., & Strafella, A. P. (2010). The neural circuitry of executive functions in healthy subjects and parkinson's disease. Neuropsychopharrmachology, 35, 70-85.
Levin, B.E., & Katzen, H.L. (1995). Early cognitive changes and nondementing behavioral abnormalities in Parkinson's disease. Advances in Neurology, 65, 85-95.
Levin, O. S., Nesterova, O. S., Otcheskaia, O. V., Zhuravleva, E., Artemova, I., Khozova, A. A., Ismailov, A. M., Lisenker, L. N., Vdovichenko, T. V., Rotor, L. D., Ganzula, P. A., Ivanov, A. K., & Boiko, A. N. (2009). Influence of dopamine agonist pramipexole (mirapex) on tremor, cognitive and affective impairment in patients with Parkinson's disease. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 109(8), 36-41.
Marnat, G. G. (2009). Handbook of Psychological Assessment. New Jersy: John Wiley and Sons.
Martin, M. A., Orsillo, M. S., and Roemer, L. (2001). Practitioner's Guide to Empirically Based Measures of Anxiety. NewYork: Plenum Publishers.
Nasreddine, Z. S., Phillips, N. A., Bedirian, V., Charbonneau, S., Whitehead, V., Collin, I., et al. (2005). The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment. Journal of the American Geriatric Society, 53, 695-699.
Owen, A. M. (2004). Cognitive Dysfunction in Parkinson's Disease: The Role of Frontostriatal Circuitry. Journal of Neurosciences, 10(3), 525- 537.
Pagonabarraga, J., Kulisevsky, J., Llebaria, G., Sanchez, C.G., Pascual-Sedano. B., and Gironell, A. (2008). Parkinson's Disease-Cognitive Rating Scale: A New Cognitive Scale Specific for Parkinson's Disease. Movement Disorders, 23(7), 998-1005.
Rowe, J. B., Hughes, B., Ghosh, B. C., Williams-Gray, C. H., Fallon, S., Barker, R. A., & Owen, A. M. (2008). Parkinson's disease and dopaminergic therapy- differential effects on movement, reward and cognition. Brain, 131, 2094-2105.
Saletu, B., Anderer, P., Semlitsch, H. V., Grunberger, J., Linzmayer, L., Chaudhry, H. R. (1992). Amantadine infusions in mild dementia: acute double-blind placebo controlled EEG mapping and psychometric studies. Archives of Gerontology and Geriatrics, 15 (1), 43-58.
Sanchez-Castaneda, C., Campdelacreu, J., Miro, J., Juncadella, M., Jauma, S., Calopa, M. (2010). Cognitive improvement after duodenal levodopa infusion in cognitively impaired Parkinson's disease patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34(1), 250-251.
Sawamoto, N., Piccini, P., Hotton, G., Pavese, N., Thielemans, K., and Brooks, D. J. (2008). Cognitive deficits and striato-frontal dopamine release in Parkinson's disease. Brain, 10, 1-9.
Sharma, N. (2008). Parkinson's Disease. CT.: Greenwood press
Shaver, R. P., and Brennan, K. A. (1991). Measures of Personality and Social Psychological Attitudes.Volume 1. San Diego, California: Elsevier.
Siderowf, A., McDermott, M., Kieburtz, K., et al. (2002). Test-retest reliability of the UPDRS in patients with early Parkinson's disease: Results of a multicenter clinical trial. Movement Disorders, 17, 758-763.
Smith, T., Gildeh, N., and Holmes, C. (2007). The Montreal Cognitive Assessment: Validity and Utility in a Memory Clinic Setting. The Canadian Journal of Psychiatry, 52(5), 329- 332.
Sollinger, B. A., Goldstein, F.C., Lah, J. J., Levey, A. I., and Factor, S.A. (2010). Mild cognitive impairment in Parkinson's disease: Subtypes and motor characteristics. Parkinsonism and Related Disorders, 16, 177-180.
Starkstein, S. E., & Merello, M. (2004). Psychiatric and Cognitive Disorders in Parkinson's Disease. Cambridge: Cambridge University Press.
William-Gray, C. H., Foltyne, T., Brayne, C. G., Robbins, T. W., Barker, R. A. (2007). Evolution of cognitive dysfunction in an incident parkinson's disease cohort. Brain, 130 (7), 1787-1798.
Wilson, K. A., Chambless, L. D., and Beurs, E. (2004). The Use of Psychological Testing for Treatment Planning and Outcomes Assessment. New Jersey: Lawrance Erlbaum Associates.
Wittich, W., Phillips, N., Nasreddine, Z. N., and Chertkow, H.(2010). Sensitivity and Specificity of the Montreal Cognitive Assessment Modified for Individuals Who Are Visually Impaired. Journal of Visual Impairment & Blindness, 104, 360- 368.
Wong, A., Xiong, Y. Y. Kwan, P. W., Chan, A. Y., Lam, W. M., Wang, K., et al. (2009). The Validity, Reliability and Clinical Utility of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in Patients with Cerebral Small Vessel Disease. Dementia and Geriatric Cognitive Disorders, 28, 81-87.
York. M. K., & Alvarez. J. A. (2008). Cognitive impairments associated with parkinson's disease. In Trail, M., Protas, E. J., & Lai, E. C (Ed.). Neurorehabilitation in parkinson's disease: an evidence-based treatment model. USA: Slack Incorporated.
Zadikoff, C., Fox, S. H., Tang-Wai, D. F., Thomsen, T., de Bie, R. M., Wadia, P., Miyasaki, J., Duff-Canning, S., Lang, A. E., & Marras, C. (2008). A comparison of the mini mental state exam to the montreal cognitive assessment in identifying cognitive deficits in Parkinson's disease. Movement Disorders, 23(2), 27-299.
Golita Emsaki , Karim Asgari , Hossein Molavi  and Ahmad Chitsaz   University of Isfahan (Iran);  Isfahan University of Medical Sciences (Iran)
 Corresponding author: GolitaEmsaki; Department of Psychology, University of Isfahan, Isfahan, Iran, telephone: +989131693745; Email: email@example.com
Table 1. Summary of the patients' demographic information. groups Mean (years) Std deviation Age Pramipexole 62.08 5.90 trihexiphenidyle 58.16 8.67 control 57.36 6.80 Duration of Pramipexole 5 1.28 the disease trihexiphenidyle 3.25 1.85 control 5.04 2.2 Years of Pramipexole 10.5 2.31 education trihexiphenidyle 9.75 3.08 control 9.36 3.61 Table 2. Summary of patients' scores in BDI, BAI and UPDRS section III. groups Mean Std deviation BDI Pramipexole 9.25 2.41 trihexiphenidyle 8.75 5.72 control 7.54 3.58 BAI Pramipexole 3.9 2.3 trihexiphenidyle 5.5 2.8 control 4.7 2.2 UPDRS Pramipexole 8.41 2.68 trihexiphenidyle 7 2.7 control 8.82 2.96 Table 3. ANCOVA for investigating the difference in the total scores of MoCA among 3 groups (* p < 0.05). Dependent source df Mean F Sig Partial eta variable square square MoCA MoCA pre 1 88.96 132.198 0.001 0.815 post test education 1 0.75 1.115 0.29 0.036 group 2 5.26 7.817 0.002 * 0.34 Dependent source Observed variable power MoCA MoCA pre 1.00 post test education 0.176 group 0.93 Table 4. Pairwise comparisons of estimated marginal means in executive function (* p < 0.05). Dependent Estimated variable Group marginal means Executive control 72.1 function control 72.1 post test pramipexole 63.2 Dependent Estimated variable Group marginal sig means Executive trihexiphenidyle 006.2 0.13 function pramipexole 63.2 0.001 * post test trihexiphenidyle 006.2 0.004 *
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|Author:||Emsaki, Golita; Asgari, Karim; Molavi, Hossein; Chitsaz, Ahmad|
|Date:||Jul 1, 2013|
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